Risk considerations

The Pfizer-BioNTech COVID‑19 Vaccine is a non-replicating and non-integrating platform. This means the delivered mRNA does not interact with the genome and does not carry a risk for infection [GAVI,2020 ].

Lipid nanoparticle (LNP)-formulated mRNA vaccine technology allows the delivery of precise genetic information together with an adjuvant effect to antigen-presenting cells. It is molecularly well defined, in principle, free of materials of animal origin [WHO, 2020 ].

Efficacy of preclinical studies on the vaccine

The immunogenicity of the Pfizer-BioNTech COVID-19 vaccine was tested in mice and non-human primates that were injected with two vaccine candidates: BNT162b1 and BNT162b2. In mice, one intramuscular dose of either candidate vaccine elicits a dose-dependent antibody response and strong T-helper-1 CD4+ and IFNγ+CD8+ T cell responses. Rhesus macaques that received 100 μg of BNT162b2 showed robust antibody and cellular responses, and no signs of SARS-CoV-2 infection 3 days after immunization [Vogel AB, 2021 ].

Efficacy of the vaccine in clinical trials

Main immunogenicity outcomes

In the phase 1 component of the C4591001 trial [Walsh EE, 2020 ], the vaccine elicited dose-dependent SARS-CoV-2-neutralizing geometric mean titers, which were similar to or higher than the geometric mean titer of a panel of SARS-CoV-2 convalescent serum samples. The results were similar in younger and older adults.

In the phase 2 portion of the trial, 360 participants were enrolled and randomized 1:1 to the vaccine or placebo. Immunogenicity results 1 month after second dose 2 vaccination, showed the vaccine elicited robust SARS-CoV-2 immune responses, defined by SARS-CoV-2 50% neutralizing titers. Titers were higher in younger participants (18 to 55 years of age) than in older ones (56 to 85 years of age) [FDA, 2020 ]

Key messages

Pfizer-BioNTech COVID-19 vaccine reduces the risk of contracting COVID-19

Pfizer-BioNTech COVID-19 vaccine probably reduces the risk of contracting severe COVID-19

Main efficacy outcomes of Pfizer-BioNTech COVID-19 vaccine

Contracting COVID-19 (measured at least 7 days after the second injection)

The relative risk of contracting COVID-19 in the group that received Pfizer-BioNTech COVID-19 vaccine versus the group that received placebo vaccine was 0.05 (95% CI 0.02 to 0.1). This means Pfizer-BioNTech COVID-19 vaccine reduced the risk of contracting COVID-19 in 95%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19. Comparison: Pfizer-BioNTech COVID-19 vaccine versus placebo vaccine

In the trials identified in this review, 850 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 21096 presented this outcome (403 per 10000) versus 77 out of 20998 in the group that did receive it (37 per 10000). In other words, 366 less people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 91%, or that the intervention reduced the risk of contracting COVID-19 by 91 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 27. Which means that 27 people need to receive the vaccine for one of them to not contracting COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high. No reasons for concern were detected in relation to risk of bias, inconsistency, indirect evidence, imprecision or publication bias.

Contracting severe COVID-19 (measured at least 7 days after the second injection)

The relative risk of contracting severe COVID-19 in the group that received Pfizer-BioNTech COVID-19 vaccine versus the group that received placebo vaccine was 0.25 (95% CI 0.03 to 2.23). This means Pfizer-BioNTech COVID-19 vaccine reduced the risk of contracting severe COVID-19 in 75%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting severe COVID-19. Comparison: Pfizer-BioNTech COVID-19 vaccine versus placebo vaccine

In the trials identified in this review, 23 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 23037 presented this outcome (10 per 10000) versus 1 out of 23040 in the group that did receive it (0 per 10000). In other words, 10 less people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 96%, or that the intervention reduced the risk of contracting severe COVID-19 by 96 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 10000. Which means that 10000 people need to receive the vaccine for one of them to not contracting severe COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate. The reason for downgrading the certainty of the evidence is imprecision because of the low number of events and wide confidence interval. No reasons for concern were detected in relation to risk of bias, inconsistency, indirect evidence or publication bias.

Mortality

The existing evidence does not allow to assess the impact of Pfizer-BioNTech COVID‑19 Vaccine on the risk of mortality. The information provided by randomized trials was not adequately powered to estimate a difference in this outcome. Deaths can occur in the intervention and control group for reasons unrelated to COVID-19 or the vaccine. Establishing that there is a reduction (or increase) in the risk of death attributable to COVID-19 would require trials with a higher statistical power.

Efficacy of the vaccine in subgroups

Contracting COVID-19 (>65y) (measured at least 7 days after the second injection)

The relative risk of contracting COVID-19 (>65y) in the group that received Pfizer-BioNTech COVID-19 vaccine versus the group that received placebo vaccine was 0.06 (95% CI 0.03 to 0.12). This means Pfizer-BioNTech COVID-19 vaccine reduced the risk of contracting COVID-19 (>65y) by 94%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (>65y). Comparison: Pfizer-BioNTech COVID-19 vaccine versus placebo vaccine

In the trials identified in this review, 124 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 21096 presented this outcome (59 per 10000) versus 7 out of 20998 in the group that did receive it (3 per 10000). In other words, 56 less people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 94%, or that the intervention reduced the risk of contracting COVID-19 (>65y) by 94 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 179. Which means that 179 people need to receive the vaccine for one of them to not contracting COVID-19 (>65y).

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Contracting COVID-19 (5-15 y) (measured at least 7 days after the second injection, with a median follow-up of < 4 month after 2nd dose )

The relative risk of contracting COVID-19 (5-15 y) in the group that received Pfizer-BioNTech COVID-19 vaccine versus the group that received placebo vaccine was 0.08 (95% CI 0.02 to 0.23). This means Pfizer-BioNTech COVID-19 vaccine reduced the risk of contracting COVID-19 (5-15 y) by 92%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (5-15 y). Comparison: Pfizer-BioNTech COVID-19 vaccine versus placebo vaccine

In the trials identified in this review, 34 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 1861 presented this outcome (183 per 10000) versus 3 out of 2636 in the group that did receive it (14 per 10000). In other words, 169 less people per did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 92%, or that the intervention reduced the risk of contracting COVID-19 (5-15 y) by 92 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 59. Which means that 59 people need to receive the vaccine for one of them to not contracting COVID-19 (5-15 y).

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Contracting COVID-19 (6 months - 4y) (measured at least 7 days after the second injection, with a median follow-up of < 4 month after 2nd dose )

The relative risk of Contracting COVID-19 (6 months - 4y) in the group that received Pfizer-BioNTech COVID-19 vaccine versus the group that received placebo vaccine was 0.27 (95% CI 0.14 to 0.54). This means Pfizer-BioNTech COVID-19 vaccine reduced the risk of Contracting COVID-19 (6 months - 4y) by 73%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (6 months - 4y). Comparison: Pfizer-BioNTech COVID-19 vaccine versus placebo vaccine

In the trials identified in this review, 21 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 351 presented this outcome (598 per 10000) versus 13 out of 794 in the group that did receive it (164 per 10000). In other words, 434 less people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 73%, or that the intervention reduced the risk of contracting COVID-19 (6 months - 4y) by 73 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 23. Which means that 23 people need to receive the vaccine for one of them to not contracting COVID-19 (6 months - 4y).

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Summary of findings table (iSoF)

Efficacy and effectiveness of the vaccine in subgroups

Age 
Randomized trials
The proportion of patients >55 years of age in the C4591001 trial was 42.2% (15921 out of 37706 participants) [Polack, Fernando P., 2020 ].
Vaccine efficacy in the different age groups was consistent with that observed in the overall population. Efficacy was 95.6% (89.4 to 98.6) in the group 16 to 55 years, 93.7% (80.6 to 98.8) in >55 years, 94.7% (66.7 to 99.9) in ≥65 years and 100.0% (−13.1 to 100.0) in ≥75 years [Polack, Fernando P., 2020 ].

The proportion of participants 12-15 years in the C4591001 trial was 67.3% (2260 out of 3358 participants)  [Frenck RW, 2021 ]. 
The proportion of participants 16-25 years in the C4591001 trial was 32.7% (1098 out of 3358 participants)  [Frenck RW, 2021 ].
In the group that included 1983 participants in the 12-to-15-year-old cohort, vaccine efficacy from 7 days after the second dose was 100% (95% CI, 75.3 to 100). In the group that included all 2229 participants in the 12-to-15-year-old cohort, vaccine efficacy from 7 days after the second dose was 100% (IC del 95%, 78,1 a 100) [Frenck RW, 2021 ].

The phase 3, randomized, double-blind trial B7471026 is currently evaluating the efficacy/safety of the vaccine in vaccinated adults 65 years of age and older [Pfizer, 2021 ].

The proportion of participants 65-85 years in the BNT162-03 was 50% (72 out of 144 participants) [Li J, 2021 ].

The older participants generally had a lower peak neutralizing antibody response than the younger participants. The vaccine-induced highest neutralizing titers were observed on day 43 (21 days after the BNT162b1 boost dose) for the older adults in the BNT162b1 group. Moreover, geometric mean neutralizing titers reached 1.3-fold in the older adults group versus a panel of COVID-19 convalescent human sera obtained at least 14 d after positive SARS-CoV-2 polymerase chain reaction test [Li J, 2021 ].

Puthanakit T et al was a phase 2 randomized clinicla trial conducted in Thailand. The study included 80 participants  aged 12 to < 18 years without previous SARS-CoV-2 vaccination. Participants were randomized to be vaccinated with CoronaVac (SV) 3 ug as the first dose followed by BNT162b2 30 µg or 20 µg as the second dose, at 3-week (3w) or 6-week interval (6w). During the Omicron-predominant period, participants were offered a BNT162b2 booster dose 30, 15, or 10 µg. Immunogenicity was determined using IgG antibody against spike-receptorbinding domain of wild type(anti-S-RBD IgG) and surrogate virus neutralization test(sVNT) against Delta variant at 14 days and 5 months after the 2nd dose. Neutralization tests(sVNT and pseudovirus neutralization test; pVNT) against Omicron strain were tested pre- and 14 days post-booster dose.  At day 14, the geometric mean(GM) of anti-S-RBD IgG in SV3w/PZ30lg was 4713 (95 %CI 4127–5382) binding-antibody unit (BAU)/ml, while geometric mean ratio(GMR) was 1.28 (1.09–1.51) in SV6w/PZ30lg. The GMs of sVNT against Delta variants at day 14 among participants in SV3w/PZ30lg and SV6wk/PZ30lg arm were 95.3 % and 99.7 %inhibition, respectively. [Puthanakit T, 2022 ]

Other comparative studies
The interventional, non-randomized study COGEVAX-BIO is currently evaluating the effectiveness/safety of the vaccine in people over age 75 institutionalized in the long-term care units [Gérond'if, 2021 ].

The non-randomized study Covid-19-Abs is currently evaluating the effectiveness/safety of the vaccine in residents and staff associated with nursing homes, extended care facilities, and over 55 communities [Dr. Sidney J. Stohs, 2021 ].

The VIVALDI study included 1317 samples from 402 residents and 632 staff fully vaccinated  (AstraZeneca=593; Pfizer=534). Data were collected 21 days after the second dose. The study showed that two-dose of AstraZeneca or Pfizer COVID-19 vaccine elicits robust and stable antibody responses in older Long-Term Care Facility residents, consistent with overall levels of vaccine-induced immunity [Oliver Stirrup, 2022 ].

The cohort study using Senior Shield data, included 43,596 residents of long term facilities,  39,482 received one dose, 37,656 received two doses, with a follow-up period of 5 months. This study shows that the Pfizer-BioNTech mRNA COVID-19 vaccine effectively prevents SARS-CoV-2 infection, COVID-19-related death, and all-cause mortality in LTCF residents [Goldin S, 2022 ].

The test-negative case-control study using COVID-19 Shared Data Resource from the Veterans Health Administration (VA), included 971,750 veterans who received the Pfizer-BioNTech vaccine. In people aged 65 and over the study showed a vaccine effectiveness against symptomatic infection of 66.3% (95 CI 55.7 to 74.4) 1 month after receiving the vaccine, and –23.3% (95 CI –40.5 to –8.2) 7 months after. The efectiveness against hospitalization was 61% (95 CI 41.3 to 74.2) 1 month after receiving the vaccine and 1.7% (95 CI –22.0 to 20.8) 7 months after receiving the vaccine. [Mayr FB, 2022 ]

Wang L et al was a retrospective cohort study of 262,847 vaccinated older adults (age 73.8 ± 6.81 years old) between December 2020 and August 2021, 2764 of whom had a diagnosis of Alzheimer disease, 1244 had a diagnosis of VD, 259 had a diagnosis of Lewy body dementia (LBD), 229 had a diagnosis of frontotemporal dementia (FTD), and 4385 had a diagnosis of mild cognitive impairment (MCI). the overall risk of breakthrough infections beginning 14 days following vaccination in older adults without dementia was 5.6%. The risks of breakthrough infections were significantly higher in patients with various types of dementias: 10.3% for AD, 12.5% for VD, 14.3 for LBD, 11.8% for FTD, and 11.6% for MCI. The overall risk for hospitalization after breakthrough infections in patients with dementia was 39.5% for AD, 46.2% for VD, and 30.4% for MCI. [Wang L, 2022 ]

Yan VKC et al was a case-control study conducted in Hong Kong. The study included 14, 984 participants to evaluate the risk of severe complications following 1-3 doses of CoronaVac and BNT162b2 using electronic health records database. Cases were adults with their first COVID-19-related severe complications between 1 January and 31 March 2022. Vaccine effectiveness against severe complications after two doses of BNT162b2 awas 82.1% (74.6-87.3) in those aged ≥65, 83.0% (69.6-90.5) in those aged 50-64, 78.3% (60.8-88.0) in those aged 18-50. Further risk reduction with the third dose was observed especially in those aged ≥65 years, 90.8% (83.4-94.9) for BNT162b2 against severe complications. The findings show that BNT162b2 vaccination were effective against COVID-19-related severe complications against the Omicron BA.2 pandemic, and risks decreased further with the third dose. [Yan VKC, 2022 ]

Fleming-Dutra et al was a test-negative case-control study conducted in the United States, based on data from the Increasing Community Access to Testing (ICATT) platform, including 121,952 tests during the Omicron variant predominance period between December 2021 and February 2022, in participants between 5 and 15 years old who received the Pfizer-BioNTech vaccine. The effectiveness 2 months after the second dose for symptomatic infection was 28.9% (95% CI, 24.5% to 33.1%) for the 5-11 years old group and 16.6% (95% CI, 8.1% to 24.3%) for the 12-15 years old group. [Fleming-Dutra KE, 2022 ]

Rane MS et al was a case control study conducted in the United States that included data from 931,972 patients with vaccine records: 39,185 with a positive test and 892,787 with a negative test. The study estimated Vaccine Effectiveness (VE) against symptomatic infection in a population of patients seeking care at CityMD, a large ambulatory care center in New York and neighboring areas. VE against symptomatic infection for the BioNTech BNT162b and mRNA-1273 vaccines combined was 96% (95% CI, 95% to 97%) in the pre-Delta period and 79% (95% CI, 77% to 81%) in the Delta period. Adjusted VE against any infection was higher in all subgroups in the pre-Delta period compared with the Delta period. VE for participants aged 12 to 15 years old was 85% (95% CI, 81% to 88%) during the Delta period. VE was lower for adults aged 64 years and older compared to <64 years, even in the pre-Delta period. [Rane MS, 2022 ]

Ronen Arbel was a retrospective cohort study conducted in Israel that included 622,701 participants aged 65 years and older: 85,314 with the Pfizer-Biontech mRNA bivalent vaccine and 537,387 without the bivalent vaccine. This study included all members of Clalit Health Services, aged ≥65, eligible for a bivalent booster. Hospitalizations and death due to COVID-19 among participants who received the bivalent vaccine were compared with those who did not. Adjusted hazard ratio of hospitalization due to COVID-19 was 0.19 (95% CI, 0.08-0.43). [Ronen Arbel, 2023 ]

Elsie MF Horne et al was a comparative cohort study conducted in United Kingdom that estimated vaccine effectiveness of two doses of the Pfizer and AstraZeneca vaccines (versus no vaccine) in participants aged 18 to 64 and over 65 years. Hazard ratio for positive SARS-CoV-2 test (18-39 years) was 0.25 (95% CI, 0.24-0.26). Hazard ratio for positive SARS-CoV-2 test (>65  years) was 0.23 (95% CI, 0.16-0.33). [Elsie MF Horne, 2023 ]

Sex
Randomized trials
The proportion of females in the C4591001 trial was 49.4% (18631 out of 37706 participants) [Polack, Fernando P., 2020 ].
Vaccine efficacy was consistent in the different sex groups. Efficacy was 96.4% (88.9 to 99.3) in males and 93.7% (84.7 to 98.0) in females.

Other comparative studies
In Bjork et al [Jonas Bjork, 2021 ], no difference in vaccine effectiveness was observed between females and males.
The phase 4, non-randomized study Shieldvacc2 is currently evaluating the effectiveness/safety of the vaccine in women of child-bearing potential using contraception, 12 years of age and older, vaccinated with two-doses of Comirnaty [Medizinische Universität Innsbruck, Institut für Virologie, 2021 ].
    
Children and adolescents
Randomized trials
The proportion of participants 12-15 years in the C4591001 trial was 67.3% (2260 out of 3358 participants)  [Frenck RW, 2021 ]. 
The proportion of participants 16-25 years in the C4591001 trial was 32.7% (1098 out of 3358 participants)  [Frenck RW, 2021 ].
In the group that included 1983 participants in the 12-to-15-year-old cohort, vaccine efficacy from 7 days after the second dose was 100% (95% CI, 75.3 to 100). In the group that included all 2229 participants in the 12-to-15-year-old cohort, vaccine efficacy from 7 days after the second dose was 100% (IC del 95%, 78,1 a 100) [Frenck RW, 2021 ].

Other comparative studies
C4591007 is an ongoing non-randomized study evaluating the efficacy of the vaccine in children and adolescents [BioNTech SE, 2021 ].

The non-randomized study COVA is currently evaluating the effectiveness/safety of the vaccine in healthy or clinically stable participants aged 11 years and older [The University of Hong Kong, 2021 ].

Levy M et al  is comparative study conducted in France. The study included pediatric patients diagnosed with multisystem inflammatory syndrome admitted to 1 of the 41 French pediatric intensive care units (PICUs) between September 1, 2021, and October 31, 2021. The HR for multisystem inflammatory syndrome in children was 0.09 (95% CI, 0.04-0.211) after the first vaccine dose compared with unvaccinated adolescents. Sensitivity analyses showed similar result. The authors suggest that COVID-19 mRNA vaccination was associated with a lower incidence of multisystem inflammatory syndrome in adolescents.

Oliveira CR et al.  is a case-control conducted in the United States. The study included adolescents (aged 12-18 years old): 186 SARs-CoV-2 PCR+ cases and 356 matched controls. Vaccine effectiveness against any infection was estimated to be 91% (95% CI, 80 to 96); against asymptomatic infection, 85% (95% CI, 57 to 95). Effectiveness after a single dose was estimated to be 74% (95% CI, 18 to 92).[Oliveira CR, 2022 ]

Florentino et al. conducted a test-negative case-control study, to estimate vaccine effectiveness (VE) against COVID-19 in adolescents aged 12-17 years in Scotland and Brazil after two doses of the Pfizer-BioNTech vaccine. They analyzed 503,776 eligible SARS-CoV-2 tests (RT-PCR or antigen) of adolescents in Brazil and 127,168 eligible tests of adolescents in Scotland. During the delta-dominant period, VE for symptomatic infection after two doses peaked at 14-27 days (80.7% [95% CI 77.8–83.3] in Brazil; 92.8% [95% CI 85.7–96.4] in Scotland). Protection started to decline reducing to 26.6% (4.1–43.9) in Brasil and 86.5% (72.2–93.4) in Scotland, at 56–69 days. Vaccines were less effective against the omicron variant than the delta variant at all intervals after two-dose vaccination in both countries: between 14-27 days was 64.7% (95% CI 63.0–66.3) in Brazil, and 82.6% (95% CI 80.6–84.5) in Scotland; and reducing to 5.9% (95% CI 2.2–9.4) in Brazil and 50.6% (42.7–57.4) at 98 days and longer [Florentino PTV, 2022 ].

Tartof SY et al was a test-negative case-control study conducted at Kaiser Permanente Southern California, an integrated health care system using electronic health records of participants aged 12 to 17 years with an emergency department (ED) or urgent care (UC) encounter from November 1, 2021, through March 18, 2022. The main outcome was vaccine effectiveness (VE) associated with BNT162b2 against the emergency department and urgent care encounters related to Delta or Omicron variant SARS-CoV-2 infection. The study included data from 3168 adolescents, including 1004 with ED visits and 2164 with UC visits. VE for 2 doses of BNT162b2 was highest within the first 2 months for both Delta (89% [95% CI, 69% to 96%]) and Omicron (73% [95% CI, 54% to 84%]) variants but waned to 49% (95% CI, 27% to 65%) for the Delta variant and 16% (95% CI, −7% to 34%) for the Omicron variant at 6 months and beyond. A third dose of BNT162b2 was associated with improved protection against the Omicron variant (87% [95% CI, 72% to 94%]) after a median (IQR) of 19 (9-32) days after dose 3 [Tartof SY, 2022 ].

Ziv et al was a case-control study conducted in Israel that evaluated the effectiveness of PfizerBioNTech vaccination among 1639 adolescents with juvenile-onset inflammatory rheumatic diseases the control group comprised 524,471 adolescents without juvenile-onset inflammatory rheumatic diseases, the estimated vaccine effectiveness for adolescents with IRD was 76.3% after the first dose, 94.8% after the second and 99.2% after the third dose [Ziv A, 2022 ].

Cohen-Stavi CJ was a comparative cohort study conducted in Israel. The study included 15,289 children aged 5 to 11 years. Vaccine effectiveness (VE) against documented severe SARS-CoV-2 infection and symptomatic Covid-19 was estimated after the first and second vaccine doses during the Omicron wave. VE against documented infection was 17% (95% CI, 7 to 25) at 14 to 27 days after the first dose and 51% (95% CI, 39 to 61) at 7 to 21 days after the second dose. VE against symptomatic Covid-19 was 18% (95% CI, −2 to 34) at 14 to 27 days after the first dose and 48% (95% CI, 29 to 63) at 7 to 21 days after the second dose. [Cohen-Stavi CJ, 2022 ].

Sacco C et al was a retrospective study conducted in Italy. The study included data from 2,965,918 children aged 5–11 years: 1,063,035 with two doses of the Pfizer vaccine, 134,386 with one dose of the Pfizer vaccine, and 1,768,497 unvaccinated. The aim of this study was to estimate the effectiveness of the paediatric BNT162b2 vaccine in preventing SARS-CoV-2 infections and severe COVID-19 (hospitalization or death) in children using routinely collected data in Italy. Adjusted vaccine effectiveness against infection in partly vaccinated group was 27.4% (95% CI 26.4-28.4) and 29.4% (95% CI 28.5-30.2) in fully vaccinated group. Adjusted vaccine effectiveness against severe disease in partly vaccinated group was 38.1% (95% CI 20.9-51.5) and 41.1 (95% CI 22.2-55.4) for fully vaccinated group [Sacco C, 2022 ].

Molteni et al was a prospective cohort study conducted in the United Kingdom. The study included 115,775 children and adolescents aged 12-17 years, among which, 25,971 received one dose of Pfizer-BioNTech. Based on data from the Covid Symptom Study between august 2021 and February 2022. Infection risk reduction was -80.4% (95%CI -82 to -78) 14-30 days after the primary dose of Pfizer-BioNTech in the august-november (Delta) period. Infection risk reduction 14-30 days after primary vaccination was -53.7% (95%CI -62 to -43) during the december-february (Omicron) period [Molteni E, 2022 ].

González S et al was a retrospective cohort study conducted in Argentina including 1,536,435 participants: 689,552 in the BIBP vaccine group and 846,883 in the mRNA vaccine group (539,093 with Pfizer/Pfizer schedule, 15,552 with Pfizer/Moderna schedule and 44,862 with Moderna/Pfizer schedule). mRNA-1273 and BNT162b2 vaccines were administered to 12−17- year subjects; and BBIBP-CorV to 3−11-year subjects. Vaccine effectiveness for the mRNA vaccine group was 80.0% (95% CI 64.3 to 88.0) for the 12−17 age (mRNA vaccines) subgroup [González S, 2022 ].

Tan SHX et al was a retrospective cohort study conducted in Singapore based on data from the National Ministry of Health registry, including 255,936 children between 5 and 11 years of age. The Pfizer-BioNTech vaccine effectiveness during the Omicron variant predominance period in partially vaccinated children was 13.6% (95% CI, 11.7% to 15.5%) against all SARS-CoV-2 infections, 24.3% (95% CI, 19.5% to 28.9%) against PCR-confirmed infections and 42.3% (95% CI, 24.9% to 55.7%) against hospitalization. In fully vaccinated children the effectiveness was 36.8% (95% CI, 35.3% to 38.2%), 65.3% (95% CI, 62.0% to 68.3%), and 82.7% (95% CI, 74.8% to 88.2%), respectively. [Tan SHX, 2022 ]

Kim J et al was a retrospective cohort study conducted in South Korea, including 3,203,985 adolescents aged 12 to 17 years. The estimated effectiveness of the Pfizer-BioNTech vaccine was 80.4% (95% CI, 77.8% to 82.7%) among those aged 16-17 years, and 79.2% (95% CI, 77.4% to 80.1%) among those aged 12 to 15 years. [Kim J, 2022 ]

Chemaitelly H et al was a retrospective cohort study conducted in Qatar, including 37,456 participants aged 5-11 years, 18,728 vaccinated with 10-μg of BNT162b2 and 18,728 unvaccinated matched participants. The overall effectiveness against Omicron was 25.7% (95% CI, 10% to 38.6%). The overall effectiveness was 46.3% (95% CI, 21.5% to 63.3%) among children 5-7 years of age and 16.6% (95% CI, −4.2% to 33.2%) among children 8-11 years of age. In the pre-Omicron period, effectiveness was 35.6% (95% CI, 31.2% to 39.6%) among adolescents 12 to 14 years of age and 20.9% (95% CI, 13.8% to 27.4%) among participants between 15-17 years of age. [Chemaitelly H, 2022 ]

Puthanakit T et al was a randomized trial conducted in Thailand, that assessed the immunogenicity of fractional doses and booster doses of Pfizer-BioNTech SARS-CoV-2 vaccine among healthy adolescents.  The GMR of Anti-S-RBD IgG post second dose compared to the 3wPZ30/30 group was 0.80 (95% CI, 0.67–0.97) for the 3wPZ30/20 group, 1.00 (95% CI, 0.83–1.20) for the 3wPZ20/20 group, 1.37 (95% CI, 1.13–1.65) for the  6wPZ30/30 group, 1.24 (95% CI, 1.02–1.50) for the 6wPZ30/20 group and 1.36 (95% CI, 1.13–1.64) for the 6wPZ20/20 group. [Puthanakit T, 2022 ]

Buchan SA et al was a case-control study with a test-negative design conducted in Canada that included participants between 12-17 years old, 9,902 Omicron cases with 19,953 controls, and 502 Delta cases with 17,930 controls. Vaccine Effectiveness (VE) against symptomatic infection with Omicron was 51% (95% CI, 38% to 61%) after two doses and 62% (95% CI, 49% to 72%) after the third dose. VE against severe outcomes with Omicron was 85% (95% CI, 74% to 91%) after two doses. VE against symptomatic infection with Delta was 97% (95% CI, 94% to 99%). [Buchan SA, 2022 ]

Prunas O et al was a case-control study conducted in Israel that included data from 11,822 cases and 226,201 controls aged 12 to 16 years. The aim was to assess the incidence of documented SARS-CoV-2 infection (regardless of symptoms) and symptomatic COVID-19 infection. Vaccine effectiveness between 2 weeks and 3 months following the second Pfizer dose was 85% (95% CI, 84% to 86%), and 90% (95% CI, 89% to 91%) against SARS-CoV-2 infection and severe COVID-19, respectively. [Prunas O, 2022 ]

Castelli JM et al was a test-negative case-control study conducted in Argentina that included 844,460 children and adolescents without previous SARS-CoV-2 infection eligible to receive a primary vaccination schedule. The aim was to assess the effectiveness of different combinations of mRNA vaccines in children and adolescents. Vaccine effectiveness (VE) during the Delta predominance period for 12-17 years old adolescents was 64.1% (95% CI, 60.5% to 67.3%) and 28.1% (95% CI, 25.2% to 30.8%) during the Omicron predominance period for Pfizer primary schedule. VE for the heterologous Pfizer/Moderna schedule was 88.9% (95% CI, 66.1% to 96.4%) during the Delta predominance period, and 40.6% (95% CI, 29.4 to 50.0) during the Omicron predominance period. [Castelli JM, 2022 ]

Saito Y et al was a cohort study conducted in Japan that included 1,835 adolescents between 13-18 years. Participants received a homologous booster dose of Pfizer between April and May 2022. The relative effectiveness of a booster dose of Pfizer-BioNTech in adolescents during the Omicron predominance period compared with the primary schedule was 86.4% (95% CI, 57.2% to 95.7%). [Saito Y, 2022 ]

Rane MS et al was a case control study conducted in the United States that included data from 931,972 patients with vaccine records: 39,185 with a positive test and 892,787 with a negative test. The study estimated Vaccine Effectiveness (VE) against symptomatic infection in a population of patients seeking care at CityMD, a large ambulatory care center in New York and neighboring areas. VE against symptomatic infection for the BioNTech BNT162b and mRNA-1273 vaccines combined was 96% (95% CI, 95% to 97%) in the pre-Delta period and 79% (95% CI, 77% to 81%) in the Delta period. Adjusted VE against any infection was higher in all subgroups in the pre-Delta period compared with the Delta period. VE for participants aged 12 to 15 years was 85% (95% CI, 81% to 88%) during the Delta period. VE was lower for adults aged 64 years and older compared to <64 years, even in the pre-Delta period. [Rane MS, 2022 ]

Jang EJ et al was a retrospective cohort study conducted in South Korea. The study included 3,062,281 children aged 5 to 11 years: 29,473 with two Pfizer doses and 3,016,913 unvaccinated. This study analyzed data from the period dominated by the Omicron variant, between 31 March and 6 August. Vaccine effectiveness against infection was 57.6% (95% CI, 51.6%-62.8%). Vaccine effectiveness against serious disease was  100% (95% CI, 100%-100%). [Jang EJ, 2023 ]

Fleming-Dutra et al was a comparative study conducted in United States that assessed monovalent mRNA vaccine effectiveness against symptomatic SARS-CoV-2 infection. This study analized data from the Increasing Community Access to Testing program, which provides SARS-CoV-2 testing to persons aged ≥3 years at pharmacy and community-based testing sites nationwide. Vaccine effectiveness of 2 vaccine doses of Moderna against symptomatic infection was 60% (95% CI, 49% to 68%). Vaccine effectiveness of monovalent Pfizer-BioNTech doses (complete primary series) against symptomatic infection was 31% (95% CI, 7% to 49%). [Fleming-Dutra KE, 2023 ]

Rosa Duque et al was a comparative cohort study conducted in China that included data from 1.360.000 doses of Pfizer and CoronaVac vaccines administered to 766,601 of 953,400 children aged 3–11 years and adolescents aged 12–18 years. Vaccine effectiveness against hospitalization for children was 65.6% (95% CI, 38.2% to 82.5%) and 86.2% (95% CI, 65.8% to 95.9%) after the first dose of the Pfizer vaccine and the second dose of the CoronaVac vaccine, respectively. Vaccine effectiveness against hospitalization for adolescents was 82.3% (95% CI, 76.9% to 86.4%) and 90.7% (95% CI, 79.2% to 96.8%) after the second dose of the Pfizer vaccine and the second dose of the CoronaVac vaccine, respectively. [Rosa Duque JS, 2023 ]

Pregnancy
Randomized trials
Pregnant females of 18 years of age and older were excluded from the C4591001 trial, so no data are available for this subgroup [Polack, Fernando P., 2020 ].

C4591015 is an ongoing phase 2/3, randomized trial evaluating the efficacy in this subgroup [BioNTech SE, 2021 ].

Other comparative studies
Kugelman N et al was a retrospective cohort study conducted in Israel that included 930 vaccinated women with at least one dose of the BNT162b2 (Pfizer/BioNTech) COVID-19 vaccine during the second or third trimester of pregnancy and 964 unvaccinated women. No effect was found of the COVID-19 vaccine on the rate of individual adverse perinatal outcomes. At least one adverse perinatal outcome was found in 108 (11.25%) unvaccinated women versus 82 (8.82%) vaccinated pregnant women (p = 0.080) [Kugelman N, 2022 ].

Jorgensen et al was a case-control test-negative design conducted in Canada that included 8,809 infants whose mothers had been vaccinated during pregnancy with Pfizer or Moderna. Vaccine Effectiveness (VE) for the primary vaccine series was 95% (95% CI, 88% to 98%) against Delta infection and 45% (95% CI, 37% to 53%) against Omicron infection. VE for the primary plus booster vaccine series was 73% (95% CI, 61% to 80%) against Omicron infection. [Jorgensen SCJ, 2023 ]

Breastfeeding
Randomized trials
Breastfeeding females were excluded from the C4591001 trial, so no data are available for this subgroup [Polack, Fernando P., 2020 ].

Other comparative studies
Golan et al. was a prospective cohort study that enrolled 50 lactating individuals who received mRNA-based vaccines for COVID-19 (mRNA-1273 and BNT162b2), blood and milk samples were collected prior to first vaccination dose, immediately prior to 2nd dose, and 4-10 weeks after 2nd dose. After vaccination, levels of anti-SARS-CoV-2 IgG and IgM increased significantly in maternal plasma and there was significant transfer of anti-SARS-CoV-2-Receptor Binding Domain (anti-RBD) IgA and IgG antibodies to milk. Anti-SARS-CoV-2 IgG antibodies were not detected in the plasma of infants whose mothers were vaccinated during lactation [Golan Y et al., 2021 ].

The cohort O'Connor DL et al is currently evaluating the effectiveness/safety of the vaccine in lactating mothers [Deborah O'Connor, 2021 ].
    
Esteve-Palau E et al was a prospective cohort study conducted in Spain. This study included 33 breastfeeding women volunteers. The primary endpoint was to determine SARS-CoV-2 vaccine-induced antibody levels in the breast milk of lactating women 4 weeks after Pfizer-BioNTech COVID-19 complete vaccination (2 doses in 21 days). Median (IQR) SARS-CoV-2 immunoglobulin G (IgG) spike protein subunit S1 (S1) vaccine-induced levels at different timepoints for serum–milk pairs were 519 (234–937) to 1 (0–2.9) arbitrary units (AU)/mL at 2 weeks after the first dose and 18 644 (9923–29 264) to 78 (33.7–128), 12 478 (6870–20 801) to 50.4 (24.3–104), 4094 (2413–8480) to 19.9 (10.8–51.9), 1350 (831–2298) to 8.9 (7.8– 31.5) AU/mL at 2, 4, 12 and 24 weeks after the second dose, respectively [Esteve-Palau E, 2022 ].

Guedalia J et al was a cohort study conducted in Israel that included 82,803 women who had a documented delivery between August 1st 2021 and March 22nd 2022. During the Delta predominance period the vaccine effectiveness (VE) of second dose against hospitalization was 61% (95% CI, 51% to 69%), 97% (95% CI, 92% to 99%) for significant disease and 96% (95% CI, 86% to 99%) for severe disease. In the same period, VE of the booster dose was 97% (95% CI, 95% to 99%) against hospitalization, 99% (95% CI, 93% to 100%) for significant disease and 99% (95% CI, 89% to 100%) for severe disease. During the Omicron predominance period, VE of second dose against hospitalization was −12% (95% CI, −36% to 8%), 51% (95% CI, −47% to 84%) against significant disease and 83% (95% CI, −47% to 98%) against severe disease. In the same period, VE of booster dose was 43% (95% CI, 31% to 53%) against hospitalization, 97% (95% CI, 72% to 100%) against significant disease and 94% (95% CI, 43% to 99%) against severe disease. [Guedalia J, 2022 ]

Immunocompromised persons
Randomized trials
Immunocompromised participants were excluded from the C4591001 trial, therefore no data are available for this subgroup [Polack, Fernando P., 2020 ].

The phase 4, a single-center, open-label, investigator-initiated randomized controlled, superiority trial BECAME is currently evaluating the efficacy/safety of the vaccine in kidney transplant recipients [dafna yahav, 2021 ].

The phase 3, multicenter randomized controlled, open-label, 2-arm sub-study pilot trial COVERALL is currently evaluating the efficacy/safety of the vaccine in patients included in the Swiss HIV Cohort Study or the Swiss Transplant Cohort Study [University Hospital, Basel, Switzerland, 2021 ].

The phase 2, randomized, single-blinded study Boost-TX is currently evaluating the efficacy/safety of the vaccine in kidney transplant recipients [Medical University of Vienna, 2021 ].

Other comparative studies
The study COVIVAC-ID [Assistance Publique - Hôpitaux de Paris, 2021 ] plans to enroll 485 vaccinated immunocompromised people (autoimmune or auto-inflammatory disease, HIV infection, multiple sclerosis, solid cancer, organ transplantation) to determine the humoral and cellular response to vaccination and efficacy against SARS-CoV-2 variants.
                     
The cohort study COVATRANS is currently evaluating the effectiveness/safety of the vaccine in kidney transplant recipients aged 15 years and older who receive Pfizer, Moderna and Astra-Zeneca vaccines [University Hospital, Strasbourg, France, 2021 ].

The non-randomized study COVAC-IC is currently evaluating the effectiveness/safety of the vaccine in immunocompromised and immunocompetent haematology patients aged 18 years and older [University Hospitals of North Midlands NHS Trust, 2021 ].

The monocentric observational study ANTICOV is currently evaluating the effectiveness/safety of the vaccine in cancer patients aged 18 years and older, to evaluate the effectiveness of BNT162b2 or mRNA-1273 vaccine [Azienda Socio Sanitaria Territoriale di Cremona, 2021 ].

The non-randomized study UNICO is currently evaluating the effectiveness/safety of the vaccine in cancer patients aged 18 years and older [Ente Ospedaliero Ospedali Galliera, 2021 ].

The non-randomized study COViNEPH-1 is currently evaluating the effectiveness/safety of the vaccine in patients on chronic dialysis vaccinated with BNT162b2 [Medical University of Gdansk, 2021 ].

The prospective, cohort, non-interventional, single-center clinical study ImmunoHaema-COVID-VAX-21 is currently evaluating the effectiveness/safety of the vaccine in patients with haematological malignancies 18 years of age and older [Ospedale di Circolo - Fondazione Macchi, 2021 ].

The phase 2, non-randomized study C4591024 is currently evaluating the effectiveness/safety of the vaccine in immunocompromised participants ≥2 Years Of Age [BioNTech SE, 2021 ].

The non-randomized study IROC is currently evaluating the effectiveness/safety of the vaccine in cancer patients 18 years of age and older [Indiana University, 2021 ].

The non-randomized study LymphVAX is currently evaluating the effectiveness/safety of the vaccine in women with a history of breast cancer [Massachusetts General Hospital, 2021 ].

The non-randomized study VIOLA is currently evaluating the effectiveness/safety of the vaccine in COVID-negative Multiple Sclerosis patients treated with ocrelizumab [NYU Langone Health, 2021 ].

The phase 4, non-randomized study Covid Vaccin Allo is currently evaluating the effectiveness/safety of the vaccine in patients allo-hematopoietic cell transplantation recipients [University of Liege, 2021 ].

The non-randomized study VAX4FRAIL is currently evaluating the effectiveness/safety of the vaccine in frail subjects with impaired immuno-competence, due to their underlying diseases or ongoing therapies that received SARS-CoV-2 with Pfizer-BioNTech or Moderna vaccines [Azienda Unità Sanitaria Locale Reggio Emilia, 2021 ].

The phase 4, non-randomized study EREVA is currently evaluating the effectiveness/safety of the vaccine in adults immunocompromised or non-immunocompromised volunteers [Centre Hospitalier Régional d'Orléans, 2021 ].

The phase 1 and 2, interventional, non-randomized study PACIFIC is currently evaluating the effectiveness/safety of the vaccine in children with acute leukemia (1 to 15 years old) and their siblings (≥12-15 years old) [Assistance Publique - Hôpitaux de Paris, 2021 ].

The non-randomized study CPAT is currently evaluating the effectiveness/safety of the vaccine in kidney transplant recipients [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ].

The phase 4, non-randomized study HHCTC_COVID-19_VACCINE_Ab is currently evaluating the effectiveness/safety of the vaccine in adults with chronic liver disease or Underlying CLD, aged 18 years and older [Humanity & Health Medical Group Limited, 2021 ].

Huang HJ et al. included 241 transplant candidates and 1,163 transplant recipients (Pfizer=858; Moderna=546). Data were collected 2 weeks to 3 months after the second dose. The study showed that transplant candidates exhibited a response to the anti-SARS-CoV-2 Total Ig of 93.5% after two doses. Anti-spike ELISA assay demonstrated that  91.9%  of transplant candidates increased in titer from <1:50 (negative) to ≥1:50 (positive) after two doses. For transplant recipients,  30.7% exhibited a response (anti-SARS-CoV-2 IgG assay)after the second dose. Results for the anti-spike titer in recipients became positive in 30.1% after two doses
[Huang HJ, 2022 ].

Spensley K et al. included 1121 patients on haemodialysis. All patients underwent weekly screening for SARS-CoV-2 infection via RT-PCR testing between December 1, 2021 and January 16, 2022. The study showed that partial vaccination did not provide protection against infection. Vaccine effectiveness against Omicron infection in patients who had received a booster vaccine was 58%. Analysing vaccine effectiveness in the 747 patients who had been boosted, significant effectiveness was seen in both patients who received AstraZeneca COVID-19 vaccine (47%)and Pfizer COVID-19 vaccine (66%).

Tenforde MW et al. included 2,952 adults (1,385 COVID-19  case-patients  and  1,567  COVID-19–negative  controls) hospitalized at 21 hospitals between August - December 2021. Among them, 1,077 adults with immunocompromising conditions (twos-dose of Pfizer= 332; two-dose Moderna=238; three dose Pfizer =120, Three-dose Moderna= 57, Both vaccines= 4). The study showed results combined for Pfizer and Moderna COVID-19 vaccine. Among patients with immunocompromising conditions, those who received 2-dose were more likely to be enrolled as a case-patient (34%) than those received 3-dose (20%).  Vaccine Effectiveness  against  COVID-19  hospitalization  among  adults  without  immunocompromising  conditions  was  82%  (95% CI 77% to 86%)  for  2  doses  and  97%  (95% CI 95% to 99%) for 3 doses . Vaccine effectiveness against COVID-19 hospitalization among adults with immunocompromising conditions was 69% (95% CI 57% to 78%) for  2  doses  and  88%  (95%  CI  81% to 93%)  for  3  doses [Tenforde MW, 2022 ].

Bassi et al was a comparative study conducted in Switzerland that evaluated the immune response elicited by mRNA COVID-19 vaccines (Pfizer-BioNTech or Moderna) in dialysis patients 143 dialysis patients (n=143, 130 on hemodiafiltration and 13 on peritoneal dialysis) compared to healthy healthcare workers (n=48). Results from plasma samples collected 2 to 3 weeks after the first and second dose show 94.4% of dialysis patients seroconverted versus 100% of healthcare workers. Importantly, 35% of dialysis patients had low or undetectable levels of antibodies while all the healthcare workers had high levels. Compared to healthcare workers, 49% of dialysis patients had no or low neutralizing activity against the Wuhan wild-type virus. Neutralizing activity against the Delta variant was low or undetectable in 76.9% of dialysis patients. Almost all participants, including healthcare workers, showed a greater than 2-fold reduction in neutralizing activity against the Delta variant. Neutralizing activity against other variants was lower compared to Delta, 7.3 lower for Beta, 1.8 for Alpha and 3.3 for Lambda. The study found that dialysis patients do not develop sufficient levels of neutralizing antibodies against SARS-CoV-2 variants after two doses of mRNA vaccines [Bassi J, 2022 ].
   
The phase 4, non-randomized study HHCTC_COVID-19_VACCINE_Ab is currently evaluating the effectiveness/safety of the vaccine in adults with chronic liver disease or Underlying CLD, aged 18 years and older [Humanity & Health Medical Group Limited, 2021 ].

Schiavetti et al. is a retrospective study conducted in Italy which analyzed data from Multiple Sclerosis centers on patients with Multiple Sclerosis undergoing the SARS-CoV-2 vaccination [Irene Schiavetti, 2022 ]. This study estimated the rate of breakthrough infections and of infection requiring hospitalization per disease-modifying therapy. The rate of breakthrough infections was significantly higher in patients treated with ocrelizumab (RR=3.55, 95% CI: 2.74-4.58) and fingolimod (RR=2.65, 95% CI: 1.75-4.00) compared to patients treated with all the other disease-modifying therapies. In the ocrelizumab group, the hospitalization rate was 16.7% vs 19.4% in pre-vaccination rates and 3.9% in all the other disease-modifying therapy groups vs 11.9% in pre-vaccination rates. The authors suggest that the risk of breakthrough SARS-CoV-2 infections is higher in patients treated with ocrelizumab and fingolimod. The rate of severe infections was significantly reduced in all the disease-modifying therapies excluding ocrelizumab [Irene Schiavetti, 2022 ].

Kennedy NA et al was a comparative cohort study conducted in United Kingdom. The aim of the study was to assess if a third dose of a messenger RNA (mRNA)-based vaccine substantially boosted anti-SARS-CoV-2 antibody responses and protective immunity in infliximab-treated patients with inflammatory bowel disease. 7224 patients were recruited to the CLARITY study from 92 UK hospitals. Anti-S RBD antibody concentrations were lower in infliximabtreated than vedolizumab-treated patients following a fourth dose with an mRNA-based vaccine (3353 U/mL (3.9) vs 18152 U/mL (2.6), p<0.0001), irrespective of whether they had received two doses of ChAdOx1 nCoV 19 (3257 U/mL (4.3) vs 17535 U/mL (2.6), p<0.0001) or BNT162b2 (3489 U/mL (3.4) vs 19183 U/mL (2.6), p<0.0001) vaccines first . There was no difference between geometric mean (SD) anti-S RBD peak antibody concentrations following third and fourth doses of an mRNA-based vaccine, irrespective of the combination of primary vaccinations received. [Kennedy NA, 2022 ]

Torres R et al was a comparative cohort study conducted in Chile. A total of 12,301 patients were evaluated; 10,615 (86.3%) received a complete vaccination (2 doses), 490 (4.0%) received incomplete vaccination, and 1196 (9.7%) were not vaccinated. The clinical effectiveness of anti-SARS-CoV-2 vaccination in end-stage renal disease patients on chronic hemodialysis from February to August 2021. Patients vaccinated with BNT162b2 compared to those vaccinated with CoronaVac had a lower infection incidence (BNT162b2: 0.421
1000 person-days, CoronaVac: 0.550
1000 person-days), hospitalization (BNT162b2: 0.083
1000 person-days, CoronaVac: 0.116
1000 person-days), and death associated with COVID-19 (BNT162b2: 0.008
1000 person-days, CoronaVac: 0.031
1000 person-days). Vaccine effectiveness against COVID-19 diagnosis for BNT162b2 complete schedule was 42.6% (95% CI 32.1% to 51.3%). Against hospitalization, vaccine effectiveness for the BNT162b2 vaccine was 68.6% (95% CI 57.6%–76.6%) [Torres R, 2022 ].

Harboe ZB et al was a prospective cohort study conducted in Denmark. The study included 626 patients diagnosed with chronic pulmonary disease who received the Pfizer-BioNTech COVID-19 vaccine. Antibody concentrations as geometric means with 95% CI of receptor binding domain (RBD)-IgG and neutralizing antibody index of inhibition of ACE-2/RBD interaction (%) were reported. A low responder was defined as a neutralizing index in the lowest quartile (primary outcome) or RBD-IgG <225 AU/mL plus neutralizing index <25% (secondary outcome), measured at 2 months. For the primary outcome, 34.7% of patients (n=157/453) and 12.9% of controls (n=46/359) were low responders (p<0.0001). For the secondary outcome, 8.6% of patients (n=39/453) and 1.4% of controls (n=5/359) were low responders (p<0.001) [Harboe ZB, 2022 ].

Wing Tak Cheng et al. conducted a retrospective cohort study in Honk Kong. In individuals with chronic kidney disease, of whom 28,374 had received no vaccine, 27,129 had received two doses of Pfizer and 47,640 two doses of CoronaVac. Vaccine efficacy was estimated to be 38% (95% CI: 34%–41%) for BNT162b2 and 4% (95% CI: 0%–8%) for CoronaVac compared to the unvaccinated group. [Tak Cheng FW, 2022 ].

Coburn SB et al was a cohort study conducted in United States. The study included 113,994 patients (33,029 people with HIV and 80,965 people without HIV). The aim of the study was to determine whether HIV status was associated with increased rate or risk of COVID-19 breakthrough infection among fully vaccinated patients in the United States by vaccination type and, among PWH, by immune and viral suppression status. The incidence rate of breakthrough infections was higher in people with HIV (55 [95% CI, 52-58] cases per 1000 person-years) vs people without HIV (43 [95% CI, 42-45] cases per 1000 person-years). The breakthrough rate was highest with the Janssen vaccine (70 [95% CI, 63-78] cases per 1000 person-years), followed by Pfizer (54 [95% CI, 52-56] cases per 1000 person-years), and Moderna (34 [95% CI, 32-36] cases per 1000 person-years) [Coburn SB, 2022 ].

Risk M et al was a retrospective cohort study conducted in the United States including 168,414 participants: 133,238 vaccinated with mRNA vaccines and 35,176 unvaccinated. Based on data from the Michigan Medicine health-care system, the Michigan State Registry and chart-reviewed COVID-19 hospitalization data. Including patients 18 years old and above, who received mRNA based COVID-19 vaccines during the Omicron dominant period December 2021 to March 2022. The effectiveness of the Pfizer-BioNTech vaccine during the Omicron period in immunocompromised participants the effectiveness was 13% (95%CI –19 to 39) for two doses and 50% (95% CI 31 to 64) for three doses [Risk M, 2022 ].

Embi P et al. conducted a case-control study with a test-negative design among eight VISION Network sites in the United States during the Delta variant predominance period. Persons aged 18 years and older with ≥1 immunocompromising conditions were included and compared with non-immunocompromised individuals. It included 8,848 emergency department/urgent care (ED/UC) events and 18,843 hospitalizations among immunocompromised (IC) patients; and 200,071 ED/UC events and 70,882 hospitalizations among non-IC patients. In the IC population, adjusted vaccine effectiveness (VE) for the Pfizer vaccine was 61% (95% CI, 54% to 67%) for ED/UC events, and 66% (95% CI, 61% to 70%) for hospitalization, measured 14 days after the second dose. After a third dose, VE was 74% (CI 95%, 62% to 82%), and 76% (CI 95%, 69% to 82%) for ED/UC encounters and hospitalization, respectively. Preprint. [Peter J. Embi, 2022 ]

Furer V et al was a prospective cohort study conducted in Israel including 729 participants with autoimmune inflammatory rheumatic diseases and 122 controls. The study assessed long-term immunogenicity of the BNT162b2 mRNA vaccine in adult patients with AIIRD. Seropositivity rates 2-to-6 weeks after the second dose were 100% for controls and 84.72% for AIIRD patients, at 6 months, 96.55% versus 74.36%, respectively. After the third vaccine dose, 100% of the controls and 82.26% of patients had detectable positive S1/S2 IgG titers. [Furer V, 2022 ]

Wagner A et al was an open-label phase 4 randomized trial conducted in Austria, including 263 patients: 63 with solid tumors, 70 with multiple myeloma, 130 with inflammatory bowel disease and 66 controls. The seronegativity rate 6 months after the primary schedule was 12.1% in the SOT group and 18.9% in the MM group. [Furer V, 2022 ]

Smith JB was a retrospective cohort studuy conducted in United States that included 3,974 patients with multiple sclerosis. The aim was to examine whether rituximab treatment is associated with an increased risk of hospitalization for COVID-19 among SARS-CoV-2–vaccinated persons with multiple sclerosis. During the study period, 437 patients (22.4%) receiving rituximab were unvaccinated. These patients were at significantly higher risk of COVID-19 hospitalizations compared with vaccinated individuals with an adjusted odds ratio of 4.07 (95% CI, 2.29-7.24). [Smith JB, 2022 ]

Bieber A was a retrospective cohort study conducted in Israel that included 43,748 autoimmune rheumatic patients, of whom 27,766 and 15,982 were in the control and fourth vaccination groups, respectively. Patients vaccinated with the fourth dose had a lower risk for COVID-19 infection (HR 0.54 [95% CI, 0.52-0.58]), COVID-19-related hospitalization (HR 0.36 [95% CI, 0.22-0.61]) and COVID-19-related death (HR 0.41 [95% CI, 0.24-0.71]). HR = Hazard Ratio. [Bieber A, 2023 ]

Vaccine effectiveness (other comparative studies)

Contracting COVID-19
Chung et al. was a nested case-control study conducted in Canada. The study enrolled 324 ,033 participants that received Moderna or Pfizer COVID-19 vaccine. Based on data from a test negative design study among patients who had symptoms consistent with covid-19 between 14 December 2020 and 19 April 2021. Results showed vaccine effectiveness of 91% (95% CI 88 to 93)[Chung H, 2021 ].

Dagan N et al. was a cohort study conducted in Israel. The study enrolled 1,193,236 general population participants that received Pfizer-BioNTech COVID-19 vaccine. Based on data from Israel’s largest health care organization (Clalit Health Services) during the period from December 20, 2020, to February 1, 2021. Results showed vaccine effectiveness against documented infection was 92% (95% CI 88 to 95) and symptomatic infection was 94% (95% CI 87 to 98) [Dagan N, 2021 ] .

Muhsen K et al. was a comparative cohort study conducted in Israel. The study enrolled 9,162 participants: 6,960 Vaccine group; 2,202 Control group. Based on data from Health care workers from a tertiary care facility adhering to routine testing since July 2020. Outcome measured at ≥ 14 days after the second dose. Results showed vaccine effectiveness of 89% (95% CI 83 to 93)
[Khitam Muhsen, 2021 ].

Cabezas C et al. was a comparative cohort study conducted in Spain. The study enrolled 116,783 participants: 98,494 Vaccine group; 18,289 Control group. Based on data from three cohorts from Catalonia from December 27 2020 to March 5, 2021. Outcomes were measured at ≥ 12 days after vaccination. Results showed vaccine effectiveness in nursing home residents was 92% (95% CI 91 to 93); nursing home staff was 88% (95% CI 85 to 90), and healthcare workers was 95% (95% CI 93 to 96) [Carmen Cabezas, 2021 ].

Haas EJ et al. was a comparative cohort study conducted in Israel. The study enrolled 6,538,911 participants: 4,714,932 Vaccine group; 1,823,979 Control group. Based on national surveillance data from the first 4 months of the nationwide vaccination campaign in people aged ≥ 16 years from Jan 24 to April 3, 2021. Outcomes were measured starting 7 days after the second dose. Results showed vaccine effectiveness against asymptomatic infection of 91.5% (95% CI 90.7 to 92.2), symptomatic infection of 97.0% (95% CI 96.7 to 97.2), and documented infection (asymptomatic and symptomatic) of 95.3% (95%CI 94.9 to 95.7) [Haas EJ, 2021 ].

Saciuk Y et al. was a comparative cohort study conducted in Israel. The study enrolled 1,650,885 participants: 575,259 in the vaccine group and 302,909 in the control group. Based on retrospective surveillance data from the nationwide vaccination program in people aged ≥ 16 years in Maccabi HealthCare Services, Israel, between January 18th to April 25th 2021. Outcomes were measured starting 7 days after the second dose. Results showed vaccine effectiveness was 93.0% (95% CI, 92.6% to 93.4%) [Saciuk Y, 2021 ].

Emborget HD et al. was a comparative cohort study conducted in Denmark. The study enrolled 864,096 participants: 850,799 Vaccine group; 13,297 Control group. Based on data from The Danish Civil Registration System from five cohorts of priority groups for vaccination (long-term care facility residents, individuals 65 years and older living at home but requiring practical help and personal care, individuals ≥85 years of age health-care workers and individuals with comorbidities) between December 27, 2020, and April 11, 2021. Outcomes were measured starting 7 days after the second dose. Results showed vaccine effectiveness of 82% (95% CI 79 to 84) [Hanne-Dorthe Emborg, 2021 ].

Bjork J et al. was a comparative cohort study conducted in Sweden. The study enrolled 805,741 participants: 26,587 Vaccine group; 779,154 Control group. Based on data from the working population from registers kept for administrative purposes at the Skåne county council, Sweden between 27 December 2020 until 28 February 2021.Outcomes were measured starting 7 days after the second dose. Results showed vaccine effectiveness of 86% (95% CI 72 to 94) [Jonas Bjork, 2021 ].

Moustsen-Helms I et al. was a comparative cohort study conducted in Denmark. The study enrolled 370,079 participants: 114,406 Vaccine group; 255,673 Control group. Based on retrospective data from population-based registries from all Long Term Care Facilities residents and all Health Care Workers, between December 27, 2020, and February 18, 2021. Outcomes were measured starting 7 days after the second dose. Results showed vaccine effectiveness in long term care facility residents was 64% (95% CI 14 to 84) and health care workers was 90% (95% CI 82 to 95)[Ida Rask Moustsen-Helms, 2021 ].

Pilishvili T et al. was a case-control study conducted in United States. The study enrolled 4,931 participants: 1,482 Vaccine group; 3,449 Control group. Based on a test-negative  case–control study involving  health  care  personnel  across 25 U.S. states, between December 28, 2020 and May 19, 2021. Outcome was measured starting at ≥ 14 days after vaccination. Results showed a vaccine effectiveness of 88.8% (95%CI 84.6 to 91.8) [Pilishvili T, 2021 ]

Trunfio M et al. was a Case-control study conducted in Italy. The study enrolled 6,910 participants: 6,800 vaccine group; 110 Control group. Based on data from all the health care workers of the entire health district ASL Città di Torino, between 27 December 2020 and 1 April 2021. Outcome measured starting at ≥ 8 days after second dose. Results showed an Incident relative risk of 0.06 (95%CI 0.05 to 0.07) [Trunfio M, 2021 ].

Chico-Sánchez P et al. was a case-control study conducted in Spain. The study enrolled 624 participants: 518 vaccine group, 106 control group. Based on electronic health records and interviews to health care personnel from the Alicante-Hospital-General health department between January 25 and June 6, 2021. Results showed a vaccine effectiveness of 96.3% (95%CI 82.5̶ to 99.2) for preventing COVID infection with the complete vaccination regimen. The results also showed a vaccine effectiveness of 68.0% (95%CI 30.0̶ to 85.4) with the incomplete vaccine regimen [Chico-Sánchez P, 2021 ].  

Amanda Zheutlin et al. was a case-control study conducted in the United States. The study included data from 168,857,729 participants with 7,926,846 receiving Pfizer vaccine. Based on claims and laboratory data from vaccinated individuals between January 1 and September 7, 2021. Odds ratios (OR) for developing incident breakthrough infection, hospitalization or ICU admission in months two through six following full vaccination were estimated relative to the first month after full vaccination. The study results showed evidence of waning protection against infections starting in month 2 from vaccination for both BNT162b2 and mRNA-1273 and in month 4 for Ad26.COV2.S. Evidence of waning protection against hospitalization started in month 2 for BNT162b2 and in month 3 for mRNA-1273. There was no evidence of waning protection against hospitalization for Ad26.COV2.S.  No waning of protection was observed at any time for ICU admissions for all three vaccines [Amanda Zheutlin, 2022 ].

Bedston S et al was a comparative cohort study in United Kingdom. The study included 82,959 health care workers. Based on data from a national cohort of health care workers to describe uptake of COVID-19 vaccines, effectiveness, and waning of the Pfizer vaccine effectiveness against PCR-confirmed infection following first and second doses up to 26 weeks post-vaccination, between from 7 December 2020 to 30 September 2021. The study results showed that the effectiveness of the Pfizer vaccine was found to be strong and consistent across the characteristics considered; 52% three to six weeks after first dose, 86% from two weeks after second dose, though this declined to 53% from 22 weeks after the second dose [Bedston S, 2022 ].

Haruka Maeda et al. was a case-control study conducted in Japan. The study enrolled 1,936 participants: 396 vaccine group; 1,540 control group.  Based on data from patients aged16 years or older visiting hospitals or clinics with signs or symptoms consistent with COVID-19 from July 1 to September 30, 2021, when the Delta variant was dominant and responsable of more than 90% of severe SARS-CoV-2 infections nationwide in Japan, the study results showed a vaccine effectiveness against symptomatic infection of  86.7% (95% CI 73.5 to 93.3) in patients 16-64 years and of 85.8% (95% CI 59.4 to 95.0) in participants aged ≥ 65 years 3 to 6 months after vaccination [Haruka Maeda, 2022 ].

Chadeau-Hyam M et al. was a cohort study conducted in United Kingdom. The study enrolled 172,862 participants: 76,291 vaccine group; 96,571 control group. Based on data from a  series of random cross-sectional surveys in the general population of England aged 5 years and older, between May 2020 and September 2021, the study results showed a vaccine effectiveness of 71.3% (95%CI 56.6 to 81.0) against infection in vaccinated individuals [Chadeau-Hyam M, 2022 ].

Chin ET et al. was a retrospective cohort study conducted in the United States. The study enrolled 60,707 participants from the California state prisons: 29,947 vaccine group; 30,760 control group. Based on data from the California Department of Corrections and Rehabilitation from December 22, 2020 through March 1, 2021, including daily data for all prison residents related to demographic, clinical, and carceral characteristics, as well as COVID-19 testing, vaccination, and outcomes, measuring outcome 14 days after second dose, the study results showed an agregated vaccine effectiveness of 97% (95% CI, 88-99%) in vaccinated individuals (Pfizer and Moderna) [Chin ET, 2022 ].

Johnson AG et al. included 6,812,040 COVID-19 cases in unvaccinated persons and 2,866,517 cases in fully vaccinated persons. Data were collected between April 4, 2021, to December 25, 2021. Combined results showed that age-standardized case incidence rate ratios among unvaccinated persons compared with fully vaccinated persons with a booster dose declined from 13.9 during October–November to 4.9 during December, representing potential decreases in crude vaccine effectiveness for infection from 93% to 80%, respectively. Comparing unvaccinated persons with fully vaccinated persons without a booster dose, age-standardized case incidence rate ratios during October–November, and December were 4.0 and 2.8 respectively, representing decreases in vaccine effectiveness from 75% to 64% [Johnson AG, 2022 ].

The VISION Network study included 222,772 encounters from 383 emergency departments (ED) and urgent care (UC), and 87,904 hospitalizations from 259 hospitals. Data were collected during periods of Delta and Omicron variant predominance between august 2021to January 2022. Based on all results combined, during the Delta-predominant period, vaccine effectiveness against Lab-confirmed COVID-19 was significantly lower among patients who received the second dose ≥180 days earlier (76%; 95% CI 75 to 77) than among those who received the third dose (94%; 95% CI 93 to 94). In the omicron-predominant period, vaccine effectiveness against the same outcome was significantly lower among those who received the second dose ≥180 days earlier (38%; 95% CI 32 to 43) than those who received the third dose (82%; 95% CI 79 to 84)[Thompson MG, 2022 ].

Butt AA et al was a cohort study conducted in the United States. The study enrolled 6,076 participants: 2,700 vaccine group; 3,376 control group. Based on the US Department of Veterans Affairs COVID-19 Shared Data Resource to identify all Veterans with chronic hemodialysis who were tested for SARS-CoV-2 between January 26, 2021 and August 31, 2021, the study results showed a vaccine effectiveness against documented infection of 68.9% (95% CI.:61.9,74.7)( Outcome measured 14 days after second dose) [Butt AA, 2022 ].

Molani S et al. was a cohort study conducted in the United States. The study included 7,620,084 records of 2,627,914 vaccinated participants with either Pfizer-BioNTech, Moderna or Janssen, and  191,722 non-vaccinated individuals with history of COVID-19 infection. The study was based on data from Providence-St. Joseph Health electronic health records. The vaccine-induced cohort period data was collected from December 12, 2020, the infection-induced cohort data was collected from the beginning of the pandemic, data collection finished in to May 11, 2021. Survival against breakthrough for Pfizer-BioNTech was 99.7% in 180 days. [Sevda Molani, 2022 ]

Goldin S et al was a cohort study conducted in Israel. The study enrolled 43,596 participants: 39,482 received one dose; 37,656 received two doses. Based on data from the Senior Shield task force. Residents began receiving Pfizer-BioNTech vaccines in December 2020. The study follow-up period ended in May 2021 (a total of 5 months). The study results showed a vaccine effectiveness against documented infection of  61.8% (95% CI: 58.2 to 65.1) after one dose(Outcome measured 10 days after vaccination) and 81.2% (95% CI: 78.6 to 83.5) after two doses (Outcome measured 7 days after second dose) [Goldin S, 2022 ]

Oster Y et al was a comparative cohort study conducted in Israel. The study enrolled 5,371 healthcare workers: 398 received two doses, 4,973 received three doses. Based on data from healthcare workers at the Hadassah tertiary care medical center in Jerusalem, who had received two vaccine doses (Pfizer-BioNTech) in early 2021 and were not infected until August 2021. The follow-up period lasted 120 days after the last dose for each group. The vaccine effectiveness against breakthrough infection was  97% ( 95% CI, 95% to 99%).  [Oster Y, 2022 ]

Draws PE et al. It was a case-control study conducted in the United States. The study included 4,547,945 participants: 1,732,112 were fully vaccinated with Pfizer and 1,066,645 were fully vaccinated with Moderna. A Pfizer booster was given to 609,153 people and a Moderna booster to 395,634 people. The study is based on statewide COVID-19 vaccination data from the Minnesota Immunization Information Connection (MIIC), linked through a privacy-preserving record-linking process with electronic medical record data. (EHR) of the 11 largest health systems in Minnesota. The main results showed that the effectiveness of the vaccine after 26 weeks of the second dose was 45% (95% CI 44 to 47) for the Pfizer-BioNTech vaccine. [Drawz PE, 2022 ]

Mallow C et al. was a case-control study conducted in the United States. The study analyzed data from 13,203 adult presentations (age ≥ 18) to the emergency department: 3,134 were fully vaccinated and negative to COVID-19, 108 were fully vaccinated and positivo to COVID-19, 8,817 not  vaccinated and COVID-19 negative, and 1,144 were not vaccinated and positive to COVID-19. The aim of the study was to assess the effectiveness of messenger RNA vaccines against SARS-COV-2 in the emergency department.  Data was collected from January 1 through August 25, 2021, from subjects with SARS-COV-2 PCR testing and symptoms of acute respiratory infection. The main results showed that Pfizer vaccine effectiveness was 73.9% (95 CI 66.3 to 79.8). [Mallow C, 2022 ]

Roberts E et al. was a case control study conducted in the United States. The study analyzed data from 170,487 positive for COVID-19 adult patients: 74,060 fully vaccinated, 18,425 partially vaccinated and 7187 fully vaccinated and had received at least 1 booster dose. The aim was to investigate the COVID-19 vaccine effectiveness against test positivity and severe COVID-19 outcomes across 2021, and to examine  vaccine effectiveness stratified by the two most common vaccines Pfizer-BioNTech and Moderna, and by sociodemographic and clinical characteristics that are associated with COVID-19 outcomes. Results reported a vaccine effectiveness for contracting COVID-19 of 82.9% (95% CI 80.7 to 84.9). [Emily Roberts, 2022 ]

Fano V et al was a comparative cohort study conducted in Italy. The study included 371,423 participants: 221,000 received Pfizer vaccine and 150,423 received AstraZeneca vaccine. The study estimated the effectiveness of Pfizer and AstraZeneca vaccines since 27/12/2020, and followed until diagnosis of SARS-CoV-2 infection or 25/4/2021, whichever came first. Adjusted hazard ratios of SARS-CoV-2 infection at weekly intervals since the first dose were estimated through a Cox regression model using 0-13 days as reference time-interval. Adjusted Pfizer vaccine effectiveness between 35 and 41 days was 81.1% ( 95%CI 71.1 to 87.7). [Fano V, 2022 ]

Winkelman TNA et al  was a comparative cohort study conducted in the USA. The study included 4,431,190 individuals: 3,013,704 fully vaccinated and 1,417,486 not vaccinated. It used data from the Minnesota Immunization Information Connection from October 25, 2020, through October 30, 2021 that were linked with electronic health record (EHR) data from health systems collaborating as part of the Minnesota EHR Consortium (MNEHRC). Vaccine Effectiveness for Medically Attended SARS-CoV-2 Infections was 53% (95% CI 52 to 54) and 38% (95% CI 35 to 41) for adults ≥ 65 years. [Winkelman TNA, 2022 ]

Goldberg Y et al was a comparative cohort study conducted in Israel. The study included 4,606,250 PCR tests. The study analyzed an updated individual-level database of the entire population of Israel to assess the protection of both prior infection and vaccination in preventing subsequent SARS-CoV-2 infection, hospitalization with COVID-19, severe disease, and death due to COVID-19. Outcome data were collected from December 20, 2020 up to March 20, 2021.Vaccine effectiveness was 94.5% (95% CI 94.3 to 94.7). [Goldberg Y, 2022 ]

Berec L was a case-control study conducted in Czechia. The study used Czech national health data from the beginning of the Covid-19 pandemic till November 2021 to estimate risks of reinfection, breakthrough infection, hospitalization, and death among fully vaccinated individuals at two time points (0-2 months and 7-8 months after the second dose) and after a booster dose. The study analyzed 5,011,115 individuals vaccinated with the Pfizer-BioNTech vaccine. The vaccine effectiveness against any PCR-confirmed SARS-CoV-2 infection declined for from 87% (95% CI 86–87) 0–2 months after the second dose to 53% (95% CI 52–54) at 7–8 months; against hospitalizations, VE declined from 90% (95% CI 89–91) at 0–2 months to 75% (95% CI 73–76) at 7–8 months. [Berec L, 2022 ]

Shrotri M et al was a comparative cohort study conducted in England. The study included data from participants from 331 long-term care facilities: 15518 residents aged 65 years or older and 19515 staff aged 18 years or older. This study estimated vaccine effectiveness against SARS-CoV-2 infection, COVID-19-related hospitalization, and COVID-19-related death after one, two, and three vaccine doses, separately by previous SARS-CoV-2 exposure. Vaccine effectiveness against infections at 14 -83 days after the second dose was 44.1% (95% CI -140.0 to 72.6) for residents (>65 years old) and 66.8% (95% CI 53.1 to 76.6) for staff (>18 years old). [Shrotri M, 2022 ]

Paternina-Caicedo A et al was a retrospective cohort study conducted in Colombia. The study included 719,735 participants over 40 years old: 539,010 unvaccinated, 76,729 with two-dose CoronaVac, and 56,140 with two-dose Pfizer vaccine. This study estimated the vaccine effectiveness (VE) against COVID-19 symptomatic cases, hospitalization, critical care admission, and deaths in a cohort of insured subjects older than 40 years in northern Colombia, a setting with a high SARS-CoV-2 transmission. VE for two doses of BNT162b2 against laboratory-confirmed symptomatic Covid-19 was 29.6% (95% CI 21.1 to 37.2). [Paternina-Caicedo A, 2022 ]

Oren Miron et al was a secondary analysis of a phase 3 randomized clinical trial conduct in 166 different locations. The study reunited data from 43,448 participants aged 16 to 91 years that were enrolled to receive two doses of Pfizer-BioNTech vaccine on days 0 and 21 (n= 21,720) and placebo group (n= 21,728). Vaccine effectiveness (VE) was defined by the ratio between the COVID-19 cumulative rate in vaccinated participants and in the placebo group participants. The study results showed that  the cumulative incidence of COVID-19 increased by 0.09% from day 0 to 7, by 0.06% from day 7 to 14, and by 0.01% from day 14 to 21. From day 21 to 111, the incidence increased on average by 0.01% per week and reached 0.29%, as oppose to controls that reached 2.22% at day 111. The BNT162b2 effectiveness at days 7, 14, and 21 was 12%, 80%, and 94% respectively, followed by a mean of 94% effectiveness until day 112. [Oren Miron, 2021 ]

Horne E et al was a cohort study conducted in England, including 7,594,195 participants, amongst which 1,951,866 were Pfizer-BioNTech recipients, 3,219,349 AstraZeneca recipients and 2,422,980 remained unvaccinated. Rates of COVID-19 related hospital admission and death were substantially lower among vaccinated than unvaccinated adults up to 26 weeks after the second dose, with estimated vaccine effectiveness ≥80% for BNT162b2. By weeks 23-26, rates of positive SARS-CoV-2 test in vaccinated people were similar to or higher than unvaccinated people (adjusted hazard ratios up to 1.72 (1.11 to 2.68) for BNT162b2. COVID-19 related hospitalizations: Estimated adjusted hazard ratios comparing BNT162b2 with unvaccinated people in the ≥65 subgroup were 0.08 (95% confidence interval 0.05 to 0.13) during weeks three to six after the second dose, waning to 0.20 (0.17 to 0.25) during weeks 23-26. [Horne EMF, 2022 ]

Lin DY et al, was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. Based on data from the North Carolina COVID-19 Surveillance System and the Covid-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Vaccine effectiveness of 2 doses of Pfizer against infection was 74.5% (95% CI 74 to 75) and 47.4% (95% CI 46.6 to 48.2), 1 and 10 months after vaccination respectively. [Lin DY, 2022 ]

Chung et al. conducted a case-control study with a test-negative design to estimate vaccine effectiveness (VE) against SARS-CoV-2 infection after the primary schedule of any combination of BNT162b2, mRNA-1273, and ChAdOx1 between January 11th and November 21th 2021 in Ontario, Canada. They included 261,360 test-positive cases (of any SARS-CoV-2 lineage) and 2,783,699 individuals as test-negative controls. VE for ChAdOx1/mRNA-1273 7-59 days after second dose was 91% (95% CI, 89% to 93%) against any infection, 96% (95% CI, 93% to 97%) against symptomatic infection and 99% (95% CI, 95% to 100%) against severe outcomes. VE for BNT162b2/BNT162b2 7-59 days after second dose was 89% (95% CI, 88% to 89%) against any infection and 93% (95% CI, 93% to 94%) against symptomatic infection. VE BNT162B2/BNT162B2 >240 days after second dose was 74% (95% CI, 71% to 77%) against any infection and 87% (95% CI, 84% to 89%) against symptomatic infection. [Chung H, 2022 ]

Rane MS et al was a case control study conducted in the United States that included data from 931,972 patients with vaccine records: 39,185 with a positive test and 892,787 with a negative test. The study estimated Vaccine Effectiveness (VE) against symptomatic infection in a population of patients seeking care at CityMD, a large ambulatory care center in New York and neighboring areas. VE against symptomatic infection for the BioNTech BNT162b and mRNA-1273 vaccines combined was 96% (95% CI, 95% to 97%) in the pre-Delta period and 79% (95% CI, 77% to 81%) in the Delta period. Adjusted VE against any infection was higher in all subgroups in the pre-Delta period compared with the Delta period. VE for participants aged 12 to 15 years was 85% (95% CI, 81% to 88%) during the Delta period. VE was lower for adults aged 64 years and older compared with <64 years, even in the pre-Delta period. [Rane MS, 2022 ]

Elsie MF Horne et al was a comparative cohort study conducted in United Kingdom that estimated vaccine effectiveness of two doses of the Pfizer and AstraZeneca vaccines (versus no vaccine) in participants aged 18 to 64 and over 65 years. Hazard ratio for positive SARS-CoV-2 test (18-39 years) was 0.25 (95% CI, 0.24-0.26). Hazard ratio for positive SARS-CoV-2 test (>65  years) was 0.23 (95% CI, 0.16-0.33). [Elsie MF Horne, 2023 ]

Weng C et al was a comparative study conducted in United States that included 38,602 participants: 22,247 with at least one SARS-CoV-2 PCR test. The aim was to assess mRNA vaccine effectiveness (VE) in preventing SARS-CoV-2 infections. Adjusted VE of 2 doses of Pfizer was 94.6% (95% CI, 83.4% to 98.3%). Adjusted VE against Omicron (2 doses of Pfizer) was 31.6% (95% CI, 19.6% to 42.5%). Adjusted VE against Omicron (3 doses of Pfizer) was 79.9% (95% CI, 44.3% to 93.5%). [Weng CH, 2023 ]

Bello-Chavolla OY et al was a retrospective cohort study conducted in Mexico, including 793,487 vaccinated and 4,792,388 unvaccinated individuals. This study estimated vaccine effectiveness (VE) against infection and hospitalization, based on data from the COVID-19 surveillance system between December 2020 and September 2021. Among 197,078 participants vaccinated with Pfizer, VE against infection was 80.34% (95% CI, 80.1% to 50.5%), and VE against hospitalization was 84.26% (95% CI, 83.6% to 84.9%). [Bello-Chavolla OY, 2023 ]

Shioda K et al was a trial emulation study conducted in the United States that included 6,128,364 participants: 2,337,570 with the Moderna vaccine and 3,790,794 with the Pfizer vaccine. The aim was to assess the effectiveness of mRNA COVID-19 vaccines (Pfizer-BioNTech and Moderna) against SARS-CoV-2 infection. Weighted risk of infection was RR 0.79 (95% CI, 0.78-0.81) for Pfizer vaccine and RR 0.90 (95% CI, 0.87-0.92) for Moderna vaccine. [Kayoko Shioda, 2023 ]
 

Contracting severe COVID-19
Chung et al. was a nested case-control study conducted in Canada. The study enrolled 324 ,033 participants that received Moderna or Pfizer COVID-19 vaccine. Based on data from a test negative design study among patients who had symptoms consistent with covid-19 between 14 December 2020 and 19 April 2021. Results showed vaccine effectiveness of 96% (95%CI 82 to 99)
[Chung H, 2021 ].

Dagan N et al. was a cohort study conducted in Israel. The study enrolled 1,193,236 general population participants that received Pfizer-BioNTech COVID-19 vaccine. Based on data from Israel’s largest health care organization (Clalit Health Services) during the period from December 20, 2020, to February 1, 2021. Results showed vaccine effectiveness against severe infection 92% (95% CI 75 to 100) and hospitalizations was 87% (95% CI 55 to 100) [Dagan N, 2021 ].

Cabezas C et al. was a comparative cohort study conducted in Spain. The study enrolled 116,783 participants: 98,494 Vaccine group; 18,289 Control group. Based on data from three cohorts from Catalonia from December 27 2020 to March 5, 2021. Outcomes were measured at ≥ 12 days after vaccination. Results showed vaccine effectiveness in nursing home residents was 97% (95%CI 95 to 98) and nursing home staff was 98% (95%CI 97 to 99)[Carmen Cabezas, 2021 ].

Haas EJ et al. was a comparative cohort study conducted in Israel. The study enrolled 6,538,911 participants: 4,714,932 Vaccine group; 1,823,979 Control group. Based on national surveillance data from the first 4 months of the nationwide vaccination campaign in people aged ≥ 16 years from Jan 24 to April 3, 2021. Outcomes were measured starting 7 days after the second dose. Results showed vaccine effectiveness against hospitalisation of 97.5% (95%CI 97.1 to 97.8) and deaths of 96.7% (95%CI 96.0 to 97.3) [Haas EJ, 2021 ].

Saciuk Y et al. was a comparative cohort study conducted in Israel. The study enrolled 1,650,885 participants: 575,259 in the vaccine group and 302,909 in the control group. Based on retrospective surveillance data from the nationwide vaccination program in people aged ≥ 16 years in Maccabi HealthCare Services, Israel, between January 18th and April 25th 2021. Outcomes were measured starting 7 days after the second dose. Results showed vaccine effectiveness against hospitalization was 93.4% (95% CI, 91.9% to 94.7%) and deaths of 91.1% (95% CI, 86.5% to 94.1%) [Saciuk Y, 2021 ].

Emborget HD et al. was a comparative cohort study conducted in Denmark. The study enrolled 864,096 participants: 850,799 Vaccine group; 13,297 Control group. Based on data from The Danish Civil Registration System from five cohorts of priority groups for vaccination (long-term care facility residents, individuals 65 years and older living at home but requiring practical help and personal care, individuals ≥85 years of age health-care workers and individuals with comorbidities) between December 27, 2020, and April 11, 2021. Outcomes were measured starting 7 days after the second dose. Results showed vaccine effectiveness against of hospitalisation of 93% (95% CI 89 to 96) and deaths of 94% (95% CI 90 to 96) [Hanne-Dorthe Emborg, 2021 ].

Sheikh A 2021, was a cohort study conducted in Scotland. This study used data from a national surveillance database to estimate vaccine effectiveness against death from delta variant infection between April 1 and August 16, 2021, among adult participants who were followed up to September 27, 2021. Mortality analysis was based on 114,706 adults who tested positive for SARS-CoV-2 and a total of 201 deaths were reported. Among participants between 40 and 59 years of age, vaccine effectiveness against death from COVID-19 was 88% (95% CI, 76 to 93) for ChAdOx1 nCoV-19 and 95% (95% CI, 79 to 99) for BNT162b2. Among participants aged 60 years or older vaccine effectiveness was 90% (95% CI, 84 to 94) and 87% (95% CI, 77 to 93), respectively. Overall, vaccine effectiveness against death from the delta variant 14 or more days after the second vaccine dose was 90% (95% CI, 83 to 94) for BNT162b2 and 91% (95% CI, 86 to 94) for ChAdOx1 nCoV-19 [Sheikh A, 2021 ].

Suah JL et al. was a Cohort study conducted in Malaysia. The study enrolled 1,239,445 participants: 489,921 Vaccine group; 749,524 Control group. This study used data from four secondary data sets constructed from national COVID-19 surveillance: (1) the COVID-19 casesline listing, (2) the ICU admissions register, (3) the COVID-19 deaths line listing, and (4)the COVID-19 vaccine recipients line listing, linked deterministically with the case and personal identification numbers, between 1 April 2021 and 15 September 2021. Outcome was measured starting 14 days after the second dose.  Results showed a Vaccine effectiveness of 90.3% (95%CI 88.8 to 91.6) for ICU admission and  92.7% (95%CI 91.7 to 93.6) for death [Suah JL, 2021 ].

Zeina Farah et al. was a case-control study conducted in Libanon. The study enrolled 1,159 participants aged 75 years or older. Based on randomly selected data from the COVID-19 database of the Epidemiological Surveillance Unit(ESU) at the Ministry of Public Health(MOPH) between April and May 2021, the study results showed a vaccine effectiveness of 82% (95%CI = 69%-90%) against COVID-19 associated hospitalization for those fully vaccinated and 53% (95%CI = 23%-71%) for those partially vaccinated (≥14 days of first or within 14 days of second dose), after adjusting for month of admission and gender [Zeina Farah, 2022 ].

Lytras T et al. included a total of 14,676,605 vaccine administered doses ( Pfizer= 11,427,784; Moderna= 1,161,905; AstraZeneca=1,505,334; Janssen= 581,582). Data were collected between 11 January 2020 and 8 December 2021. The study showed that two doses of Pfizer, Moderna, or AstraZeneca COVID-19 vaccines offered vaccine effectiveness >90% against both intubation and death across all age groups. The effectiveness of the Janssen COVID-19 vaccine ranged between 61-81%. There was some waning over time but vaccine effectiveness remained >80% at six months, and three doses increased vaccine effectiveness again to near 100%. Vaccination prevented an estimated 19,691 COVID-19 deaths (95% CI 18,890 to 20,788) over the study period [Theodore Lytras, 2022 ].

Wright BJ et al. was a case-control study conducted in the United States. It included data from 9,667 admissions for severe COVID-19 and 38,668 controls. Based on hospital admission registries from a large health-care system (Providence). to analyze vaccine effectiveness against severe COVID-19 over time. Between April 1, 2021, and Oct 26, 2021. The effectiveness of the vaccine was 94.9% (95% CI 93.2 to 96.2) between 50 to 100 days after the 2nd dose and it wanted to 74.1% (95% CI 69.6 to 77.9) between 200-250 days after the 2nd dose [Wright BJ, 2022 ].

Arregocés-Castillo et al was a retrospective cohort study conducted in Colombia. The study included 2,828,294 participants: 1,414,147 fully vaccinated (any vaccine) and 1,414,147 unvaccinated. The study evaluated the effectiveness of vaccines against COVID-19-related hospitalization and death in people aged 60 years and older. Participant follow-up was done between March 11, 2021, and Oct 26, 2021. It was estimated the overall effectiveness of being fully vaccinated, as well as the effectiveness of each vaccine. The aim results showed that vaccine effectiveness against hospitalization without death was 83% (95% CI 78.4 to 86.6) in adults > 60 years. Effectiveness against death after hospitalization was 94.8% (95% CI 93.3 to 96) and against death without hospitalization was 88.3% (95% CI 84.1 to 91.4) in adults > 60 years [Arregocés-Castillo L, 2022 ].

Winkelman TNA et al  was a comparative cohort study conducted in the USA. The study included 4,431,190 individuals: 3,013,704 fully vaccinated and 1,417,486 not vaccinated. It used data from the Minnesota Immunization Information Connection from October 25, 2020, through October 30, 2021 that were linked with electronic health record (EHR) data from health systems collaborating as part of the Minnesota EHR Consortium (MNEHRC). Vaccine Effectiveness for SARS-CoV-2–Related Hospitalizations: was 81% (95% CI 79 to 82) and 55% (95% CI 50 to 59) [Winkelman TNA, 2022 ].

Goldberg Y et al was a comparative cohort study conducted in Israel. The study included 4,606,250 PCR tests. The study analyzed an updated individual-level database of the entire population of Israel to assess the protection of both prior infection and vaccination in preventing subsequent SARS-CoV-2 infection, hospitalization with COVID-19, severe disease, and death due to COVID-19. Outcome data were collected from December 20, 2020 up to March 20, 2021.Vaccine effectiveness against hospitalization 95.8% (95% CI 95.2 to 96.2) [Goldberg Y, 2022 ].
Elsie MF Horne et al. was a comparative cohort study conducted in England. The study included data from the OpenSAFELY-TPP database. The study included 1,773,970 individuals with BNT162b2 vaccine, 2,961,011 individuals with ChAdOx1 vaccine and 2,433,988 unvaccinated individuals. The study compared individuals who had received two doses of BNT162b2 or ChAdOx1 with unvaccinated individuals during six 4-week comparison periods, separately by age subgroups. The Hazard Ratio versus unvaccinated for COVID-19 hospitalization ranged from (≥ 65 years) 1.23 (95% CI 1.15 to 1.32) to 1.27 (95% IC 1.20 to 1.34) for the BNT162b2 vaccine. Rates of COVID-19 hospitalization and COVID-19 death at week 26 showed HRs <0.20 (>80% vaccine effectiveness) for the BNT162b vaccine.

Pálinkás A et al was a retrospective cohort study conducted in Hungary including 4,026,849 fully vaccinated participants (1,604,250 with the Pfizer vaccine) and 2,377,853 unvaccinated. This study aimed to describe all-cause mortality rates by COVID-19 vaccination groups in Hungary between an epidemic period (1 April to 20 June 2021) and a nonepidemic period (21 June to 15 August 2021) and to determine the vaccines’ effectiveness in preventing all-cause mortality utilizing non-epidemic effectiveness measures. Hazard ratio (HR) reduction in epidemic period corrected with nonepidemic period’s HR with 95% confidence interval for each vaccine was used to describe the vaccine effectiveness (VE). The hazard ratio for the Pfizer vaccine was 0.384 (95% CI 0.370 to 0.399). The difference in hazard ratio was 0.513 (95% CI 0.487 to 0.539). The effectiveness in preventing all-cause mortality was 0.487 (95% CI 0.461 to 0.513) [Pálinkás A, 2022 ].

Berec L was a case-control study conducted in Czechia. The study used Czech national health data from the beginning of the Covid-19 pandemic till November 2021 to estimate risks of reinfection, breakthrough infection, hospitalization, and death among fully vaccinated individuals at two time points (0-2 months and 7-8 months after the second dose) and after a booster dose. The study analyzed 5,011,115 individuals vaccinated with the Pfizer-BioNTech vaccine. The vaccine effectiveness against any PCR-confirmed SARS-CoV-2 infection declined for from 87% (95% CI 86–87) 0–2 months after the second dose to 53% (95% CI 52–54) at 7–8 months; against hospitalizations, VE declined from 90% (95% CI 89–91) at 0–2 months to 75% (95% CI 73–76) at 7–8 months [Berec L, 2022 ].

Shrotri M et al was a comparative cohort study conducted in England. The study included data from participants from 331 long-term care facilities: 15518 residents aged 65 years or older and 19515 staff aged 18 years or older. This study estimated vaccine effectiveness against SARS-CoV-2 infection, COVID-19-related hospitalization, and COVID-19-related death after one, two, and three vaccine doses, separately by previous SARS-CoV-2 exposure. Vaccine effectiveness against hospitalization at 14 - 83 days after the second dose was 91.8% (95% CI 39.8 to 98.9) for residents (>65 years old) and 92.1% (95% CI 69.3 to 97.9) for staff (>18 years old) [Shrotri M, 2022 ].

Paternina-Caicedo A et al was a retrospective cohort study conducted in Colombia. The study included 719,735 participants over 40 years old: 539,010 unvaccinated, 76,729 with two-dose CoronaVac, and 56,140 with two-dose Pfizer vaccine. This study aimed to estimate vaccine effectiveness (VE) to prevent COVID-19 symptomatic cases, hospitalization, critical care admission, and deaths in a cohort of insured subjects older than 40 years in northern Colombia, a setting with a high SARS-CoV-2 transmission. Effectiveness of two-dose vaccination with BNT162b2 (with laboratory-confirmed Covid-19) against hospitalization, critical care admission and death were 54.2% (95% CI 34.6 to 67.9), 82.1% (95% CI 56.5 to 92.6) and 93.5% (95% CI 73.9 to 98.4) respectively [Paternina-Caicedo A, 2022 ].

Lin DY et al, was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. Based on data from the North Carolina COVID-19 Surveillance System and the Covid-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Vaccine effectiveness of two doses of Pfizer against hospitalization was 77.2% (95% CI, 74-79.9) and 70.9% (95% CI, 65.3-75.6), 1 and 10 months after vaccination respectively. [Lin DY, 2022 ].

Grasselli G et al was a cohort study conducted in Italy that included 10,107,674 residents, among which 7,863,417 were vaccinated. The study was based on data from the Italian National Health Service, from August 2021 to August 2022. The study included participants vaccinated with Pfizer, Moderna, AstraZeneca and Janssen. The effectiveness of mRNA vaccines against ICU Admission was IRR 0.10 (95 CI%, 0.08-0.12). [Lin DY, 2022 ]

Chung et al. conducted a case-control study with a test-negative design to estimate vaccine effectiveness (VE) against SARS-CoV-2 infection after the primary schedule of any combination of BNT162b2, mRNA-1273, and ChAdOx1 between January 11th and November 21st 2021 in Ontario, Canada. It included 261,360 test-positive cases (of any SARS-CoV-2 lineage) and 2,783,699 individuals as test-negative controls. VE for BNT162b2/BNT162b2 7-59 days after second dose was 98% (95% CI, 97% to 98%) against severe outcomes (hospitalization/death). VE for BNT162B2/BNT162B2 >240 days after second dose was 98% (95% CI, 95% to 99%) against severe outcomes (hospitalization/death). [Chung H, 2022 ]

Yuanyuan F et al. was an observational study to analyze vaccination status and SARS-CoV-2 infection data from more than 10.4 million participants in the national COVID Cohort Collaborative during an 18-month-period (December 2020 to June 2022) in the United States. Vaccine Effectiveness against COVID-19-related death was 58.07% (95% CI, 56.88% to 59.23%) for a Pfizer primary schedule. [Yuanyuan Fu, 2022 ]

Nittayasoot et al was a test negative case-control study to examine the effectiveness of COVID-19 vaccines during January to April 2022 in Thailand. They analyzed secondary data from four main national health data bases: Co-Lab, Co-Ward, COVID-10 Death and MOPH-IC, using the national identification numbers of each individual as a unique identifier to link the same person across databases. They obtained a total of 3,059,616 records including: 1,015 cases of COVID-19 pneumonia requiring invasive ventilation from 652,854 cases with SARS-CoV-2 detection and 2,046,762 controls or non-SARS-CoV-2 detection. Vaccine Effectiveness against pneumonia requiring invasive ventilation for Pfizer + Pfizer schedule was 71.74% (95% CI, 49.71% to 84.12%). [Nittayasoot N, 2022 ]

Anzalone AJ et al was a retrospective cohort study conducted in the United States that included 2,290,674 participants: 566,128 participants with 2 doses of mRNA vaccine and 1,724,546 non vaccinated participants. The aim was to explore associations between community factors and breakthrough infections. Adjusted odds ratio of hospitalization within 30 days of testing positive for SARS-CoV-2 was 0.58 (95% CI, 0.55-0.62) corresponding to a vaccine effectiveness against hospitalization of 42% (95% CI, 38% to 45%). [Anzalone AJ, 2023 ]

Bello-Chavolla OY et al was a retrospective cohort study conducted in Mexico, including 793,487 vaccinated and 4,792,388 unvaccinated individuals. This study estimated vaccine effectiveness (VE) against infection and hospitalization, based on data from the COVID-19 surveillance system between December 2020 and September 2021. Among 197,078 participants vaccinated with Pfizer, VE against infection was 80.34% (95% CI, 80.1% to 50.5%), and VE against hospitalization was 84.26% (95% CI, 83.6% to 84.9%). [Bello-Chavolla OY, 2023 ]

Pietrzak L et al was a retrospective cohort study conducted in Poland that included 36,362,777 participants: 14,441,506 fully vaccinated and 14,220,548 without vaccines. The aim was to describe the effectiveness of the Pfizer vaccine. Vaccine effectiveness in preventing COVID-19 death was 92.62%. The mortality rate was significantly higher in the unvaccinated group compared to the fully vaccinated group in the entire cohort. [Pietrzak ?, 2023 ]

Bouillon K et al was a comparative cohort study conducted in France that included data from 28,611,967 vaccinated participants: 7,161,658 with the Pfizer vaccine, 856,599 with the Moderna vaccine and 3,238,575 with the AstraZeneca vaccine. The aim was to estimate the effectiveness of two doses of Pfizer, Moderna and AstraZeneca vaccines. Vaccine effectiveness against hospitalization was 91% (95% CI, 91% to 92%), 95% (95% CI, 93% to 96%) and 91% (95% CI, 89% to 94%), for the Pfizer, Moderna and AstraZeneca vaccines, respectively. [Bouillon K, 2022 ]

de Arriba Fernández et al was a retrospective cohort study conducted in Spain that included data from 110,726  vaccinated participants: 50,639 with the Pfizer vaccine, 27,914 with the Moderna vaccine, 7,551 with the Janssen vaccine and 8,065 with the AstraZeneca vaccine. The aim was to assess the risk of developing persistent COVID-19 or SARS-CoV-2 virus reinfection. Risk of reinfection or persistent COVID-19 was OR 0.09 (95% CI, 0.07-0.12), OR 0.09 (95% CI, 0.06-0.13), OR 0.15 (95% CI, 0.09-0.25) and OR 0.08 (95% CI, 0.04-0.16), for the Pfizer, Moderna, Janssen and AstraZeneca vaccines, respectively. [de Arriba Fernández A, 2023 ]

Transmission
Abu-Raddad LJ et al. was a retrospective cohort study conducted in Qatar. The study enrolled 384,246 participants: 192,123 received Moderna vaccine; 192,123 received Pfizer vaccine. Based on data from national Covid-19 electronic health databases of the two matched cohort of participants between December 21, 2020, and October 20, 2021 and measuring the outcome 1 to 6 months after the second dose, the study results showed that vaccination with COVID-19 vaccines was associated with a lower incidence of SARS-CoV-2 breakthrough infection, with an adjusted Hazard Ratio (HR) for breakthrough infection of 0.82 (95%CI 0.60 to 1.12).[Abu-Raddad LJ, 2022 ]

Zaidi A et al. was a retrospective cohort study conducted in the United Kingdom that enrolled 1,779,448 index cases and 4,110,051 contacts. Based on data from the HOSTED dataset and the National Immunisation Management System in England. Data from February to September, 2021. The adjusted hazard ratio for contracting COVID-19 among unvaccinated contacts of Pfizer-vaccinated individuals was 0.74 (95% CI, 0.72-0.76). [Zaidi A, 2022 ]

Efficacy and effectiveness against SARS-CoV-2 variants

Immunogenicity outcomes
Alpha (B.1.1.7)
Tarke A et al. was a comparative cohort study conducted in the United States. The study enrolled 80 healthy adults (14 received Pfizer, 13 received Moderna, 28 COVID-19 group, 23 unexposed group). This study evaluated T cell responses from individuals recovered from COVID-19 and T cell responses from recent Moderna mRNA-1273 or Pfizer/BioNTech BNT162b2 vaccines for their capacity to recognize peptides derived from the ancestral reference sequence and the alpha variant. Comparison of the variant to the ancestral sequence showed no significant differences for CD4+ and CD8+ T cell reactivity in the activation-induced marker assay for B.1.1.7. CD4 + T cells (p = 0.41) and CD8 + T cells (p = 0.10) [Tarke A, 2021 ].

PRIBIVAC was a randomized controlled trial conducted in Singapore. 100 participants who had received a primary vaccine schedule with two doses of the Pfizer-BioNTech vaccine were randomized to either homologous (BNT162b2 + BNT162b2 + BNT162b2; 'BBB', n= 51) or heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; 'BBM'; n= 49). The primary endpoint was the level of neutralizing antibodies against SARS-CoV-2 wild-type and Variants of Concern (VOCs) on day 28 after the booster dose. The results of the study showed that both vaccine schedules induced increases in the level of neutralizing antibodies against the Alpha variant (BBB group: 98.0% (95% CI 96.3 to 98.6); BBM group: 98.4% (95% CI 98.0 to 98.7). There was statistical difference of neutralizing activity against the Gamma variant between the homologous and the heterologous booster dose groups (p= 0.0184) [Poh XY, 2022 ].

Beta (B.1.351)
Tarke A et al. was a comparative cohort study conducted in the United States. The study enrolled 80 healthy adults (14 received Pfizer, 13 received Moderna, 28 COVID-19 groups, 23 unexposed groups). This study evaluated the T cell responses from individuals recovered from COVID-19 and T cell responses from recent Moderna mRNA-1273 or Pfizer/BioNTech BNT162b2 vaccines for their capacity to recognize peptides derived from the ancestral reference sequence and the beta variant. Comparison of the variant to the ancestral sequence showed significant differences for CD4+ and CD8+ T cell reactivity in the activation-induced marker assay for B.1351. Decreases of 14% and 22%, respectively, were observed with the B.1.351 pools for CD4+ and CD8+ T cells (B.1.351: p < 0.01 for both comparisons) [Tarke A, 2021 ].

Angkasekwinai N et al. was a cohort study conducted in Thailand. Data was collected from a single-tertiary care hospital between July to September 2021. Results showed that for both Sinovac and AstraZeneca prime-vaccination groups, the PRNT50 GMT against the Delta and Beta variant was significantly higher among those participants who received a booster dose of Pfizer (30µg or 15µg) compared to those who received AstraZeneca or Sinopharm/ BIBP. In addition, there was no statistically significant difference in the PRNT50 between boosting with 30µg or 15µg of Pfizer vaccine, regardless of the primary vaccination series and the type of variant evaluated. The study showed that the PRNT50 against the Beta variant was 1.5-fold lower compared to Delta variant for CoronaVac and AstraZeneca prime-vaccination groups. The GMTs of the PRNT50 observed between post-boost, and post-primary vaccination series were highest among participants who received Pfizer boosting in both Sinovac and AstraZeneca groups [ ].

Lu et al. was a prospective cohort study that recruited 135 COVID-19 recovered individuals scheduled to receive either a Sinovac or Pfizer vaccine. The study compared the neutralizing response against the vaccinated individuals' Beta, Delta, and Omicron variants to the unvaccinated ones. The study found that one dose of the Pfizer vaccine greatly increased the neutralizing titers against all three variants and seropositivity rate. Neutralizing titers against the Delta and Beta variants were not significantly different than against the ancestral lineage [Lu Lu, 2022 ].

Niyomnaitham et al. was a comparative study conducted in Thailand. The study recruited 210 participants equally divided (n=30) to receive Sinovac, AstraZeneca and Pfizer-BioNTech vaccines either as a first or second dose. Participants who received only Sinovac or AstraZeneca first and second doses also received a booster dose with Pfizer-BioNTech. The study found antibody levels were highest among the groups that received Pfizer-BioNTech as a second dose. Levels were similar between homologous and heterologous regimens. These levels were significantly higher compared with the groups who received AstraZeneca or Sinovac as a second dose.  The groups who were given Pfizer-BioNTech as the second dose had significantly higher neutralizing titers against Delta and Beta than those that received AstraZeneca or Sinovac as the second dose. Neutralizing titers against the Beta variant were reduced by 2 to 5-fold compared to the Delta variant. Overall, neutralization against Omicron was low across the groups and was 28- to 229-fold lower than Delta. Neutralization against the Delta and Omicron variants was significantly lower among groups who received Sinovac as a second dose than the other groups. Seropositivity rate for the Omicron variant was of 80% (45/56), 50% (30/60) and 21% (21/58) for the groups that received  Pfizer-BioNTech, AstraZeneca and Sinovac as a second dose respectively [Suvimol Niyomnaitham, 2022 ].

PRIBIVAC was a randomized controlled trial conducted in Singapore. 100 participants who had received a primary vaccine schedule with two doses of the Pfizer-BioNTech vaccine were randomized to either homologous (BNT162b2 + BNT162b2 + BNT162b2; 'BBB', n= 51) or heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; 'BBM'; n= 49). The primary endpoint was the level of neutralizing antibodies against SARS-CoV-2 wild-type and Variants of Concern (VOCs) on day 28 after the booster dose. The results of the study showed that both vaccine schedules induced increases in the level of neutralizing antibodies against the Beta variant (BBB group: 95.0% (95% CI 92.0 to 96.3); BBM group: 96.0% (95% CI 93.7 to 97.1). There was statistical difference of neutralizing activity against the Gamma variant between the homologous and the heterologous booster dose groups (p= 0.0293) [Poh XY, 2022 ].

Behrens et al. conducted a longitudinal monitoring of ChAd/ChAd (n = 41) and ChAd/BNT (n = 88) vaccinated individuals and the impact of a third vaccination with BNT. Whilst the majority of participants had neutralizing antibodies against the Wuhan strain in plasma before the third vaccination, neutralizing antibodies against Beta variant were particularly in the ChAd/ChAd group less frequent or virtually absent. In the ChAd/ChAd group, the third immunization profoundly increased neutralization of the Beta variant, which was virtually absent after prime/boost. All BNT-boosted ChAd/BNT vaccines had efficient neutralizing activity against Beta variant and titers were mostly above those identified after the second vaccination [Behrens GMN, 2022 ].

Gamma (P.1)
Tarke A et al. was a comparative cohort study conducted in the United States. The study enrolled 80 healthy adults (14 received Pfizer, 13 received Moderna, 28 COVID-19 groups, and 23 unexposed groups). This study evaluated the T cell responses from individuals recovered from COVID-19 and T cell responses from recent Moderna mRNA-1273 or Pfizer/BioNTech BNT162b2 vaccines for their capacity to recognize peptides derived from the ancestral reference sequence and the gamma variant. Comparison of the variant to the ancestral sequence showed no significant differences for CD4+ and CD8+ T cell reactivity in the activation-induced marker assay for P.1 (CD4+ T cells: p = 0.29) (CD8+ T cells: p = 0.09) [Tarke A, 2021 ].
Roanne Keeton et al. was a non-comparative study conducted in South Africa. The study enrolled 138 participants: 40 Vaccine groups (15 participants received Pfizer vaccine) and was based on data from peripheral blood mononuclear cells samples of vaccinated and unvaccinated convalescent individuals. The study results showed that CD4 T cell frequencies to Omicron spike were consistently and significantly lower than ancestral spike, with a median decrease of 14-30% of the CD4 response to Omicron and a median reduction of 17-25% of the CD8 response to Omicron compared to the ancestral virus. 70-80% of the CD4 and CD8 T cell response to spike was maintained [Roanne Keeton, 2021 ].

PRIBIVAC was a randomized controlled trial conducted in Singapore. 100 participants who had received a primary vaccine schedule with two doses of the Pfizer-BioNTech vaccine were randomized to either homologous (BNT162b2 + BNT162b2 + BNT162b2; 'BBB', n= 51) or heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; 'BBM'; n= 49). The primary endpoint was the level of neutralizing antibodies against SARS-CoV-2 wild-type and Variants of Concern (VOCs) at day 28 after the booster dose. The results of the study showed that both vaccine schedules induced increases in the level of neutralizing antibodies against the Gamma variant (BBB group: 96.0% (95% CI 92.9 to 97.2); BBM group: 97.1% (95% CI 94.9 to 97.9). There was statistical difference of neutralizing activity against the Gamma variant between the homologous and the heterologous booster dose groups (p= 0.0254) [Poh XY, 2022 ].

Delta (B.1.617.2)
Angkasekwinai N et al. was a cohort study conducted in Thailand. Data was collected from a single-tertiary care hospital between July to September 2021. Results showed that for both Sinovac and AstraZeneca prime-vaccination groups, the PRNT50 GMT against the Delta and Beta variant was significantly higher among those participants who received a booster dose of Pfizer (30µg or 15µg) compared to those who received AstraZeneca or Sinopharm/ BIBP. In addition, there was no statistically significant difference in the PRNT50 between boosting with 30µg or 15µg of Pfizer vaccine, regardless of the primary vaccination series and the type of variant evaluated. The study showed that the PRNT50 against the Beta variant was 1.5-fold lower compared to Delta variant for CoronaVac and AstraZeneca prime-vaccination groups. The GMTs of the PRNT50 observed between post-boost, and post-primary vaccination series were highest among participants who received Pfizer boosting in both Sinovac and AstraZeneca groups [ ].

Perez-Then et al. was a cohort study conducted in the Dominican Republic. The study compared the neutralizing capabilities of plasma from 101 non-hospitalized adults who received two doses of CoronaVac plus a Pfizer vaccine booster dose to a cohort of healthcare workers immunized with two doses of an mRNA vaccine (Pfizer or Moderna). The results showed increased neutralizing activity against the Omicron variant of the boosted cohort (1.4 fold increase) compared to the mRNA and CoronaVac-only regimens. Neutralization against the Delta variant was similar in the boosted and mRNA groups but lower in the CoronaVac-only group [Pérez-Then E, 2022 ].

Roanne Keeton et al. was a non-comparative study conducted in South Africa. The study enrolled 138 participants: 40 Vaccine groups (15 participants received Pfizer vaccine) and was based on data from peripheral blood mononuclear cells samples of vaccinated and unvaccinated convalescent individuals. The study results showed that CD4 T cell frequencies to Omicron spike were consistently and significantly lower than ancestral spike, with a median decrease of 14-30% of the CD4 response to Omicron and a median reduction of 17-25% of the CD8 response to Omicron compared to the ancestral virus. 70-80% of the CD4 and CD8 T cell response to spike was maintained [Roanne Keeton, 2021 ].

Alidjinou et al. was a cohort study conducted in France. The study assessed the immune response generated by a booster dose of the Pfizer vaccine against the Omicron and Delta variants. The study included 106 adults older than 65 who received the Pfizer COVID-19 vaccine booster dose. The study assessed the antibody response generated against the Delta and Omicron variants on COVID-19 naive and recovered individuals after vaccination. Results showed COVID-19 recovered individuals had higher neutralizing titers overall. A booster vaccination increased the number of participants who had neutralizing antibodies for the Delta and Omicron variants. The response against the Omicron variant was ~35 fold lower than for the Delta variant [Enagnon Kazali Alidjinou, 2022 ].

Lu et al. was a prospective cohort study that recruited 135 COVID-19 recovered individuals scheduled to receive either a Sinovac or Pfizer vaccine. The study compared the neutralizing response against the vaccinated individuals' Beta, Delta, and Omicron variants to the unvaccinated ones. The study found that one dose of the Pfizer vaccine greatly increased the neutralizing titers against all three variants and seropositivity rate. Neutralizing titers against the Delta and Beta variants were not significantly different than against the ancestral lineage [Lu Lu, 2022 ].

Kanokudom et al. recruited 222 adults with a complete CoronaVac schedule who received a booster dose of 15μg Pfizer-BioNTech vaccine (n=59), and 50μg Moderna vaccine (n=51), standard Pfizer-BioNTech vaccine (n=54), or standard Moderna vaccine (n=58). The study found no significant differences in binding antibody levels between standard and reduced doses. The booster dose induced a neutralizing response against the Delta and Omicron variants in previously seronegative participants unaffected by dosage. On day 28, the GMT of neutralizing antibodies against the Delta variant were 1 505 and 2 088 in the reduced dose Pfizer-BioNTech and Moderna vaccine groups [Kanokudom S, 2022 ].

Niyomnaitham et al was a phase 2 randomized clinical trial conducted in Thailand. The study included 1243 participants with CoronaVac primary schedule: 312 in the AstraZeneca booster (half dose) group, 307 in the AstraZeneca booster (full dose) group, 316 in the Pfizer booster (half dose) group and 308 in the Pfizer booster (half dose) group. Vaccination-induced immunogenicity to Ancestral, Delta and Omicron BA.1 strains were evaluated by assessing anti-spike (‘anti-S’), anti-nucleocapsid antibodies, pseudovirus neutralization (‘PVNT’), micro-neutralization titers, and T-cells assays. Within platforms and irrespective of dose or platform, seroconversions were greater than 97%, and greater than 90% for neutralising antibodies against pseudovirus, but similar against SARS-CoV-2 strains. Anti Spike RBD IgG Geometric means concentration (U/mL) at day 28 were 8237.0 (95% CI, 7679.3-8835.2) for the AstraZeneca half dose group, 8973.6 (95% CI, 8328.1-9669.2) for the AstraZeneca full dose group, 14073.9 (95% CI, 13236.4-14964.4) for the Pfizer half dose group and 15920.7 (95% CI, 15135.7-16746.4) for the Pfizer full dose group. Pseudovirus Neutralizing Antibody Titer (PVNT50) against Omicron (GMT) were 118.9 (95% CI, 97.3-145.2) for the AstraZeneca full dose group and 255.9 (95% CI, 222.9-293.7) for the Pfizer full dose group. Immunogenicity according to Pseudovirus Neutralizing Antibody Titer (PVNT50) against delta variant at day 28 were 468.3 (95% CI, 409.8-535.2) for AstraZeneca half dose group, 530.6 (95% CI, 470.4-598.5) for AstraZeneca full dose group, 801.5 (95% CI, 715.4-897.8) for Pfizer half dose group and 856.1 (95% CI, 777.8-942.1) for Pfizer full dose group. [Suvimol Niyomnaitham, 2022 ]

PRIBIVAC was a randomized controlled trial conducted in Singapore. 100 participants who had received a primary vaccine schedule with two doses of the Pfizer-BioNTech vaccine were randomized to either homologous (BNT162b2 + BNT162b2 + BNT162b2; 'BBB', n= 51) or heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; 'BBM'; n= 49). The primary endpoint was the level of neutralizing antibodies against SARS-CoV-2 wild-type and Variants of Concern (VOCs) at day 28 after the booster dose. The results of the study showed that both vaccine schedules induced increases in the level of neutralizing antibodies against the Delta variant (BBB group: 98.1% (95% CI 96.6 to 98.7); BBM group: 98.52% (95% CI 97.7 to 99.0). There was no statistical difference of neutralizing activity against the Delta variant between the homologous and the heterologous booster dose groups (p= 0.0617) [Poh XY, 2022 ].

Choi JY et al was a comparative cohort study conducted in Korea. The study analyzed 170 samples of sera from 75 participants: 50 samples from ChAd-ChAd-BNT, 60 samples from ChAd-BNT-BNT, and 60 samples from BNT-BNT-BNT. This study investigated neutralizing activities against Omicron and Delta variants in each schedule. After the 2nd vaccine dose, geometric mean titers of PRNT ND50: against wild type, Delta, and Omicron were highest after ChAd-BNT vaccination (2,463, 1,097, and 107) followed by BNT-BNT (2,364, 674, and 38) and ChAd-ChAd (449, 163, and 25). After the 3rd dose of BNT, the increase of PRNT ND50 against WT, Delta, and Omicron was most robust in ChAd-ChAd-BNT (4,632, 988, and 260), while the BNT-BNT-BNT group showed the most augmented neutralizing activity against Delta and Omicron variants (2,315 and 628). [Choi JY, 2022 ]

Nantanee R et al was a randomized clinical trial conducted in Thailand. The study included 100 adults with a median age of 59.3 years (IQR 33.4–65.5) with two-dose AZD1222: 50 received half-Dose BNT162b2 Booster (15 µg/Dose) and 50 received a standard-Dose BNT162b2 Booster (30 µg/Dose). The participants were randomized to receive the BNT162b2 vaccine intramuscularly half (15 µg) vs. the standard dose (30 µg). The immunogenicity was evaluated by a surrogate virus neutralization test (sVNT) against Omicron variants and anti-spike-receptor-bindin-domain IgG (anti-S-RBD IgG). At day 14, both groups had sVNT against delta variant GMs of 100.0% inhibition [Nantanee R, 2022 ].

García-Pérez J was a randomized clinical trial conducted in Spain. The study included 676 adults primed with ChAdOx1-S. 441 participants were randomized to the intervention group and received Pfizer as a second dose. 223 participants were randomized to the control group and did not receive a second vaccine. Humoral immunogenicity, measured by immunoassay for SARS-CoV-2 receptor binding domain (RBD), antibody functionality using pseudovirus neutralization assays for the reference (G614), Alpha, Beta, Delta, and Omicron variants, as well as cellular immune response using interferon-g and IL-2 immunoassays, were assessed at day 28 after BNT162b2 in both groups, at day 90 (planned only in the interventional group) and at day 180. NT50 against Delta variant on day 28 after second dose was 717.13 (95%CI 587.27−876.13) in the interventional group and 837.14 (95%CI 609.7−1149.41) in the control group [García-Pérez J, 2022 ].

Renia L et al was a cohort study that included 312 participants vaccinated with the Pfizer COVID-19 vaccine.  This study compared the kinetics of specific antibodies, B and T cell memory responses in a cohort of BNT162b2-vaccinated healthcare workers and elderly individuals in Singapore up to 6 months postimmunization and for a subset of elderly low responders after a third dose. After the second dose, all but one of the participants developed anti-Spike protein antibodies by day 90. Immunoglobulin isotyping showed that the proportion of vaccinees with detectable IgM (above both cohort and individual baseline) was >85% at day 21 but dropped to 12% by day 90 (12%) and was negligible by day 180. After the second dose, all individuals seroconverted by day 90. However, 36.5% of individuals mounted a poor anti-RBD IgG response. More than 79.1% of the plasma had neutralizing antibodies above individual baseline after the first dose, 99% after the second dose and 93% at day 180. The antibody response against the Delta variant was lower than the Wildtype ancestral strain and extremely low or non-existent against the Omicron variant. The third dose strongly boosted the antibody responses against the total Spike protein or its RBD. The boosting injection also induced a strong antibody response against the spike protein of the Delta and Omicron variants [Renia L, 2022 ].

Omicron (B.1.1.529.1)
Roanne Keeton et al. was a non-comparative study conducted in South Africa. The study enrolled 138 participants: 40 Vaccine group (15 participants received Pfizer vaccine) and was based on data from peripheral blood mononuclear cells samples of vaccinated individuals and unvaccinated convalescent individuals. The study results showed that CD4 T cell frequencies to Omicron spike were consistently and significantly lower than ancestral spike, with a median decrease of 14-30% of the CD4 response to Omicron and a  median reduction of 17-25% of the CD8 response to Omicron compared to the ancestral virus. 70-80% of the CD4 and CD8 T cell response to spike was maintained [Roanne Keeton, 2021 ]. 
     
Gao Y et al . was a non-comparative study conducted in Sweden. The study enrolled 40 healthy individual volunteers (Pfizer recipients) and was based on data from peripheral blood mononuclear cells samples of vaccinated individuals and unvaccinated convalescent individuals. The study results showed that SARS-CoV-2 spike-specific CD4+ and CD8+ T cells cross-recognized B.1.1.529 less comprehensively in convalescent versus Pfizer-vaccinated individuals, suggesting that booster immunization may provide benefits that extend beyond the induction of broadly neutralizing antibodies to enhance natural protection against recurrent episodes of COVID-19 [Gao Y, 2022 ].

Angkasekwinai N et al. was a cohort study conducted Thailand. Based on data from a single-center, tertiary care university-based hospital in Bangkok, between July to September 2021. Results showed that for both the Sinovac-prime and AstraZeneca-prime groups, the PRNT50 GMT against the Delta and Beta variant were significantly higher among those who received a booster dose of Pfizer (30µg or 15µg) compared to those who received AstraZeneca or Sinopharm/ BIBP. In addition, there was no statistical difference in PRNT50 between boosting with 30µg and 15µg- Pfizer regardless of the primary series vaccine and the type of variants. However, the PRNT50 against the Beta variant was in general around 1.5-fold lower than the Delta variants for both CoronaVac-prime and ChAdOx1-prime groups. The GMRs of the PRNT50 between post-boost and post-primary series were highest among the participants who received Pfizer boosting vaccination in bothSinovac-prime and AstraZeneca-prime groups. The SARS-CoV-2 RBD IgG levels and the neutralizing titers against Delta variant or Beta variant were strongly correlated.[ ].

XiaH et al. was a noncomparative study conducted in the United States. The study included serum panels containing 22 samples collected on the day of the third dose of Pfizer 30 µg administered between 7.9 and 8.8 months after the second dose and 1 and 4 months after the third dose. The results of the study showed that three doses of Pfizer elicited substantial neutralizing activity against Omicron-spike SARS-CoV-2, while two doses showed a significant reduction [Hongjie Xia, 2022 ].

Niyomnaitham et al. was a comparative study conducted in Thailand. The study recruited 210 participants equally divided (n=30) to receive Sinovac, AstraZeneca and Pfizer-BioNTech vaccines either as a first or second dose. Participants who received only Sinovac or AstraZeneca first and second doses also received a booster dose with Pfizer-BioNTech. The study found antibody levels were highest among the groups that received Pfizer-BioNTech as a second dose, levels were similar between homologous and heterologous regimens. These levels were significantly higher compared with the groups who received AstraZeneca or Sinovac as a second dose.  The groups who were given Pfizer-BioNTech as the second dose had significantly higher neutralizing titers against Delta and Beta than those that received AstraZeneca or Sinovac as the second dose. Neutralizing titers against the Beta variant were reduced by 2 to 5-fold compared to the Delta variant. Overall, neutralization against Omicron was low across the groups and was 28- to 229-fold lower than Delta, depending on the vaccine schedules. Neutralization against the Delta and Omicron variants was significantly lower among groups who received Sinovac as a second dose than the other groups. Seropositivity rate for the Omicron variant was : 80% (45/56), 50% (30/60) and 21% (21/58) for the groups that received  Pfizer-BioNTech, AstraZeneca and: Sinovac as a second dose respectively [Suvimol Niyomnaitham, 2022 ].
 

Lu et al. was a prospective cohort study that recruited 135 COVID-19 recovered individuals scheduled to receive either a Sinovac or Pfizer vaccine. The study compared the neutralizing response against the vaccinated individuals' Beta, Delta, and Omicron variants to the unvaccinated ones. The study found that one dose of the Pfizer vaccine greatly increased the neutralizing titers against all three variants and seropositivity rate. Neutralizing titers against the Delta and Beta variants were not significantly different than against the ancestral lineage [Lu Lu, 2022 ].
 

Kanokudom et al. recruited 222 adults with a complete CoronaVac schedule who received a booster dose of 15μg Pfizer-BioNTech vaccine (n=59), and 50μg Moderna vaccine (n=51), standard Pfizer-BioNTech vaccine (n=54), or standard Moderna vaccine (n=58). The study found no significant differences in binding antibody levels between standard and reduced doses. The booster dose induced a neutralizing response against the Delta and Omicron variants in previously seronegative participants unaffected by dosage. On day 28, the GMT of neutralizing antibodies against the Omicron variant increased to 343.3 and 541.2 in the reduced dose Pfizer-BioNTech and Moderna vaccine groups [Kanokudom S, 2022 ].

Suntronwong N et al was a cohort study conducted in Thailand. 167 participants primed with heterologous CoronaVac/Oxford-AstraZeneca vaccination were enrolled to receive a booster dose of Oxford-AstraZeneca (n= 60), Pfizer-BioNTech (n= 55) of Moderna (n= 52) vaccines. This study assessed the capability of the booster vaccination to induce an increase in neutralizing antibodies and T-cell responses against SARS-CoV-2, Omicron (BA.1 and BA.2), and Delta variants. Individuals boosted with mRNA vaccines demonstrated a higher level of neutralizing activity than those boosted with Oxford-AstraZeneca. Median neutralizing activity to Omicron (day 28) were 10,1% for AstraZeneca, 55,6 for Pfizer and 78,2% for Moderna. NAb titers at day 28 for Omicron BA.a variant were 40.3 (3.16-fold increase) for AstraZeneca, 171.0 (9.91-fold increase) for Pfizer, and 271.6 (24.78-fold increase) for Moderna. NAb titers at day 28 for Omicron BA.2 were 59.3 (2.43-fold increase) for AstraZeneca, 130.7 (4.63 fold-increase) for Pfizer, and 235.3 (19.67 fold-increase) for Moderna. [Suntronwong N, 2022 ]

PRIBIVAC was a randomized controlled trial conducted in Singapore. 100 participants who had received a primary vaccine schedule with two doses of the Pfizer-BioNTech vaccine were randomized to either homologous (BNT162b2 + BNT162b2 + BNT162b2; 'BBB', n= 51) or heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; 'BBM'; n= 49). The primary endpoint was the level of neutralizing antibodies against SARS-CoV-2 wild-type and Variants of Concern (VOCs) at day 28 after the booster dose. The results of the study showed that both vaccine schedules induced increases in the level of neutralizing antibodies against the Omicron variant (BBB group: 82.5% (95% CI 68.5 to 90.3); BBM group: 84.2% (95% CI 78.2 to 91.0). There was no statistical difference of neutralizing activity against the Omicron variant between the homologous and the heterologous booster dose groups (p= 0.110) [Poh XY, 2022 ].

Choi JY et al was a comparative cohort study conducted in Korea. The study analyzed 170 samples of sera from 75 participants: 50 samples from ChAd-ChAd-BNT, 60 samples from ChAd-BNT-BNT, and 60 samples from BNT-BNT-BNT. Neutralizing activities were evaluated using plaque-reduction neutralization test (PRNT) against wild-type (WT) SARS-CoV-2, Delta variant, and Omicron variant. After the 2nd vaccine dose, geometric mean titers of PRNT ND50: against wild type, Delta, and Omicron were highest after ChAd-BNT vaccination (2,463, 1,097, and 107) followed by BNT-BNT (2,364, 674, and 38) and ChAd-ChAd (449, 163, and 25). After the 3rd dose of BNT, the increase of PRNT ND50 against WT, Delta, and Omicron was most robust in ChAd-ChAd-BNT (4,632, 988, and 260), while the BNT-BNT-BNT group showed the most augmented neutralizing activity against Delta and Omicron variants (2,315 and 628)[Choi JY, 2022 ].

Nantanee R et al was a randomized clinical trial conducted in Thailand. The study included 100 adults with a median age of 59.3 years with two-dose AZD1222: 50 received a half-Dose BNT162b2 Booster (15 µg/Dose) and 50 received a standard-Dose BNT162b2 Booster (30 µg/Dose). The immunogenicity was evaluated by a surrogate virus neutralization test (sVNT) against Omicron variants and anti-spike-receptor-bindin-domain IgG (anti-S-RBD IgG). At day 14, the geometric means of sVNT against the omicron variant were 74.4% (95% CI 68.8–80.5)  inhibition post-half-dose BNT162b2 boosters and 67.3% inhibition (95% CI 57.9 to 78.1) post-standard-dose boosters. At day 14, anti-S-RBD IgGs were comparably boosted with GMs of 2329.8 BAU/mL (95% CI 2109.3–2573.4) post-half-dose BNT162b2 boosters and 2574.7 BAU/mL (2262.5–2929.9) post-standard-dose boosters. At 14 days after boosters, the T cell responses were significantly enhanced to 406 SFU/106 PBMCs (IQR 206–718, p < 0.001) in the half-dose and 402 SFU/106 PBMCs (148–678, p < 0.001) in the full-dose groups, without a difference between the dosage groups (p 0.80) [Nantanee R, 2022 ].

García-Pérez J was a randomized clinical trial conducted in Spain. The study included 676 adults primed with ChAdOx1-S. 441 participants were randomized to the intervention group and received Pfizer as a second dose and 223 participants were randomized to the control group and did not receive a second vaccine. Humoral immunogenicity, measured by immunoassay for SARS-CoV-2 receptor binding domain (RBD), antibody functionality using pseudovirus neutralization assays for the reference (G614), Alpha, Beta, Delta, and Omicron variants, as well as cellular immune response using interferon-g and IL-2 immunoassays, were assessed at day 28 after BNT162b2 in both groups, at day 90 (planned only in the interventional group) and at day 180. By SARS-CoV-2 variants, the poorest neutralization capability at day 28 post-vaccination was found with the Omicron variant in both interventional and control groups (GMT 144.84 [95%CI 116.65−179.85] and 204.84 [95%CI 151.99−276.06]). A decrease in NT50 was also observed for the Beta variant in both interventional and control groups (GMT 293.21 [95%CI 234.8−366.15] and 483.89 [95%CI 352.53−664.2]) [García-Pérez J, 2022 ].

Renia L et al was a cohort study that included 312 participants vaccinated with the Pfizer COVID-19 vaccine. This study compared the kinetics of specific antibodies, B and T cell memory responses in a cohort of BNT162b2-vaccinated healthcare workers and elderly individuals in Singapore up to 6 months postimmunization and for a subset of elderly low responders after a third dose. After the second dose, all but one of the participants developed anti-Spike protein antibodies by day 90. Immunoglobulin isotyping showed that the proportion of vaccinees with detectable IgM (above both cohort and individual baseline) was >85% at day 21 but dropped to 12% by day 90 (12%) and was negligible by day 180. After the second dose, all individuals seroconverted by day 90. However, 36.5% of individuals mounted a poor anti-RBD IgG response. More than 79.1% of the plasma had neutralizing antibodies above the individual baseline after the first dose, 99% after the second dose, and 93% at day 180. The antibody response against the Delta variant was lower than the Wildtype ancestral strain and extremely low or non-existent against the Omicron variant. The third dose strongly boosted the antibody responses against the total Spike protein or its RBD. The boosting injection also induced a strong antibody response against the spike protein of the Delta and Omicron variants. [Renia L, 2022 ].

Niyomnaitham et al was a phase 2 randomized clinical trial conducted in Thailand. The study included 1243 participants with CoronaVac primary schedule: 312 in the AstraZeneca booster (half dose) group, 307 in the AstraZeneca booster (full dose) group, 316 in the Pfizer booster (half dose) group and 308 in the Pfizer booster (half dose) group. Vaccination-induced immunogenicity to Ancestral, Delta and Omicron BA.1 strains were evaluated by assessing anti-spike (‘anti-S’), anti-nucleocapsid antibodies, pseudovirus neutralization (‘PVNT’), micro-neutralization titers, and T-cells assays. Within platforms and irrespective of dose or platform, seroconversions were greater than 97%, and greater than 90% for neutralising antibodies against pseudovirus, but similar against SARS-CoV-2 strains. Anti Spike RBD IgG Geometric means concentration (U/mL) at day 28 were 8237.0 (95% CI, 7679.3-8835.2) for the AstraZeneca half dose group, 8973.6 (95% CI, 8328.1-9669.2) for the AstraZeneca full dose group, 14073.9 (95% CI, 13236.4-14964.4) for the Pfizer half dose group and 15920.7 (95% CI, 15135.7-16746.4) for the Pfizer full dose group. Pseudovirus Neutralizing Antibody Titer (PVNT50) against Omicron (GMT) were 118.9 (95% CI, 97.3-145.2) for the AstraZeneca full dose group and 255.9 (95% CI, 222.9-293.7) for the Pfizer full dose group. Immunogenicity according to Pseudovirus Neutralizing Antibody Titer (PVNT50) against delta variant at day 28 were 468.3 (95% CI, 409.8-535.2) for AstraZeneca half dose group, 530.6 (95% CI, 470.4-598.5) for AstraZeneca full dose group, 801.5 (95% CI, 715.4-897.8) for Pfizer half dose group and 856.1 (95% CI, 777.8-942.1) for Pfizer full dose group. [Suvimol Niyomnaitham, 2022 ]

Gilboa M et al was a prospective cohort study conducted in Israel, including 3,972 healthcare workers who received 3 vaccine doses and 4,868 healthcare workers who received 2 doses. The study measured the neutralizing response against Omicron, 5 months after vaccination. The GMT of neutralizing antibodies with the booster dose was 4,315 (95% CI, 4,051-4,595) compared to 611 (95% CI, 557-671) after 2 doses, and the response waned to 132 (95% CI, 121-144) and 1,001 (95% CI, 895-1,119) with 3 and 2 doses respectively, after 140 days. [Gilboa M, 2022 ]

SWITCH ON was an open-label randomized trial conducted in the Netherlands that included 187 healthcare workers: 42 with Ad26.COV2.S primary schedule and BNT162b2 Omicron BA.1 booster, 45 with Ad26.COV2.S primary schedule and mRNA-1273.214 Omicron BA.1 booster, 44 with mRNA-based primary schedule and BNT162b2 Omicron BA.1 booster and 56 mRNA-based primary schedules and mRNA-1273.214 Omicron BA.1 booster. The aim was to assess the fold change in S1-specific IgG antibodies before and 28 days after booster vaccination. Fold change of S1-specific binding antibody levels between baseline and 28 days after bivalent booster vaccination was 2.9, 3.6, 4.3, and 3.5-fold for participants with Ad26.COV2.S+BNT162b2 Omicron BA.1 booster, mRNA-based primary schedule+BNT162b2 Omicron BA.1 booster, Ad26.COV2.S+mRNA-1273.214 Omicron BA.1 booster, and mRNA-based primary schedule+mRNA-1273.214 Omicron BA.1 booster, respectively. [Ngoc Tan, 2022 ]

Prasert Assantachai et al was a randomized controlled trial conducted in Thailand that included 210 participants aged ≥65 years with AstraZeneca primary schedule: 35 received intradermal mRNA-1273, 35 intramuscular mRNA-1273, 70 intradermal BNT162b2, and 70 intramuscular BNT162b2. The group that reported the highest geometric mean titers against the ancestral strain and Omicron BA.1 variant was the group that received the intramuscular mRNA-1273 vaccine (GMT 1,717.9 and 617), followed by the group that received the intradermal mRNA-1273 vaccine (GMT 1,212 and 318), the group that received the intramuscular BNT162b2 vaccine (GMT 713 and 230 and the group that received the intradermal BNT162b2 vaccine (GMT 587 and 148), respectively. [Prasert Assantachai, 2022 ]

Akerman A et al was a comparative study conducted in Australia that included 29 participants with three doses of Pfizer and 23 participants with four doses of Pfizer. This study monitored the potency and breadth of antibody neutralization responses to emerging variants. Mean antibody titers (IC50) against ancestral strain was 203 ng/µl after the third dose and 1,075 ng/µl after the fourth dose. Mean antibody titers (IC50) against Omicron BA5 variant was 63 ng/µl after the third dose and 257 ng/µl after the fourth dose [Anouschka Akerman, 2022 ].

Yamamoto S et al was a case control study conducted in Japan that included data from 1,456 participants: 863 with two doses of Pfizer and 593 with three doses of Pfizer. This study compared the pre-infection live-virus neutralizing antibodies (NAb) against Omicron. GMT (NT50) of NAb against Omicron BA.1 were 221 (95% CI, 141–349) for cases and 223 (95% CI, 129–383) for controls. GMT (NT50) of NAb against Omicron BA.2 were 102 (95% CI, 72–143) for cases and 108 (95% CI, 75–155) for controls [Yamamoto S, 2023 ].

Branche AR et al was a phase 2 randomized trial conducted in the USA that included 202 participants: 101 received a WT+BA.1 bivalent booster dose and 101 received a WT+BA.4-5 bivalent booster dose. Participants were aged between 18 and 49 years old, with or without a history of prior SARS-CoV-2 infection, who had received a primary series and a single homologous or heterologous boost. This study assessed pseudovirus neutralization titers at baseline, 15 and 29 days after vaccination against D614G, Omicron BA.1, Omicron BA.4-5. At day 29, GMT against Omicron BA.1 was 5166 (95% CI, 4156–6421) in the WT+BA.1 booster group and 5070 (95% CI, 3928–6542) in the WT+BA.4-5 booster group. GMT against Omicron BA.4-5 was 3076 (95% CI, 2479–3817) in the WT+BA.1 booster group and 4915 (95% CI, 3829 –6310) in the WT+BA.4-5 booster group [Angela R Branche, 2023 ].

Efficacy outcomes
Beta (B.1.351)
C4591001 was a phase 1/2/3 randomized trial conducted in the United States. The study recruited 567 participants from South Africa (291 vaccine group and 276 placebo group), where the beta variant of SARS-CoV-2 predominated from 16 years of age. Efficacy was measured up to seven days after receiving the second dose among participants with no evidence of infection. In South Africa, where the worrying variant B.1.351 (or beta) of SARS-CoV-2 was predominant, a vaccine efficacy of 100% was observed (95% CI, 53.5 to 100) [Thomas SJ, 2021 ].

Effectiveness outcomes
Alpha (B.1.1.7)
Nasreen S. et al was a case-control (test- negative) study conducted in Canada that included 44,688 symptomatic cases of Alpha variant positive test (159 received two doses of Pfizer) and 599,191 negative symptomatic controls of SARS-CoV-2 (36,328 received two doses of Pfizer). The study evaluated the vaccine effectiveness against Alpha variant measured 7 days after two doses of vaccine between 14 December 2020 and 3 August 2021. The results showed an effectiveness against symptomatic infection of 88% in patients <60 years (95% CI 85 to 90) and 91% in patients ≥60 years (95% CI 87 to 94). In addition, 99% VE against hospitalization or death was evidenced in patients <60 years (95% CI 94 to 100) and 95% in patients ≥60 years (95% CI 92 to 96) [Nasreen, S., 2021 ].

Arjun Puranik et al. conducted a comparative cohort study in the United States that included 47,054 participants (22,064 vaccinated group and 24,990 unvaccinated group). The study evaluated the effectiveness of two full-length Spike protein-encoding mRNA vaccines from Moderna and Pfizer/BioNTech in the Mayo Clinic Health System over time from January to July 2021, during which either the Alpha or Delta variant was highly prevalent. The results showed a COVID-19 vaccine efficacy of 83% (CI 95% 69 to 91.3) and a COVID-19 severe disease vaccine efficacy of 87% (CI 95% 57 to 97.5)  [Arjun Puranik, 2021 ].

Fabiani M et al conducted a comparative cohort study in Italy that included 33,250,344 individuals aged ≥16 years who received a first dose of BNT162b2 (Pfizer-BioNTech) or mRNA1273 (Moderna) vaccine and did not have a previous diagnosis of SARS-CoV-2 infection. The aim of the study was to estimate the effectiveness of mRNA vaccines against SARS-CoV-2 infection and severe covid-19 at different times after vaccination during predominant circulation of the delta variant. The results showed a vaccine effectiveness against infection during Alpha variant predominance period (aggregated data from 2 mRNA vaccines: Pfizer and Moderna) was 79.0% (95% CI 76.8 to 80.9), >14 days after the second dose. Furthermore, Vaccine effectiveness against severe infection during Alpha variant predominance period (aggregated data from 2 mRNA vaccines: Pfizer and Moderna) was 89.4% (95 CI 87.6 to 91.0), > 14 days after second dose [Fabiani M, 2022 ].

Bansal D et al. was a case-control study that included individuals with first infection (irrespective of vaccination status) with SARS-CoV-2 reported in the state of Qatar between 1 January 2021 and 20 February 2022 (BNT162b2 30μg: 33,599; BNT162b2 10μg: 104; mRNA-1273: 17,767; ChAdOx1: 120). This study assessed how much the risk of requiring intensive care is decreased if someone does get detected with infection (conditional vaccine effectiveness). The predominant circulating variants in the wave from March to April 2021 were the alpha and beta variants, while in December 2021 to January 2022 wave, omicron was predominant. From March to April 2021, the percentage of infections by month for alpha and delta variants increased by 30 and above, compared to 5 and under between December 2021 and January 2022 (Omicron Wave) [Bansal D, 2022 ].

Beta (B.1.351)
Nasreen S. et al was a case-control (negative test) study conducted in Canada that included 378 positive beta variant test symptomatic cases (≤5 received two doses of Pfizer) and 599,191 SARS-CoV- negative symptomatic controls. 2 (36,328 received two doses of Pfizer). The study evaluated the vaccine effectiveness against the beta variant measured 7 days after two doses of vaccine between 14 December 2020 and 3 August 2021. The results showed efficacy against symptomatic infection of 83% in patients <60 years (95% CI -22 to 98) and an estimated 100% in patients ≥60 years based on zero vaccinated cases with a positive test. In addition, 89% efficacy against hospitalization or death was evidenced in patients ≥60 years (95% CI 13 to 99) (results for this outcome were not reported in patients <60 years due to an extremely imprecise 95% CI) [Nasreen, S., 2021 ].

Bansal D et al. was a case-control study that included individuals with first infection (irrespective of vaccination status) with SARS-CoV-2 reported in the state of Qatar between 1 January 2021 and 20 February 2022 (BNT162b2 30μg: 33,599; BNT162b2 10μg: 104; mRNA-1273: 17,767; ChAdOx1: 120). This study assessed how much the risk of requiring intensive care is decreased if someone does get detected with infection (conditional vaccine effectiveness). The predominant circulating variants in the wave from March to April 2021 were the alpha and beta variants, while in December 2021 to January 2022 wave, omicron was predominant. From March to April 2021, the percentage of infections by month for alpha and delta variants increased by 30 and above, compared to 5 and under between December 2021 and January 2022 (Omicron Wave) [Bansal D, 2022 ].

Gamma (P.1)
Nasreen S. et al was a case-control (test negative) study conducted in Canada that included 1,969 Gamma variant positive test symptomatic cases (9 received two doses of Pfizer) and 599,191 SARS-CoV-2 negative symptomatic controls. (36,328 received two doses of Pfizer). The study evaluated the vaccine effectiveness against the gamma variant measured 7 days after two doses of vaccine between 14 December 2020 and 3 August 2021. The results showed efficacy against symptomatic infection of 93% in patients <60 years (95% CI: 78 to 98) and 58% in patients ≥60 years (95% CI: -26 to 86). In addition, an estimated efficacy against hospitalization or death of 100% in patients ≥60 years based on zero vaccinated cases with a positive test was evidenced and 87% in patients ≥60 years (95% CI: 45 to 97) [Nasreen, S., 2021 ].
 

Delta (B.1.617.2)
Nasreen S. et al was a case-control (negative test) study conducted in Canada that included 3,136 Gamma variant positive test symptomatic cases (121 received two doses of Pfizer) and 599,191 SARS-CoV-2 negative symptomatic controls. (36,328 received two doses of Pfizer). The study evaluated the vaccine effectiveness against the delta variant measured 7 days after two doses of vaccine between 14 December 2020 and 3 August 2021. The results showed effectiveness with symptomatic infection of 92% in patients <60 years (95% CI: 90 to 94) and 89% in patients ≥60 years (95% CI: 83 to 93). Furthermore, there was evidence of 99% effectiveness against hospitalization or death in patients <60 years (95% CI: 96 to 100) and 96% in patients ≥60 years (95% CI: 95 to 98) [Nasreen, S., 2021 ].

Arjun Puranik et al. conducted a comparative cohort study in the United States that included 47,054 participants (22,064 vaccinated group and 24,990 unvaccinated group). The study evaluated the effectiveness of two full-length Spike protein-encoding mRNA vaccines from Moderna and Pfizer/BioNTech in the Mayo Clinic Health System over time from January to July 2021, during which either the Alpha or Delta variant was highly prevalent. Results showed a COVID-19 vaccine efficacy of 75% (95% CI 24 to 93.9) and COVID-19 severe disease vaccine efficacy of 42% (95% CI : 13 to 62) [Arjun Puranik, 2021 ].

C4591014 was a case-control study (Test-negative) conducted in United States. The study included 14,137 admissions. Based on data from members of Kaiser Permanente Southern California (KPSC), which contains a large integrated health-care system (CA, USA), between December 1, 2021, through January 11, 2022. The study results showed that Pfizer 2-dose protection against delta waned: Emergency department admission: 80% (95% CI 69 to 87) at <3 months to 63% (95% CI 57 to 69) at ≥6 months; hospital admission: 88% (95% CI 71to 95) at <3 months to 74% ( 95% CI 65 to 80) at ≥6 months.  A third dose restored high vaccine effectiveness against delta, with 88% (95% CI 84 to 91) against Emergency department admission and 93% (95% CI 89 to 96) against hospital admission  [Sara Y. Tartof, 2022 ].

Accorsi EK et al included 23 391 cases and 46 764 controls (3 doses= 12 476; 2 doses=19839; Unvaccinated= 17 177). Data were collected ≥14 days after dose 3 and ≥6 months between doses 2 and 3. The study showed that receiving three doses of Pfizer COVID-19 vaccine compared to not receiving any and receiving only two doses, was associated with protection against both the Omicron and Delta. Comparison of 3 Doses vs Unvaccinated showed for Omicron variant OR 0.35 (95% CI 0.32 to 0.38) and for Delta variant OR 0.077 (95% CI 0.070 to 0.086). Comparison of 3 Doses vs 2 Doses showed for Omicron variant OR 0.35 (95% CI 0.32 to 0.37) and for Delta variant OR 0.17 (95% CI,0.16 to 0.19) [Accorsi EK, 2022 ].

Buchan SA et al. included 20,348 tests (Omicron-positive cases=16,087;  Delta-positive cases= 4,261 test-negative controls= 114,087). Data were collected from December 6 to 26, 2021.  The study showed that 2 doses of COVID-19 vaccines only offer modest and short-term protection against symptomatic Omicron infection. A third dose improves protection against symptomatic infection and provides excellent protection against severe outcomes for Delta and Omicron variants. Vaccine efficacy against Delta variant was 97% (95% CI 96 to 98) and 60% (95% CI 55 to 65)  for Omicron in symptomatic infection 7 days after a third dose [Buchan, S. A., 2022 ].

Johnson AG et al was a cohort study conducted in the United States. The study enrolled 6,812,040 COVID-19 cases in unvaccinated persons and 2,866,517 cases in fully vaccinated persons. Based on data collected between April  4, 2021, to December  25,  2021. During periods of Delta and Omicron variant emergence. The protection against infection during the Delta predominant period (October-November) was higher among booster recipients, especially among persons over 50 years of age. The average weekly IRR  was 3.7 (95% CI 3.4 to 4.1)  for the group without a booster and IRR 12.9 (95% CI 11.4 to 14.5) for the booster group [Johnson AG, 2022 ].

Kislaya I et al. was a case-control study conducted in Portugal, the study enrolled 15,001 participants, 3.737 were eligible for a booster dose of Pfizer-BioNTech. Based on data from RT-PCR SARS-CoV-2 positive cases notified in the mandatory National Epidemiological Surveillance Information System (SINAVE) in Portugal from December 6 to 26, 2021. The effectiveness against the Delta variant was 62.5% (95% CI: 61 to 63.9) for the primary scheme, and 94% (95% CI: 93.4 to 94.6) for the booster [Irina Kislaya, 2022 ].

McKeigue PM et al. was a case-control study conducted in Scotland, the study registered 5,645 severe cases and 50,096 controls, based on data from a subset of patients  from   REACT-SCOTpresenting from Dec 1, 2020, to Sept 8, 2021, ensuring follow-up for at least 14 days after presentation date. Pooled effectiveness against developing severe COVID-19 during the Delta variant predominant period for mRNA vaccines was 32% (95%CI: 20 to 42) for one dose and 89% (95%CI: 86 to 91) for two doses [McKeigue PM, 2022 ].

Fabiani M et al conducted a comparative cohort study in Italy that included 33,250,344 individuals aged ≥16 years who received a first dose of BNT162b2 (Pfizer-BioNTech) or mRNA1273 (Moderna) vaccine and did not have a previous diagnosis of SARS-CoV-2 infection. The aim of the study was to estimate the effectiveness of mRNA vaccines against SARS-CoV-2 infection and severe covid-19 at different times after vaccination during predominant circulation of the delta variant. The results showed a vaccine effectiveness against infection during Delta variant predominance period (aggregated data from 2 mRNA vaccines: Pfizer and Moderna) was 69% (95% CI 66.7 to 71.2), >14 days after the second dose. Furthermore,Vaccine effectiveness against severe infection during Delta variant predominance period (aggregated data from 2 mRNA vaccines: Pfizer and Moderna) was 91.1% (95% CI 89.7 to 92.2), > 14 days after second dose ​​[Fabiani M, 2022 ].

Abu-Raddad LJ et al. was a study conducted in Qatar including data from 2,239,193 vaccinated individuals: 1,299,010 with Pfizer-BioNTech and 890,619 with Moderna, the study also included matched unvaccinated controls. The study analyzed information from national, federated databases regarding Covid-19 vaccination, laboratory testing, hospitalization, and death from December 19, 2021, through January 26, 2022. The vaccine effectiveness against the Delta variant of the booster dose compared to the two dose regimen was 86.1% (95% CI 67.3 to 94.1) for symptomatic infection [Abu-Raddad LJ, 2022 ].

Andrews N et al. was a case-control study conducted in England. The study enrolled 2,663,549 vaccinated participants: 204,154 cases for Delta variant, 886,774 cases for Omicron variant and 1,572, 621 test-negative controls. The study analyzed information from national databases, Pillar 1, Pillar 2, NIMS and NHS regarding Covid-19 vaccination, testing, and variants  from November 25, 2021, through January 12, 2022.  Pfizer-BioNTech effectiveness against Delta variant for symptomatic infection was 72.3% (95% CI 69.4 to 74.9) 4 weeks after the first dose, 62.7% (95% CI 61.6 to 63.7) 25 weeks after the second dose, 89.9% (95% CI 89.2 to 90.5) 10 weeks after a Pfizer-BioNTech booster and 94.9% (95% CI 93.0 to 96.2)        10 weeks after a Moderna booster [Andrews N, 2022 ].

Florentino et al. conducted a test-negative case-control study, to estimate vaccine effectiveness (VE) against COVID-19 in adolescents aged 12-17 years in Scotland and Brazil after two doses of the Pfizer-BioNTech vaccine. They analyzed 503,776 eligible SARS-CoV-2 tests (RT-PCR or antigen) of adolescents in Brazil and 127,168 eligible tests of adolescents in Scotland. In Brazil, the estimated vaccine effectiveness against severe COVID-19 during the omicron-dominant period 14 days or longer after the first dose was 56.3% (95% CI 45.9–64.6). From 14 days to 27 days after the second dose, protection increased to 75.6% (58.1–85.8). More than 27 days after the second dose, vaccine effectiveness reached more than 80% and remained at a similar level of protection at 98 days and longer after the second dose (82.7% [68.8–90.4]) [Florentino PTV, 2022 ]

Young-Xu Y et al. was a case-control study with matched test-negative design conducted in the United States. The study used records and COVID-19 laboratory test data from the Veterans Health Administration (VHA), which includes 1,293 healthcare facilities that attend US veterans. Positive tests during November 2021 were presumed to be delta SARS-CoV-2 infections. Each case (positive test) was matched with up to four controls (negative tests). Vaccine effectiveness was estimated through the number of infections, hospitalizations, and death within 30 days of a positive test. The vaccine effectiveness (VE) against delta infection after two mRNA vaccine doses was 54% (95% CI 50 to 57) and increased to 90% (95% CI 88 to 92) after the booster mRNA dose. The VE against hospitalizations was 75% (95% CI 69 to 80) after two mRNA vaccine doses and increased to 94% (95% CI 90 to 96) after the booster mRNA dose. The VE against death after two mRNA vaccine doses was 95% (95% CI 85 to 97) and was similar after the booster mRNA dose (96%; 95% CI 87 to 99) [Young-Xu Y, 2022 ].

Vokó Z et al was a comparative cohort study conducted in Hungary. The study population included 8,087,988 individuals who were 18–100 years old at the beginning of the pandemic. This study examined vaccine effectiveness (VE) and durability of primary immunization and single booster vaccinations in the prevention of SARS-CoV-2 infection, Covid-19-related hospitalization, and mortality during the Delta wave, compared to an unvaccinated control population without prior SARS-CoV-2 infection. Adjusted VE against registered SARS-CoV-2 infection during the Delta wave was 70.3% (95% CI 69.2 to 71.3) for primary Pfizer vaccination at 14 to 120 days, and 82.2% (95% CI 81.5 to 82.8) for the homologous booster vaccination (Pfizer/Pfizer) during the Delta wave [Vokó Z, 2022 ].

Tartof SY et al was a test-negative case-control study conducted at Kaiser Permanente Southern California, an integrated health care system using electronic health records in the US. Participants included 3168 members ages 12 to 17 years with an ED or UC encounter from November 1, 2021, through March 18, 2022. The main outcome was VE associated with BNT162b2 against the emergency department and urgent care encounters related to Delta or Omicron variant SARS-CoV-2 infection.  Vaccine effectiveness (VE) associated with 2 doses of BNT162b2 was highest within the first 2 months for both Delta (89% [95% CI, 69% to 96%]) and Omicron (73% [95% CI, 54% to 84%]) variants but waned to 49% (95% CI, 27% to 65%) for the Delta variant and 16% (95% CI, −7% to 34%) for the Omicron variant at 6 months and beyond. A third dose of BNT162b2 was associated with improved protection against the Omicron variant (87% [95% CI, 72% to 94%]) after a median (IQR) of 19 (9-32) days after dose 3 [Tartof SY, 2022 ].

Arashiro T et al was a multi-center test-negative design case-control study conducted in Japan. The study included 5795 participants: 2595 positive cases and 3200 controls from 16 healthcare facilities in Japan 8 during the Delta-dominant period (August-September 2021) and the Omicron-dominant period (January-March 2022). Vaccine effectiveness (VE) against symptomatic SARS-CoV-2 infection was calculated for 2 doses for the Delta-dominant period and 2 or 3 doses for the Omicron-dominant period, compared to unvaccinated individuals. VE during the Delta-dominant period was 65% (95% CI 54 to 74) for participants who received dose 1 only or were ≤13 days since dose 2, 88% (95% CI 82 to 93) for participants with 14 days to 3 months after dose 2 and 87% (95% CI: 38 to 97) for participants with 3 to 6 months after dose 2 (*Aggregated data for Pfizer vaccine (55.8%), Moderna (40.4%), and other mRNA vaccines) [Arashiro T, 2022 ].

Suphanchaimat R et al was a test-negative case-control study conducted in Thailand. The study included 1,460,458 participants: 482,372 cases and 978,086 controls aimed to explore the vaccine effectiveness (VE) of various schedules against the SARS-CoV2 Delta variant in Thailand during September–December 2021. VE against any infection according to vaccine regimens was: 62.4% (95% CI 59.4 to 65.1) for BNT162b2 + BNT162b2, 88.7% (95% CI 85.6 to 91.1) for ChAdOx1 + BNT162b2, 82.3% (95% CI 74.3–87.7) and 94.0% (95% CI 93.4 to 94.6) for CoronaVac + BNT162b2 [Suphanchaimat R, 2022 ].

Hatfield KM et al. was a comparative cohort that included 4,315 nursing home residents during December 14, 7 2020  to November 9, 2021 (BNT162b2:1861; mRNA-1273:833; Ad26.COV2.S: 52; Unknown vaccine:192). The study assessed the effectiveness of COVID-19 vaccination in preventing SARS-CoV-2 infections before and during predominance of the Delta variant. During the Delta period, vaccine effectiveness measured >150 days after the second dose was 33% (95% CI -2% to 56%) for Pfizer-BioNTech [Hatfield KM, 2022 ].

Rennert L was a observational study conducted in United States. The study included 21,261 university students undergoing repeated surveillance testing during which the delta was the dominant SARS-CoV-2 variant. Estimated BNt162B2 effectiveness against any SARS-CoV-2 infection was 65.7% (95% CI: 61.6 - 69.8). Between 0 to 6 months post-vaccination estimated protection decreased from 80.2% to 49.2%, with a significant increase in the risk of SARS-CoV-2 infection with each month since full vaccination (HR = 1.17, 95% CI: 1.09,1.26) [Rennert L, 2022 ].

Kerr S was a test-negative design and cohort study conducted in Scotland, which used the Scotland-wide Early Pandemic Evaluation and Enhanced Surveillance (EAVE-II) platform to estimate the vaccine effectiveness (VE) of the ChAdOx1, BNT162b2, and mRNA-1273 vaccines. The test-negative design (TND) was used to analyse the VE against symptomatic COVID-19 infection and the cohort design to analyse the VE against hospitalisation or death caused by the Delta variant. The study included 5.4 million individuals, with 269 719 cases of RT-PCR confirmed SARS-CoV-2 infections. In the TND anaysis, VE of those who had received a second dose of any vaccine >28 days before their positive test was 87.2% (95% CI 74.7 to 93.5) and was 78.7% (CI 95% 69.9 to 85) for participants  that had received the second dose of the   Pfizer BioNTech vaccine.The hazard ratio (HR) for COVID-19 emergency hospital admission or death 28 days after two doses of any vaccine was 0,13 (95% IC 0.06 to 0.25) and VE was 87.2% (CI 95% 74.7 to 93.5) [Kerr S, 2022 ].

Richterman A et al was a test-negative case-control study that analyzed data from 7098 tests during the Omicron period (2270 SARS-CoV-2 PCR Positive) and 7422 tests during the Delta period (506 SARS-CoV-2 PCR Positive). The aim of this study was to estimate BNT162b2 and mRNA1273 primary vaccination and booster effectiveness against SARS-CoV-2 infection and symptomatic coronavirus disease 2019 during an Omicron surge among employees of the University of Pennsylvania Health System. Vaccine effectiveness (VE) for 2 doses of Pfizer was 41% (95% CI −17% to 87%) during the Omicron period and 75% (95% CI 52% to 87%) during the Delta period. VE for 3 doses of Pfizer was 54% (95% CI 23% to 73%) during the Omicron period and 93% (95% CI 78% to 98%) during Delta period [Richterman A, 2022 ].

Buchan et al. conducted a test-negative case-control study using linked provincial databases for SARS-CoV-2 laboratory testing, reportable disease, COVID-19 vaccination, and health administration in Ontario (Canada) to estimate the vaccine effectiveness (VE) against symptomatic infections and severe outcomes associates with these infections. Of 134,435 total participants (> 18 years), 4261 were Delta-positive cases, and 114 087 were test-negative controls. VE against Delta symptomatic Infection was 97% (95% CI, 96-98), and 99% (95% CI 98-99) against Delta-related severe disease [Buchan SA, 2022 ].

Rudan I et al was an observational study conducted in Scotland. The analysis of the vaccine uptake was based on information from the Turas Vaccination Management Tool, inclusive of Mar 1, 2022. Vaccine safety was evaluated using national data on hospital admissions and General Practice (GP) consultations, through a self-controlled case series (SCCS) design and Vaccine effectiveness (VE) against symptomatic COVID-19 disease for Delta and Omicron variants was estimated using a test-negative design (TND). Vaccine effectiveness against Delta variant for 16-17 year olds  was 96.7% (95% CI, 51.3-99.8) after at least 6 weeks from the second dose. Among 12-15 year olds for the Delta period, the first dose led to a 65.4% (95% CI, 61.5-68.8) reduction in the period 2-5 weeks after vaccination. No symptomatic cases were observed in the period 2-5 weeks after the second dose, suggesting a VE of 100%, which decreased to 92.9% (95% CI, 42.5-99.1) in the period 10-13 weeks after the second dose. Vaccine effectiveness against Omicron variant for 16-17 year olds  was 43.3% (95% CI, 26.9-56.2) after at least 6 weeks from the second dose. [Rudan I, 2022 ]

Chiew CJ et al was a national cohort study conducted in Singapore. This study assessed the incidence of confirmed SARS-CoV-2 infection and hospitalisation among adolescents aged 12–17 years vaccinated with BNT162b2 from Sept 1 to Dec 15, 2021, during the delta variant wave, and from Jan 21 to April 28, 2022, during the omicron variant wave. Adjusted vaccine effectiveness against Confirmed SARS-CoV-2 infection during delta variant wave was 0.66% (95% CI, 0.63-0.69). Vaccine effectiveness against hospitalisation during delta variant wave was 0.83 (95% CI, 0.74-0.89). Adjusted vaccine effectiveness against Confirmed SARS-CoV-2 infection during omicron variant wave was 0.25% (95% CI, 0.21-0.29) with 2 doses and 0.56 (95% CI 0.53-0.58) with homologous booster dose. Vaccine effectiveness against hospitalisation during omicron variant wave was 0.75 (95% CI, 0.56-0.86) and 0.94 (95% CI, 0.86-0.97) with homologous booster dose. [Chiew CJ, 2022 ]

Ferdinands JM et al was a test-negative case-control study conducted in United States. The study included data from 259,006 hospital admissions: 213,103 with SARS-CoV-2 negative test and 45,903 with SARS-CoV-2 positive test. The main outcome was waning of vaccine effectiveness with BNT162b2 or mRNA-1273 vaccine during the omicron and delta periods. Vaccine effectiveness (VE) against COVID-19-associated hospitalizations during the Delta-predominant period for Pfizer vaccine was 95% (95% CI, 93-96) (less than two months after the second dose) and 95% (95% CI, 94-96) with the third booster dose. [Ferdinands JM, 2022 ]

Andrews et al conducted a test-negative case-control design to estimate vaccine effectiveness (VE) against symptomatic COVID-19 and related hospitalization and death in England. 6,056,673 SARS-CoV-2 PCR test with a sample within 10 days after symptom onset were successfully linked to the NIMS database for vaccination status. VE against symptomatic Covid-19 with the delta variant peaked in the early weeks after receipt of the second dose and then decreased by 20 weeks to 66.3% (95% CI 65.7 to 66.9) with the BNT162b2 vaccine. Waning of VE was greater in persons 65 years of age or older than in those 40 to 64 years of age. At 20 weeks or more after vaccination, VE decreased less against hospitalization to 91.7% (95% CI, 90.2 to 93.0) with the BNT162b2 vaccine, and death to 91.9% (95% CI, 88.5 to 94.3). Greater waning in VE against hospitalization was observed in persons 65 years of age or older in a clinically extremely vulnerable group and in persons 40 to 64 years of age with underlying medical conditions than in healthy adults. Results from the sensitivity analysis with the use of only hospitalizations that had been coded as respiratory admissions were similar to those of the primary analysis, showing VE of 93.5% (95% CI, 91.9 to 94.7) for the BNT162b2 vaccine against the delta variant at 20 weeks or more after vaccination. [Andrews N, 2022 ]

Castelli JM et al was a test-negative case-control study conducted in Argentina that included 844,460 children and adolescents without previous SARS-CoV-2 infection eligible to receive a primary vaccination schedule. The aim was to assess the effectiveness of different combinations of mRNA vaccines in children and adolescents. Vaccine effectiveness during the Delta predominance period for 12-17 years old adolescents was 64.1% (95% CI, 60.5% to 67.3%), and 88.9% (95% CI, 66.1% to 96.4%) for the heterologous Pfizer/Moderna schedule. [Castelli JM, 2022 ]

Yuanyuan F et al. was an observational study to analyze vaccination status and SARS-CoV-2 infection data from more than 10.4 million participants in the national COVID Cohort Collaborative during an 18-month-period (December 2020 to June 2022) in the United States. Vaccine Effectiveness (VE) against COVID-19 infection during the Delta predominance period was 45.11% (95% CI, 43.55% to 46.63%) for the Pfizer/Pfizer/Pfizer schedule, 36.15% (95% CI, 29.02% to 42.56%) for the Moderna/Moderna/Pfizer schedule, and 34.19% (95% CI, 26.21% to 41.3%) for the Pfizer/Pfizer/Moderna schedule. VE against COVID-19-related death during the Delta predominance period was 81.48% (95% CI, 79.93% to 82.92%) for the Pfizer/Pfizer/Pfizer schedule, 91.87% (95% CI, 84.88% to 95.63%) for a Pfizer/Pfizer/Moderna schedule, and 83.99% (95% CI, 77.19% to 88.76%) for the Moderna/Moderna/Pfizer schedule. [Yuanyuan Fu, 2022 ]

Rane MS et al was a case control study conducted in the United States thatincluded data from 931,972 patients with vaccine records: 39,185 with a positive test and 892,787 with a negative test. The study estimated Vaccine Effectiveness (EV) against symptomatic infection in a population of patients seeking care at CityMD, a large ambulatory care center in New York and neighboring areas. VE against symptomatic infection for the BioNTech BNT162b and mRNA-1273 vaccines combined was 96% (95% CI, 95% to 97%) in the pre-Delta period and 79% (95% CI, 77% to 81%) in the Delta period. Adjusted VE against any infection was higher in all subgroups in the pre-Delta period compared to the Delta period. VE for participants aged 12 to 15 years was 85% (95% CI, 81% to 88%) during the Delta period. VE was lower for adults aged 64 years and older compared to <64 years, even in the pre-Delta period. [Rane MS, 2022 ]

Anne J. Huiberts et al was a prospective cohort study conducted in Netherlands that included 27,646 participants from the Omicron period: 3,802 received primary vaccination schedule, 23,352 received first booster dose and 492 were unvaccinated. The primary outcome was contracting SARS-CoV-2 between July 12th 2021 and June 6th 2022. Vaccine effectiveness (VE) against contracting COVID-19 during the Omicron BA.1-2 period was 45% (95% CI, 20.3% to 62.1%), 51.1% (95% CI, 44.1% to 57.3%) and 58.4% (95% CI, 48.8% to 66.1%) for Pfizer primary schedule, mRNA primary schedule with Pfizer booster and AstraZeneca primary schedule with Pfizer booster, respectively. VE against contracting COVID-19 during the Delta period was 81.3% (95% CI, 69.2% to 88.6%), 97.4% (95% CI, 81.2% to 99.6%) and 90.9% (95% CI, 34% to 98.8%) for Pfizer primary schedule, mRNA primary schedule with Pfizer booster and AstraZeneca primary schedule with Pfizer booster, respectively. [Anne J. Huiberts, 2023 ]

Albreiki M et al was a case control study conducted in the United Arab Emirates that included data from 4,618 participants: 541 hospitalized and 4,077 non hospitalized. The aim was to assess the effectiveness against hospitalization of the Sinopharm and Pfizer vaccines between May 28th 2021 and January 13th 2022, during the Delta and Omicron outbreaks. Vaccine effectiveness (VE) against hospital admission during the Omicron outbreak was 94% (95% CI, 53% to 99%) for ≤ 45 years and 83% (95% CI, 0% to 99%) for participants older than 45 years. VE against hospital admission during the Delta outbreak was 95% (95% CI, 58% to 99%) for ≤ 45 years and 98% (95% CI, 78% to 99.6%) for participants older than 45 years. [Albreiki M, 2023 ]

Veneti L et al was a retrospective population-based cohort study conducted in Norway that included data from 372,179 participants. The aim was to assess vaccine effectiveness (VE) against any (symptomatic or not) SARS-CoV-2 Delta and Omicron infection among adolescents (12-17 years old) in Norway from August 2021 to January 2022. VE against Delta infection was 68% (95% CI, 64% to 71%) after the first dose among 12–15 year olds. Among 16–17 year olds that received two doses, VE against Delta infection was 93% (95% CI, 90% to 95%). Among participants 16–17 years old, VE against Omicron infection was 53% (95%CI, 43% to 62%). [Veneti L, 2023 ]

Omicron (B.1.1.529.1)
Collie S et al. conducted a Case-control study in South Africa that included 78,173 participants (32,325 fully vaccinated and 26,331 not vaccinated). The study was based on data from Discovery Health, a South  African managed care organization and estimated the vaccine effectiveness of two doses of the BNT162b2 vaccine (i.e., full vaccination) against hospitalization for Covid-19 caused by the omicron variant. The study resutls showed a vaccine effectiveness of 70% (95%CI 62 to 76) against hospitalization in the vaccinated individuals [Collie S, 2021 ].

C4591014 was a case-control study (Test-negative) conducted in United States. The study included 14,137 admissions. Based on data from members of Kaiser Permanente Southern California (KPSC), which contains a large integrated health-care system (CA, USA), between December 1, 2021, through January 11, 2022. The study results showed that protection against omicron-related emergency department admission appeared to wane after two doses, from 60% (95% CI 43 to 72) at <3 months to 41% (95% CI  32 to 50) at ≥6 months. Vaccine effectiveness of three doses against omicron-related emergency department admission also waned, from 78% (95% CI 73 to 82) <3 months to 48% (95% CI 14 to 69) at ≥3 months. Against hospital admission, two-dose vaccine effectiveness against omicron was 68% (95% CI 58 to 75), and three-dose effectiveness was 89% (95% CI 84 to 92). Waning two- or three-dose effectiveness against omicron-related hospitalization was not observed [Sara Y. Tartof, 2022 ].

Accorsi EK et al included 23,391 cases and 46,764 controls (3 doses= 12,476; 2 doses=19,839; Unvaccinated= 17,177). Data were collected ≥14 days after dose 3 and ≥6 months between doses 2 and 3. The study showed that receiving three doses of Pfizer COVID-19 vaccine compared to not receiving any and receiving only two doses, was associated with protection against both the Omicron and Delta. Comparison of 3 Doses vs Unvaccinated showed for Omicron variant OR 0.35 (95% CI 0.32 to 0.38) and for Delta variant OR 0.077 (95% CI 0.070 to 0.086). Comparison of 3 Doses vs 2 Doses showed for Omicron variant OR 0.35 (95% CI 0.32 to 0.37) and for Delta variant OR 0.17 (95% CI,0.16 to 0.19) [Accorsi EK, 2022 ].

Spensley K et al. included 1,121 patients on haemodialysis. All patients underwent weekly screening for SARS-CoV-2 infection via RT-PCR testing between December 1, 2021 and January 16, 2022. The study showed that partial vaccination did not provide protection against infection. Vaccine effectiveness against Omicron infection in patients who had received a booster vaccine was 58%. Analyzing vaccine effectiveness in the 747 patients who had been boosted, significant effectiveness was seen in both patients who received AstraZeneca COVID-19 vaccine (47%)and Pfizer COVID-19 vaccine (66%) [Katrina Spensley, 2022 ].

Buchan SA et al. included 20,348 tests (Omicron-positive cases=16,087; Delta-positive cases= 4,261 test-negative controls= 114,087). Data were collected from December 6 to 26, 2021. The study showed that 2 doses of COVID-19 vaccines only offer modest and short-term protection against symptomatic Omicron infection. A third dose improves protection against symptomatic infection and provides excellent protection against severe outcomes for Delta and Omicron variants. Vaccine efficacy against Delta variant was 97% (95% CI 96 to 98) and 60% (95% CI 55 to 65) for Omicron in symptomatic infection 7 days after a third dose [Buchan, S. A., 2022 ].

Johnson AG et al was a cohort study conducted in the United States. The study enrolled 6,812,040 COVID-19 cases in unvaccinated persons and 2,866,517 cases in fully vaccinated persons. Based on data collected between April  4, 2021, to December  25,  2021. During periods of Delta and Omicron variant emergence. The protection against infection during the Omicron emergence period (December) was higher among booster recipients, especially among persons over 50 years of age. The average weekly IRR  was 2.6 (95% CI 1.4 to 4.7)  for the group without a booster and IRR 4.5 (95% CI 2.4 to 8.3) for the booster group [Johnson AG, 2022 ].

Kislaya I et al. was a case control study conducted in Portugal, the study enrolled 15,001 participants, 3.737 were eligible for a booster dose of Pfizer-BioNTech. Based on data from RT-PCR SARS-CoV-2 positive cases notified in the mandatory National Epidemiological Surveillance Information System (SINAVE) in Portugal from December 6 to 26, 2021. The effectiveness against Omicron variant was 28.1% (95% CI: 12.2 to 40.9) for the primary scheme, and  68.8% (95% CI: 46.4 to 81.7) for the booster [Irina Kislaya, 2022 ].
 

Abu-Raddad LJ et al. was a study conducted in Qatar including data from 2,239,193 vaccinated individuals: 1,299,010 with Pfizer-BioNTech and 890,619 with Moderna, the study also included matched unvaccinated controls. The study analyzed information from national, federated databases regarding Covid-19 vaccination, laboratory testing, hospitalization, and death from December 19, 2021, through January 26, 2022. The vaccine effectiveness against the Omicron variant of the booster dose compared to the two dose regimen was 49.4% (95% CI 47.1 to 51.6)  for symptomatic infection and 76.5% (95% CI 55.9  to 87.5) for hospitalization and death [Abu-Raddad LJ, 2022 ].

Andrews N et al. was a case-control study conducted in England. The study enrolled 2,663,549 vaccinated participants: 204,154 cases for Delta variant, 886,774 cases for Omicron variant and 1,572, 621 test-negative controls. The study analyzed information from national databases, Pillar 1, Pillar 2, NIMS and NHS regarding Covid-19 vaccination, testing, and variants  from November 25, 2021, through January 12, 2022.  Pfizer-BioNTech effectiveness against Omicron variant for symptomatic infection was 31.5% (95% CI 29.9 to 33.1) 4 weeks after the first dose, 8.8% (95% CI 7.0 to 10.5) 25 weeks after the second dose, 45.7%  (95% CI 44.7 to 46.7) 10 weeks after a Pfizer-BioNTech booster and 64.4% (95% CI 62.6 to 66.1)10 weeks after a Moderna booster [Andrews N, 2022 ].
 

Hansen C et al was a comparative cohort study conducted in Denmark. The study included 202,896 unvaccinated individuals, 874,421  vaccinated with BNT162b2 (2 doses), 1,553,188 vaccinated with BNT162b2 (3 doses), 216,976 vaccinated with mRNA-1273 (2 doses) and 243,352 vaccinated with mRNA-1273 (3 doses). In this nationwide cohort analysis, from 28 December , 2021 to February 15, 2022 during which Omicron was the predominant variant, PCR testing data are combined with other national register data with near-complete information on all vaccinations, hospitalisations and comorbidities in the population. Vaccine effectiveness against infection after 2 doses was 37.0 (95% CI 35.6 to 38.3), against hospitalization after 2 doses was 50.5 (95% CI 33.9 to 63.0), against infection after 3 doses was 47.9 (95% CI 47.4 to 48.3) and against hospitalization after 3 doses was 88.8 (95% CI 87.3 to 90.1) [Hansen C, 2022 ].

Price AM was a case control study that assessed vaccine effectiveness against laboratory-confirmed Covid-19 leading to hospitalization and against critical Covid-19 (i.e., leading to receipt of life support or to death). From July 1, 2021, to February 17, 2022, we enrolled case patients with Covid-19 and controls without Covid-19 at 31 hospitals in 23 states. The study enrolled 1,185 case patients (1,043 [88%] of whom were unvaccinated, 291 [25%] of whom received life support, and 14 of whom died) and 1,627 controls.During the delta-predominant period, vaccine effectiveness against hospitalization for Covid-19 among adolescents 12 to 18 years of age was 93% (95% confidence interval [CI], 89 to 95) 2 to 22 weeks after vaccination and was 92% (95% CI, 80 to 97) at 23 to 44 weeks. Among adolescents 12 to 18 years of age (median interval since vaccination, 162 days) during the omicron-predominant period, vaccine effectiveness was 40% (95% CI, 9 to 60) against hospitalization for Covid-19, 79% (95% CI, 51 to 91) against critical Covid-19, and 20% (95% CI, −25 to 49) against noncritical Covid-19. During the omicron period, vaccine effectiveness against hospitalization among children 5 to 11 years of age was 68% (95% CI, 42 to 82; median interval since vaccination, 34 days) [Price AM, 2022 ].

Ranzani O et al was a case-control study (test negative design) conducted in Brazil including 1,386,544 positive antigen/PCR SARS-CoV-2 tests and matched controls. The study estimated the vaccine effectiveness (VE) for homologous and heterologous (BNT162b2) booster doses in adults who received two doses of CoronaVac during the Omicron predominance period. VE against symptomatic COVID-19 for the homologous CoronaVac booster was 8.1% (95% CI, 4.6% to 11.4%) and 57.3% (95% CI, 56.8% to 57.9%) for the Pfizer heterologous booster, measured 8-59 days after the third dose. For hospitalization or death, VE was 86% (95% CI, 71.7% to 93.1%) and 92.1% (95% CI, 90.2% to 93.7%) after 8-59 days of the homologous and heterologous booster schedules, respectively [Ranzani OT, 2022 ].

Grewal R et al was a case-control study (test negative design) conducted in the United States. The aim of this study was to estimate the marginal effectiveness of a fourth versus third dose and the vaccine effectiveness of mRNA covid-19 vaccines BNT162b2 and mRNA-1273 against any infection, symptomatic infection, and severe outcomes (hospital admission or death) related to the omicron variant. Vaccine effectiveness of three doses of Pfizer vaccine against omicron variant against any infection was 32% (95%CI 24 to 38), against symptomatic infection was 53% (95%CI 39 to 63) and against severe outcomes 77% (95% CI 67 to 83) [Grewal R, 2022 ].

Florentino et al. conducted a test-negative case-control study, to estimate vaccine effectiveness (VE) against COVID-19 in adolescents aged 12-17 years in Scotland and Brazil after two doses of the Pfizer-BioNTech vaccine. They analyzed 503,776 eligible SARS-CoV-2 tests (RT-PCR or antigen) of adolescents in Brazil and 127,168 eligible tests of adolescents in Scotland. During the omicron-dominant period, after the second BNT162b2 dose, vaccine effectiveness peaked between 14–27 days in Brazil (64.7% [95% CI 63.0–66.3]). Protection started to decline after 27 days (at 28–41 days protection was 53.0% [51.3–54.7]), reducing to 5.9% (95% CI 2.2–9.4) at 98 days and longer. In Scotland, vaccine effectiveness for symptomatic infection during the omicron-dominant period also peaked at 14–27 days after the second dose (82.6% [95% CI 80.6–84.5]), and after 98 days and more was 50.6% (42.7–57.4). In Brazil, the estimated vaccine effectiveness against severe COVID-19 during the omicron-dominant period 14 days or longer after the first dose was 56.3% (95% CI 45.9–64.6). From 14 days to 27 days after the second dose, protection increased to 75.6% (58.1–85.8). More than 27 days after the second dose, vaccine effectiveness reached more than 80% and remained at a similar level of protection at 98 days and longer after the second dose (82.7% [68.8–90.4]) [Florentino PTV, 2022 ].

Young-Xu Y et al. was a case-control study with matched test-negative design conducted in the United States. The study used records and COVID-19 laboratory test data from the Veterans Health Administration (VHA), which includes 1,293 healthcare facilities that attend US veterans. Positive tests during January 2022 were presumed to be Omicron SARS-CoV-2 infections. Each case (positive test) was matched with up to four controls (negative tests). Vaccine effectiveness was estimated through the number of infections, hospitalizations, and death within 30 days of a positive test. The vaccine effectiveness (VE) against omicron infection after two mRNA vaccine doses was 12% (95% CI 10 to 15) and increased to 64% (95% CI 63 to 65) after the booster mRNA dose. The VE against hospitalizations was 63% (95% CI 58 to 67) after two mRNA vaccine doses and increased to 89% (95% CI 88 to 91) after the booster mRNA dose. The VE against death after two mRNA vaccine doses was 77% (95% CI 67 to 83) and after the booster mRNA dose increased to 94% (95% CI 90 to 96) [Young-Xu Y, 2022 ].

Tartof SY et al was a test-negative case-control study conducted at Kaiser Permanente Southern California, an integrated health care system using electronic health records in the US. Participants included 3168 members ages 12 to 17 years with an ED or UC encounter from November 1, 2021, through March 18, 2022. The main outcome was VE associated with BNT162b2 against the emergency department and urgent care encounters related to Delta or Omicron variant SARS-CoV-2 infection.  Vaccine effectiveness (VE) associated with 2 doses of BNT162b2 was highest within the first 2 months for both Delta (89% [95% CI, 69% to 96%]) and Omicron (73% [95% CI, 54% to 84%]) variants but waned to 49% (95% CI, 27% to 65%) for the Delta variant and 16% (95% CI, −7% to 34%) for the Omicron variant at 6 months and beyond. A third dose of BNT162b2 was associated with improved protection against the Omicron variant (87% [95% CI, 72% to 94%]) after a median (IQR) of 19 (9-32) days after dose 3 [Tartof SY, 2022 ].

Arashiro T et al was a multi-center test-negative design case-control study conducted in Japan. The study included 5795 participants: 2595 positive cases and 3200 controls from 16 healthcare facilities in Japan 8 during the Delta-dominant period (August-September 2021) and the Omicron-dominant period (January-March 2022). Vaccine effectiveness (VE) against symptomatic SARS-CoV-2 infection was calculated for 2 doses for the Delta-dominant period and 2 or 3 doses for the Omicron-dominant period, compared to unvaccinated individuals. VE during the Omicron-dominant period was 34% (95% CI -20 to 64) for participants who received dose 1 only or was ≤13 days since dose 2, 56% (95% CI 37 to 70) for participants with14 days to 3 months after dose 2, 52% (95% CI 40 to 62) for participants with 3 to 6 months after dose 2 and  49% (95% CI 34 to 61) for participants with at least 6 months after the second dose. VE estimated after third dose was 67% (95% CI: 47-79) ( ≤13 days after dose 3) and 74% (95% CI: 62-83) (≥14 days after dose 3) (*Aggregated data for Pfizer vaccine (55.8%), Moderna (40.4%), and other mRNA vaccines) [Arashiro T, 2022 ].

González S et al was a retrospective cohort study conducted in Argentina including 1,536,435 participants: 689,552 in the BIBP vaccine group and 846,883 in mRNA vaccine group (539,093 with Pfizer/Pfizer schedule, 15,552 with Pfizer/Moderna schedule and 44,862 with Moderna/Pfizer schedule. mRNA-1273 and BNT162b2 vaccines were administered to 12−17- year subjects; and BBIBP-CorV to 3−11-year subjects. Vaccine effectiveness for the mRNA vaccine group was 80.0% (95% CI 64.3 to 88.0) for the 12−17 age (mRNA vaccines) subgroup [González S, 2022 ].

Bansal D et al. was a case-control study that included individuals with first infection (irrespective of vaccination status) with SARS-CoV-2 reported in the state of Qatar between 1 January 2021 and 20 February 2022 (BNT162b2 30μg: 33,599; BNT162b2 10μg: 104; mRNA-1273: 17,767; ChAdOx1: 120). This study assessed how much the risk of requiring intensive care is decreased if someone does get detected with infection (conditional vaccine effectiveness). The predominant circulating variants in the wave in March to April 2021 were the alpha and beta variant, while in the December 2021 to January 2022 wave, omicron was the variant. From March to April 2021, the percentage of infections by month for alpha and delta variants increased by 30 and above, compared to 5 and under between December 2021 and January 2022 (Omicron Wave) [Bansal D, 2022 ].

Cohen-Stavi CJ was a comparative cohort study conducted in Israel. The study included 15,289 children aged 5 to 11 years: 94728 in the vaccinated group and 94,728 in the unvaccinated group. Vaccine effectiveness (VE) was estimated after the first and second vaccine doses during the Omicron wave. VE against documented infection was 17% (95% CI, 7 to 25) at 14 to 27 days after the first dose and 51% (95% CI, 39 to 61) at 7 to 21 days after the second dose. VE against symptomatic Covid-19 was 18% (95% CI, −2 to 34) at 14 to 27 days after the first dose and 48% (95% CI, 29 to 63) at 7 to 21 days after the second dose [Cohen-Stavi CJ, 2022 ].

Patalon T et al was a test-negative case-control study conducted in Israel. This study assessed the association between booster breakthrough infections with the Omicron variant and time-since-vaccination, leveraging data from Maccabi Healthcare Services (MHS). Vaccine effectiveness against infection of ‘newly’ vaccinated individuals was 53.4% (95% CI 47.7 to 8.6%). VE declined rapidly with each month since vaccination, with 35.7% (95% CI, 29.8–41.2%) VE for those who were vaccinated two months prior to the outcome period compared to the earliest vaccinees (of August 2021). [Patalon T, 2022 ].

Richterman A et al was a test-negative case-control study that analyzed data from 7098 tests during the Omicron period (2270 SARS-CoV-2 PCR Positive) and 7422 tests during the Delta period (506 SARS-CoV-2 PCR Positive). The aim of this study was to estimate BNT162b2 and mRNA1273 primary vaccination and booster effectiveness against SARS-CoV-2 infection and symptomatic coronavirus disease 2019 during an Omicron surge among employees of the University of Pennsylvania Health System. Vaccine effectiveness (VE) for 2 doses of Pfizer was 41% (95% CI −17% to 87%) during the Omicron period and 75% (95% CI 52% to 87%) during the Delta period. VE for 3 doses of Pfizer was 54% (95% CI 23% to 73%) during the Omicron period and 93% (95% CI 78% to 98%) during Delta period [Richterman A, 2022 ].

Buchan et al. conducted a test-negative case-control study using linked provincial databases for SARS-CoV-2 laboratory testing, reportable disease, COVID-19 vaccination, and health administration in Ontario (Canada) to estimate the vaccine effectiveness (VE) against symptomatic infections and severe outcomes associates with these infections. Of 134,435 total participants (> 18 years), 16,087 were Omicron-positive cases, and 114 087 were test-negative controls. VE against Omicron symptomatic Infection was 60% (95% CI, 55-65), and 95% (95% CI 87-98) against Omicron-related severe disease [Buchan SA, 2022 ].

Lin DY et al was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. Based on data from the North Carolina COVID-19 Surveillance System and the Covid-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Vaccine effectiveness for two doses of Pfizer-BioNTech was 43.7% (95% CI, 42.3% to 45.1%) during the Omicron variant predominance [Lin DY, 2022 ].

Risk M et al was a retrospective cohort study conducted in the United States including 168,414 participants: 133,238 vaccinated with mRNA vaccines and 35,176 unvaccinated. Based on data from the Michigan Medicine healthcare system, the Michigan State Registry, and chart-reviewed COVID-19 hospitalization data. Including patients 18 years old and above, who received mRNA-based COVID-19 vaccines. During the Omicron dominant period December 2021 to March 2022. The effectiveness of the Pfizer-BioNtech vaccine during the Omicron period in immunocompetent participants was −6%(95% CI –14 to 4) for two doses and 35%(95CI 29 to 41) for three doses. In immunocompromised participants, the effectiveness was 13% (95%CI –19 to 39) for two doses and 50% (95% CI 31 to 64) for three doses. [Risk M, 2022 ].

Molteni et al was a prospective cohort study conducted in the United Kingdom, the study included 115,775 children and adolescents aged 12-17 years, among which, 25,971 received one dose of Pfizer-BioNTech. Based on data from the Covid Symptom Study between august 2021 and February 2022. Infection risk reduction 14-30 days after primary vaccination was -53.7% (95%CI -62 to -43) during the December-February (Omicron) period [Molteni E, 2022 ].

Monge S et al was a nationwide cohort study conducted in Spain. This study included 7,036,433 participants older than 40 years: 3,111,159 in the booster group and 3,111,159 in the no-booster group. The aim of this study was to estimate the effectiveness of mRNA-based vaccine boosters against infection during the period of the predominance of the omicron variant in Spain. The vaccine effectiveness of Pfizer booster after AstraZeneca, Janssen, Moderna, or Pfizer primary schedule was 46.2% (95% CI 43.5–48.7). Vaccine effectiveness of an mRNA booster (Pfizer or Moderna) following a Pfizer primary schedule was 49.7% (95% CI, 48.3–51.1) [Monge S, 2022 ].

Stowe et al. conducted a test-negative case-control study in UK, to estimate Vaccine Effectiveness (VE) against hospitalisation with the Omicron and Delta variants using PCR testing linked hospital records (Emergency Care Data Set; ECDS). The total number of tests in the study period was 409,985 of which 115,720 were cases and 294,265 controls.  Vaccine effectivenes against hospital admissions from ECDS within 14 days of the test date by the Omicron variant in symptomatic individuals 18 to 64 years of age was 61.0% (95% CI 55.3-65.9) after 14-174 days and 33.0% (95% CI 21.3-42.9) after 175+ days. Vaccine effectiveness against hospital admissions from ECDS within 14 days of the test date by the Omicron variant in symptomatic individuals 65 years of age and older was 85.8% (95% CI, 69.4-93.4) after 14-174 days and 75.6% (95% CI, 61.4-84.6) after 175+ days. [Stowe J, 2022 ]

Rudan I et al was an observational study conducted in Scotland. The analysis of the vaccine uptake was based on information from the Turas Vaccination Management Tool, inclusive of Mar 1, 2022. Vaccine safety was evaluated using national data on hospital admissions and General Practice (GP) consultations, through a self-controlled case series (SCCS) design and Vaccine effectiveness (VE) against symptomatic COVID-19 disease for Delta and Omicron variants was estimated using a test-negative design (TND). Vaccine effectiveness against Delta variant for 16-17 year olds  was 96.7% (95% CI, 51.3-99.8) after at least 6 weeks from the second dose. Among 12-15 year olds for the Delta period, the first dose led to a 65.4% (95% CI, 61.5-68.8) reduction in the period 2-5 weeks after vaccination. No symptomatic cases were observed in the period 2-5 weeks after the second dose, suggesting a VE of 100%, which decreased to 92.9% (95% CI, 42.5-99.1) in the period 10-13 weeks after the second dose. Vaccine effectiveness against Omicron variant for 16-17 year olds  was 43.3% (95% CI, 26.9-56.2) after at least 6 weeks from the second dose. [Rudan I, 2022 ]

Chiew CJ et al was a national cohort study conducted in Singapore. This study assessed the incidence of confirmed SARS-CoV-2 infection and hospitalisation among adolescents aged 12–17 years vaccinated with BNT162b2 from Sept 1 to Dec 15, 2021, during the delta variant wave, and from Jan 21 to April 28, 2022, during the omicron variant wave. Adjusted vaccine effectiveness against Confirmed SARS-CoV-2 infection during delta variant wave was 0.66% (95% CI, 0.63-0.69). Vaccine effectiveness against hospitalisation during delta variant wave was 0.83 (95% CI, 0.74-0.89). Adjusted vaccine effectiveness against Confirmed SARS-CoV-2 infection during omicron variant wave was 0.25% (95% CI, 0.21-0.29) with 2 doses and 0.56 (95% CI 0.53-0.58) with homologous booster dose. Vaccine effectiveness against hospitalisation during omicron variant wave was 0.75 (95% CI, 0.56-0.86) and 0.94 (95% CI, 0.86-0.97) with homologous booster dose. [Chiew CJ, 2022 ]

Ferdinands JM et al was a test-negative case-control study conducted in United States. The study included data from 259,006 hospital admissions: 213,103 with SARS-CoV-2 negative test and 45,903 with SARS-CoV-2 positive test. The main outcome was waning of vaccine effectiveness with BNT162b2 or mRNA-1273 vaccine during the omicron and delta periods. Vaccine effectiveness (VE) against COVID-19-associated hospitalizations during the Omicron-predominant period for Pfizer vaccine was 63% (95% CI, 46-74) (less than two months after the second dose) and 88% (95% CI, 86-90) with the third booster dose. [Ferdinands JM, 2022 ]

Ioannu et al was a retrospective matched-cohort study conducted in the United States. The study included 981,676 participants: 490,838 boosted individuals and 490,838 non-boosted individuals. Based on data from the Veterans Association's (VA) Corporate Data Warehouse, a database of VA enrollees' comprehensive electronic health records, and the VA COVID-19 Shared Data Resource. Including patients 18 years old and above, who received mRNA based COVID-19 boosters and a matched cohort of participants that did not. During the Omicron dominant period between December 2021 and March 2022. The effectiveness of Pfizer-BioNTech vaccine booster during the Omicron period was 39.0% (95% CI, 36.4% to 41.6%) against infection and 54.0% (95% CI, 46.1% to 60.8%) against hospitalization. [Ioannou GN, 2022 ]

Tartof et al was a case-control, test-negative study conducted in the United States, based on data from the Kaiser Permanente Southern California (KPSC), which is a large, integrated health-care system. The study included 16,994 participants: 10,620 cases and 8,503 controls. Eligible patients were admitted to one of 15 KPSC hospitals or Emergency Departments between December 27th 2021, and June 4th 2022. The effectiveness of the Pfizer-BioNTech vaccine against BA.1 variant was 40% (95% CI, 27% to 50%) for 2 doses and 79% (95% CI, 74% to 83%) for 3 doses against hospital admission. For Emergency Department admission the effectiveness was 29% (95% CI, 18% to 38%) for 2 doses and 72% (95% CI, 67% to 77%) for 3 doses. Effectiveness against BA.2 variant was 56% (95% CI, 31% to 72%) for 2 doses and  71% (95% CI, 55% to 81%) for 3 doses against hospital admission. Effectiveness against Emergency Department admission was 16% (95% CI, −5% to 33%) for 2 doses and 21% (95% CI, 1% to 37%) for 3 doses. [Tartof SY, 2022 ]

Fleming-Dutra et al was a test-negative case-control study conducted in the United States, based on data from the Increasing Community Access to Testing (ICATT) platform, including 121,952 tests during the Omicron variant period between December 2021 and February 2022, in participants between 5 and 15 years old who received the Pfizer-BioNTech vaccine. The effectiveness 2 months after the second dose for symptomatic infection was 28.9% (95% CI, 24.5% to 33.1%) for the 5-11 years old group and 16.6% (95% CI, 8.1% to 24.3%) for the 12-15 years old group. [Fleming-Dutra KE, 2022 ]

Tan SHX et al was a retrospective cohort study conducted in Singapore based on data from the national ministry of health registry, including 255,936 children between 5 and 11 years of age. The Pfizer-BioNTech vaccine effectiveness during Omicron variant predominance period in partially vaccinated children was 13.6% (95% CI, 11.7-15.5) against all SARS-CoV-2 infections, 24.3% (95% CI, 19.5-28.9) against PCR-confirmed infection and 42.3% (95% CI, 24.9 to 55.7) against hospitalization, in fully vaccinated children the effectiveness was 36.8% (95% CI, 35.3-38.2), 65.3% (95% CI, 62.0-68.3), and 82.7% (95% CI, 74.8-88.2), respectively. [Tan SHX, 2022 ]

Agrawal et al was a retrospective cohort study conducted in the United Kingdom that included 16,208,600 participants, of which 7,589,080 received a Pfizer-BioNTech primary schedule and 8,619,520 participants received a ChAdOx1 primary schedule. The study was based on data from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database, Vaccine Management System, Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II), and Secure Anonymised Information Linkage Databank platform, during the Omicron period between December 2021 and February 2022. The adjusted Rate Ratio (aRR) 3-5 weeks after booster vaccination against hospitalization was 0.33 (95% CI, 0.28-0.38) for the Pfizer-BioNTech primary schedule and booster group, 0.43 (95% CI, 0.37-0.50) for the ChAdOx1 primary schedule and Pfizer-BioNTech booster group and 0.58 (95% CI, 0.46-0.73) for the Pfizer-BioNTech primary schedule and Moderna booster group. [Agrawal U, 2022 ]

Wan EYF was a case control study conducted in China. The study included data from 78,326 individuals: 7,293 death related to COVID-19 cases and 71,033 controls. This study analyzed data available between January and March 2022 from the electronic health databases in Hong Kong and enrolled individuals aged 60 or above. Vaccine effectiveness against COVID-19 infection (60-79 years old) was 20.3% (95% CI, 18.4-22.1), 50.9% (95% CI, 49.6-52.1), -2.9% (95% CI, -24-14.6) and 30.9% (95% CI, 28.5-33.2) for 2 Pfizer doses schedule, 3 Pfizer doses schedule, pfizer primary schedule with CoronaVac booster and CoronaVac primary schedule with Pfizer booster schedule respectively. Vaccine effectiveness against COVID-19 related hospitalization was 74.9% (95% CI, 72.6-77), 91.4% (95% CI, 90.1-92.5), 87.4% (95% CI, 59.6-96.1) and 86.9% (95% CI, 84.3-89.1) for 2 Pfizer doses schedule, 3 Pfizer doses schedule, pfizer primary schedule with CoronaVac booster and CoronaVac primary schedule with Pfizer booster schedule respectively. [Wan EYF, 2022 ]

Cerqueira-Silva T et al was a case-control study with a test-negative design conducted in Brazil that enrolled 2,471,576 participants, including 1,431,108 cases and 1,040,468 controls, with data from the nationwide linked database during the Omicron period in Brazil (January to Appril 2022), including participants who received CoronaVac plus a Pfizer-BioNTech booster. Vaccine effectiveness against symptomatic infection was 1.7% (95% CI, 0.1% to 3.2%) and 89.4% (95% CI, 87.8% to 90.7%) against severe infection. [Cerqueira-Silva T, 2022 ]

Tartof SY et al was a case-control study with a test-negative design conducted in the United States that enrolled 24,356 participants, including 12,566 boosted individuals, 5,997 with the primary schedule and 5,793 unvaccinated individuals. The study was based on data from Kaiser Permanente, a health insurance provider from Southern California, including participants vaccinated with Pfizer-BioNTech and unvaccinated controls. This study analyzed data from May to August 2022 during the Omicron BA.4/5 outbreak. The adjusted effectiveness of Pfizer-BioNTech primary schedule was −4% (95% CI, −116% to 50%) against hospitalization, 44% (95% CI, 19% to 61%) against emergency department admission, 21% (95% CI, 11% to 30%) against outpatient care. The effectiveness of 3 Pfizer-BioNTech doses was 50% (95% CI, −1% to 76%) against hospitalization, 39% (95% CI, 14% to 57%) against emergency department admission and 17% (95% CI, 7% to 26%) against outpatient care, the effectiveness of 4 Pfizer doses was 60% (95% CI, 11% to 82%) against hospitalization, 69% (95% CI, 44% to 83%) against emergency department admission and 25% (95% CI, 7% to 39%) against outpatient care. [Tartof SY, 2022 ]

Baum U et al was a cohort study conducted in Finland including 896,220 participants aged 70 years and older. The study was based on a nationwide register-based cohort, between December 27th 2020 and March 31st 2022. Vaccine effectiveness (VE) against hospital admission during the Omicron period was 91% (95% CI, 83% to 95%) for the primary schedule, 94% (95% CI, 92% to 95%) for the Pfizer schedule + Pfizer booster, 91% (95% CI, 87% to 94%) for the Pfizer schedule + Moderna booster, 92% (95% CI, 80% to 97%) for the Moderna schedule + Pfizer booster and 99% (95% CI, 91% to 100%) for the AstraZeneca schedule + Pfizer booster. [Baum U, 2022 ]

Castelli JM et al was a test-negative case-control study conducted in Argentina that included 844,460 children and adolescents without previous SARS-CoV-2 infection eligible to receive primary vaccination schedule. The aim was to assess the effectiveness of different combinations of mRNA vaccines in children and adolescents. Vaccine effectiveness during the Omicron predominance period for 12-17 years old adolescents was 28.1% (95% CI, 25.2% to 30.8%) for Pfizer primary schedule and 40.6% (95% CI, 29.4% to 50.0%) for the Pfizer/Moderna heterologous schedule. [Castelli JM, 2022 ]

Intawong K et al was a test-negative case-control study conducted in Thailand. The study included 36,170 participants, 14,682 cases and 21,488 controls. Based on data from the Epid-CM platform, including participants aged 18 years or older, between October 2021 and April 2022.The aim was to assess the effectiveness of different booster doses. The adjusted vaccine effectiveness against infection during the omicron period after the third dose was 31% (95% CI, 15% to 44%) for the Pfizer-BioNTech booster, 26% (95% CI, 8% to 40%) for the AstraZeneca booster, and 31% (95% CI, 13% to 45%) for the Moderna booster. The adjusted VE after the fourth dose was 71% (95% CI, 60% to 79%) for the Pfizer-BioNTech booster, 73% (95% CI, 48% to 89%) for the AstraZeneca booster and 71% (95% CI, 59% to 79%) for the Moderna booster. [Intawong K, 2022 ]

Saito Y et al was a cohort study conducted in Japan that included 1,835 adolescents between 13-18 years. Participants received a homologous booster dose of Pfizer between April and May 2022. The relative effectiveness of a booster dose of Pfizer-BioNTech in adolescents during the Omicron predominance period compared with the primary schedule was 86.4% (95% CI, 57.2% to 95.7%). [Saito Y, 2022 ]

Kirsebom FCM et al was a cohort study conducted in England including participants who received an AstraZeneca primary schedule: 43,171 received an AstraZeneca booster and 13,038,908 received a Pfizer booster dose. Based on data from the National Immunisation Management System on all adults aged 18 years and older in England who had received a ChAdOx1-S primary schedule followed by a ChAdOx1-S or BNT162b2 booster, until March 14th 2022. The vaccine effectiveness against symptomatic infection was 63.8% (95% CI, 63% to 64.5%), and 90.9% (95% CI, 88.7% to 92.7%) against hospitalization. [Kirsebom FCM, 2022 ]

Anne J. Huiberts et al was a prospective cohort study conducted in Netherlands that included 27,646 participants during the Omicron period: 3,802 received primary vaccination schedule, 23,352 received first booster dose and 492 were unvaccinated. The primary outcome was contracting SARS-CoV-2 between July 12th 2021 and June 6th 2022. Vaccine effectiveness (VE) against contracting COVID-19 during the Omicron BA.1-2 period was 45% (95% CI, 20.3% to 62.1%), 51.1% (95% CI, 44.1% to 57.3%) and 58.4% (95% CI, 48.8% to 66.1%) for Pfizer primary schedule, mRNA primary schedule with Pfizer booster and AstraZeneca primary schedule with Pfizer booster, respectively. VE against contracting COVID-19 during the Delta period was 81.3% (95% CI, 69.2% to 88.6%), 97.4% (95% CI, 81.2% to 99.6%) and 90.9% (95% CI, 34% to 98.8%) for Pfizer primary schedule, mRNA primary schedule with Pfizer booster and AstraZeneca primary schedule with Pfizer booster, respectively. [Anne J. Huiberts, 2023 ]

Jang EJ et al was a retrospective cohort study conducted in South Korea that included 3,062,281 children aged 5 to 11 years: 29,473 with two Pfizer doses and 3,016,913 unvaccinated. This study analyzed data from the period dominated by the Omicron variant, between March 31st and August 6th. Vaccine effectiveness (VE) against infection was 57.6% (95% CI, 51.6% to 62.8%). VE against serious disease was 100% (95% CI, 100% to 100%). [Jang EJ, 2023 ]

Cerqueira-Silva T et al was a case-control study, test-negative design, conducted in Brazil and Scotland. The study included 5,832,210 participants: 5,276,385 from Brazil and 555,825 from Scotland. This study assessed vaccine effectiveness of a mRNA booster after AstraZeneca or Pfizer primary schedule during the period of Omicron dominance. Vaccine effectiveness against severe outcomes was 93.5% (95% CI, 93% to 94%), 94.4% (95% CI, 87.7% to 97.5%) and 92.7% (95% CI, 91% to 94%) with AstraZeneca primary schedule and Pfizer booster, AstraZeneca primary schedule and Moderna booster and Pfizer homologous booster, respectively. [Cerqueira-Silva T, 2023 ]

Ionescu IG was a case-control study, test-negative design, conducted in Canada. The study included data from two cohorts. Quebec cohort with 193,899 participants and  British Columbia cohort with 60,903. This study assessed vaccine effectiveness against SARS-CoV-2 infection, including Delta and Omicron variants. Vaccine effectiveness against any SARS-CoV-2 infection (Delta-to-Omicron transition period) was 82.8% (95% CI, 81.0% to 84.4%) and 88.0% (95% CI, 85.1% to 90.3%) for Quebec cohort and British Columbia cohort, respectively. Vaccine effectiveness against any SARS-CoV-2 infection during Omicron-dominant period was 41.9% (95%CI, 37.7% to 45.8%) and 33.9% (95% CI, 25.7% to 41.1%) for Quebec cohort and British Columbia cohort, respectively. [Ionescu IG, 2023 ].

Weng C et al was a comparative study conducted in United States that included 38,602 participants: 22,247 with at least one SARS-CoV-2 PCR test. The aim was to assess mRNA vaccine effectiveness (VE) in preventing SARS-CoV-2 infections. Adjusted VE of 2 doses of Pfizer was  94.6% (95% CI, 83.4% to 98.3%). Adjusted VE against Omicron (2 doses of Pfizer) was 31.6% (95% CI, 19.6% to 42.5%). Adjusted VE against Omicron (3 doses of Pfizer) was 79.9% (95% CI, 44.3% to 93.5%). [Weng CH, 2023 ]

Tsang et al was a prospective cohort study conducted in Hong Kong that included 8,636 participants. The aim was to assess vaccine effectiveness (VE) in preventing SARS-CoV-2 BA.2 infections. The VE of 3 doses of Pfizer was 41% (95% CI, 23% to 55%) against overall infection, and 51% (95% CI, 31% to 65%) against symptomatic infection. [Nicole Ngai Yung Tsang, 2022 ]

Wei et al was a case-control study conducted in Hong Kong that included 164,151 participants: 32,823 cases and 131,328 controls. The study assessed the Vaccine Effectiveness (VE) against SARS-CoV-2 Omicron infection. VE against death or hospitalization was 58% (95% CI, 52.9% to 61.8%) after 1 dose, 77.4% (95% CI, 75.5% to 79%) after 2 doses, and 85.8% (95% CI, 83.3% to 88.3%) after 3 doses. [Wei Y, 2023 ]

Vella et al was a cohort study conducted in Italy that included 913,382 participants: 456,690 received 2 doses and 456,692 received a booster (3 doses). Based on data from the Sicilian Regional Health Office, from January 1st to March 31st 2022. This study included all residents in Sicily aged ≥ 18 years without previous SARS-CoV-2 infection and with a complete mRNA vaccine primary cycle. The vaccine effectiveness of the booster dose was 76.5% (95% CI, 74.5% to 78.5%) against infection, 85.7% (95% CI, 83.4% to 87.9%) against severe disease and 84.1% (95% CI, 81.8% to 86.4%) against intubation/death. [Vella G, 2023 ]

Albreiki M et al was a case control study conducted in the United Arab Emirates that included data from 4,618 participants: 541 hospitalized and 4,077 non hospitalized. The aim was to assess the effectiveness against hospitalization of the Sinopharm and Pfizer vaccines between May 28th 2021 and January 13th 2022, during the Delta and Omicron outbreaks. Vaccine effectiveness (VE) against hospital admission during the Omicron outbreak was 94% (95% CI, 53% to 99%) for ≤ 45 years and 83% (95% CI, 0% to 99%) for participants older than 45 years. VE against hospital admission during the Delta outbreak was 95% (95% CI, 58% to 99%) for ≤ 45 years and 98% (95% CI, 78% to 99.6%) for participants older than 45 years. [Albreiki M, 2023 ]

Chun Yan VK et al was a case control study conducted in Hong Kong that included data from 36,434 COVID-19 cases, 2,231 COVID-19-related hospitalizations and 918 severe COVID-19 cases that were matched to 109,004, 21,788 and 18,823 controls, respectively. Individuals aged 3-17 with COVID-19 confirmed by polymerase chain reaction were included in the study. The aim was to estimate vaccine effectiveness (VE) in preventing COVID-19, hospitalization and severe outcomes, during the Omicron predominance period. Three doses of Pfizer were associated with a reduction in the risk of infection with a VE of 56% (95% CI, 49.6% to 61.6%). VE against hospitalization and severe outcomes was 58.9% (95% CI, 36.1% to 73.6%) and 60.2% (95% CI, 33.7% to 76.1%), respectively. [Chun Yan VK, 2023 ]

Piché-Renaud PP et al was a test negative design study conducted in Canada that included  6,284 test-positive cases and 8,389 test-negative controls. The aim was to estimate BNT162b2 vaccine effectiveness (VE) against symptomatic infection and severe outcomes caused by Omicron in children aged 5 to 11 years. VE against symptomatic infection was 66% (95% CI, 60% to 71%) 7 to 29 days after 2 doses. VE against severe outcomes was 94% (95% CI, 57% to 99%) 7 to 29 days after 2 doses. [Piché-Renaud PP, 2023 ]

Tenforde MW et al was a case-control study conducted in the United States. The study included data from 78,170 emergency department encounters: 8,986 cases and 69,184 controls. This study assessed the effectiveness of a bivalent booster dose among immunocompetent adults during September 13–November 18, 2022, a period during which the Omicron BA.5 sublineage predominated. Vaccine effectiveness of bivalent booster dose against Emergency department or urgency care encounters was 56% (95% CI,  50%-61%). [Tenforde MW, 2023 ]

Veneti L et al was a retrospective population-based cohort study conducted in Norway. The study included data from 372,179 participants. The aim was to assess vaccine effectiveness against any (symptomatic or not) SARS-CoV-2 Delta and Omicron infection among adolescents (12-17- years-old) in Norway from August 2021 to January 2022. Vaccine effectiveness against Delta infection was 68% (95% CI, 64%-71%) after the first dose among 12–15-year-olds. Among 16–17-year-olds that received two doses, vaccine effectiveness against Delta infection was 93% (95% CI,90%-95%). Among participants of 16–17 years vaccine effectiveness against Omicron infection was 53% (95%CI, 43–62%). [Veneti L, 2023 ]

Maeda H et al was a case-control study (test-negative design) conducted in Japan that included data from 7,931 participants: 3,055 test-positive cases and 4,876 test-negative cases. The aim was to assess vaccine effectiveness of primary and booster vaccination against symptomatic SARS-CoV-2 infections during the Omicron outbreak. Vaccine effectiveness was 67.1% (95% CI, 56.6 to 75.1%), 69.9% (95% CI, 49.3% to 82.2%) and 75.7% (95% CI, 57.7% to 86.0%) for Pfizer homologous booster, Pfizer primary schedule and Moderna booster, and Moderna homologous booster, respectively. [Maeda H, 2023 ]

Glatman-Freedman A et al was a case control study conducted in Israel that included data from 214,259 children (5–11 years old) with 2 doses of the Pfizer vaccine. The aim was to assess the effectiveness of the Pfizer vaccine against infection with the B.1.1.529 (Omicron) variant. Vaccine effectiveness after the second vaccine dose was 58.1% (95% CI, 55.5% to 60.6%). [Glatman-Freedman A, 2023 ]

Vaccine efficacy and effectiveness for booster dose

Immunogenicity outcomes
Tobudic S et al. was a clinical trial that evaluated the efficacy and safety of a booster dose in patients in whom serconversion did not occur after the second dose. The additional booster dose was delivered with the AstraZeneca or mRNA vaccines against COVID-19. Efficacy was measured by the difference in the SARS-CoV-2 antibody seroconversion rate between patients vaccinated with the AstraZeneca vaccine (heterologous) and the mRNA vaccines (homologous) at the fourth week. The results demonstrated that seroconversion rates at week four were comparable between patients who received the AstraZenaca vaccine (6/27 patients, 22%) versus the mRNA vaccines (9/28, 32%) (p = 0, 6). Overall, 27% of the patients seroconverted; furthermore, no serious adverse events related to immunization were observed [Michael Bonelli, 2021 ].

Eliakim-Raz N et al. was a before-after study conducted in Israel, assessing antispike (anti-S) IgG antibody titers before and after a third BNT162b2 dose in patients aged 60 years and older. Titers of anti-S IgG antibodies were determined with theSARS-CoV-2 IgG II Quant assay (Abbott Laboratories). The study enrolled 97 participants and the results showed a median titer level increased significantly after the third dose, froma median of 440 AU/mL (IQR, 294-923) to 25 468 AU/mL (IQR,14 203-36 618) [Eliakim-Raz N, 2021 ].

Biyan Zhang et al. was a cohort study conducted in Singapore. The study enrolled 52 participants and evaluated the levels of antibodies for Omicron variant and compared to the ancestral strain (Wuhan-Hu-1) and Delta variant, in four groups of volunteers receiving 1) Two doses of mRNA vaccines plus an mRNA vaccine booster (Homologous mRNA vaccine booster) 2) Two doses of inactivated virus vaccines plus an inactivated virus vaccine booster (Homologous inactivated virus vaccine booster) 3) Two doses of mRNA vaccines plus an inactivated virus vaccine booster (Heterologous inactivated virus vaccine booster) and 4) Two doses of inactivated virus vaccines plus an mRNA vaccine booster (Heterologous mRNA vaccine booster). The study results showed that only the mRNA vaccine booster was able to effectively increase the median levels of neutralizing capabilities against the Omicron variant (Group 1, median 90.45% [IQR 78.71-94.33%]; Group 4, median 77.85% [IQR 47.80-92.18%]) by 4.5-fold and 3-fold, respectively. Inactivated virus booster shot was unable to significantly increase the median levels of neutralizing capabilities against the Omicron variant regardless of whether the individuals received 2 priming doses of mRNA vaccines (Group 3, median 30.65% [IQR 19.98- 36.03%]) or 2 priming doses of inactivated virus vaccines (Group 4, median 26.80% [IQR 18.35- 36.15%]) [Biyan Zhang, 2022 ]

Yavlinksy et al was a prospective community cohort study conducted in England and Wales. The study evaluated the immune response generated by a booster dose of the Pfizer COVID-19 vaccine on Pfizer or AstraZeneca primary vaccination recipients. The study included 8,680 adults aged 18 or older who received a Pfizer vaccine booster after either Pfizer or AstraZeneca primary vaccination. The study found the Pfizer booster dose increased peak antibody levels compared to after primary vaccination regardless of the primary regimen. For the Pfizer primary vaccination group anti S antibody levels increased from 2,386 U/mL (95%CI: 9,801-15,653) to 22,185 U/mL (95%CI: 21,406-22,990) after the booster dose. In the AstraZeneca group antibody levels increased from 1,192 U/mL (95%CI: 818-1735) to 19,203 U/mL (95%CI: 18,094-20,377) after the booster dose [Alexei Yavlinsky, 2022 ].

Poh et al. is an ongoing phase 4 randomized clinical trial, conducted in Singapore, assessing the humoral response elicited by homologous and heterologous booster vaccination regimens based on a primary regimen with Pfizer-BioNTech. Interim results of two groups have been published. The study recruited 100 participants who either received a Pfizer-BioNTech (n=51) booster or a Moderna booster (n=49). Results show a booster dose increases antibody titers in all participants by 35- to 49- fold at day 7 with only a modest increase by day 17. Antibody titers were higher in the Moderna group, particularly in the ≥60 years age subgroup. On day 28 antibody titers reached 29.751 (IC 95%: 25.281-35.011) UI/mL for the Moderna group and 22 382 (IC del 95 %: 18 210-27 517) UI/mL for the Pfizer-BioNTech group. Neutralization against the Omicron variant was higher in the Moderna group at day 7 but similar at day 28 [Xuan Ying Poh, 2022 ].

Medina-Pestana J et al was a comparative cohort study conducted in Brazil. This study included kidney transplant recipients without previous COVID-19. Patients received a third heterologous (BNT162b2) (n=307) or homologous dose (n=777) at least 4 weeks after 2 doses of the CoronaVac vaccine. Immediately before the third dose, IgG seroprevalence (36% versus 34%; P = 0.597) and antibody titers (246 versus 268 AU/mL; P = 0.279) were similar. After booster, seroconversion was higher in the heterologous group (49% versus 32%; P < 0.0001), resulting in a higher seroprevalence (67% versus 55%; P = 0.0003); however, 42% of all patients remained seronegative. Antibody titers after booster in seropositive patients were higher in the heterologous group (7771 versus 599 AU/mL; P < 0.0001) [Medina-Pestana J, 2022 ].

Heinzel et al was a secondary analysis of a randomized controlled trial conducted in Austria. The study enrolled  201 Kidney Transplant Recipients without detectable SARS-CoV-2 specific antibodies following two doses of an mRNA vaccine. Participants were randomized to a 3rd dose of the same mRNA vaccine (the mRNA group) or a dose of the vector vaccine Ad26COVS1. A total of 169 patients were available for the 3-month follow-up. Overall, seroconversion at 3 months was similar between both groups (45 vs. 50% for mRNA and the vector group, respectively; p = 0.539). However, when applying higher cut-off levels, a significantly larger number of individuals in the vector group reached antibody levels > 141 and > 264 BAU/ml at the 3-month follow-up (141 BAU/ml: 4 vs. 15%, p = 0.009 and 264 BAU/ml: 1 vs. 10%, p = 0.018 for mRNA vs. the vector vaccine group, respectively) [Heinzel A, 2022 ].

PRIBIVAC was a randomized controlled trial conducted in Singapore. 100 participants who had received a primary vaccine schedule with two doses of the Pfizer-BioNTech vaccine were randomized to either homologous (BNT162b2 + BNT162b2 + BNT162b2; 'BBB', n= 51) or heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; 'BBM'; n= 49). Primary endpoint was the level of neutralizing antibodies against SARS-CoV-2 wild-type and Variants of Concern (VOCs) at day 28 after the booster dose. The results demonstrated that there was a significant increase in wild-type SARS-CoV-2 antibody titers after the booster dose compared to baseline. Antibody titers were higher in the BBM group (22,382 IU/mL; 95% CI:18,210 to 27,517) compared to the BBB group (29,751 IU/mL; 95% CI: 25,281 to 35,011; p=0.034) [Poh XY, 2022 ].

Shinkai M et al was a phase 2/3 randomized clinical trial conducted in Japan. The study included 206 healthy adults vaccinated with 2 doses of Pfizer ≥ 6 months ago. 101 participants received a booster dose with S-268019-b vaccine and 103 with Pfizer vaccine. The primary objective of the study was to assess the noninferiority of S-268019-b versus BNT162b2 as a booster dose in inducing SARS-CoV-2 neutralizing antibodies against the live wildtype virus strain (WK-521) on day 29. The co-primary endpoints included day 29 geometric mean titer (GMT) and seroresponse rate (SRR) for SARS-CoV-2 neutralizing antibodies. SRR was defined as the proportion of participants with a post–vaccination antibody titer 4-fold higher than the baseline. GMTs (95% CIs) for neutralizing antibodies at baseline was 6.65 (95% CI 5.73 to 7.72) for Pfizer vaccine. GMT on day 29 after pfizer booster dose increased to 109.70 (95.73–125.70). The SRR was 100% for both groups (SRR difference 0.0; 95% CI 5.9 to 5.9; noninferiority P-value, 0.0004). [Shinkai M, 2022 ]

Choi JY et al was a comparative cohort study conducted in Korea. The study analyzed 170 samples of sera from 75 participants: 50 samples from ChAd-ChAd-BNT, 60 samples from ChAd-BNT-BNT, and 60 samples from BNT-BNT-BNT. Neutralizing activities were evaluated using plaque-reduction neutralization test (PRNT) against wild-type (WT) SARS-CoV-2, Delta variant, and Omicron variant. After the 2nd vaccine dose, geometric mean titers of PRNT ND50: against wild type, Delta, and Omicron were highest after ChAd-BNT vaccination (2,463, 1,097, and 107) followed by BNT-BNT (2,364, 674, and 38) and ChAd-ChAd (449, 163, and 25). After the 3rd dose of BNT, the increase of PRNT ND50 against WT, Delta, and Omicron was most robust in ChAd-ChAd-BNT (4,632, 988, and 260), while the BNT-BNT-BNT group showed the most augmented neutralizing activity against Delta and Omicron variants (2,315 and 628) [Choi JY, 2022 ].

Puthanakit T et al was a phase 2 randomized clinical trial conducted in Thailand. The study included 80 participants  aged 12 to < 18 years without previous SARS-CoV-2 vaccination. Participants were randomized to be vaccinated with CoronaVac (SV) 3 ug as the first dose followed by BNT162b2 30 µg or 20 µg as the second dose, at 3-week (3w) or 6-week interval (6w). During the Omicron-predominant period, participants were offered a BNT162b2 booster dose 30, 15, or 10 µg. Immunogenicity was determined using IgG antibody against spike-receptorbinding domain of wild type(anti-S-RBD IgG) and surrogate virus neutralization test(sVNT) against Delta variant at 14 days and 5 months after the 2nd dose. Neutralization tests(sVNT and pseudovirus neutralization test; pVNT) against Omicron strain were tested pre- and 14 days post-booster dose.  At day 14, the geometric mean(GM) of anti-S-RBD IgG in SV3w/PZ30lg was 4713 (95 %CI 4127–5382) binding-antibody unit (BAU)/ml, while geometric mean ratio(GMR) was 1.28 (1.09–1.51) in SV6w/PZ30lg. The GMs of sVNT against Delta variants at day 14 among participants in SV3w/PZ30lg and SV6wk/PZ30lg arm were 95.3 % and 99.7 %inhibition, respectively. [Puthanakit T, 2022 ]

Cobovax study was a randomized clinical trial conducted in China. The study enrolled 219 adults who previously received two doses of CoronaVac and randomized to CoronaVac ("CC-C", n=101) or BNT162b2 ("CC-B", n=118) third dose; and 232 adults who previously received BNT162b2 and randomized to CoronaVac ("BB-C", n=118) or BNT162b2 ("BB-B", n=114). The aim was to assessed immunogenicity and cell-mediated immune responses and vaccine efficacy against infections during follow-up. Third-dose vaccination increased PRNT50 titers against ancestral virus 315 by 14-, 94-, 3- and 19-folds, and against Omicron BA.2 by 1-, 16-, 1- and 13-folds, in CC-C, CC-B, BB-C and BB-B arms respectively. Antibody responses to a BNT162b2 third dose were substantially and statistically significantly greater than responses to a CoronaVac third dose regardless of prior two-dose vaccine type. [Nancy H. L. Leung, 2022 ]

Behrens et al. conducted a longitudinal monitoring of ChAd/ChAd (n = 41) and ChAd/BNT (n = 88) vaccinated individuals and the impact of a third vaccination with BNT. Anti-SARS-CoV-2 spike IgG (anti-S IgG) levels were significantly higher in the ChAd/BNT group short after prime-boost vaccination when compared to the ChAd/ChAd group but declined significantly over time in both groups, with lower anti-S IgG after homologous vaccination prior to the third immunization. Following a third immunization, they found greatly increased anti-S IgG responses in both groups. Additional immunization of the homologous ChAd/ChAd immunized group led to a significant 46.9 -fold increase in anti-S IgG (p<0.0001) and 8.0-fold increase in individuals after heterologous ChAd/BNT vaccination (p<0.0001). In both groups, anti-S IgG levels were considerably higher when compared to the situation observed 14 days after the second vaccination (the third vaccination diminished previous differences between the heterologous ChAd/BNT and homologous ChAd/ChAd prime-boost vaccination groups, since anti-S IgG were comparable in both groups after the third vaccination). The numbers of spike-specific memory B cells generated after prime-boost vaccination gradually increased during the following months with no significant difference between the ChAd/ChAd and the ChAd/BNT group, in line with increased amounts of spike-specific antibodies, highlighting the impact of the third vaccination for better protection from SARS-CoV-2 infection. 2 weeks after a third immunization with BNT, spike-specific memory B cells were significantly higher in the ChAd/ChAd as compared to the ChAd/BNT prime-boost group. The frequencies of spike-specific CD4+ and CD8+ T cells in blood samples collected after the second vaccination were significantly higher in the ChAd/BNT than in the ChAd/ChAd group. Both cell populations declined over time after heterologous immunization, while they remained at low levels after homologous vaccination. Whilst spike-specific CD4+ T cells declined to frequencies similar to individuals after homologous ChAd/ChAd vaccination, spike-specific CD8+ T cells remained above the frequencies of the heterologous vaccinated group. A third immunization with BNT in the ChAd/ChAd group significantly raised numbers of spike-specific CD4+ T cells above levels observed after the second vaccination. A third vaccination of the ChAd/BNT group only regained spike-specific CD4+ T cell to levels present after the second vaccination. A third vaccination with with BNT did not result in an expansion of spike-specific CD8+ T cells above levels observed after second vaccination in ChAd/BNT vaccinees, but did so in ChAd/ChAd vaccinated individuals. Like for spike-specific CD4+ T cells, raised numbers in spike-specific IFN-γ-producing T cells in the ChAd/ChAd as well as the ChAd/BNT group after the additional BNT vaccination was confirmed by cytokine measurement in supernatants after SARS-CoV-2 spike peptide stimulation. The third vaccination did not further increase spike-specific IFN-γ-producing T cells in ChAd/BNT vaccinated subjects above levels obtained already after the second vaccination [Behrens GMN, 2022 ].

Renia L et al was a cohort study that included 312 participants vaccinated with the BNT162b2 SARS-CoV-2 mRNA vaccine.  This study compared the kinetics of specific antibodies, B and T cell memory responses in a cohort of BNT162b2-vaccinated healthcare workers and elderly individuals in Singapore up to 6 months postimmunization and for a subset of elderly low responders after a third dose. After the second dose, all but one of the participants developed anti-Spike protein antibodies by day 90. Immunoglobulin isotyping showed that the proportion of vaccinees with detectable IgM (above both cohort and individual baseline) was >85% at day 21 but dropped to 12% by day 90 (12%) and was negligible by day 180. After the second dose, all individuals seroconverted by day 90. However, 36.5% of individuals mounted a poor anti-RBD IgG response. More than 79.1% of the plasma had neutralizing antibodies above individual baseline after the first dose, 99% after the second dose and 93% at day 180. The antibody response against the Delta variant was lower than the Wildtype ancestral strain and extremely low or non-existent against the Omicron variant. The third dose strongly boosted the antibody responses against the total Spike protein or its RBD. The boosting injection also induced a strong antibody response against the spike protein of the Delta and Omicron variants. [Renia L, 2022 ]

Gilboa M et al was a prospective cohort study conducted in Israel, including 3,972 healthcare workers who received 3 vaccine doses and 4,868 healthcare workers who received 2 doses. The study measured the neutralizing response against Omicron, 5 months after vaccination. The GMT of neutralizing antibodies with the booster dose was 4,315 (95% CI, 4,051-4,595) compared to 611 (95% CI, 557-671) after 2 doses, and the response waned to 132 (95% CI, 121-144) and 1,001 (95% CI, 895-1,119) with 3 and 2 doses respectively, after 140 days. [Gilboa M, 2022 ]

Althaus T et al was a cohort study conducted in Monaco, including 7,537 vaccinated individuals: 1,864 with a documented SARS-CoV-2 infection and 5,673 remained uninfected. The median neutralizing antibody (nAb) levels after the third dose was 882.5 (IQR, 820.5-914.8) IU/mL. The adjusted nAb ratio compared with the primary scheme was 4.39 (95% CI, 3.56-5.42). [Thomas Althaus, 2022 ]

Akerman A was a comparative study conducted in Australia that included 29 participants with three doses of Pfizer and 23 participants with four doses of Pfizer. This study monitored the potency and breadth of antibody neutralization responses to emerging variants. Mean antibody titers (IC50) against ancestral strain was 203 ng/µl after third dose and 1,075 ng/µl after fourth dose. Mean antibody titers (IC50) against Omicron BA5 variant was 63 ng/µl after third dose and 257 ng/µl after fourth dose. [Anouschka Akerman, 2022 ]

Irrgang P et al was a comparative cohort study conducted in Germany that included 29 health care workers with three doses of the Pfizer vaccine. This study reported  immunogenicity of a cohort of vaccinated healthcare workers from five to seven months after the second mRNA immunization with Pfizer. IgG4 antibodies among all spike-specific IgG antibodies increased on average from 0.04% shortly after the second vaccination to 19.27% late after the third vaccination. [Irrgang P, 2022 ]

Samoud S et al was a randomized controlled trial conducted in Tunisia that included 216 participants: 108 randomized to the heterologous booster group (CoronaVac/Pfizer) and 108 to the homologous booster group (CoronaVac/CoronaVac). The aim was to compare the immunogenicity of the heterologous prime-boost CoronaVac/BNT162b2 vaccination to the homologous CoronaVac/CoronaVac regimen. Anti-spike IgG after the first dose was 1,187 UI/ml (95% CI, 225-2,475) and 827 UI/ml (95% CI, 4-2,109) for the heterologous booster group and the homologous booster group, respectively. Anti-spike IgG after the second dose was 13,460 UI/ml (95% CI, (2,557-29,930) and 1190 UI/ml (95% CI,347-4964) for the heterologous booster group and the homologous booster group, respectively [Samar Samoud, 2023 ].

Yamamoto S et al was a case control study conducted in Japan that included data from 1,456 participants: 863 with two doses of Pfizer and 593 with three doses of Pfizer. This study compared the pre-infection live-virus neutralizing antibodies (NAb) against Omicron. GMT (NT50) of NAb against Omicron BA.1 were 221 (95% CI, 141–349) for cases and 223 (95% CI, 129–383) for controls. GMT (NT50) of NAb against Omicron BA.2 were 102 (95% CI, 72–143) for cases and 108 (95% CI, 75–155) for controls. [Yamamoto S, 2023 ]

Uwamino Y et al was a cohort study conducted in Japan that included data from 406 healthcare workers who received a Pfizer booster dose. The geometric mean RBD-IgG titer was elevated to 20,558.9 AU/mL 3 weeks after the third dose and decreased to 6,622.2 AU/mL 6 months after the third dose, which was close to the titer 8 weeks after the second dose (5,248.1 AU/mL). [Uwamino Y, 2023 ]

Jäger M et al was a comparative cohort study conducted in Austria that included 137 participants, of which 79 were vaccinated with AstraZeneca primary schedule and mRNA vaccine booster and 40 with 3 doses of mRNA vaccine. The aim was to assess humoral and cellular response. Median IgG titer were 1655.0 (95% CI, 1163.0-1901.0), 2673.0 (95% CI, 2189.0-3517.0) and 2891.0 (95% CI, 1582.0-4458.0) for particpants with 2 AstraZeneca doses and Pfizer booster group, 2 AstraZeneca doses and Moderna booster and 3 Pfizer doses, respectively. [Jäger M, 2023 ]

Dedroogh S et al was a prospective cohort study conducted in Germany that included 1,338 participants with Pfizer booster dose: 565 Pfizer primary schedule and 773 AstraZeneca primary schedule. The aim was to assess SARS-CoV-2- antibodies booster immunization with the Pfizer and AstraZeneca vaccines. Mean of anti-S RBD antibody levels were 25,000 U/mL (95% CI, 18,474 − 25,000) for homologous Pfizer booster and 16,488 U/mL (95% CI, 11,192-24,785) for Pfizer primary schedule and AstraZeneca booster, respectively. [Dedroogh S, 2023 ]

Efficacy outcomes
C4591031 was a phase 3 randomized trial. The study enrolled 10,136 participants: 5,081 in the vaccine group and 5,044 in the placebo group. Participants who had received two 30-μg doses of the BNT162b2 vaccine for at least 6 months were assigned to be injected with a third dose of the BNT162b2 vaccine or with placebo. The study assessed vaccine safety and efficacy against COVID-19 starting 7 days after the third dose. The main results showed that relative vaccine efficacy for individuals without evidence of infection 7 days before the third dose was 95.3% (95 CI 89.5 to 98.3). Relative vaccine efficacy for individuals with or without evidence of infection 7 days before the third dose was  94.6% (95% CI 88.5 to 97.9) [Moreira ED, 2022 ].

Effectiveness outcomes
Barda N et al. was a case-control study conducted in Israel. The study enrolled 1,158,269 participants: 728,321 third dose group; 728,321 second dose group. Based on data from Clalit Health Services, which provides mandatory health-care coverage for over half of the Israeli population, between July 30, 2020, and Sept 23, 2021, with outcomes measured 7 days after the third dose, the study results showed a vaccine effectiveness for admission to hospital of 93% (95% CI 88–97), for severe disease of 92% (95%CI  82–97) and for death of 81% (95%CI  59–97) [Barda N, 2021 ]. 

Arbel R et al. was a cohort study conducted in Israel. The study enrolled 843,208 participants: 758,118 third dose group, and 85,090 second dose group. Based on data for all members of Clalit Health Services who were 50 years of age or older at the start of the study and had received two doses of BNT162b2 at least 5 months earlier, between August and September 2021. Main outcomes were measured 7 days after the third dose. The study results showed a adjusted hazard ratio for death of 0.10 (95%CI 0.07 to 0.14) [Arbel R, 2021 ]. 

Bar-On YM et al. was a cohort study conducted in Israel. The study enrolled 4,696,865 participants and was based on data from the Israel Ministry of Health database regarding 4,696,865 persons 16 years of age or older who had received two doses of BNT162b2 at least 5 months earlier, for the period from July 30 to October 10, 2021. Outcome was measured 7 days after the third dose. The study results showed an adjusted rate difference ranging from 57.0 to 89.5 infections per 100,000 person-days for confirmed infection and an adjusted rate difference ranging from 5.4 and 1.9 cases of severe illness per 100,000 person-days for severe illness [Bar-On YM, 2021 ].
         
Andrews N et al. was a case-control study (Test-negative) conducted in United Kingdom. The study included 893,845 eligible tests in those aged 18 years and over. The objective was to estimate the effectiveness of the Pfizer and Moderna booster vaccines against symptomatic disease, hospitalization, and death in adults in England. The study results showed that the booster dose was associated with an absolute vaccine efficacy from 14-34 days after a Pfizer booster of 94.4% (95% CI 94.1 to 94.7) following either an AstraZeneca or Pfizer primary scheme in individuals 50 years and older [Andrews N, 2022 ].

Muhsen K et al. is a non-randomized study that assessed the incidence of COVID-19 among long-care residents who were 60 years of age or older. After 36 weeks, the incidence rate ratio reached 0.29 for overall infection and 0.20 for hospitalization, corresponding to a relative rate reduction of 71% and 80%, respectively. In addition, study results showed a consistent reduction in the COVID-19 mortality among persons in the same age group living in long-term care facilities [Muhsen K, 2021 ]."

mBoost was an open-label trial conducted in Qatar. The study included 2,232,224 vaccinated persons with at least two doses. This study compared protection afforded by booster dose of the Pfizer vaccine, compared to the primary series of only two doses in Qatar. Study results showed that there were fewer cases of severe COVID-19 in booster-dose cohorts than in primary-series cohorts, but cases of severe COVID-19 were rare in all cohorts. Booster effectiveness relative to primary series was 50.1% (95% CI: 47.3-52.8%).[Laith J Abu-Raddad, 2022 ].

Accorsi EK et al included 23 391 cases and 46 764 controls (3 doses= 12 476; 2 doses=19839; Unvaccinated= 17 177). Data were collected ≥14 days after dose 3 and ≥6 months between doses 2 and 3. The study showed that receiving three doses of Pfizer COVID-19 vaccine compared to not receiving any and receiving only two doses, was associated with protection against both the Omicron and Delta. Comparison of 3 Doses vs Unvaccinated showed for Omicron variant OR 0.35 (95% CI 0.32 to 0.38) and for Delta variant OR 0.077 (95% CI 0.070 to 0.086). Comparison of 3 Doses vs 2 Doses showed for Omicron variant OR 0.35 (95% CI 0.32 to 0.37) and for Delta variant OR 0.17 (95% CI,0.16 to 0.19) [Accorsi EK, 2022 ].
McConeghy KW et al. included 14,259 participants (8,538 control and 5,721 boosted residents). Data were collected 42 days after the booster dose. The combined results showed that a booster dose of Pfizer or Moderna COVID-19 vaccine reduced infections by 50.4% (95% CI 29.4% to 64.7%) in nursing homes residents and 58.2% (95% CI 32.3% to 77.8%) in veterans residing in community living centers. Nursing homes residents with booster dose also had a 97.3% (95% CI 86.9% to 100.0%) reduction in SARS-CoV-2 associated death, but too few events for comparison in veterans residing in community living centers [Kevin W McConeghy, 2022 ].

Buchan SA et al. included 20,348 tests (Omicron-positive cases=16,087;  Delta-positive cases= 4,261 test-negative controls= 114,087). Data were collected from December 6 to 26, 2021.  The study showed that 2 doses of COVID-19 vaccines only offer modest and short-term protection against symptomatic Omicron infection. A third dose improves protection against symptomatic infection and provides excellent protection against severe outcomes for Delta and Omicron variants. Vaccine efficacy against Delta variant was 97% (95% CI 96 to 98) and 60% (95% CI 55 to 65)  for Omicron in symptomatic infection 7 days after a third dose [Buchan, S. A., 2022 ].

The VISION Network study included 222,772 encounters from 383 emergency departments (ED) and urgent care (UC), and 87,904 hospitalizations from 259 hospitals. Data were collected during periods of Delta and Omicron variant predominance between august 2021to January 2022. Based on all results combined, during the Delta-predominant period, vaccine effectiveness against Lab-confirmed COVID-19 was significantly lower among patients who received the second dose ≥180 days earlier (76%; 95% CI 75 to 77) than among those who received the third dose (94%; 95% CI 93 to 94). In the omicron-predominant period, vaccine effectiveness against the same outcome was significantly lower among those who received the second dose ≥180 days earlier (38%; 95% CI 32 to 43) than those who received the third dose (82%; 95% CI 79 to 84). In addition, vaccine effectiveness against hospitalization was 90% (95% CI 89 to 90) in those who received the second dose <180 days earlier, 81% (95% CI 80 to 82) in those who received the second dose ≥180 days earlier and 94% (95% CI 93 to 95) in those who received the third dose, during Delta period. In the Omicron period, vaccine effectiveness against hospitalization was 81% (95% CI 65 to 90) in those who received the second dose <180 days earlier, 57% (95% CI 39 to 70) in those who received the second dose ≥180 days earlier and 90% (95% CI 80 to 94) in those who received a third dose [Thompson MG, 2022 ].

Drawz PE et al. was a case-control study conducted in the United States.  The study enrolled 4,547,945 participantes:1,732,112 were fully vaccinated with Pfizer and 1,066,645 were fully vaccinated with Moderna. A Pfizer booster was administered to 609,153 individuals and a Moderna booster was administered to 395,634 individualsThe study is based on statewide COVID-19 vaccination data from the Minnesota Immunization Information Connection (MIIC) linked via a privacy preserving record linkage process with distributed electronic health record (EHR) data from the 11 largest health systems in Minnesota. The main results showed that the booster dose effectiveness was 88% (95% CI 87 to 88) and 88% (95% CI 86 to 90)  for preventing Hospitalization for the  Pfizer-BioNTech vaccine [Drawz PE, 2022 ].

Chemaitelly H et al was a case-control study conducted in Qatar, it enrolled 85,623 participants: 58,274 cases and 27,419 controls. Based on data from a test negative design study that seeks to assess the duration of protection of Pfizer-BioNTech after second dose and after third/booster dose against symptomatic Omicron infection and against COVID-19 hospitalization and death, between December 23, 2021 and February 2, 2022.  The vaccine effectiveness waned after the second those to less than 10% five months after vaccination, the effectiveness four to five weeks after booster rose  to 56.6% (50.8% to 61.7%) [Hiam Chemaitelly, 2022 ].

Oster Y et al. was a comparative cohort study conducted in Israel, it included 5,371 healthcare workers: 398 received two doses and 4,973 received three doses. Based on data from healthcare workers at the Hadassah tertiary care medical center in Jerusalem, who had received two vaccine doses (Pfizer-BioNTech) in early 2021 and were not infected until August 2021. The follow-up period lasted 120 days after the last dose for each group. The effectiveness against breakthrough infection was 97% ( 95% CI, 95% to 99%) [Oster Y, 2022 ].

Kislaya I et al. was a case control study conducted in Portugal, the study enrolled 15,001 participants, 3.737 were eligible for a booster dose of Pfizer-BioNTech. Based on dat from RT-PCR SARS-CoV-2 positive cases notified in the mandatory National Epidemiological Surveillance Information System (SINAVE) in Portugal. The booster effectiveness against Delta variant was 94% (95% CI: 93.4 to 94.6) and for Omicron variant the booster effectiveness was  68.8% (95% CI: 46.4 to 81.7) [Irina Kislaya, 2022 ].

YM Bar-On et al. was a case-control study conducted in Israel, it included 57,705 cases: 42,693 with three doses, 5,445 with 4 to 7 days after the fourth dose, and 9,071 with at least 12 days after the fourth dose. Based on data from the Israeli Ministry of Health database regarding 1,138,681 persons aged over 60 years and eligible for the fourth dose from January 15 through January 27, 2022. The rate ratio compared to the third dose was 2.0 (95%CI 2.0 to 2.1) for those between 4 and 7 days after the fourth dose, and those with more than 12 days after the fourth dose had a rate ratio of 1.9 (95%CI 1.8 to 2.0) [Yinon M. Bar-On, 2022 ].

Shrestha NK et al. was a cohort study conducted in the United States, based on data from Cleveland Clinic Health System in Ohio, United States, all employees who had been vaccinated (with either Pfizer-BioNTech or Moderna) or had previous COVID-19 infection by November 26, 2021, were included. With a follow-up period of 90 days. The vaccine effectiveness during the Omicron surge was 57% (95%CI: 54% to 59%) for the complete scheme and a booster of mRNA vaccine [Nabin K Shrestha, 2022 ].

Tan SHX et al was a comparative cohort study conducted in China. Rates and severity of SARS-CoV-2 infections between September 15 and October 31, 2021, among those eligible to receive vaccine boosters between September 15 and October 15, 2021, were analyzed based on official data reported to the Singapore Ministry of Health. The adjusted incidence rate ratios (3 doses of BNT162b2) for individuals with PCR–confirmed infections was 0.272 (95% CI 0.258 to 0.286) and 0.047 (95% CI 0.026 to 0.084) for severe infections [Tan SHX, 2022 ].

Abu-Raddad LJ et al. was a study conducted in Qatar including data from 2,239,193 vaccinated individuals: 1,299,010 with Pfizer-BioNTech and 890,619 with Moderna, the study also included matched unvaccinated controls. The study analyzed information from national, federated databases regarding Covid-19 vaccination, laboratory testing, hospitalization, and death from December 19, 2021, through January 26, 2022. The vaccine effectiveness against the Delta variant of the booster dose compared to the two dose regimen was 86.1% (95% CI 67.3 to 94.1) for symptomatic infection, the effectiveness against the Omicron variant of the booster dose compared to the two dose regimen was 49.4% (95% CI 47.1 to 51.6)  for symptomatic infection and 76.5% (95% CI 55.9  to 87.5) for hospitalization and death  [Abu-Raddad LJ, 2022 ].

Andrews N et al. was a case-control study conducted in England. The study enrolled 2,663,549 vaccinated participants: 204,154 cases for Delta variant, 886,774 cases for Omicron variant and 1,572, 621 test-negative controls. The study analyzed information from national databases, Pillar 1, Pillar 2, NIMS and NHS regarding Covid-19 vaccination, testing, and variants  from November 25, 2021, through January 12, 2022.  Pfizer-BioNTech effectiveness against Delta and Omicron variants for symptomatic infection 10 weeks after a Pfizer-BioNTech booster were 89.9% (95% CI 89.2 to 90.5) and 45.7% (95% CI 44.7 to 46.7) [Andrews N, 2022 ].

Arbel R was a comparative cohort study conducted in Israel. The study included 563,465 participants and 328,597 received a second-booster dose during the 40-day study period. The study included all members of Clalit Health Services, aged 60 or older, who received a BNT162b2 booster dose at least 4 months earlier. Mortality due to Covid-19 among participants who received the second-booster was compared with that among participants who received one booster dose. Adjusted hazard ratio for mortality was  0.22 (95% CI 0.17 to 0.28) [Ronen Arbel, 2022 ].

Grewal R et al was a case-control study (test negative design) conducted in the United States. The aim of this study was to estimate the marginal effectiveness of a fourth versus third dose and the vaccine effectiveness of mRNA covid-19 vaccines BNT162b2 and mRNA-1273 against any infection, symptomatic infection, and severe outcomes (hospital admission or death) related to the omicron variant. Vaccine effectiveness of three doses of Pfizer vaccine against omicron variant against any infection was 32% (95%CI 24 to 38), against symptomatic infection was 53% (95%CI 39 to 63) and against severe outcomes 77% (95% CI 67 to 83) [Grewal R, 2022 ].

Low EV et al. was a retrospective cohort study conducted in Malaysia. The study included 13,840,240 individuals: 5,714,979 with 2 doses BNT162b2, 3,043,620 with 2 doses of CoronaVac, 1,265,436 with 3 doses of BNT162b2, 3,225,428 with 2 doses of CoronaVac plus BNT162b2 booster and 590 777 with 3 doses of CoronaVac. The aim of this study was to compare the odds of symptomatic SARS-CoV-2 infection and COVID-19–related outcomes after heterologous and homologous boosting of CoronaVac at 3-month intervals and homologous boosting of BNT162b2 at 6-month intervals, with BNT162b2 primary series (2 doses) as the reference group. The adjusted odds against symptomatic SAR-CoV-2 infection were lower for individuals who received the primary series CoronaVac plus a BNT162b2 (adjusted odds ratio [aOR], 0.06 [95% CI, 0.05-0.06]), 3 doses of CoronaVac (aOR, 0.08 [95% CI, 0.06-0.10]), or 3 doses of BNT162b2 (aOR, 0.01 [95% CI, 0.00-0.01]). Receipt of heterologous booster (primary series of CoronaVac plus a BNT162b2 booster) was associated with lower odds of SARS-CoV-2 infection (aOR, 0.17 [95% CI, 0.17-0.18]) compared with homologous booster (3 doses of CoronaVac) for individuals aged 60 years and older (aOR, 0.19 [95% CI, 0.19-0.20]) [Low EV, 2022 ].

Tartof SY et al was a test-negative case-control study conducted at Kaiser Permanente Southern California, an integrated health care system using electronic health records in the US. Participants included 3168 members ages 12 to 17 years with emergency department (ED) and urgent care (UC) encounters from November 1, 2021, through March 18, 2022. Vaccine effectiveness (VE) associated with 2 doses of BNT162b2 against ED or UC encounters was highest within the first 2 months for both Delta (89% [95% CI, 69% to 96%]) and Omicron (73% [95% CI, 54% to 84%]) variants but waned to 49% (95% CI, 27% to 65%) for the Delta variant and 16% (95% CI, −7% to 34%) for the Omicron variant at 6 months and beyond. A third dose of BNT162b2 was associated with improved protection against the Omicron variant (87% [95% CI, 72% to 94%]) after a median (IQR) of 19 (9-32) days after dose 3 [Tartof SY, 2022 ].

Ziv et al was a case-control study conducted in Israel, the study evaluated the effectiveness of PfizerBioNTech vaccination among 1639 adolescentes with juvenile-onset inflammatory rheumatic diseases, the control group comprised 524,471 adolescents without juvenile-onset inflammatory rheumatic diseases. The estimated vaccine effectiveness for adolescents with IRD was 99.2% after the Pfizer-BioNTech booster dose [Ziv A, 2022 ].

McMenamin et al was a cohort study conducted in Hong Kong based on individual level-case study, vaccination programme and census information. The study evaluated the effectiveness of Pfizer-BioNTech vaccination, including cases between December 31, 2021 and March 16, 2022. Vaccine effectiveness of three doses of Pfizer-BioNTech against mild or moderate disease was 73.5% (95 CI 66.6 to 79.2), and 98.8% (95 CI 97.5 to 99.5) against severe disease [McMenamin ME, 2022 ].

Berec L was a case-control study conducted in Czechia. The study used Czech national health data from the beginning of the Covid-19 pandemic till November 2021 to estimate risks of reinfection, breakthrough infection, hospitalization, and death among fully vaccinated individuals at two time points (0-2 months and 7-8 months after the second dose) and after a booster dose. The study analyzed 5,011,115 individuals vaccinated with the Pfizer-BioNTech vaccine. The vaccine effectiveness against any PCR-confirmed SARS-CoV-2 infection declined for from 87% (95% CI 86–87) 0–2 months after the second dose to 53% (95% CI 52–54) at 7–8 months; against hospitalizations, VE declined from 90% (95% CI 89–91) at 0–2 months to 75% (95% CI 73–76) at 7–8 months [Berec L, 2022 ].

Shrotri M et al was a comparative cohort study conducted in England. The study included data from participants from 331 long-term care facilities: 15518 residents aged 65 years or older and 19515 staff aged 18 years or older. This study estimated vaccine effectiveness against SARS-CoV-2 infection, COVID-19-related hospitalization, and COVID-19-related death after one, two, and three vaccine doses, separately by previous SARS-CoV-2 exposure. Vaccine effectiveness against infections for Pfizer homologous booster dose was 72.1% (95% CI 51.7 to 83.9) for residents (>65 years) and 78.9% (95% CI 69.6 to 85.4) for staff (>18 years)[Shrotri M, 2022 ].

Patalon T et al was a test-negative case-control study conducted in Israel. This study assessed the association between booster breakthrough infections with the Omicron variant and time-since-vaccination, leveraging data from Maccabi Healthcare Services (MHS). Vaccine effectiveness against infection of ‘newly’ vaccinated individuals was 53.4% (95% CI 47.7 to 8.6%). VE declined rapidly with each month since vaccination, with 35.7% (95% CI, 29.8–41.2%) VE for those who were vaccinated two months prior to the outcome period compared to the earliest vaccinees (of August 2021). [Patalon T, 2022 ].

Richterman A et al was a test-negative case-control study that analyzed data from 7098 tests during the Omicron period (2270 SARS-CoV-2 PCR Positive) and 7422 tests during the Delta period (506 SARS-CoV-2 PCR Positive). The aim of this study was to estimate BNT162b2 and mRNA1273 primary vaccination and booster effectiveness against SARS-CoV-2 infection and symptomatic coronavirus disease 2019 during an Omicron surge among employees of the University of Pennsylvania Health System. Vaccine effectiveness (VE) for 2 doses of Pfizer was 41% (95% CI −17% to 87%) during the Omicron period and 75% (95% CI 52% to 87%) during the Delta period. VE for 3 doses of Pfizer was 54% (95% CI 23% to 73%) during the Omicron period and 93% (95% CI 78% to 98%) during Delta period [Richterman A, 2022 ].

Butt AA et al was a retrospective study conducted in United States that included data from 2,165,107 individuals. 395 686 participants were matched who received a third dose of the same ARNm vaccine. This study  assessed effectiveness of a third dose against symptomatic infection, hospitalization, and intensive care unit (ICU) admission or death after SARS-CoV-2–positive test. Vaccine effectiveness against Symptomatic infection for the third dose of Pfizer vaccine (in comparisson with 2 doses) was 84% (95% CI 78 to 88). Vaccine effectiveness against hospitalization (3 versus 2 doses) was 77% (95% CI 65 to 85) [Butt AA, 2022 ].

Zee ST et al, was a retrospective study was performed to compare the rate and outcome of COVID-19 in healthcare workers with various vaccination regimes during a territory-wide Omicron BA.2.2 outbreak in Hong Kong between 1 February to 31 March 2022 . The study included 3167 healthcare workers.  Compared two-dose vaccination, three-dose vaccination reduced infection risk by 31.7% and 89.3% in household contact and non-household close contact, respectively. Vaccine effectiveness against infections for Pfizer homologous booster dose was (HR 0.4778 p< 0.0001) [Zee ST, 2022 ]

Yan VKC et al was a case-control study conducted in Hong Kong. The study included 14, 984 participants to evaluate the risk of severe complications following 1-3 doses of BNT162b2 using electronic health records database. Cases were adults with their first COVID-19-related severe complications between 1 January and 31 March 2022. Booster dose vaccine effectiveness was  90.8% (95% CI: 83.4-94.9) in those aged ≥65, 94.3% (95% CI: 83.7-98.0)  in those aged 51-64 , 75.5% (95% CI: 38.9-90.2) in those aged 18-50 . The findings show that BNT162b2 vaccination were effective against COVID-19-related severe complications against the Omicron BA.2 [Yan VKC, 2022 ]

Ng OT et al was cohort study conducted in Singapore. The study included 2,441,581 eligible individuals. It was based on data from the Singapore Ministry of Health’s (MOH) official COVID-19 database, including individuals who had received 2 or 3 doses of mRNA vaccines (by Pfizer-BioNTech or Moderna) or inactivated vaccines (by Sinovac or Sinopharm) and notified infections from December 27th 2021 to March 10th 2022. Effectiveness of booster dose against COVID Infeccion was 31.7% (95% CI 30.0 to 33.4) and 85.2% (95% CI 80.2 to 88.9) against Severe COVID Infeccion. [Ng OT, 2022 ]

Wan EYF was a case-control study conducted in China. The study included 82,587 cases of COVID-19 infection, 10,241 COVID-19 related hospital admission cases, 539 cases of ICU admission and 135 cases of post-infection incident. This study evaluated the vaccine effectiveness (VE) of each dose of BNT162b2 and CoronaVac against any COVID-19 infection, COVID-19-related hospital admission, ICU admission, and incident cardiovascular disease (CVD) in the Hong Kong Hospital Authority outbreak dominated by Omicron BA.2 sublineage. Vaccine effectiveness against COVID-19 infection was -0.3% (95% CI -2.7 to -2.1) with 2 doses of CoronaVac, 22.1% (95% CI 20.0 to 24.2) with 2 doses of Pfizer, 19.8% (95% CI 17.2 to 22.3) with 3 doses of CoronaVac, 54.2% (95% CI 52.4 to 55.9) with 3 doses of Pfizer, 12.1% (-15.8 to 33.3) with Pfizer primary schedule and CoronaVac booster, and 39.9% (95% CI 36.6 to 42.9) with CoronaVac primary schedule and Pfizer booster. Vaccine effectiveness against COVID-19 hospitalization was 64.2 (95% CI 61.8 to 66.4) with 2 doses of CoronaVac, 74.2 (95% CI 71.7 to 76.4) with 2 doses of Pfizer, 85.4% (95% CI 83.2 to 87.3) with 3 doses of CoronaVac, 91.4% (95% CI 89.5 to 92.9) with 3 doses of Pfizer and 89.5% (95% CI 85.9 to 92.2) with CoronaVac primary schedule and Pfizer booster. [Wan EYF, 2022 ].

Lin DY et al was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. Based on data from the North Carolina COVID-19 Surveillance System and the COVID-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Vaccine effectiveness of the Pfizer homologous booster was 61.2% (95%CI  60 to 62.4) after 1 month [Lin DY, 2022 ].

Risk M et al was a retrospective cohort study conducted in the United States including 168,414 participants: 133,238 vaccinated with mRNA vaccines and 35,176 unvaccinated. Based on data from the Michigan Medicine healthcare system, the Michigan State Registry and chart-reviewed COVID-19 hospitalization data. Including patients 18 years old and above, who received mRNA based COVID-19 vaccines. During the Omicron dominant period December 2021 to March 2022. The effectiveness of the Pfizer-BioNtech vaccine during the Omicron period in immunocompetent participants was −6%(95% CI –14 to 4) for two doses and 35%(95% CI, 29 to 41) for three doses. In immunocompromised participants the effectiveness was 13% (95% CI –19 to 39) for two doses and 50% (95% CI 31 to 64) for three doses [Risk M, 2022 ].

Monge S et al was a nationwide cohort study conducted in Spain. This study included 7,036,433 participants older than 40 years: 3,111,159 in the booster group and 3,111,159 in the no-booster group. The aim of this study was to estimate the effectiveness of mRNA-based vaccine boosters against infection during the period of the predominance of the omicron variant in Spain. The vaccine effectiveness of Pfizer booster after AstraZeneca, Janssen, Moderna, or Pfizer primary schedule was 46.2% (95% CI 43.5–48.7). Vaccine effectiveness of an mRNA booster (Pfizer or Moderna) following a Pfizer primary schedule was 49.7% (95% CI, 48.3–51.1) [Monge S, 2022 ].

Stowe et al. conducted a test-negative case-control study in UK, to estimate Vaccine Effectiveness (VE) against hospitalization with the Omicron and Delta variants using PCR testing linked hospital records (Emergency Care Data Set; ECDS). The total number of tests in the study period was 409,985 of which 115,720 were cases and 294,265 controls. Vaccine effectivenes against hospital admissions from ECDS within 14 days of the test date by the Omicron variant in symptomatic individuals 18 to 64 years of age, 82.8% (95% CI 78.4-86.3) after 14-34 days, 67.7% (95% CI 58.2-75.0) after 105+ days. Vaccine effectiveness against hospital admissions from ECDS within 14 days of the test date by the Omicron variant in symptomatic individuals 65 years of age and older, 97.4% (95% CI 92.8-99.1) after 14-34 days and 88.0% (95% CI 83.4-91.4) after 105+ days.
[Stowe J, 2022 ]

Chiew CJ et al was a national cohort study conducted in Singapore. This study assessed the incidence of confirmed SARS-CoV-2 infection and hospitalization among adolescents aged 12–17 years vaccinated with BNT162b2 from Sept 1 to Dec 15, 2021, during the delta variant wave, and from Jan 21 to April 28, 2022, during the omicron variant wave. Adjusted vaccine effectiveness against Confirmed SARS-CoV-2 infection during delta variant wave was 0.66% (95% CI, 0.63-0.69). Vaccine effectiveness against hospitalization during delta variant wave was 0.83 (95% CI, 0.74-0.89). Adjusted vaccine effectiveness against Confirmed SARS-CoV-2 infection during omicron variant wave was 0.25% (95% CI, 0.21-0.29) with 2 doses and 0.56 (95% CI 0.53-0.58) with homologous booster dose. Vaccine effectiveness against hospitalization during omicron variant wave was 0.75 (95% CI, 0.56-0.86) and 0.94 (95% CI, 0.86-0.97) with homologous booster dose. [Chiew CJ, 2022 ]

Ferdinands JM et al was a test-negative case-control study conducted in United States. The study included data from 259,006 hospital admissions: 213,103 with SARS-CoV-2 negative test and 45,903 with SARS-CoV-2 positive test. The main outcome was waning of vaccine effectiveness with BNT162b2 or mRNA-1273 vaccine during the omicron and delta periods. Vaccine effectiveness (VE) against COVID-19-associated hospitalizations during the Omicron-predominant period for Pfizer vaccine was 63% (95% CI, 46-74) (less than two months after the second dose) and 88% (95% CI, 86-90) with the third booster dose. Vaccine effectiveness (VE) against COVID-19-associated hospitalizations during the Delta-predominant period for Pfizer vaccine was 95% (95% CI, 93-96) (less than two months after the second dose) and 95% (95% CI, 94-96) with the third booster dose. [Ferdinands JM, 2022 ]

Tartof et al was a case-control, test-negative study conducted in the United States, based on data from the Kaiser Permanente Southern California (KPSC), which is a large, integrated healthcare system. The study included 16,994 participants: 10,620 cases and 8,503 controls. Eligible patients were admitted to one of 15 KPSC hospitals or Emergency Departments between December 27th 2021, and June 4th 2022. The effectiveness of the Pfizer-BioNTech booster vaccine against BA.1 variant was 79% (95% CI, 74% to 83%) against hospital admission, for Emergency Department admission the effectiveness was 72% (95% CI, 67% to 77%). Effectiveness against BA.2 variant was 71% (95% CI, 55% to 81%) for 3 doses against hospital admission and the effectiveness against Emergency Department admission was 21% (95% CI, 1% to 37%). [Tartof SY, 2022 ]

Agrawal et al was a retrospective cohort study conducted in the United Kingdom that study included 16,208,600 participants, of which 7,589,080 received a Pfizer-BioNTech primary schedule and 8,619,520 received a ChAdOx1 primary schedule. The study was based on data from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database, Vaccine Management System, Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II), and Secure Anonymised Information Linkage Databank platform, during the Omicron period between December 2021 and February 2022. The adjusted Rate Ratio (aRR) 3-5 weeks after booster vaccination against hospitalization was 0.33 (95% CI, 0.28-0.38). [Agrawal U, 2022 ]

Mehta HB et al was a retrospective cohort study conducted in the United States that included 3,940,475 boosted individuals and 3,940,475 controls. Based on data from Medicare beneficiaries who received 2 doses of the Pfizer vaccine or 2 doses of the Moderna vaccine as the primary vaccination series from December 11th 2020 to December 31st 2021. The vaccine effectiveness against hospitalization of an mRNA booster dose after an mRNA primary schedule was 81% (95% CI, 80% to 82%). [Mehta HB, 2022 ]

Wan EYF was a case control study conducted in China that included data from 78,326 individuals: 7,293 deaths related to COVID-19 and 71,033 controls. This study analyzed data available between January and March 2022 from the electronic health databases in Hong Kong and enrolled individuals aged 60 or above. Vaccine effectiveness against COVID-19 infection (60-79 years old) was 20.3% (95% CI, 18.4% to 22.1%), 50.9% (95% CI, 49.6% to 52.1%), -2.9% (95% CI, -24.0% to 14.6%) and 30.9% (95% CI, 28.5% to 33.2%) for 2 Pfizer doses schedule, 3 Pfizer doses schedule, Pfizer primary schedule with CoronaVac booster and CoronaVac primary schedule with Pfizer booster schedule, respectively. Vaccine effectiveness against COVID-19-related hospitalization was 74.9% (95% CI, 72.6% to 77.0%), 91.4% (95% CI, 90.1% to 92.5%), 87.4% (95% CI, 59.6% to 96.1%) and 86.9% (95% CI, 84.3% to 89.1%) for 2 Pfizer doses schedule, 3 Pfizer doses schedule, Pfizer primary schedule with CoronaVac booster and CoronaVac primary schedule with Pfizer booster schedule, respectively. [Wan EYF, 2022 ]

Tartof SY et al was a case-control study with a test-negative design conducted in the United States that enrolled 24,356 participants, including 12,566 boosted individuals, 5,997 with the primary schedule and 5,793 unvaccinated individuals. The study was based on data from Kaiser Permanente, a health insurance provider from Southern California, including participants vaccinated with Pfizer-BioNTech and unvaccinated controls. This study analyzed data from May to August 2022 during the Omicron BA.4/5 outbreak. The adjusted effectiveness of 3 Pfizer-BioNTech doses was 50% (95% CI, −1% to 76%) against hospitalization, 39% (95% CI, 14% to 57%) against emergency department admission and 17% (95% CI, 7% to 26%) against outpatient care. The effectiveness of 4 Pfizer doses was 60% (95% CI, 11% to 82%) against hospitalization, 69% (95% CI, 44% to 83%) against emergency department admission and 25% (95% CI, 7% to 39%) against outpatient care. [Tartof SY, 2022 ]

Baum U et al was a cohort study conducted in Finland, the study included 896,220 participants aged 70 years and older. The study was based on a nationwide register-based cohort, starting on December 27th 2020 and ending on March 31st 2022. Vaccine effectiveness of the booster against hospital admission was 95% (95% CI, 94% to 96%) and 98% (95% CI, 95% to 99%) against ICU admission. [Baum U, 2022 ]

Saito Y et al was a cohort study conducted in Japan that included 1,835 adolescents between 13-18 years. Participants received a homologous booster dose of Pfizer between April and May 2022. The relative effectiveness of a booster dose of Pfizer-BioNTech in adolescents during the Omicron predominance period compared with the primary schedule was 86.4% (95% CI, 57.2% to 95.7%). [Saito Y, 2022 ]

Yuanyuan F et al. conducted an observational study to analyze vaccination status and SARS-CoV-2 infection data from more than 10.4 million participants in the national COVID Cohort Collaborative during an 18-month-period (December 2020 to June 2022) in the United States. Vaccine Effectiveness for a Pfizer homologous booster against COVID-19 infection was 36.98% (95% CI, 36.20% to 37.76%), and 84.43% (95% CI, 83.50% to 85.32%) against COVID-19-related death. [Yuanyuan Fu, 2022 ]

Anne J. Huiberts et al was a prospective cohort study conducted in Netherlands that included 27,646 participants from the Omicron period: 3,802 received primary vaccination schedule, 23,352 received first booster dose and 492 were unvaccinated. The primary outcome was contracting SARS-CoV-2 between July 12th 2021 and June 6th 2022. Vaccine effectiveness (VE) against contracting COVID-19 during the Omicron BA.1-2 period was 45% (95% CI, 20.3% to 62.1%), 51.1% (95% CI, 44.1% to 57.3%) and 58.4% (95% CI, 48.8% to 66.1%) for Pfizer primary schedule, mRNA primary schedule with Pfizer booster and AstraZeneca primary schedule with Pfizer booster, respectively. VE against contracting COVID-19 during the Delta period was 81.3% (95% CI, 69.2% to 88.6%), 97.4% (95% CI, 81.2% to 99.6%) and 90.9% (95% CI, 34% to 98.8%) for Pfizer primary schedule, mRNA primary schedule with Pfizer booster and AstraZeneca primary schedule with Pfizer booster, respectively. [Anne J. Huiberts, 2023 ]

Cerqueira-Silva T et al was a case-control study, test-negative design, conducted in Brazil and Scotland. The study included 5,832,210 participants: 5,276,385 from Brazil and 555,825 from Scotland. This study assessed vaccine effectiveness of a mRNA booster after AstraZeneca or Pfizer primary schedule during the period of Omicron dominance. Vaccine effectiveness against severe outcomes was 93.5% (95% CI, 93% to 94%), 94.4% (95% CI, 87.7% to 97.5%) and 92.7% (95% CI, 91% to 94%) with AstraZeneca primary schedule and Pfizer booster, AstraZeneca primary schedule and Moderna booster and Pfizer homologous booster, respectively. [Cerqueira-Silva T, 2023 ]

Lai F et al was a cohort study conducted in China that included 248,042 participants: 33,435 with 2 doses of Pfizer, 87,289 with 3 doses of Pfizer, 32,341 with 2 doses of CoronaVac and 94,977 with 3 doses of CoronaVac. The aim was to compare the effectiveness of the primary schedule against homologous booster dose. Among Pfizer recipients, booster vaccinated people had fewer COVID-19– related deaths than those who received 2 doses incidence rate ratio was 0.05 (95% CI, 0.02–0.16). Among CoronaVac recipients, booster vaccinated people had fewer COVID-19– related deaths than those who received 2 doses Incidence rate ratio was 0.08 (95% CI, 0.05–0.12). [Lai FTT, 2023 ]

Weng C et al was a comparative study conducted in United States that included 38,602 participants: 22,247 with at least one SARS-CoV-2 PCR test. The aim was to assess mRNA vaccine effectiveness (VE) in preventing SARS-CoV-2 infections. Adjusted VE of 2 doses of Pfizer was  94.6% (95% CI, 83.4% to 98.3%). Adjusted VE against Omicron (2 doses of Pfizer) was 31.6% (95% CI, 19.6% to 42.5%). Adjusted VE against Omicron (3 doses of Pfizer) was 79.9% (95% CI, 44.3% to 93.5%). [Weng CH, 2023 ]

Kamal SM et al was a comparative cohort study conducted in Saudi Arabia that included data from 1500 vaccinated participants: 503 AstraZeneca, 521 Pfizer, and 476 Moderna, and 1500 in the control group. The aim was to assess the effectiveness of the AstraZeneca, Pfizer and Moderna vaccines and two Pfizer boosters. Relative risk of infection after the first booster was 0.014 (95% CI, 0.0044-0.0425). [Kamal SM, 2023 ]

Maeda H et al was a case-control study (test-negative design) conducted in Japan that included data from 7,931 participants: 3,055 test-positive cases and 4,876 test-negative cases. The aim was to assess vaccine effectiveness of primary and booster vaccination against symptomatic SARS-CoV-2 infections during the Omicron outbreak. Vaccine effectiveness was 67.1% (95% CI, 56.6 to 75.1%), 69.9% (95% CI, 49.3% to 82.2%) and 75.7% (95% CI, 57.7% to 86.0%) for Pfizer homologous booster, Pfizer primary schedule and Moderna booster, and Moderna homologous booster, respectively. [Maeda H, 2023 ]

dos Santos et al was a comparative cohort study conducted in Brazil that included data from 108,625,066 booster-vaccinated participants. The aim was to assess the effectiveness of the primary series of COVID-19 vaccination and booster shots in protecting against severe cases. Vaccine effectiveness against severe outcomes were 66.5% (95% CI, 62.8% to 70.0%), 73.0% (95% CI, 67.8% to 77.6%), 39.9% (95% CI, −15.3% to 77.2%) and 82.4% (95% CI, 63.2% to 93.7%) for AstraZeneca primary schedule and Pfizer booster, CoronaVac primary schedule and Pfizer booster, Pfizer primary schedule and AstraZeneca booster and Janssen primary schedule and Pfizer booster, respectively. Vaccine effectiveness against severe outcomes were 81.1% (95% CI , 80.3% to 81.9%), 84.7% (95% CI, 83.7% to 85.5%), 70.7% (95% CI, 66.9% to 74.2%) and 90.3% (95% CI, 89.5% to 91.0%) for AstraZeneca, CoronaVac, Janssen and Pfizer, respectively. [Santos CVBD, 2023 ]

Vaccine efficacy and effectiveness for heterologous schedule

Immunogenicity outcomes
Com-COV was a multi-center single-blind phase II randomized parallel study. The trial included 830 healthy adults 50 years and older: 115 Pfizer/ AstraZeneca vaccine; 114 ​​AstraZeneca/ Pfizer vaccine group; 234 Control group (Two doses of AstraZeneca or Pfizer COVID-19 vaccine). Immunogenicity was measured at anti-SARS-CoV-2-spike binding antibody (bAb) levels 28 days following the second dose. Results showed SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher versus homologous vaccine schedules [Liu X, 2021 ].

Com-Cov was an open-label randomized controlled trial that included 664 participants. Participants were divided into two groups: one group received the primary schedule with a 14-week interval between doses (83 participants received a ChAd-ChAd schedule, 83 ChAd-BNT schedule, 84 BNT-BNT schedule, and 83 BNT-ChAd schedule) and the other group received the primary schedule with a 12-week interval between doses (89 received ChAd-ChAd schedule, 77 ChAd-BNT schedule, 81 BN-BNT schedule and 78 BNT-ChAd schedule). The aim of the study was to assess the effect of priming interval on humoral response 28 days and 6 months post-second dose. Anti-spike IgG (ELU/mL) at 28 days after the second dose for the 4-week interval study groups were 1,444 (95% CI, 1,205−1,732), 12,979 (95% CI, 11,217−15,018), 14,349 (95% CI, 12,470−16,511) and  7,530 (95% CI, 6,811−8,325) for ChAd-ChAd schedule, ChAd-BNT schedule, BNT-BNT schedule, and BNT-ChAd schedule, respectively. Anti-spike IgG (ELU/mL) at 28 days after the second dose for the 12-week interval study groups were 2,622 (95% CI, 2,152−3,195), 13,465 (95% CI, 11,391−15,917), 19,011 (95% CI, 16,468−21,947) and 10,642 (95% CI, 8,936−12,673) for ChAd-ChAd schedule, ChAd-BNT schedule, BNT-BNT schedule, and BNT-ChAd schedule, respectively [Shaw RH, 2022 ].

CombiVacS was a phase 2, open-label, randomized, controlled trial. The trial included 676 adults aged 18-60 years: 450 Intervention group (ChAd/BNT ); 226 Control group. Immunogenicity was measured 14 days following the second dose. BNT162b2 given as a second dose in individuals prime vaccinated with ChAdOx1-S induced a robust immune response  [Borobia AM, 2021 ].

ComFluCOV was a phase 4, randomized controlled trial. The trial included 679 volunteers aged ≥ 18 years: 139 Pfizer /QIVc group; 79 Pfizer/ aTIV group; 58 Pfizer/ QIVr group; 129 AstraZeneca /QIVc group; 146 AstraZeneca /aTIV group; 128 AstraZeneca /QIVr group. Immunogenicity was measured 21 days after receiving Pfizer COVID-19 vaccine. Results showed concomitant vaccination with Pfizer COVID-19 vaccine plus an age-appropriate influenza vaccine raises antibody responses [Lazarus R, 2021 ].

COV-ADAPT was a prospective cohort study conducted in Germany. The study assessed the immune response elicited by the use of heterologous and homologous vaccine schedules of Pfizer and AstraZeneca vaccines and included 382 participants 18 to 65 years old who received either 2 doses of Pfizer COVID-19 vaccine or 2 doses of AstraZeneca Covid-19 vaccine or 1 dose of each one. The study measured the neutralizing antibody levels and T-cell responses from blood samples taken up to 2 weeks prior to the second dose and 2 weeks to 3 months after the second dose. Results showed an increase in neutralizing antibody titers that were higher in the participants who received the Pfizer vaccine. After the first dose, all groups had similar T-cell responses, however, the Pfizer vaccine as a second dose yielded a significant increase in T-cell responses while the AstraZeneca vaccine generated no booster effect [Hollstein MM, 2022 ].

Nickel O et al. was a prospective cohort study conducted in Germany. The study compared antibody production against the S1 subunit and the RBD of the spike protein, the whole virion of SARS-CoV-2, and monitored neutralizing antibodies in sera and saliva of 104 participants vaccinated with Pfizer-BioNTech, 57 individuals with natural SARS-CoV-2 infection, and 11 participants who received a heterologous AstraZeneca/Pfizer schedule. After the first dose, the AstraZeneca cohort showed similar neutralizing titers compared to the Pfizer recipients. However, after the second dose neutralizing antibody levels were 4 times higher than for the homologous Pfizer group. No mucosal antibodies were detected two weeks after the second dose for any of the vaccine recipients while COVID-19 patients had detectable levels 15-30 days after symptoms onset [Olaf Nickel, 2022 ].

Niyomnaitham et al. was a comparative study conducted in Thailand. The study recruited 210 participants equally divided (n=30) to receive Sinovac, AstraZeneca and Pfizer-BioNTech vaccines either as a first or second dose. Participants who received only Sinovac or AstraZeneca first and second doses also received a booster dose with Pfizer-BioNTech. The study found antibody levels were highest among the groups that received Pfizer-BioNTech as a second dose, levels were similar between homologous and heterologous regimens. These levels were significantly higher compared with the groups who received AstraZeneca or Sinovac as a second dose.  The groups who were given Pfizer-BioNTech as second dose had significantly higher neutralizing titers against Delta and Beta than the groups that received AstraZeneca or Sinovac as the second dose. Neutralizing titers against the Beta variant were reduced by 2 to 5-fold compared to the Delta variant. Overall, neutralization against Omicron was low across the groups and were 28- to 229-fold lower than Delta, depending on the vaccine schedules. Neutralization against both the Delta and Omicron variants were significantly lower among groups who received Sinovac as a second dose compared to the other groups. Seropositivity rate for the Omicron variant was : 80% (45/56), 50% (30/60) and 21% (21/58) for the groups that received  Pfizer-BioNTech, AstraZeneca and: Sinovac as a second dose respectively [Suvimol Niyomnaitham, 2022 ].

García-Pérez et al was a secondary analysis of the CombiVac study. It was a phase 2 randomized controlled trial conducted in Spain. The study included 676 adults: 441 in the interventional group and 223 in the control group. Subjects primed with ChAdOx1-S were randomized to receive BNT162b2 as second dose or no vaccine. Subjects from the control group received BNT162b2 as second dose and also on day 28, as planned based on favorable results on day 14. At day 28 post vaccine, geometric mean titres (GMT) of RBD antibodies were 5616.91 BAU/mL (95% CI 5296.49–5956.71) in the IG and 7298.22 BAU/mL (6739.41–7903.37) in the CG (p < 0.0001). RBD antibodies titres decreased at day 180 (1142.0 BAU/mL [1048.69–1243.62] and 1836.4 BAU/mL [1621.62–2079.62] in the IG and CG, respectively; p < 0.0001). Neutralizing antibodies also waned from day 28 to day 180 in both the IG (1429.01 [1220.37–1673.33] and 198.72 [161.54–244.47], respectively) and the CG (1503.28 [1210.71–1866.54] and 295.57 [209.84–416.33], respectively). The lowest variant-specific response was observed against Omicron-and Beta variants, with low proportion of individuals exhibiting specific neutralizing antibody titres (NT50) >1:100 at day 180 (19% and 22%, respectively) [José Alcamí Pertejo, 2022 ].

ARNCOMBI was a randomized controlled trial conducted in France. The study included 414 individuals who received a first dose mRNA vaccine and a second dose of Pfizer-BioNTech or Moderna after 28 days. The primary outcome was to compare the immune response generated by the homologous Pfizer-BioNTech schedule to Pfizer-BioNtech/Moderna schedule. The titers of the anti-spike antibodies were higher in the BNT162b2/mRNA-1273 group with a geometric mean of 3706.1 (95% CI, 3201.5 to 42903) versus 2697.9 (95% CI, 2277.6 to 3195.7) for BNT162b2/BNT162b2. No difference was demonstrated on anti-spike antibodies between the BNT162b2/mRNA-1273 group (geometric mean, 3706.1; 95% CI, 3201.5 to 4290.3) and mRNA1273/BNT162b2 group (geometric mean, 2689.9; 95% CI, 2296.2 to 3151.1) groups. [Janssen C, 2022 ].

García-Pérez J was a randomized clinical trial conducted in Spain. The study included 676 adults primed with ChAdOx1-S. 441 participants were randomized to the intervention group and received Pfizer as a second dose and 223 participants were randomized to the control group and did not receive a second vaccine. Humoral immunogenicity, measured by immunoassay for SARS-CoV-2 receptor binding domain (RBD), antibody functionality using pseudovirus neutralization assays for the reference (G614), Alpha, Beta, Delta, and Omicron variants, as well as cellular immune response using interferon-g and IL-2 immunoassays, were assessed at day 28 after BNT162b2 in both groups, at day 90 (planned only in the interventional group) and at day 180. At day 28 post-vaccine, geometric mean titres (GMT) of RBD antibodies were 5616.91 BAU/mL (95% CI 5296.49−5956.71) in the IG and 7298.22 BAU/mL (6739.41−7903.37) in the CG (p < 0.0001). RBD antibody titers decreased at day 180 (1142.0 BAU/mL [1048.69−1243.62] and 1836.4 BAU/mL [1621.62−2079.62] in the IG and CG, respectively [García-Pérez J, 2022 ].

Bánki Z et al was a randomized clinical trial conducted in Austria. The study included 234 participants between 18 and 65 years with no prior history of SARS-CoV-2 infection and a first dose of AZ or BNT were included. The AZ/AZ and the AZ/BNT arms were randomized, the third arm (BNT/BNT) was observational. 116 participants received AstraZeneca as second dose and 118 Pfizer as second dose. This study compared the reactogenicity between the study groups and immunogenicity for the heterologous AZ/BNT compared to the homologous AZ/AZ regimen using neutralizing antibody titers as primary endpoint. The antibody levels after the boost vaccination were statistically significant higher in the heterologous AZ/BNT group than in the homologous AZ/AZ group (p<0.0001). Median IgG titers for AZ/BNT were 2538 BAU/ml (95% CI 2217 - 3045) at day 10 and 1478 BAU/ml (95% CI 1234 - 1826) at day 30 [Bánki Z, 2022 ].

Puthanakit T et al was a phase 2 randomized clinicla trial conducted in Thailand. The study included 80 participants  aged 12 to < 18 years without previous SARS-CoV-2 vaccination. Participants were randomized to be vaccinated with CoronaVac (SV) 3 ug as the first dose followed by BNT162b2 30 µg or 20 µg as the second dose, at 3-week (3w) or 6-week interval (6w). During the Omicron-predominant period, participants were offered a BNT162b2 booster dose 30, 15, or 10 µg. Immunogenicity was determined using IgG antibody against spike-receptorbinding domain of wild type(anti-S-RBD IgG) and surrogate virus neutralization test(sVNT) against Delta variant at 14 days and 5 months after the 2nd dose. Neutralization tests(sVNT and pseudovirus neutralization test; pVNT) against Omicron strain were tested pre- and 14 days post-booster dose.  At day 14, the geometric mean(GM) of anti-S-RBD IgG in SV3w/PZ30lg was 4713 (95 %CI 4127–5382) binding-antibody unit (BAU)/ml, while geometric mean ratio(GMR) was 1.28 (1.09–1.51) in SV6w/PZ30lg. The GMs of sVNT against Delta variants at day 14 among participants in SV3w/PZ30lg and SV6wk/PZ30lg arm were 95.3 % and 99.7 %inhibition, respectively. [Puthanakit T, 2022 ]

Niyomnaitham S et al was a randomized clinical trial conducted in Thailand. This study evaluated the immunogenicity and reactogenicity of heterologous COVID-19 primary schedules in healthy adults, as well as booster response to BNT162b2 following heterologous CoronaVac and ChAdOx1 nCoV-19 regimens. 210 adults participated in the study: 30 with CoronaVac/AstraZeneca primary schedule, 30 with CoronaVac/Pfizer, 30 with AstraZeneca/CoronaVac, 30 with  AstraZeneca/Pfizer, 30 with Pfizer/CoronaVac, 30 with Pfizer/AstraZeneca and 30 with Pfizer/Pfizer. At 2 weeks after the second dose, the anti-RBD IgG levels were  2181.8 BAU/mL (95%CI 1558.2 to 3055.1) for CoronaVac/Pfizer schedule, 2132.7 BAU/mL (95%CI 1696.1 to 2,681.7) for AstraZeneca/Pfizer schedule, 2248.8 BAU/mL (95% CI 1691.3 to 2,990.0) for Pfizer/Pfizer schedule, 851.4 BAU/mL (95% CI 649.5 to 1116.1) for CoronaVac/AstraZeneca schedule, 1201.2 BAU/mL (95%CI 947.9 to 1522.1) for Pfizer/AstraZeneca schedule, 137.04 BAU/mL (95% CI 103.6 to 186.4) for AstraZeneca/CoronaVac schedule and 225.2 BAU/mL (95% CI 177.1 to 286.4) for Pfizer/CoronaVac schedule. [Niyomnaitham S, 2022 ]

Fernández-Ciriza et al. conducted a prospective study enrolling 709 healthcare workers receiving two doses of mRNA-1273, BNT162b2, ChAdOx1, ChAdOx1/BNT162b2 or ChAdOx1 single dose to compare humoral and cellular immunogenicity across 9 months. The mean age was 44 ± 11 years old and 85.9% were women. At 21 and 90 days after the second dose, mRNA-1273/mRNA-1273 and ChAdOx1/BNT162b2 were the most highly immunogenic schedules among COVID-19 naïve individuals, and ChAdOx1/ChAdOx1 yielded the lowest level of Anti-S-RBD up to 6 months after the second dose. The half-life of anti-S-RBS antibody concentration in those participants who received ChAdOx1/BNT162b2 was 36 days. For those who received ChAdOx1/BNT162b2 combinations, cellular immunity was found in 92.3%, after 6-months, among COVID-19 naïve participants. All tests to assess cellular immunity among individuals with a previous infection were reactive. [Fernández-Ciriza L, 2022 ]

Alfouzan W et al was a cross sectional study conducted in Kuwai that included data from 19,363 participants in the pre-vaccination period and 4,973 participants in the post-vaccination period. The aim was to assess pre-vaccination and post-vaccination seroprevalences of anti-SARS-CoV-2 antibodies. SARS-CoV-2 seroprevalence in the post-vaccination period in general population with AstraZeneca/Pfizer primary schedule was 95.86% (95% CI, 76.39% to 99.11%). [Alfouzan W, 2023 ]

Effectiveness outcomes
Suphanchaimat R et al was a test-negative case-control study conducted in Thailand. The study included 1,460,458 participants: 482,372 cases and 978,086 controls aimed to explore the vaccine effectiveness (VE) of various schedules against the SARS-CoV2 Delta variant in Thailand during September–December 2021. VE against any infection according to vaccine regimens was: 62.4% (95% CI 59.4 to 65.1) for BNT162b2 + BNT162b2, 88.7% (95% CI 85.6 to 91.1) for ChAdOx1 + BNT162b2, 82.3% (95% CI 74.3–87.7) and 94.0% (95% CI 93.4 to 94.6) for CoronaVac + BNT162b2. [Suphanchaimat R, 2022 ]

Chung et al. was a case-control study with a test-negative design to estimate vaccine effectiveness (VE) against SARS-CoV-2 infection after the primary schedule of any combination of BNT162b2, mRNA-1273, and ChAdOx1 between January 11th and November 21st 2021 in Ontario, Canada. It included 261,360 test-positive cases (of any SARS-CoV-2 lineage) and 2,783,699 individuals as test-negative controls. VE for ChAdOx1/BNT162B2 7-59 days after second dose was 89% (95% CI, 87% to 91%) against any infection, 95% (95% CI, 92% to 97%) against symptomatic infection and 98% (95% CI, 94% to 99%) against severe outcomes (hospitalization/death). VE ChAdOx1/BNT162B2 120-179 days after second dose was 77% (95% CI, 73% to 80%) against any infection, 89% (95% CI, 86% to 91%) against symptomatic infection and 98% (95% CI, 96% to 99%) against severe outcomes (hospitalization/death). [Chung H, 2022 ]

Castelli JM et al was a test-negative case-control study conducted in Argentina that included 844,460 children and adolescents without previous SARS-CoV-2 infection eligible to receive a primary vaccination schedule. The aim was to assess the effectiveness of different combinations of mRNA vaccines in children and adolescents. Vaccine effectiveness for a heterologous Pfizer/Moderna schedule was 88.9% (95% CI, 66.1% to 96.4%) during the Delta predominance period, and 40.6% (95% CI, 29.4% to 50.0%) during the Omicron predominance period. [Castelli JM, 2022 ]

Yuanyuan F et al. was an observational study to analyze vaccination status and SARS-CoV-2 infection data from more than 10.4 million participants in the national COVID Cohort Collaborative during an 18-month-period (December 2020 to June 2022) in the United States. Vaccine effectiveness for a Moderna/Pfizer heterologous schedule against COVID-19 infection was 35.17% (95% CI, 31.71% to 38.50%). [Yuanyuan Fu, 2022 ]

Nittayasoot et al was a test negative case-control study to examine the effectiveness of COVID-19 vaccines during January to April 2022 in Thailand. They analyzed secondary data from four main national health data bases: Co-Lab, Co-Ward, COVID-10 Death and MOPH-IC, using the national identification numbers of each individual as a unique identifier to link the same person across databases. They obtained a total of 3,059,616 records including: 1,015 cases of COVID-19 pneumonia requiring invasive ventilation from 652,854 cases with SARS-CoV-2 detection and 2,046,762 controls or non-SARS-CoV-2 detection. Vaccine Effectiveness against pneumonia requiring invasive ventilation for schedule: Coronavac + Pfizer was 79.79% (95% CI, 7.36% to 95.59%) and ChAdOx1 + Pfizer was 83.18% (95% CI, 62.37% to 92.48%). [Nittayasoot N, 2022 ]

Vaccine efficacy and effectiveness for heterologous booster schedule

Immunogenicity outcomes
Tobudic S et al. was a clinical trial that evaluated the efficacy and safety of a booster dose in patients in whom seroconversion did not occur after the second dose. The additional booster dose was delivered with the AstraZeneca or mRNA vaccines against COVID-19. Efficacy was measured by the difference in the SARS-CoV-2 antibody seroconversion rate between patients vaccinated with the AstraZeneca vaccine (heterologous) and the mRNA vaccines (homologous) at the fourth week. The results demonstrated that seroconversion rates at week four were comparable between patients who received the AstraZeneca vaccine (6/27 patients, 22%) versus the mRNA vaccines (9/28, 32%) (p = 0, 6). Overall, 27% of the patients seroconverted; furthermore, no serious adverse events related to immunization were observed [Michael Bonelli, 2021 ].

COV-BOOST et al. was a clinical trial that evaluated the immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford–AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer–BioNtech, hereafter referred to as BNT). Efficacy was measured by neutralizing antibody titers at 28 days post-boost dose. The results demonstrated that all study vaccines boosted antibody and neutralizing responses after AstraZeneca/AstraZeneca initial course and all except one after Pfizer/Pfizer, with no safety concerns [Munro, Alasdair P S, 2021 ].

SWITCH  was a randomized trial sponsored by Erasmus Medical Center and conducted in the Netherlands between June 2021 to September 2022. Immunogenicity was assessed 28 days after homologous or heterologous booster vaccination. Results showed that Janssen COVID-19 vaccine and mRNA boosters vaccines were immunogenic in health care workers who had received a priming dose of the Janssen vaccine. In addition, the Moderna and Pfizer COVID-19 boosters vaccines led to higher T-cell responses than the Janssen COVID-19 booster vaccine. The immune response was 91.7% with the Moderna booster and 91.5% with the Pfizer booster; both performed better than the homologous booster (response, 72.7%) [Sablerolles RSG, 2022 ].

Angkasekwinai N et al. was a cohort study conducted in Thailand. Based on data from a single-center, tertiary care university-based hospital in Bangkok, between July to September 2021. Results showed that heterologous boosting vaccination with Pfizer following the Sinovac or AstraZeneca primary series is the most immunogenic against SARS-CoV-2 variants. A lower dose Pfizer may be used as a booster in settings with limited vaccine supply [ ].          

Andrews N et al. was a case-control study (Test-negative) conducted in United Kingdom. The study included 893,845 eligible tests in those aged 18 years and over. The objective was to estimate the effectiveness of the Pfizer and Moderna booster vaccines against symptomatic disease, hospitalization, and death in adults in England. The study results showed that the booster dose was associated with an absolute vaccine efficacy from 14-34 days after a Pfizer booster of 94.4% (95% CI 94.1 to 94.7) following either an AstraZeneca or Pfizer primary scheme in individuals 50 years and older. With a Moderna booster, absolute vaccine effectiveness was 97.0 (95% CI 96.0 to 97.8) after an AstraZeneca primary scheme and 94.8% (95% CI 92.7 to 96.3%) Pfizer primary scheme. [Andrews N, 2022 ].

mBoost was an open-label trial conducted in China. The study included 436 adults aged ≥30 years who had previously received two doses of an inactivated COVID-19 vaccine. The study assessed the immunogenicity and reactogenicity of a third dose of Pfizer COVID-19 vaccine in adults who had previously received two doses of inactivated COVID-19 vaccination. Study results showed that a third dose of Pfizer COVID-19 vaccine substantially increased antibody titers measured by the various assays. Mean ELISA levels increased from a OD of 0.3 to 2.1 , and mean sVNT levels increased from an inhibition of 17% to 96% [Nancy H. L. Leung, 2022 ].

Vargas L et al. was an immunogenicity study conducted in Chile. The study included blood samples from different individuals; healthcare personnel volunteers from Hospital La Florida, and adult healthy volunteers aged 18 years and over. The study analyzed the impact of the booster doses of Sinovac, Pfizer, or AstraZeneca COVID-19 vaccines, administered to individuals vaccinated with the two-dose scheme with CoronaVac six months earlier. The study results showed that two doses of Sinovac COVID-19 vaccine induce antibody titers against the SARS-CoV-2 ancestral strain which are lower in magnitude than those induced by the Pfizer vaccine. However, the response induced by Sinovac can be greatly potentiated with a heterologous booster scheme with Pfizer or AstraZeneca vaccines [Leonardo Vargas, 2022 ].

Cheng SMS et al. was an immunogenicity study conducted in China. The study included subsets of sera from 7 groups of vaccinated individuals, convalescent individuals, and individuals with breakthrough infections The study evaluated sera from vaccinated individuals with no evidence of prior COVID-19 infection 3-5 weeks after receiving two doses of Pfizer or two doses of Sinovac and individuals 3-5 weeks after receiving the third dose of Sinovac or a heterologous booster dose of Pfizer after two prior doses of Sinovac. The study results showed a markedly reduced serum antibody titres against the Omicron variant (GMT)<10 as compared to wild-type virus 3-5 weeks after two doses of Pfizer (GMT 218.8) or Sinovac COVID-19 vaccines (GMT 32.5). In addition, a Pfizer booster dose elicited Omicron PRNT50 titres ≥25.6 in 88% of individuals who previously received 2 doses of Pfizer and 80% of individuals who previously received Sinovac [Cheng SMS, 2022 ].

Pérez-Then E et al. was a cohort study conducted in Dominican Republic. The study included plasma samples from 101 adults who received a Pfizer booster after 2 doses of Sinovac. The study analyzed antibody levels and neutralizing activity of plasma samples taken after 2 doses of Sinovac COVID-19 vaccine after booster dose with Pfizer COVID-19 vaccine. The study results showed a 10.1 fold increase in neutralizing activity 28 days after the booster dose compared before the booster. However, this was not significantly different than the response obtained after a two-dose mRNA vaccination schedule (Pfizer or Moderna vaccine)[Pérez-Then E, 2022 ].

Biyan Zhang et al. was a cohort study conducted in Singapore. The study enrolled 52 participants and evaluated the levels of antibodies for Omicron variant and compared to the ancestral strain (Wuhan-Hu-1) and Delta variant, in four groups of volunteers receiving 1) Two doses of mRNA vaccines plus an mRNA vaccine booster (Homologous mRNA vaccine booster) 2) Two doses of inactivated virus vaccines plus an inactivated virus vaccine booster (Homologous inactivated virus vaccine booster) 3) Two doses of mRNA vaccines plus an inactivated virus vaccine booster (Heterologous inactivated virus vaccine booster) and 4) Two doses of inactivated virus vaccines plus an mRNA vaccine booster (Heterologous mRNA vaccine booster). The study results showed that only the mRNA vaccine booster was able to effectively increase the median levels of neutralizing capabilities against the Omicron variant (Group 1, median 90.45% [IQR 78.71-94.33%]; Group 4, median 77.85% [IQR 47.80-92.18%]) by 4.5-fold and 3-fold, respectively. Inactivated virus booster shot was unable to significantly increase the median levels of neutralizing capabilities against the Omicron variant regardless of whether the individuals received 2 priming doses of mRNA vaccines (Group 3, median 30.65% [IQR 19.98- 36.03%]) or 2 priming doses of inactivated virus vaccines (Group 4, median 26.80% [IQR 18.35- 36.15%]) [Biyan Zhang, 2022 ].

Yavlinksy et al was a prospective community cohort study conducted in England and Wales. The study evaluated the immune response generated by a booster dose of the Pfizer COVID-19 vaccine on Pfizer or AstraZeneca primary vaccination recipients. Yavlinsky et al included 8,680 adults aged 18 or older who received a Pfizer vaccine booster after either Pfizer or AstraZeneca primary vaccination. The study found the Pfizer booster dose increased peak antibody levels compared to after primary vaccination regardless of the primary regimen. For the Pfizer primary vaccination group anti S antibody levels increased from 2,386 U/mL (95%CI: 9,801-15,653) to 22,185 U/mL (95%CI: 21,406-22,990) after the booster dose. In the AstraZeneca group antibody levels increased from 1,192 U/mL (95%CI: 818-1735) to 19,203 U/mL (95%CI: 18,094-20,377) after the booster dose [Alexei Yavlinsky, 2022 ].

Kanokudom et al. recruited 222 adults with a complete CoronaVac regimen who received a booster dose of 15μg Pfizer-BioNTech vaccine (n=59), 50μg Moderna vaccine (n=51), standard Pfizer-BioNTech vaccine (n=54)or standard Moderna vaccine (n=58). The study found no significant differences in binding antibody levels between standard and reduced doses. 28 days after the booster dose binding antibody levels were 28,413 U/mL and 31,793 U/mL for the reduced and standard Pfizer-BioNTech vaccines respectively and 41,171 U/mL and 51,979 U/mL for the reduced and standard Moderna vaccines. Boosting elicited an increase in median IFN-γ CD4+ T cell and CD4+ CD8+ T cell counts; there were no differences in T cell counts between the standard and reduced dose groups. The booster dose induced a neutralizing response against the Delta and Omicron variants in previously seronegative participants that was not affected by dosage [Kanokudom S, 2022 ].

Poh et al. is an ongoing phase 4 randomized clinical trial, conducted in Singapore, assessing the humoral response elicited by homologous and heterologous booster vaccination regimens based on a primary regimen with Pfizer-BioNTech. Interim results of two groups have been published. The study recruited 100 participants who either received a Pfizer-BioNTech (n=51) booster or a Moderna booster (n=49). Results show a booster dose increases antibody titers in all participants by 35- to 49- fold at day 7 with only a modest increase by day 17. Antibody titers were higher in the Moderna group, particularly in the ≥60 years age subgroup. On day 28 antibody titers reached 29.751 (IC 95%: 25.281-35.011) UI/mL for the Moderna group and 22 382 (IC del 95 %: 18 210-27 517) UI/mL for the Pfizer-BioNTech group. Neutralization against the Omicron variant was higher in the Moderna group at day 7 but similar at day 28 [Xuan Ying Poh, 2022 ].

RHH-001 was a phase 4 randomized study, conducted in Brazil and El Salvador, that analyzed the immune response generated by homologous and heterologous booster vaccines based on a primary vaccination regimen with the Sinovac vaccine.  The study recruited 1240 participants randomly assigned to receive a booster dose with Janssen (n=306), Pfizer-BioNTech (n=340), AstraZeneca (n=304), and Sinovac (n=290) vaccines at least 6 months after the second dose. Results found all booster doses substantially increased binding and neutralizing antibody levels, the geometric fold-rise at day 28 post booster was 77 (67–88) for Janssen, 152 (134–173) for Pfizer-BioNTech, 90 (95% CI 77–104) for AstraZeneca, and 12 (11–14) for Sinovac. Heterologous booster regimens were superior to the homologous regimen with GMRs of 8.7 (5.9–12.9) for Janssen, 21.5 (14.5–31.9) for Pfizer-BioNTech, and 10.6 (7.2–15.6) for AstraZeneca. Neutralizing antibody titres were above the lower limit of detection in 75 (94%) of 80 participants tested at day 28 for the delta variant and in 61 (76%) of 80 participants for the omicron variant [Costa Clemens SA, 2022 ].

COV-BOOST  was a phase 2 randomized clinical trial conducted in the United Kingdom. This study enrolled 166 participants who had received Pfizer-BioNTech as their third dose and randomly assigned them to receive a fourth dose of either Pfizer-BioNTech (30 µg in 0.30 mL; full dose) or Moderna  (50 µg in 0.25 mL; half dose). Immunogenicity was compared at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. The geometric mean anti-spike protein IgG concentration on day 28 after the third dose of BNT162b2 was 23325 (ELU)/mL (95% CI 20030–27162). With the four dose Increased to 37460 ELU/mL (31996–43857) after the fourth dose. The fold change of the geometric mean was 1.59 (95% CI 1·41–1·78). [Munro APS, 2022 ].

Suntronwong N et al was a cohort study conducted in Thailand. 167 participants primed with heterologous CoronaVac/Oxford-AstraZeneca vaccination were enrolled to receive a booster dose of Oxford-AstraZeneca (n= 60), Pfizer-BioNTech (n= 55) of Moderna (n= 52) vaccines. This study assessed the capability of the booster vaccination to induce an increase in neutralizing antibodies and T-cell responses against SARS-CoV-2, Omicron (BA.1 and BA.2), and Delta variants. Individuals boosted with mRNA vaccines demonstrated a higher level of neutralizing activity than those boosted with Oxford-AstraZeneca. Median neutralizing activity to Omicron (day 28) were 10,1% for AstraZeneca, 55,6 for Pfizer and 78,2% for Moderna. NAb titers at day 28 for Omicron BA.a variant were 40.3 (3.16-fold increase) for AstraZeneca, 171.0 (9.91-fold increase) for Pfizer, and 271.6 (24.78-fold increase) for Moderna. NAb titers at day 28 for Omicron BA.2 were 59.3 (2.43-fold increase) for AstraZeneca, 130.7 (4.63 fold-increase) for Pfizer, and 235.3 (19.67 fold-increase) for Moderna. [Suntronwong N, 2022 ]

Özyurda et al. was a case-control study conducted in Turkey, the study assessed the immunogenic response of a booster dose in 100 healthcare workers from the TOBB ETU Hospital who received a primary schedule of SinoVac vaccine and a booster dose of Pfizer-BioNTech (n=60) or a SinoVac booster dose (n=40). The study found that at 2.5 to 3.5 months after receiving the booster dose 25% of those vaccinated with a homologous booster ellicited a positive humoral immune response, as opposed to 93.3% in those vaccinates with a Pfizer-BioNTech booster. The cellular immune response was positive in 70% of the participants who received a SinoVac booster dose and in 88.3% of those who received a Pfizer-BioNTech booster. [Özyurda F, 2022 ].

Catry et al was a study conducted in Belgium assessing the immunogenicity after a Pfizer-BioNTech booster dose in 49 Lung Transplant Recipients who had a previously received an AstraZeneca primary schedule vaccination. At day 238 the Anti-SARS-CoV-2 IgG titers reached 197.8 BAU/mL (0.0–491.4) which represents a seropositivity of 32.3%, the NAbs titers reached 76.6 AU/mL (0–159.6) which represents a 32.2% of seropositivity [Catry E, 2022 ].

Choi JY et al was a comparative cohort study conducted in Korea. The study analyzed 170 samples of sera from 75 participants: 50 samples from ChAd-ChAd-BNT, 60 samples from ChAd-BNT-BNT, and 60 samples from BNT-BNT-BNT. Neutralizing activities were evaluated using plaque-reduction neutralization test (PRNT) against wild-type (WT) SARS-CoV-2, Delta variant, and Omicron variant. After the 2nd vaccine dose, geometric mean titers of PRNT ND50: against wild type, Delta, and Omicron were highest after ChAd-BNT vaccination (2,463, 1,097, and 107) followed by BNT-BNT (2,364, 674, and 38) and ChAd-ChAd (449, 163, and 25). After the 3rd dose of BNT, the increase of PRNT ND50 against WT, Delta, and Omicron was most robust in ChAd-ChAd-BNT (4,632, 988, and 260), while the BNT-BNT-BNT group showed the most augmented neutralizing activity against Delta and Omicron variants (2,315 and 628) [Choi JY, 2022 ].

CVIM 4 was a randomized controlled trial conducted in Thailand. The study included 77 kidney transplant recipients (per protocol analysis) who had already been vaccinated with a primary regimen of ChAdOx1, or CoronaVac and boosted with the ChAdOx1 vaccine. The participants were randomized two receive an additional dose of either an mRNA vaccine (Moderna or Pfizer BioNTech, n= 40,) or a viral vector vaccine (ChAdOx1, n= 37). The rate of seroconversion for the mRNA group was 70%, and 61% viral-vector group; the median interquartile range (IQR) of anti-RBD IgG levels were 51.8 (95% CI 5.1 to 591) and 28.3 (95% CI 2.4 to 87.1), respectively. Median (IQR) for S1-specific T cells for the mRNA group was 230 (I41 to 420), and 232 (116 to 400) for the viral-vector group [Bruminhent J, 2022 ].

Nantanee R et al was a randomized clinical trial conducted in Thailand. The study included 100 adults with a median age of 59.3 years with two-dose AZD1222: 50 received a half-Dose BNT162b2 Booster (15 µg/Dose) and 50 received a standard-Dose BNT162b2 Booster (30 µg/Dose). The immunogenicity was evaluated by a surrogate virus neutralization test (sVNT) against Omicron variants and anti-spike-receptor-bindin-domain IgG (anti-S-RBD IgG). At day 14, the geometric means of sVNT against the omicron variant were 74.4% (95% CI 68.8–80.5)  inhibition post-half-dose BNT162b2 boosters and 67.3% inhibition (95% CI 57.9 to 78.1) post-standard-dose boosters. At day 14, anti-S-RBD IgGs were comparably boosted with GMs of 2329.8 BAU/mL (95% CI 2109.3–2573.4) post-half-dose BNT162b2 boosters and 2574.7 BAU/mL (2262.5–2929.9) post-standard-dose boosters. At 14 days after boosters, the T cell responses were significantly enhanced to 406 SFU/106 PBMCs (IQR 206–718, p < 0.001) in the half-dose and 402 SFU/106 PBMCs (148–678, p < 0.001) in the full-dose groups, without a difference between the dosage groups (p 0.80) [Nantanee R, 2022 ].

Bonelli et al conducted a randomized controlled trial in Austria. This study assigned 60 patients under rituximab treatment, who did not seroconvert after their primary mRNA vaccination with either BNT162b2 or mRNA-1273, to receive a third dose, either using the same mRNA (28/30) or the vector vaccine ChAdOx1 nCoV-19 (27/30). Seroconversion rates at week 4 were comparable between vector (6/27 patients, 22%) and mRNA (9/28, 32%) vaccines (p=0.6). Overall, 27% of patients seroconverted; specific T cell responses were observed in 20/20 (100%) vector versus 13/16 (81%) mRNA vaccinated patients. Newly induced humoral and/or cellular responses occurred in 9/11 (82%) patients. 3/37 (8%) of patients without and 12/18 (67%) of the patients with detectable peripheral B cells seroconverted. No serious adverse events, related to immunization, were observed [Bonelli M, 2022 ].

BOOST-TX was a randomized controlled trial conducted in Austria, of a third dose of vaccine against SARS-CoV-2 in kidney transplant recipients who had not developed SARS-CoV-2 spike protein antibodies after 2 doses of an mRNA vaccine. 197 patients were analyzed, 99 receives a homologous booster (mRNA) vaccine, 98 received a heterologous (Ad26COVS1) vaccine. The 39% developed SARS-CoV-2 antibodies after the third vaccine. There was no statistically significant difference between groups, with an antibody response rate of 35% and 42% for the mRNA and vector vaccines, respectively. Only 22% of seroconverted patients had neutralizing antibodies. Similarly, T-cell response assessed by IGRA was low with only 17 patients showing a positive response after the third vaccination. Receiving nontriple immunosuppression (odds ratio [OR], 3.59; 95% CI, 1.33-10.75), longer time after kidney transplant (OR, 1.44; 95% CI, 1.15-1.83, per doubling of years), and torque teno virus plasma levels (OR, 0.92; 95% CI, 0.88-0.96, per doubling of levels) were associated with vaccine response. The third dose of an mRNA vaccine was associated with a higher frequency of local pain at the injection site compared with the vector vaccine, while systemic symptoms were comparable between groups. [Reindl-Schwaighofer R, 2021 ]

Cobovax study was a randomized clinical trial conducted in China. The study enrolled 219 adults who previously received two doses of CoronaVac and randomized to CoronaVac ("CC-C", n=101) or BNT162b2 ("CC-B", n=118) third dose; and 232 adults who previously received BNT162b2 and randomized to CoronaVac ("BB-C", n=118) or BNT162b2 ("BB-B", n=114). The aim was to assessed immunogenicity and cell-mediated immune responses and vaccine efficacy against infections during follow-up. Third-dose vaccination increased PRNT50 titers against ancestral virus 315 by 14-, 94-, 3- and 19-folds, and against Omicron BA.2 by 1-, 16-, 1- and 13-folds, in CC-C, CC-B, BB-C and BB-B arms respectively. Antibody responses to a BNT162b2 third dose were substantially and statistically significantly greater than responses to a CoronaVac third dose regardless of prior two-dose vaccine type. [Nancy H. L. Leung, 2022 ]

Fadlyana et al was a randomized controlled trial conducted in Indonesia that included 949 participants primed with CoronaVac that received one booster dose: 193 half-dose ChAdOx1, 192 full-dose ChAdOx1, 190 half-dose BNT162b2, 193 full-dose BNT162b2 and 192 full-dose parameter CoronaVac. The primary outcome was to evaluate the seroconversion rate and geometric mean titres (GMTs) of IgG anti S-RBD 28 days after the booster in the per-protocol population. Seroconversion rates were highest for BNT162b2 (97.8% and 92.0% for full and half-dose, respectively), followed by ChAdOx1-S (87.9% and 81.5% for full and half dose, respectively) and CoronaVac (41.3% to 66.3%). For participants primed within 6–9 months before booster, GMT values 28 days post-booster were highest for BNT162b2 (19999.84 and 17017.62 for full and half-dose, respectively), followed by ChAdOx1-S (11258 and 7853.04 for full and half-dose, respectively) and CoronaVac (1440.55). [Fadlyana E, 2023 ]

Intapiboon P et al was a randomized clinical trial conducted in China. The study included 80 participants who had received two doses of CoronaVac: 40 with Pfizer booster and 40 with CoronaVac booster. The primary outcome was antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) measured by surrogate Virus Neutralization Test (sVNTs), plaque reduction neutralization tests (PRNTs), and N-terminal domain (NTD) ELISA in plasma samples collected 1 month after the third dose of vaccination. One month after the third dose of vaccination, the mean percentage of inhibition in the sVNT in the plasma for the BNT1626 and CoronaVac groups was 96.83% and 57.75%, respectively (P < 0.0001). The 90% plaque reduction neutralization (PRNT90) geometric mean titers in the BNT162b2 and CoronaVac groups were 207.49 and 16.53, respectively. PRNT50 geometric mean titers were 303.79 and 56.67, respectively. [Mok CKP, 2022 ]

Niyomnaitham S et al was a randomized clinical trial conducted in Thailand. This study evaluated the immunogenicity and reactogenicity of heterologous COVID-19 primary schedules in healthy adults, as well as booster response to BNT162b2 following heterologous CoronaVac and ChAdOx1 nCoV-19 regimens. 210 adults participated in the study: 30 with CoronaVac/AstraZeneca primary schedule, 30 with CoronaVac/Pfizer, 30 with AstraZeneca/CoronaVac, 30 with  AstraZeneca/Pfizer, 30 with Pfizer/CoronaVac, 30 with Pfizer/AstraZeneca and 30 with Pfizer/Pfizer. At two weeks after the booster dose with Pfizer, the anti-RBD IgG levels against the ancestral strain were 2518.8 BAU/mL ( 95%CI 1960.4 to 3236.4) for participants primed with CoronaVac/AstraZeneca and 2610.6 BAU/mL (95%CI 2037.7–3344.5) for participants primed with AstraZeneca/CoronaVac. GMR were 2.5 and 18.9 for CoronaVac/AstraZeneca/Pfizer  and AstraZeneca/CoronaVac/Pfizer groups, respectively. [Niyomnaitham S, 2022 ]

Buathong et al conducted an observational study to determine the levels of neutralizing antibodies against the SARS-CoV-2 ancestral strain, Delta and Omicron variants of concern (VOCs), in 125 healthcare workers who received CoronaVac as their primary vaccination and later received either a single ChAdOx1 or a combination of two consecutive boosters using either two ChAdOx1 doses or a ChAdOx1 or BNT162b2 as the primary and second boosters, respectively, or two doses of BNT162b2. Coronavac Coronavac + ChAdOx1 Pfizer: - 100% of the subjects were NT positive against the ancestral strain at day 0 (MI of 84.5%, 95% CI: 80.5–88.6%; and MI of 84.6%, 95% CI: 73.2–95.9%, respectively) and at 1 week (MI of 85.2%, 95% CI: 81.8–88.7%; and MI of 93.3%, 95% CI: 86.3–100.3%, respectively) after their second booster dose. Coronavac Coronavac + Pfizer Pfizer: - 100% of the subjects were NT positive against the ancestral strain at day 0 (MI of 84.5%, 95% CI: 80.5–88.6%; and MI of 84.6%, 95% CI: 73.2–95.9%, respectively) and at 1 week (MI of 85.2%, 95% CI: 81.8–88.7%; and MI of 93.3%, 95% CI: 86.3–100.3%, respectively) after their second booster dose. [Buathong R, 2022 ]

Niyomnaitham et al was a phase 2 randomized clinical trial conducted in Thailand. The study included 1243 participants with CoronaVac primary schedule: 312 in the AstraZeneca booster (half dose) group, 307 in the AstraZeneca booster (full dose) group, 316 in the Pfizer booster (half dose) group, and 308 in the Pfizer booster (half dose) group. Vaccination-induced immunogenicity to Ancestral, Delta, and Omicron BA.1 strains were evaluated by assessing anti-spike (‘anti-S’), anti-nucleocapsid antibodies, pseudovirus neutralization (‘PVNT’), micro-neutralization titers, and T-cells assays. Within platforms and irrespective of dose or platform, seroconversions were greater than 97%, and greater than 90% for neutralizing antibodies against pseudovirus, but similar against SARS-CoV-2 strains. Anti Spike RBD IgG Geometric means concentration (U/mL) at day 28 were 8237.0 (95% CI, 7679.3-8835.2) for the AstraZeneca half dose group, 8973.6 (95% CI, 8328.1-9669.2) for the AstraZeneca full dose group, 14073.9 (95% CI, 13236.4-14964.4) for the Pfizer half dose group and 15920.7 (95% CI, 15135.7-16746.4) for the Pfizer full-dose group. Pseudovirus Neutralizing Antibody Titer (PVNT50) against Omicron (GMT) were 118.9 (95% CI, 97.3-145.2) for the AstraZeneca full-dose group and 255.9 (95% CI, 222.9-293.7) for the Pfizer full-dose group. Immunogenicity according to Pseudovirus Neutralizing Antibody Titer (PVNT50) against delta variant at day 28 were 468.3 (95% CI, 409.8-535.2) for AstraZeneca half dose group, 530.6 (95% CI, 470.4-598.5) for AstraZeneca full dose group, 801.5 (95% CI, 715.4-897.8) for Pfizer half dose group and 856.1 (95% CI, 777.8-942.1) for Pfizer full-dose group. [Suvimol Niyomnaitham, 2022 ]

REFUERZO was a phase 3 randomized trial conducted in Chile that included 523 participants with 2 doses of CoronaVac: 127 with AstraZeneca booster, 134 with CoronaVac booster, 91 with Pfizer booster, and with 95 placebo. This study reported results of the immunogenicity arm, which determined neutralizing antibody titers in plasma, measured at baseline as well as 14, 30, 60 and 90 days post-booster inoculation. Mean of the fold-increase, with respect to the baseline value, of the geometric mean of ID50 at day 30 was: 129.4 (95% CI, 98.9-166.4) for AstraZeneca booster, 12.1 (95% CI, 9.4-15.4) for CoronaVac Booster, 214.2 (95% CI, 160.7-280.5) for Pfizer booster and 0.8 (95% CI, 0.6-1.1) for placebo. [Acevedo J, 2022 ]

SWITCH ON was an open-label randomized trial conducted in the Netherlands that included 187 healthcare workers: 42 with Ad26.COV2.S primary schedule and BNT162b2 Omicron BA.1 booster, 45 with Ad26.COV2.S primary schedule and mRNA-1273.214 Omicron BA.1 booster, 44 with mRNA-based primary schedule and BNT162b2 Omicron BA.1 booster and 56 mRNA-based primary schedules and mRNA-1273.214 Omicron BA.1 booster. The aim was to assess the fold change in S1-specific IgG antibodies before and 28 days after booster vaccination. Fold change of S1-specific binding antibody levels between baseline and 28 days after bivalent booster vaccination was 2.9, 3.6, 4.3, and 3.5-fold for participants with Ad26.COV2.S+BNT162b2 Omicron BA.1 booster, mRNA-based primary schedule+BNT162b2 Omicron BA.1 booster, Ad26.COV2.S+mRNA-1273.214 Omicron BA.1 booster, and mRNA-based primary schedule+mRNA-1273.214 Omicron BA.1 booster, respectively. [Ngoc Tan, 2022 ]

Prasert Assantachai et al was a randomized controlled trial conducted in Thailand that included 210 participants aged ≥65 years with AstraZeneca primary schedule: 35 received intradermal mRNA-1273, 35 intramuscular mRNA-1273, 70 intradermal BNT162b2, and 70 intramuscular BNT162b2. The group that reported the highest geometric mean titers against the ancestral strain and Omicron BA.1 variant was the group that received the intramuscular mRNA-1273 vaccine (GMT 1,717.9 and 617), followed by the group that received the intradermal mRNA-1273 vaccine (GMT 1,212 and 318), the group that received the intramuscular BNT162b2 vaccine (GMT 713 and 230 and the group that received the intradermal BNT162b2 vaccine (GMT 587 and 148), respectively. [Prasert Assantachai, 2022 ]

Samoud S et al was a randomized controlled trial conducted in Tunisia that included 216 participants: 108 randomized to the heterologous booster group (CoronaVac/Pfizer) and 108 to the homologous booster group (CoronaVac/CoronaVac). The aim was to compare the immunogenicity of the heterologous prime-boost CoronaVac/BNT162b2 vaccination to the homologous CoronaVac/CoronaVac regimen. Anti-spike IgG after the first dose was 1,187 UI/ml (95% CI, 225-2,475) and 827 UI/ml (95% CI, 4-2,109) for the heterologous booster group and the homologous booster group, respectively. Anti-spike IgG after the second dose was 13,460 UI/ml (95% CI, (2,557-29,930) and 1190 UI/ml (95% CI,347-4964) for the heterologous booster group and the homologous booster group, respectively. [Samar Samoud, 2023 ]

Sauré D et al was a cross-sectional study conducted in Chile that included 101,070 participants: 65,902 with CoronaVac primary schedule, 10,095 with Pfizer booster, 5,435 with AstraZeneca booster and 608 with CoronaVac booster. The aim was to assess IgG seropositivity dynamics after primary and booster vaccination. After homologous booster with CoronaVac the proportion of participants with IgG positivity was 95.7% (95% CI, 89.8-100). After heterologous booster with Pfizer the proportion of participants with IgG positivity was 99.7% (95% CI, 99.3-100.0). After heterologous booster with AstraZeneca the proportion of participants with IgG positivity was 99.5% (95% CI, 98.8–100.0). [Sauré D, 2023 ]

Jäger M et al was a comparative cohort study conducted in Austria that included 137 participants, of which 79 were vaccinated with AstraZeneca primary schedule and mRNA vaccine booster and 40 with 3 doses of mRNA vaccine. The aim was to assess humoral and cellular response. Median IgG titer were 1655.0 (95% CI, 1163.0-1901.0), 2673.0 (95% CI, 2189.0-3517.0) and 2891.0 (95% CI, 1582.0-4458.0) for particpants with 2 AstraZeneca doses and Pfizer booster group, 2 AstraZeneca doses and Moderna booster and 3 Pfizer doses, respectively. [Jäger M, 2023 ]

Dedroogh S et al was a prospective cohort study conducted in Germany that included 1,338 participants with Pfizer booster dose: 565 Pfizer primary schedule and 773 AstraZeneca primary schedule. The aim was to assess SARS-CoV-2 antibodies booster immunization with the Pfizer and AstraZeneca vaccines. Mean of anti-S RBD antibody levels were 25,000 U/mL (95% CI, 18,474 − 25,000) for homologous Pfizer booster and 16,488 U/mL (95% CI, 11,192-24,785) for Pfizer primary schedule and AstraZeneca booster, respectively. [Dedroogh S, 2023 ]

2019nCoV-307 was a phase 3 randomized trial conducted in United States that included data from 911 participants boosted with three different manufacturing lots of NVXCoV2373 COVID-19 vaccines: 298 from group 1, 303 from group 2 and 304 from group 3. This study assessed whether NVX-CoV2373 would induce similar responses when used as a heterologous or homologous booster. Geometric mean fold rise (day 29 vs baseline) was 4.0 (95% CI, 1.0-16.0) for homologous booster. Geometric mean fold rise (day 29 vs baseline) was 2.7 (95% CI, 2.3-3.2), 2.4 (95% CI, 1.9-2.9) and 2.7 (95% CI, 1.6-4.4) for participants with Pfizer, Moderna and Janssen primary schedules. [Dunkle, L. M., 2023 ]

Effectiveness outcomes
Andrews N et al. was a case-control study (Test-negative) conducted in United Kingdom. The study included 893,845 eligible tests in those aged 18 years and over. The objective was to estimate the effectiveness of the Pfizer and Moderna booster vaccines against symptomatic disease, hospitalization, and death in adults in England. The study results showed that the booster dose was associated with an absolute vaccine efficacy from 14-34 days after a Pfizer booster of 94.4% (95% CI 94.1 to 94.7) following either an AstraZeneca or Pfizer primary scheme in individuals 50 years and older. With a Moderna booster, absolute vaccine effectiveness was 97.0 (95% CI 96.0 to 97.8) after an AstraZeneca primary scheme and 94.8% (95% CI 92.7 to 96.3%) Pfizer primary scheme. [Andrews N, 2022 ].

Sritipsukho P et al was a case-control study conducted in Thailand. The study enrolled 3,353 participants. Based on a test negative design of consecutive individuals (age ≥18 years) at-risk for COVID-19 who presented for nasopharyngeal real-time polymerase chain reaction (RT-PCR) testing between 5 July 2021 and 23 October 2021 that were prospectively enrolled and followed up for disease development, the study results showed a vaccine effectiveness with two doses of sinovac+ one dose of Astrazeneca vaccine of 86% (95% CI, 74–93) and with two doses of Sinovac+one dose of Pfizer vaccine of 98% (95% CI, 87–100) [Sritipsukho P, 2022 ].

Silva T et al. was a case-control study conducted in Brazil. The study included 7,314,318 participants: 3,279,280 in the vaccine group and 4,035,038 in the control group. Based on national Brazilian databases, the study assessed the effectiveness of two doses of CoronaVac against confirmed SARS-CoV-2 infection and severe COVID-19 outcomes (hospitalization and death). Also estimated the effectiveness of the BNT162b2 mRNA vaccine as a booster dose. The main results showed that Vaccine effectiveness with booster (BNT162b2) was 92.7% (95% CI 91.0–94.0) 14-30 days after receiving the booster dose. Effectiveness against hospitalization or death with booster (BNT162b2) was 97.3% (95% CI 96.1–98.1) 14–30 days after booster dose [Cerqueira-Silva T, 2022 ].

Mallow C et al. It was a case-control study conducted in the United States. The study analyzed data from 13,203 adult (age ≥ 18 years) visits to the emergency department: 3,134 were fully vaccinated and negative for COVID-19, 108 were fully vaccinated and positive for COVID-19, 8,817 were unvaccinated and were negative for COVID-19, and 1,144 were unvaccinated and were positive for COVID-19. The objective of the study was to evaluate the effectiveness of messenger RNA vaccines against SARS-COV-2 in the emergency department. Data was collected from January 1 to August 25, 2021, from subjects with PCR tests for SARS-COV-2 and symptoms of acute respiratory infection. The main results showed that the effectiveness of the Pfizer vaccine was 73.9% (95% CI: 66.3 to 79.8) [Mallow C, 2022 ].

Tan SHX et al was a comparative cohort study conducted in China. Rates and severity of SARS-CoV-2 infections between September 15 and October 31, 2021, among those eligible to receive vaccine boosters between September 15 and October 15, 2021, were analyzed based on official data reported to the Singapore Ministry of Health. The adjusted incidence rate ratio (2 doses of BNT162b2 plus mRNA-1273 booster) for PCR–confirmed infections was  0.177 (95% CI 0.138 to 0.227) and 0.078 (95% CI 0.011 to 0.560) for severe infection. The Adjusted incidence rate ratio (2 doses of mRNA-1273 plus BNT162b2) for PCR–confirmed infections was 0.140 (95% CI 0.052 to 0.376) [Tan SHX, 2022 ].

Andrews N et al. was a case-control study conducted in England. The study enrolled 2,663,549 vaccinated participants: 204,154 cases for Delta variant, 886,774 cases for Omicron variant and 1,572, 621 test-negative controls. The study analyzed information from national databases, Pillar 1, Pillar 2, NIMS and NHS regarding Covid-19 vaccination, testing, and variants  from November 25, 2021, through January 12, 2022.  The effectiveness of the Pfizer-BioNTech booster after AstraZeneca primary scheme against the Delta variant for symptomatic infection was 88.1% (95% CI 86.7 to 89.3) and 39.6% (95% CI 38.0 to 41.1) for Omicron. The effectiveness of the Pfizer-BioNTech booster after Moderna primary vaccination was 94.7% (95% CI 89.3 to 97.3) against the Delta variant and 64.9% (95% CI 62.3 to 67.3) for Omicron [Andrews N, 2022 ].

Low EV et al. was a retrospective cohort study conducted in Malaysia. The study included 13,840,240 individuals: 5,714,979 with 2 doses BNT162b2, 3,043,620 with 2 doses of CoronaVac, 1,265,436 with 3 doses of BNT162b2, 3,225,428 with 2 doses of CoronaVac plus BNT162b2 booster and 590 777 with 3 doses of CoronaVac. The aim of this study was to compare the odds of symptomatic SARS-CoV-2 infection and COVID-19–related outcomes after heterologous and homologous boosting of CoronaVac at 3-month intervals and homologous boosting of BNT162b2 at 6-month intervals, with BNT162b2 primary series (2 doses) as the reference group. The adjusted odds against symptomatic SAR-CoV-2 infection were lower for individuals who received the primary series CoronaVac plus a BNT162b2 (adjusted odds ratio [aOR], 0.06 [95% CI, 0.05-0.06]), 3 doses of CoronaVac (aOR, 0.08 [95% CI, 0.06-0.10]), or 3 doses of BNT162b2 (aOR, 0.01 [95% CI, 0.00-0.01]). Receipt of heterologous booster (primary series of CoronaVac plus a BNT162b2 booster) was associated with lower odds of SARS-CoV-2 infection (aOR, 0.17 [95% CI, 0.17-0.18]) compared with homologous booster (3 doses of CoronaVac) for individuals aged 60 years and older (aOR, 0.19 [95% CI, 0.19-0.20]) [Low EV, 2022 ].

Young-Xu Y et al. was a case-control study with matched test-negative design conducted in the United States. The study used records and COVID-19 laboratory test data from the Veterans Health Administration (VHA), which includes 1293 healthcare facilities that attend US veterans. Positive tests during January 2022 were presumed to be Omicron SARS-CoV-2 infections. Each case (positive test) was matched with up to four controls (negative tests). Vaccine effectiveness was estimated through the number of infections, hospitalizations, and death within 30 days of a positive test. The vaccine effectiveness (VE) against omicron infection after two mRNA vaccine doses was 12% (95% CI 10 to 15) and increased to 64% (95% CI 63 to 65) after the booster mRNA dose. The VE against hospitalizations was 63% (95% CI 58 to 67) after two mRNA vaccine doses and increased up to 89% (95% CI 88 to 91) after the booster mRNA dose. The VE against death after 2 mRNA vaccine doses was 77% (95% CI 67 to 83) and increased to 94% (CI 95% CI 90 to 96) after the booster mRNA dose [Young-Xu Y, 2022 ].

Vokó Z et al was a comparative cohort study conducted in Hungary. The study population included 8,087,988 individuals who were 18–100 years old at the beginning of the pandemic. This study examined vaccine effectiveness (VE) and durability of primary immunization and single booster vaccinations in the prevention of SARS-CoV-2 infection, Covid-19-related hospitalization, and mortality during the Delta wave, compared to an unvaccinated control population without prior SARS-CoV-2 infection. Adjusted VE against registered SARS-CoV-2 infection during the Delta wave was 70.3% (95% CI 69.2 to 71.3) for primary Pfizer vaccination at 14 to 120 days, and 82.2% (95% CI 81.5 to 82.8) for the homologous booster vaccination (Pfizer/Pfizer) during the Delta wave [Vokó Z, 2022 ].

Sonmezer MC et al was a comparative cohort study conducted in Turkey. The study included 5243 participants: 1047 with two doses of CoronaVac, 3727 with two doses of CoronaVac and one dose of Pfizer, and 469 with three doses of CoronaVac. Effectiveness of the third dose of CoronaVac or BNT162b2 following a two-dose CoronaVac regimen in preventing COVID-19 cases after 14 days was  87.27%(95% CI 84.21 to 89.74) for two doses of CoronaVac and one dose of Pfizer and 58.24% (95% CI 43.43 to 69.17) for Three doses of CoronaVac [Sonmezer MC, 2022 ].

Suphanchaimat R et al was a test-negative case-control study conducted in Thailand. The study included 1,460,458 participants: 482,372 cases and 978,086 controls aimed to explore the vaccine effectiveness (VE) of various schedules against the SARS-CoV2 Delta variant in Thailand during September–December 2021. VE against any infection according to vaccine regimens was: 62.4% (95% CI 59.4 to 65.1) for BNT162b2 + BNT162b2, 88.7% (95% CI 85.6 to 91.1) for ChAdOx1 + BNT162b2, 82.3% (95% CI 74.3–87.7) and 94.0% (95% CI 93.4 to 94.6) for CoronaVac + BNT162b2 [Suphanchaimat R, 2022 ].

Shrotri M et al was a comparative cohort study conducted in England. The study included data from participants from 331 long-term care facilities: 15518 residents aged 65 years or older and 19515 staff aged 18 years or older. This study estimated vaccine effectiveness against SARS-CoV-2 infection, COVID-19-related hospitalization, and COVID-19-related death after one, two, and three vaccine doses, separately by previous SARS-CoV-2 exposure. Vaccine effectiveness against infections for Pfizer heterologous booster dose (AstraZeneca primary schedule and Pfizer booster) was 72.8% (95% CI 51.9 to 84.6) for residents (>65 years) and 76.1% (95% CI 62 to 85) for staff (>18 years).Vaccine effectiveness against hospitalization after heterologous booster dose was 93.5% (95% CI 83.3 to 97.4). [Shrotri M, 2022 ].

Zee ST et al, was a retrospective study was performed to compare the rate and outcome of COVID-19 in healthcare workers with various vaccination regimes during a territory-wide Omicron BA.2.2 outbreak in Hong Kong between 1 February to 31 March 2022 . The study included 3167 healthcare workers. Vaccine effectiveness against infections for Pfizer heterologous booster dose (CoronaVac primary schedule and Pfizer booster)  (HR 0.4862 p = 0.0157) were associated with a lower risk of infection.  [Zee ST, 2022 ]

Yan VKC et al was a case-control study conducted in Hong Kong. The study included 14, 984 participants to evaluate the risk of severe complications following 1-3 doses of CoronaVac and BNT162b2 using electronic health records database. Cases were adults with their first COVID-19-related severe complications between 1 January and 31 March 2022. Vaccine effectiveness heterologus booster doses (Sinovac +  BNT162b2) was 95.2% (95% CI: 80.5-98.8) in those aged ≥65, 88.6% (95% CI: 50.4-97.4)  in those aged 50-64, 73.9% (95% CI: -106.8-96.7)  in those aged 18-50. Further risk reduction with the third dose was observed especially in those aged ≥65 years, against severe complications in the Omicron BA.2 pandemic. [Yan VKC, 2022 ]

Ng OT et al was cohort study conducted in Singapore. The study included 2,441,581 eligible individuals. It was based on data from the Singapore Ministry of Health’s (MOH) official COVID-19 database, including individuals who had received 2 or 3 doses of mRNA vaccines (by Pfizer-BioNTech or Moderna) or inactivated vaccines (by Sinovac or Sinopharm) and notified infections from December 27th 2021 to March 10th 2022. Effectiveness Heterologous Booster against COVID-19 Infeccion was 35.6% (95%CI 32.8-38.3) (wo doses of Moderna and  booster dose with Pfizer.[Ng OT, 2022 ].

Wan EYF was a case-control study conducted in China. The study included 82,587 cases of COVID-19 infection, 10,241 COVID-19 related hospital admission cases, 539 cases of ICU admission and 135 cases of post-infection incident. This study evaluated the vaccine effectiveness (VE) of each dose of BNT162b2 and CoronaVac against any COVID-19 infection, COVID-19-related hospital admission, ICU admission, and incident cardiovascular disease (CVD) in the Hong Kong Hospital Authority outbreak dominated by Omicron BA.2 sublineage. Vaccine effectiveness against COVID-19 infection was -0.3% (95% CI -2.7 to -2.1) with 2 doses of CoronaVac, 22.1% (95% CI 20.0 to 24.2) with 2 doses of Pfizer, 19.8% (95% CI 17.2 to 22.3) with 3 doses of CoronaVac, 54.2% (95% CI 52.4 to 55.9) with 3 doses of Pfizer, 12.1% (-15.8 to 33.3) with Pfizer primary schedule and CoronaVac booster, and 39.9% (95% CI 36.6 to 42.9) with CoronaVac primary schedule and Pfizer booster. Vaccine effectiveness against COVID-19 hospitalization was 64.2 (95% CI 61.8 to 66.4) with 2 doses of CoronaVac, 74.2 (95% CI 71.7 to 76.4) with 2 doses of Pfizer, 85.4% (95% CI 83.2 to 87.3) with 3 doses of CoronaVac, 91.4% (95% CI 89.5 to 92.9) with 3 doses of Pfizer and 89.5% (95% CI 85.9 to 92.2) with CoronaVac primary schedule and Pfizer booster. [Wan EYF, 2022 ]

Buchan et al. conducted a test-negative case-control study using linked provincial databases for SARS-CoV-2 laboratory testing, reportable disease, COVID-19 vaccination, and health administration in Ontario (Canada) to estimate the vaccine effectiveness (VE) against symptomatic infections and severe outcomes associates with these infections. Of 134,435 total participants (> 18 years), 16,087 were Omicron-positive cases, 4261 Delta-positive cases, and 114 087 were test-negative controls. VE against symptomatic infection was 60% (95% CI, 55-65) for omicron, and 97% (95% CI, 96-98) for delta-related disease. VE for severe COVID-19 was 95% (95% CI 87-98) against Omicron, and 99% (95% CI 98-99) against Delta-related severe disease [Buchan SA, 2022 ].

Lin DY et al, was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. Based on data from the North Carolina COVID-19 Surveillance System and the Covid-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Vaccine effectiveness of Moderna booster after Pfizer-BioNTech primary schedule was 68.4% (95% CI, 66.2-70.5) after 1 month, the effectiveness of Pfizer-BioNTech vaccine booster after Moderna primary schedule was 
66.1% (95% CI, 61.9-70.0) [Lin DY, 2022 ].

Vivaldi et al conducted a population-based cohort study (COVIDENCE UK) to identify risk factors for SARS-CoV-2 infection after primary and booster vaccinations. This UK study in adults (≥16 years) vaccinated against SARS-CoV-2, assessed the risk of breakthrough SARS-CoV-2 infection up to February 2022, for participants who completed a primary vaccination course (ChAdOx1 nCoV-19 or BNT162b2) and those who received a booster dose (BNT162b2 or mRNA-1273). Primary vaccination with ChAdOx1 (vs BNT162b2) was associated with higher risk of infection in both post-primary analysis (adjusted hazard ratio 1,63, 95% CI 1,41–1,88) and after an mRNA-1273 booster (1,26 [1,00–1,57] vs primary and booster BNT162b2 schedules) [Vivaldi G, 2022 ].

Monge S et al was a nationwide cohort study conducted in Spain. This study included 7,036,433 participants older than 40 years: 3,111,159 in the booster group and 3,111,159 in the no-booster group. The aim of this study was to estimate the effectiveness of mRNA-based vaccine boosters against infection during the period of the predominance of the omicron variant in Spain. The vaccine effectiveness of Pfizer booster after AstraZeneca, Janssen, Moderna, or Pfizer primary schedule was 46.2% (95% CI 43.5–48.7). Vaccine effectiveness of an mRNA booster (Pfizer or Moderna) following a Pfizer primary schedule was 49.7% (95% CI, 48.3–51.1) [Monge S, 2022 ].

Stowe et al. conducted a test-negative case-control study in the UK, to estimate Vaccine Effectiveness (VE) against hospitalization with the Omicron and Delta variants using PCR testing linked hospital records (Emergency Care Data Set; ECDS). The total number of tests in the study period was 409,985 of which 115,720 were cases and 294,265 controls. Vaccine effectiveness against hospital admissions from ECDS within 14 days of the test date by the Omicron variant in symptomatic individuals 18 to 64 years of age of primary schedule BNT162b2 booster mRNA-1273 was 87.3% (95% CI, 81.2-91.3) after 14-34 days and 60.6% (95% CI, 27.7-78.5) after 70+ days.  Vaccine effectiveness against hospital admissions ECDS within 14 days of the test date by the Omicron variant in symptomatic individuals 65 years of age and older of primary schedule BNT162b2 booster mRNA-1273 89.0% (95% CI, 17.2-98.5) after 7-13 days and 91.2% (95% CI 75.5-96.9) after 14-34 days. [Stowe J, 2022 ]

Agrawal et al was a retrospective cohort study conducted in the United Kingdom that included 16,208,600 participants, 7,589,080 who received a Pfizer-BioNTech primary schedule and 8,619,520 participants who received a ChAdOx1 primary schedule. The study was based on data from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database, Vaccine Management System, Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II), and Secure Anonymised Information Linkage Databank platform during the Omicron period between December 2021 and February 2022. The adjusted Rate Ratio (aRR) 3-5 weeks after booster vaccination against hospitalization was 0.43 (95% CI, 0.37-0.50) for the ChAdOx1 primary schedule and Pfizer-BioNTech booster group and 0.58 (95% CI, 0.46-0.73) for the Pfizer-BioNTech primary schedule and Moderna booster group. [Agrawal U, 2022 ]

Wan EYF was a case control study conducted in China that included data from 78,326 individuals: 7,293 deaths related to COVID-19 and 71,033 controls. This study analyzed data available between January and March 2022 from the electronic health databases in Hong Kong and enrolled individuals aged 60 or above. Vaccine effectiveness against COVID-19 infection (60-79 years old) was 20.3% (95% CI, 18.4% to 22.1%), 50.9% (95% CI, 49.6% to 52.1%), -2.9% (95% CI, -24% to 14.6%) and 30.9% (95% CI, 28.5% to 33.2%) for 2 Pfizer doses schedule, 3 Pfizer doses schedule, Pfizer primary schedule with CoronaVac booster and CoronaVac primary schedule with Pfizer booster schedule respectively. Vaccine effectiveness against COVID-19-related hospitalization was 74.9% (95% CI, 72.6% to 77%), 91.4% (95% CI, 90.1% to 92.5%), 87.4% (95% CI, 59.6% to 96.1%) and 86.9% (95% CI, 84.3% to 89.1%) for 2 Pfizer doses schedule, 3 Pfizer doses schedule, Pfizer primary schedule with CoronaVac booster and CoronaVac primary schedule with Pfizer booster schedule respectively. [Wan EYF, 2022 ]

Cerqueira-Silva T et al, was a case-control study with a test-negative design conducted in Brazil, the study enrolled 2,471,576 participants, including 1,431,108 cases and 1,040,468 controls, including data from the nationwide linked database during the Omicron period in Brazil, including participants who received CoronaVac plus a Pfizer-BioNTech booster, from January to April 2022. The vaccine effectiveness against symptomatic infection was 1.7% (95% CI 0.1 to 3.2) and 89.4% (95% CI 87.8 to 90.7) against severe infection. [Cerqueira-Silva T, 2022 ]

Ranzani O et al was a case-control study (test negative design) conducted in Brazil including 1,386,544 positive antigen/PCR SARS-CoV-2 tests and matched controls. The study estimated the vaccine effectiveness (VE) for homologous and heterologous (BNT162b2) booster doses in adults who received two doses of CoronaVac during the Omicron predominance period. VE against symptomatic COVID-19 for the homologous CoronaVac booster was 8.1% (95% CI, 4.6% to 11.4%) and 57.3% (95% CI, 56.8% to 57.9%) for the Pfizer heterologous booster, measured 8-59 days after the third dose. For hospitalization or death, VE was 86% (95% CI, 71.7% to 93.1%) and 92.1% (95% CI, 90.2% to 93.7%) after 8-59 days of the homologous and heterologous booster schedules, respectively. [Ranzani OT, 2022 ]

Baum U et al was a cohort study conducted in Finland including 896,220 participants aged 70 years and older. The study was based on a nationwide register-based cohort, between December 27th 2020 and March 31st 2022. Vaccine effectiveness (VE) against ICU admission was 92% (95% CI, 79% to 97%) for the Pfizer schedule + Moderna booster, 100% for the Moderna schedule + Pfizer booster, and 100% for the AstraZeneca schedule + Pfizer booster. [Baum U, 2022 ]

Intawong K et al was a test-negative case-control study conducted in Thailand. The study included 36,170 participants, 14,682 cases and 21,488 controls. Based on data from the Epid-CM platform, including participants aged 18 years or older, between October 2021 and April 2022.The aim was to assess the effectiveness of different booster doses. The adjusted vaccine effectiveness against infection during the omicron period after the third dose was 31% (95% CI, 15% to 44%) for the Pfizer-BioNTech booster, 26% (95% CI, 8% to 40%) for the AstraZeneca booster, and 31% (95% CI, 13% to 45%) for the Moderna booster. The adjusted VE after the fourth dose was 71% (95% CI, 60% to 79%) for the Pfizer-BioNTech booster, 73% (95% CI, 48% to 89%) for the AstraZeneca booster and 71% (95% CI, 59% to 79%) for the Moderna booster. [Intawong K, 2022 ]

Yuanyuan F et al. was an observational study to analyze vaccination status and SARS-CoV-2 infection data from more than 10.4 million participants in the national COVID Cohort Collaborative during an 18-month-period (December 2020 to June 2022) in the United States. Vaccine Effectiveness (VE) against COVID-19 infection was 46.19% (95% CI, 43.28% to 48.99%) for the Pfizer/Pfizer/Moderna schedule, and 42% (95% CI, 39.38% to 44.54%) for the Moderna/Moderna/Pfizer schedule. VE against COVID-19 death was 89.56% (95% CI, 85.75% to 92.61%) for the Pfizer/Pfizer/Moderna schedule, and 85.83% (95% CI, 82.49% to 88.70%) for the Moderna/Moderna/Pfizer schedule. [Yuanyuan Fu, 2022 ]

Kirsebom FCM et al was a cohort study conducted in England including participants who received an AstraZeneca primary schedule: 43,171 received an AstraZeneca booster and 13,038,908 received a Pfizer booster dose. Based on data from the National Immunisation Management System on all adults aged 18 years and older in England who had received a ChAdOx1-S primary schedule followed by a ChAdOx1-S or BNT162b2 booster, until March 14th 2022. Vaccine effectiveness against symptomatic infection was 63.8% (95% CI, 63% to 64.5%), and 90.9% (95% CI, 88.7% to 92.7%) against hospitalization. [Kirsebom FCM, 2022 ]

Nittayasoot et al was a test negative case-control study to examine the effectiveness of COVID-19 vaccines during January to April 2022 in Thailand. They analyzed secondary data from four main national health data bases: Co-Lab, Co-Ward, COVID-10 Death and MOPH-IC, using the national identification numbers of each individual as a unique identifier to link the same person across databases. They obtained a total of 3,059,616 records including: 1,015 cases of COVID-19 pneumonia requiring invasive ventilation from 652,854 cases with SARS-CoV-2 detection and 2,046,762 controls or non-SARS-CoV-2 detection. Vaccine Effectiveness against pneumonia requiring invasive ventilation for schedule: Coronavac + Coronavac + Pfizer was 100.00% (95% CI, 99.99% to 100.00%), BIBP + BIBP + Pfizer was 81.37% (95% CI, 36.08% to 94.57%), ChAdOx1 + ChAdOx1 + Pfizer was 85.84% (95% CI, 74.00% to 92.29%), Coronavac + ChAdOx1 + Pfizer was 86.05% (95% CI, 70.67% to 93.37%), Coronavac + Pfizer + Pfizer 100.00% (95% CI, 99.99% to 100.00%), ChAdOx1 + Pfizer + Moderna was 100.00% (95% CI, 99.99% to 100.00%), Coronavac + Coronavac + ChAdOx1 + Pfizer was 100.00% (95% CI, 99.99% to 100.00%) and Coronavac + Coronavac + Pfizer + Pfizer was 100.00% (95% CI, 99.99% to 100.00%). [Nittayasoot N, 2022 ] 

Arbel R et al. was a retrospective cohort study conducted in Israel that included 622,701 participants aged 65 years and older: 85,314 with the Pfizer-Biontech mRNA bivalent vaccine and 537,387 without bivalent vaccine. The study included all members of Clalit Health Services, aged ≥65, eligible for a bivalent booster. Hospitalizations and death due to COVID-19 among participants who received the bivalent vaccine were compared with those who did not. Adjusted hazard ratio of hospitalization due to COVID-19 was 0.19 (95% CI, 0.08-0.43). [Ronen Arbel, 2023 ]

Anne J. Huiberts et al was a prospective cohort study conducted in Netherlands the included 27,646 participants from the Omicron period: 3,802 received primary vaccination schedule, 23,352 received first booster dose and 492 were unvaccinated. The primary outcome was contracting SARS-CoV-2 between July 12th 2021 and June 6th 2022. Vaccine effectiveness (VE) against contracting COVID-19 during the Omicron BA.1-2 period was 45% (95% CI, 20.3% to 62.1%), 51.1% (95% CI, 44.1% to 57.3%) and 58.4% (95% CI, 48.8% to 66.1%) for Pfizer primary schedule, mRNA primary schedule with Pfizer booster and AstraZeneca primary schedule with Pfizer booster, respectively. Vaccine effectiveness against contracting COVID-19 during the Delta period was 81.3% (95% CI, 69.2% to 88.6%), 97.4% (95% CI, 81.2% to 99.6%) and 90.9% (95% CI, 34% to 98.8%) for Pfizer primary schedule, mRNA primary schedule with Pfizer booster and AstraZeneca primary schedule with Pfizer booster, respectively. [Anne J. Huiberts, 2023 ]

Cerqueira-Silva T et al was a case-control study, test-negative design, conducted in Brazil and Scotland. The study included 5,832,210 participants: 5,276,385 from Brazil and 555,825 from Scotland. This study assessed vaccine effectiveness of a mRNA booster after AstraZeneca or Pfizer primary schedule during the period of Omicron dominance. Vaccine effectiveness against severe outcomes was 93.5% (95% CI, 93% to 94%), 94.4% (95% CI, 87.7% to 97.5%) and 92.7% (95% CI, 91% to 94%) with AstraZeneca primary schedule and Pfizer booster, AstraZeneca primary schedule and Moderna booster and Pfizer homologous booster, respectively. [Cerqueira-Silva T, 2023 ]

Sritipsukho P et al was a case-control study, test-negative design conducted in Thailand that study included data from 7,971 participants: 3,104 cases and 4,867 controls. The aim was to assess the vaccine effectiveness after receiving 2, 3 and 4 doses. Vaccine effectiveness was 76% (95% CI, 52% to 88%), 58% (95% CI, 28% to 75%), 69% (95% CI, 36% to 85%), 57% (95% CI, 7% to 80%) and 82% (95% CI, 59% to 92%) after CoronaVac primary schedule and Pfizer booster, AstraZeneca primary schedule and Pfizer booster, CoronaVac primary schedule and AstraZeneca booster, CoronaVac primary schedule and 2 doses of Pfizer booster and CoronaVac primary schedule, AstraZeneca booster and Pfizer second booster, respectively. [Sritipsukho P, 2023 ]

Tenforde MW et al was a case-control study conducted in the United States that included data from 78,170 emergency department encounters: 8,986 cases and 69,184 controls. This study assessed the effectiveness of a bivalent booster dose among immunocompetent adults during September 13th to November 18th 2022 (Omicron BA.5 sublineage predominance). Vaccine effectiveness of bivalent booster dose against emergency department or urgency care encounters was 56% (95% CI,  50% to 61%). [Tenforde MW, 2023 ]

Oliveira EA et al was a case control study conducted in Brazil that included data from 6,950 participants: 1,102 cases and 5,848 controls. The aim was to estimate vaccine effectiveness against Omicron variant infection and severe disease in children aged 5-11 years hospitalized with acute respiratory syndrome. Vaccine effectiveness against hospitalization for the Pfizer vaccine was 45% (95% CI, 20% to 61%) and 40% (95% CI, 17% to 56%) for the CoronaVac vaccine. [Oliveira EA, 2023 ]

Maeda H et al was a case control study (test-negative design) conducted in Japan that included data from 7,931 participants: 3,055 test-positive cases and 4,876 test-negative cases. The aim was to assess vaccine effectiveness of primary and booster vaccination against symptomatic SARS-CoV-2 infections during the Omicron outbreak. Vaccine effectiveness was 67.1% (95% CI, 56.6% to 75.1%), 69.9% (95% CI, 49.3% to 82.2%) and 75.7% (95% CI, 57.7% to 86.0%) for Pfizer homologous booster, Pfizer primary schedule and Moderna booster, and Moderna homologous booster, respectively. [Maeda H, 2023 ]

dos Santos et al was a comparative cohort study conducted in Brazil that included data from 108,625,066 booster-vaccinated participants. The aim was to assess the effectiveness of the primary series of COVID-19 vaccination and booster shots in protecting against severe cases. Vaccine effectiveness against severe outcomes were 66.5% (95% CI, 62.8% to 70.0%), 73.0% (95% CI, 67.8% to 77.6%), 39.9% (95% CI, −15.3% to 77.2%) and 82.4% (95% CI, 63.2% to 93.7%) for AstraZeneca primary schedule and Pfizer booster, CoronaVac primary schedule and Pfizer booster, Pfizer primary schedule and AstraZeneca booster and Janssen primary schedule and Pfizer booster, respectively. Vaccine effectiveness against severe outcomes were 81.1% (95% CI , 80.3% to 81.9%), 84.7% (95% CI, 83.7% to 85.5%), 70.7% (95% CI, 66.9% to 74.2%) and 90.3% (95% CI, 89.5% to 91.0%) for AstraZeneca, CoronaVac, Janssen and Pfizer, respectively. [Santos CVBD, 2023 ]

Safety of the vaccine in preclinical studies

The Pfizer-BioNTech COVID-19 vaccine was tested in mice and non-human primates. No cases of death or obvious clinical signs were observed for any of the vaccine candidates. Therefore, a favorable safety pattern provides reassurance for clinical translation [Vogel AB, 2021 ].

Safety of the vaccine in clinical trials

Key messages

Pfizer-BioNTech COVID-19 vaccine increase the risk of any adverse events.

Pfizer-BioNTech COVID-19 vaccine increase the risk of serious adverse events.

Main safety outcomes of Pfizer-BioNTech COVID-19 vaccine

Any adverse events (measured at 2 months )

The relative risk of any adverse events in the group that received Pfizer-BioNTech COVID-19 vaccine versus the group that received placebo vaccine was 2.19 (95% CI 2.1 to 2.28). This means that, in relative terms, Pfizer-BioNTech COVID-19 vaccine increased the risk of any adverse events in 119%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse events. Comparison: Pfizer-BioNTech COVID-19 vaccine versus placebo vaccine

In the available trial, 2638 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 21631 presented this outcome (1220 per 10000) versus 5770 out of 21621 in the group that did receive it (2670 per 10000). In other words, 1450 more people per 10000 did develop the outcome because of the vaccine. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTH is 7.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Non-serious adverse events

The total number of non-serious adverse events was not reported as a group, so it was not possible to estimate the effect for this outcome.

The most common adverse reactions associated with Pfizer-BioNTech COVID-19 vaccine were fatigue (59% versus 23% among younger vaccine recipients and 51% vs 17% in older recipients%); headache (52% versus 24% among younger vaccine recipients and 39% versus 14% in older recipients) and fever after the second dose (16% among younger vaccine recipients and 11% in older recipients) [Walsh EE, 2020 ].

Serious adverse events (measured at 2 months )

The relative risk of serious adverse events in the group that received Pfizer-BioNTech COVID-19 vaccine versus the group that received placebo vaccine was 1.14 (95% CI 0.88 to 1.46). This means that, in relative terms, Pfizer-BioNTech COVID-19 vaccine increased the risk of serious adverse events in 14%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: serious adverse events. Comparison: Pfizer-BioNTech COVID-19 vaccine versus placebo vaccine

In the available trial, 111 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 21631 presented this outcome (51 per 10000), versus 126 out of 21621 in the group that did receive it (58 per 10000). In other words, 1 more person per 1000 experienced serious adverse events due to receiving the vaccine. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTH is 1429.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate. The reason for downgrading the certainty of the evidence is imprecision because of the low number of events and wide confidence interval. No reasons for concern were detected in relation to risk of bias, inconsistency, indirect evidence or publication bias.

Safety of the vaccine in subgroups

Any adverse events (5-15y) (measured at 2 months )

The relative risk of any adverse events (5-15y) in the group that received Pfizer-BioNTech COVID-19 vaccine versus the group that received placebo vaccine was 1.12 (95% CI 0.91 to 1.37). This means Pfizer-BioNTech COVID-19 vaccine increased the risk of any adverse events (5-15y) by 12%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse events (5-15y). Comparison: Pfizer-BioNTech COVID-19 vaccine versus placebo vaccine

In the trials identified in this review, 136 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 1879 presented this outcome (724 per 10000) versus 234 out of 2649 in the group that did receive it (807 per 10000). In other words, 83 more people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk increase of 12%, or that the intervention increased the risk of any adverse events (5-15y) by 12 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTH is 120. Which means that 120 people need to receive the vaccine for one of them to not any adverse events (5-15y).

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Summary of findings table (iSoF)

Safety of the vaccine in subgroups

Sex
Randomized trials
The proportion of females in the C4591001 trial was 49.4% (18631 out of 37706 participants). [Polack, Fernando P., 2020 ]

The proportion of females that experienced adverse effects with Pfizer-BioNTech COVID‑19 Vaccine versus the group that received placebo vaccine was not reported in detail. However, no specific safety concerns were identified in this subgroup.

Other comparative studies
The phase 4, non-randomized study Shieldvacc2 is currently evaluating the effectiveness/safety of the vaccine in women of child-bearing potential using contraception, 12 years of age and older, vaccinated with two-doses of Comirnaty. [Medizinische Universität Innsbruck, Institut für Virologie, 2021 ]

Dagan et al. report an increased risk of myocarditis mostly among young male adolescents and adults (16 to 39 years of age), with 8.62 excess events per 100,000 persons (95% CI,  2.82 to 14.35) among vaccinated individuals. [Dagan N, 2021 ]

Li LL et al. included 3,118,802 participants who had received one dose of a SARS-CoV-2 mRNA vaccine and 2,979,326 who had received two doses (1,389,401 Pfizer and  1,589,925 Moderna). Data were collected during the period from December 12, 2020, to August 21, 2021. The study results showed that, Overall, two-dose mRNA vaccine regimens are safe in a population with many comorbidities.  Weakness, muscle aches, fever, mental status changes, falls, dehydration and acute kidney injury were transiently increased after vaccination, especially after the second dose. Among patients with prior SARS-CoV-2 infection, there was an increased risk of hospitalization (absolute risk 1:1000). [Li LL, 2022 ]

Caspersen IH et al was a cohort study that included 7,565 girls. The study assessed menstrual disturbances in 12- to 15-year-old girls after one dose of Pfizer-BioNTech, from March 2020 to September 2021. The relative risk of menstrual disturbances during the first cycle after vaccination compared the the last cycle prior to vaccination was 1.60 (95% CI, 1.43-1.80) for heavier bleeding, 1.39 (95% CI, 1.22-1.59) for prolonged bleeding, 1.19 (95% CI, 1.07-1.32) for shorter interval, 1.15 (95% CI, 1.05-1.27) for longer interval, 1.06 (95% CI, 0.92-1.23) for spot bleeding, 1.14 (95% CI, 1.04-1.26) for stronger period pains, 1.00 (95% CI, 0.90-1.11) for period pains without bleeding, and 0.97 (95% CI, 0.76-1.25) for other symptoms from the pelvic region. [Caspersen IH, 2022 ]

Age
Randomized trials
The proportion of patients >55 years in study C4591001 was 25% (15,921 of 37,706 participants) [Polack, Fernando P., 2020 ].

Pain at the injection site was the most commonly reported local reaction, and occurred more frequently in the younger group (participants 16-55 years of age) than in the older group (>55 years of age) [FDA, 2020 ].

Systemic adverse events were more frequently reported in the younger group compared with the older age group. Across all age groups, systemic adverse events resolved within a median duration of 1 day [Polack, Fernando P., 2020 ].

The phase 3, randomized, double-blind trial B7471026 is currently evaluating the efficacy/safety of the vaccine in vaccinated adults 65 years of age and older [Pfizer, 2021 ].
            
The proportion of participants 65-85 years in the BNT162-03 was 50% (72 out of 144 participants) [Li J, 2021 ].
           
In the 65-85 years old group, 83% of participants in the 10 µg BNT162b1 dose group, 92% of participants in the 30 µg BNT162b1 dose group, and 8% of participants in the placebo group reported at least one solicited adverse reaction. Reactogenicity was dose-level dependent and was most evident in the group receiving 30 µg, BNT162b1. Older participants did not have increased reactogenicity after the BNT162b1 boost dose [Li J, 2021 ]. 
        
Grade 3 fever was reported in 8% of older participants who received 30 µg BNT162b1. One male participant in the older age group experienced an episodic grade 3 fever accompanied by pain and pruritus at the injection site after the prime BNT162b1 dose at 30 µg and electively withdrew before receiving the boost vaccination   [Li J, 2021 ].

Other comparative studies
The interventional, non-randomized study COGEVAX-BIO is currently evaluating the effectiveness/safety of the vaccine in people over age 75 institutionalized in the long-term care units [Gérond'if, 2021 ].

The non-randomized study Covid-19-Abs is currently evaluating the effectiveness/safety of the vaccine in residents and staff associated with nursing homes, extended care facilities, and over 55 communities [Dr. Sidney J. Stohs, 2021 ].
    
Dagan et al. report an increased risk of myocarditis mostly among young male adolescents and adults (16 to 39 years of age), with 8.62 excess events per 100,000 persons (95% CI,  2.82 to 14.35) among vaccinated individuals [Dagan N, 2021 ].

Li LL et al. included 3,118,802 participants who had received one dose of a SARS-CoV-2 mRNA vaccine and 2,979,326 who had received two doses (1,389,401 Pfizer and  1,589,925 Moderna). Data were collected during the period from December 12, 2020, to August 21, 2021. The study results showed that, Overall, two-dose mRNA vaccine regimens are safe in a population with many comorbidities.  Weakness, muscle aches, fever, mental status changes, falls, dehydration and acute kidney injury were transiently increased after vaccination, especially after the second dose. Among patients with prior SARS-CoV-2 infection, there was an increased risk of hospitalization (absolute risk 1:1000).

Chen PY et al. was a comparative cohort study that included 30,832 people who received booster doses in the Taipei Veterans General Hospital.  The study analyzed the reported incidence rate, and factors associated with adverse events, including short-term serious adverse events and short-term non-serious adverse events, among different vaccine products through the hospital-based Vaccine Adverse Event Reporting System. A total of 7,432 records were collected during the three-month study period.  Respondents under 39 years of age had a higher incidence rate of adverse events (61.9%) than those between 40 and 64 years of age (48.7%), and those over 65 years of age (26.3%). The incidence of adverse events in Moderna COVID-19 vaccine is higher than in Pfizer COVID-19 vaccine and MVC-COV1901 (IRR Moderna vs. Pfizer COVID-19 vaccine: 1.22, 95% CI: 1.11 to 1.34; Pfizer COVID-19 vaccine vs. MVC-COV1901: 2.77, 95% CI: 2.27 to 3.3 [Chen PY, 2022 ]

Yamin D et al was a retrospective cohort study conducted in Israel that included 863,886 people aged 60 years and above who received the first, second monovalent and/or bivalent BNT162b2 mRNA COVID-19 vaccine boosters between July 2021 and November 2022. The risk difference after the bivalent booster was -3.03 (95% CI, -5.45 to -0.61) for arrhythmia, 0.2 (95% CI, -0.4 to 1.01) for Deep Vein Thrombosis, 0.4 (95% CI, -1.41 to 2.22) for heart failure, 0.2 (95% CI, -0.4 to 0.81) for intracranial hemorrhage, -0.61 (95% CI, -2.02 to 0.81) for ischemic stroke, 0.81 (95% CI, -0.2 to 2.02) for myocardial infarction and 0.61 (95% CI, 0.0 to 1.41) for other thrombosis [Yamin D, 2023 ].

Children and adolescents
Randomized trials
In the phase 2/3 components of the C4591001 trial, reactogenicity was measured in a subset that included 8183 participants (≥12 years of age). Reactogenicity data were collected by participants’ e-diary reporting local reactions and systemic events for 7 days after each dose.
This preliminary data provides support of safety on adolescents 12 to 15 years of age [FDA, 2020 ].

Younger adolescents 12 to 15 years of age (49/100 in the vaccine group and 51/100 in the placebo group) contributed to a preliminary reactogenicity data analysis. In this age group, pain at the injection site was the most frequent local reaction, reported in 71.4% of participants in the vaccine group, compared to 17.6% in the placebo group after Dose 1 [FDA, 2020 ].

Most systemic events in younger adolescents were mild to moderate in severity. Severe events were relatively infrequent in both groups, occurring in no more than 1 or 2 participants after either dose [FDA, 2020 ]

The proportion of participants 12-15 years in the C4591001 trial was 67.3% (2260 out of 3358 participants)  [Frenck RW, 2021 ]. 
The proportion of participants 16-25 years in the C4591001 trial was 32.7% (1098 out of 3358 participants)  [Frenck RW, 2021 ].
In both age cohorts (12-5 years and 16-25 years), BNT162b2 recipients reported more local events than placebo recipients. Local events were generally mild to moderate in severity, reported at similar frequencies in both age cohorts ), and typically resolved within 1 or 2 days. Injection-site pain was the most common local reaction in all groups. Severe injection-site pain after any BNT162b2 dose was reported in 1.5% of 12-to-15-year-old participants and in 3.4% of 16-to-25-year-old participants; no severe pain was reported after placebo administration  [Frenck RW, 2021 ].
In both age cohorts (12-5 years and 16-25 years), headache and fatigue were the most frequently reported systemic events. After BNT162b2 injection, severe headache and severe fatigue were reported in a lower percentage of 12-to-15-year-old participants than of 16-to-25-year-old participants. Fever with a temperature ≥38°C occurred after the second dose of BNT162b2 in 20% of 12 to 15-year-old recipients and in 17% of 16 to 25 years old recipients. Fever with a temperature higher than 40°C occurred 1 day after the first dose of BNT162b2 in 0.1% of the 12-to-15-year-old participants [Frenck RW, 2021 ].

Other comparative studies
C4591007 is an ongoing non-randomized study evaluating the safety in healthy children ages 12 years and less [BioNTech SE, 2021 ]
The non-randomized study COVA is currently evaluating the effectiveness/safety of the vaccine in healthy or clinically stable participants aged 11 years and older [The University of Hong Kong, 2021 ].

Cheng DR  et al was a comparative study conducted in Australia. The study included 454,974 12 to 17 years old participants who had received 871,689 mRNA doses (782,964 Pfizer and 88,725 Moderna). The aim was to describe myocarditis adverse events following any COVID-19 mRNA vaccines in the adolescent population. Confirmed myocarditis reporting rates were 8.3 per 100 000 doses in this age group (aggregated data for both mRNA vaccines) [Cheng DR, 2022 ].

CoVacU5 was a retrospective cohort study conducted in Germany that included 7,806 children younger than 5 years old who received 3 to 10 μg of the BNT162b2 vaccine. The study aimed to report short-term safety data in children from birth to younger than 60 months. In the active-comparator analysis of symptoms occurring after Pfizer-BioNTech vaccination versus non-Pfizer-BioNTech vaccination showed ORs of 1.62 (95% CI, 1.43-1.84) for any symptoms, 1.68 (95% CI, 1.38-2.05) for local injection-site symptoms, 2.55 (95% CI, 1.32-4.94) for musculoskeletal symptoms, 2.18 (95% CI, 10.7-4.45) for dermatologic symptoms and 6.37 (95% CI, 1.50-27.09) for otolaryngological symptoms. [Toepfner N, 2022 ].

Cristina Morciano et al was a self-controlled case series study that included 15,986,009 participants who received at least one dose of COVID-19 vaccine: 10,833,284 with Pfizer vaccine, 1,706,979 with Moderna vaccine, 2,863,950 with AstraZeneca vaccine and 581,796 with Janssen vaccine. This study investigated the risk of Guillain Barré Syndrome after vaccination with anti-COVID-19 vaccines. Relative incidence of Guillain Barré Syndrome for the second dose of Pfizer vaccine was 0.85 (95% CI, 0.49-1.48). [Cristina Morciano, 2023 ]

Mangat et al was an observational study conducted in the United States that analyzed data from 177,679 reports of adverse events following immunization attributed to the Pfizer vaccine. The overall crude cumulative reported rate of solicited adverse events per 100,000 fully vaccinated was 3.06 (95% CI, 2.70–3.47) for the 5–11 years age group, 18.25 (95% CI, 17.57–18.95) for the 12–17 years age group and 33.74 (95% CI, 33.36–34.13) for the 18–65 years group. [Mangat HS, 2023 ]

Buchan SA et al was a cohort study conducted in Canada that analyzed data from 1.65 million doses of Pfizer administered to indiviuals aged 12 to 17 years. The aim was to estimate the incidence of reported myocarditis or pericarditis after vaccination.The reported incidence after the first dose was 3.1 (95% CI, 2.0-4.5) per 100,000 doses administered. The reported incidence after the seconde dose was 6.3 (95% CI, 4.7-8.3) per 100,000 doses administered. [Buchan SA, 2023 ]

Ahsan M et al was a cross sectional study conducted in India that included data from 385 children between 5-17 years. The aim was to assess the frequency and severity of adverse events following immunization with the Pfizer vaccine. The frequency of adverse events following immunization was reported to be higher after the first dose than after the second with an Odds Ratio (OR) of 2.12 (95% CI, 1.57–2.86). [Ahsan M, 2023 ]
    
Pregnancy
Randomized trials
A total of 23 participants reported pregnancy during the trial. Nine of them withdrew from the study but the follow-up on these participants continues in order to assess pregnancy outcomes [Polack, Fernando P., 2020 ].

C4591015 is an ongoing phase 2/3, randomized trial evaluating the safety in this subgroup [BioNTech SE, 2021 ].
     
Other comparative studies 
Shimabukuro et al. (CDC report) was a safety monitoring non-comparative study that enrolled 16,439 pregnant women that received Moderna or Pfizer COVID-19 vaccine. Results showed that the most frequent local and systemic reactions wer: 95.6% injection-site pain, 80.6% fatigue, 65.0% headache, 46.0% fever or felt feverish. Adverse neonatal outcomes included preterm birth (in 9.4%) and small size for gestational age (in 3.2%); no neonatal deaths were reported (Data based on 827 participants in the v-safe pregnancy registry who received an mRNA Covid-19 vaccine, BNT162b2 or mRNA-1273). Among 221 pregnancy-related adverse events reported to the VAERS, the most frequently reported event was spontaneous abortion (46 cases) [Shimabukuro TT, 2021 ].

An analysis of the CDC v-safe COVID-19 Pregnancy Registry in 19,252 pregnant people who received the vaccine did not show obvious safety signals [Shimabukuro TT, 2021 ].

Nakahara A et al.  included 83 vaccinated pregnant women that received mRNA COVID-19 vaccines (Moderna or Pfizer). These pregnant women were age-matched with 166 female controls. Safety was assessed as any vaccine-related complaint as defined in the original safety data. Results showed a frequency of complaint following vaccine administration of  18.1% in the pregnant group and  16.9% in the non-pregnant group. The most frequent local and systemic reactions in Pregnant females were:  fever 4.8%, Cough/Shortness of Breath 4.8 %, Vomiting/Diarrhea 4.8%. Complaint frequency was higher after the second dose (12.3 %) than after the first dose (6%) [Nakahara A, 2022 ].

Aharon D et al. included 222 vaccinated (Pfizer =119 or Moderna =103) patients and 983 unvaccinated patients who underwent controlled ovarian hyperstimulation cycles between February and September 2021. Data collected included oocyte, fertilization, and embryo development parameters, as well as results of preimplantation genetic testing for aneuploidy among cycles in which testing was performed. The study showed that the administration of Pfizer or Moderna COVID-19 vaccine was not associated with an adverse effect on stimulation or early pregnancy outcomes after in vitro fertilization. The fertilization rate for the controlled ovarian hyperstimulation cohort was  80.7% (95% CI 78.4 to 83.0) in the vaccinated group and 78.7% in unvaccinated groups (95% CI 77.5 to 80.0). No differences were observed between vaccinated and unvaccinated patients on univariate analysis in the secondary outcomes of eggs retrieved, mature oocytes retrieved, mature oocytes ratio, or blastulation rate. In cycles in which preimplantation genetic testing for aneuploidy was performed, vaccinated patients had a proportion of euploid embryos of 48.8% (95% CI 44.1 to 53.6) compared with 42.5% (95% CI 40.2 to 44.9) in unvaccinated patients [Aharon D, 2022 ].

Montalti M et al. was a cross-sectional study that enrolled 600 female physicians aged from 24 to 60  years old; 131 pregnant and 469 breastfeedings that received Moderna or Pfizer COVID-19 vaccine. Results showed that 16  of the 31 immunized pregnant women,  reported at least one symptom after the first, and 14  after the second vaccine dose. After the first dose, 64.5% had nausea/vomiting, 25.8% fatigue, and 12.9% headache and arthralgia/myalgia; flushing and low back pain were rare. After the second dose, 76.5% of respondents had nausea/vomiting, 70.6% fatigue, and 41.2% arthralgia/myalgia [Montalti M, 2022 ].

Botton J et al. was a self-controlled case series conducted in France. The study included participants  (8,358  first dose of ChAdOx1; 4,887 Second dose of ChAdOx1; and5 third ChAdOx1 dose) aged 18 to 74 years hospitalized for pulmonary embolism, acute myocardial infarction, hemorrhagic stroke, or ischemic stroke between December 27, 2020, and December 20, 2021. This study assessed the short-term risk for severe cardiovascular events after COVID-19 vaccination in France's 46.5 million adults. The primary outcome was hospitalizations for cardiovascular events (Myocardial infarction, pulmonary embolism, or stroke). There was an increase in the incidence of myocardial infarction and pulmonary embolism after adenoviral-based vaccines (ChAdOx1 nCoV-19 vaccine). The RI during the second week after the dose of the ChAdOx1 vaccine for Myocardial Infarction was 0.84 (95% CI, 0.53-1.34),  1.29 (95% CI, 0.94-1.78) for Pulmonary Embolism,  0.88 (95% CI, 0.69-1.12) for  Ischemic Stroke, and  1.36 (95% CI, 0.89-2.07) for  Hemorrhagic Stroke [Botton J, 2022 ].

Rottenstreich et al conducted a multicenter retrospective study. Parturients who delivered in Israel between August and December 2021 with complete records of COVID-19 disease and vaccination status were included. A total of 2583 women were included in the analysis: 626 received the third booster dose of the BNT162b2, 1094 received two doses of the vaccine, and 863 were unvaccinated. Receiving the third booster was not associated with an increase in either composite adverse maternal or neonatal outcome (aOR 0.9; 95% CI [0.65–1.22], p= 0.47; aOR 0.7; 95% CI [0.53–1.035], p=0.09, respectively) when compared to those who received two doses of the vaccine. Administration of the third booster dose during pregnancy was associated with a reduced composite adverse neonatal outcome compared to unvaccinated women (aOR 0.6; 95% CI [0.42–0.86], p=0.01) [Rottenstreich M, 2022 ].

Kachikis et al analyzed a convenience sample of adults enrolled in the online prospective study. Participants who were pregnant, lactating, or neither pregnant nor lactating at the time of their booster or third dose were eligible for this follow-up survey; 17,014 (97.2%) completed the follow-up survey. 16,989 individuals reported their vaccine type for booster or third dose, most of them received the BNT162b2 (10,319 [60.7%]) or mRNA-1273 (6651 [39.2%]) vaccines. After a COVID-19 booster or third dose, 82.8% reported a local reaction, and 67.9% reported at least 1 systemic symptom. Compared with individuals who were neither pregnant nor lactating, pregnant participants were more likely to report any local reaction to a COVID-19 booster or third dose (aOR 1.2, 95% CI, 1.0-1.4; p = 0.01) but less likely to report any systemic reaction (aOR 0.7, 95% CI, 0.6-0.8; p<0.001). Most pregnant (1961 of 2009 [97.6%]) and lactating (9866 of 10,277 [96.0%]) individuals reported no obstetric or lactation concerns after vaccination. aOR = adjusted odds ratio [Kachikis A, 2022 ]

Sadarangani M et al was a cohort study conducted in Canada. This study aimed to determine the frequency and nature of significant health events among pregnant females after COVID-19 vaccination, compared with unvaccinated pregnant controls and vaccinated non-pregnant individuals. Data were collected primarily by self-reported survey after both vaccine doses. Most pregnant participants had received BNT162b2 (3414 received dose one and 1892 received dose two) or mRNA-1273 (2183 received dose one and 1216 received dose two) COVID-19 vaccines. Pregnant vaccinated females had decreased odds of a significant health event compared with non-pregnant vaccinated females after both dose one (aOR 0.63 95% CI 0.55 to 0.72]) and dose two (aOR 0.62 [0.54 to 0.71]) of any mRNA vaccination. Pregnant vaccinated females had an increased odds of a significant health event within 7 days of the vaccine after dose two of mRNA-1273 (adjusted odds ratio 4.4 95% CI 2.4 to 8.3]) compared with pregnant unvaccinated controls and 1.3 (95% CI 0.67 to 2.42) after the second dose of Pfizer vaccine. [Sadarangani M, 2022 ].

DeSilva et al. was a retrospective matched-cohort study including 45,232 pregnant women between 16-49 years, who received Pfizer-BioNTech, Moderna or Janssen vaccines and matched unvaccinated controls. The adjusted Rate Ratios (aRR) for acute maternal outcomes during days 0-21 after receiving Pfizer-BioNTech vaccines were 1.71 (95% CI, 1.08-2.7) for skin and soft tissue or local allergic reactions, 1.87 (95% CI, 0.96-3.65) for fever, 1.77 (95% CI, 1.22-2.56) for malaise and 2.39 (95% CI, 1.37-4.17) for lymphadenopathy. [DeSilva M, 2022 ].

Covas D et al was a cross-sectional study conducted in Brazil that included 2,486 pregnant and postpartum women vaccinated with: 187 Sinovac, 572 Pfizer, 1,712 AstraZeneca and 15 Janssen. The aim was to describe the adverse events of COVID-19 vaccines in pregnant and postpartum women in the early stage of the vaccination campaign in Brazil. Incidence of adverse events notified for pregnant women was 92.5 (95% CI, 78.95-106.04), 150.14 (95% CI, 137.72-162.57), 4463.3 (95% CI, 4255.55-4671.04) and 4087.19 (95% CI, 2061.54-6112.85) for Sinovac, Pfizer, AstraZeneca and Janssen vaccine, respectively. Incidence of adverse events notified for postpartum women was 15.28 (95% CI, 5.3-25.26), 10.78 (95% CI, 4.68-16.88), 65.5 (95% CI, 35.25-95.75 and 0 (95% CI, 0-0) for Sinovac, Pfizer, AstraZeneca and Janssen vaccine, respectively [Covas DT, 2023 ].

Mansour O et al was a prospective cohort study conducted in the United States including 2,129 pregnant women from the C-VIPER cohort who received at least one dose of Pfizer or Moderna vaccines. The estimated overall cumulative risk of spontaneous abortion (SAB) by gestational week 20 was 13.4% (95% CI, 8.3% to 16.9%), which is within the range estimated by both population-based cohorts and v-safe. The cumulative risk of SAB by week 20 for Pfizer was 10.9% (95% CI, 5.9% to 14.7%), The cumulative risk of SAB by week 20 for Moderna was 20.6% (95% CI, 8.8% to 29.4%). [Mansour O, 2023 ]

Morgan et al was a retrospective cohort study conducted in the United States that included 15,865 pregnant patients: 2,069 in the vaccinated group and 13,796 in the unvaccinated group. The study compared the frequency of adverse outcomes in between pregnant patients who received mRNA vaccines and unvaccinated patients. Vaccination was associated with a lower incidence of perinatal death (aOR 0.20 [95% CI, 0.05–0.88]), rates of preterm delivery (aOR 0.63 [95% CI, 0.48–0.82]), neonates with very low birth weight (aOR 0.35 [95% CI, 0.15–0.84]), and neonatal intensive care unit admission (aOR 0.66 [95% CI, 0.52–0.85]). aOR = adjusted Odds Ratio [Morgan JA, 2023 ].

Woestenberg PJ et al was a cohort study conducted in the Netherlands, including 4,348 pregnant women who received at least one dose of Pfizer, Moderna or AstraZeneca. After the first dose, 59% of the women reported 1 or more adverse reactions: 68% for Moderna, 87% for AstraZeneca and 56% for Pfizer. After the first dose, injection site reaction was most commonly reported (32% of women), followed by myalgia (26%) and fatigue (20%). After the second dose, fatigue was most commonly reported (28% of women), followed by myalgia (24%) and injection site reaction (23%).
[Woestenberg PJ, 2022 ].

Breastfeeding
Randomized trials
Breastfeeding females were excluded from the C4591001 trial, so no data are available for this subgroup [Polack, Fernando P., 2020 ].

Other comparative studies
The cohort O'Connor DL et al is currently evaluating the effectiveness/safety of the vaccine in lactating mothers [Deborah O'Connor, 2021 ].
    
Golan et al. was a prospective cohort study that enrolled 50 lactating individuals who received mRNA-based vaccines for COVID-19 (mRNA-1273 and BNT162b2), blood and milk samples were collected prior to first vaccination dose, immediately prior to 2nd dose, and 4-10 weeks after 2nd dose. Results showed no severe maternal or infant adverse effects. Vaccine-related products, PEGylated proteins, were not found at significant levels in milk after vaccination [Golan Y et al., 2021 ].

Kachikis et al . analyzed a convenience sample of adults enrolled in the online prospective study. Participants who were pregnant, lactating, or neither pregnant nor lactating at the time of their booster or third dose were eligible for this follow-up survey; 17,014 (97.2%) completed the follow-up survey. 16,989 individuals reported their vaccine type for their booster or third dose, most received the BNT162b2 (10,319 [60.7%]) or mRNA-1273 (6651 [39.2%]) vaccines. After a COVID-19 booster or third dose, 82.8% reported a local reaction, and 67.9% reported at least 1 systemic symptom. Compared with individuals who were neither pregnant nor lactating, pregnant participants were more likely to report any local reaction to a COVID-19 booster or third dose (aOR 1.2; 95% CI, 1.0-1.4; p = 0.01) but less likely to report any systemic reaction (aOR 0.7; 95% CI, 0.6-0.8; p<0.001). Most pregnant (1961 of 2009 [97.6%]) and lactating (9866 of 10,277 [96.0%]) individuals reported no obstetric or lactation concerns after vaccination. aOR = adjusted odds ratio [Kachikis A, 2022 ]

Montalti M et al. was a cross-sectional study that enrolled 600 female physicians aged from 24 to 60  years old; 131 pregnant and 469 breastfeedings that received Moderna or Pfizer COVID-19 vaccine. Among 315 immunized breastfeeders, 75.2% (n = 237) reported at least one symptom after the first dose, and 81.6% (n = 142) after the second. The most common adverse events occurring after the first dose were nausea/vomiting (60%), fatigue (28.3%), and headache (26.3%). Rarer events included dizziness, shivering, and limb paresthesia. After the second dose, 51.1% of them reported nausea/vomiting, 48.9% fatigue, and 49.4% arthralgia/myalgia [Montalti M, 2022 ].

Persons with comorbidities
Randomized trials
Available data are currently insufficient to assess safety in individuals with comorbidities.

Other comparative studies
The phase 4, non-randomized study HHCTC_COVID-19_VACCINE_Ab is currently evaluating the effectiveness/safety of the vaccine in adults with chronic liver disease or Underlying CLD, aged 18 years and older [Humanity & Health Medical Group Limited, 2021 ].

Apaydin H et al. was a cross-sectional study that enrolled 450 Behçet syndrome patients followed in a clinic who met the criteria of the International Study Group that received the Pfizer or Sinovac COVID-19 vaccine. 287 patients received at least one dose of the COVID-19 vaccine. Adverse events were reported by 151 (52.6%) patients after the first dose, 135 (49.4%) after the second vaccine dose, 29 (42.6%) after the third vaccine dose, and 3 (30%) patients after the fourth vaccine dose. Injection site pain/swelling was the most common adverse effect at all vaccine doses, followed by fatigue, and arthralgia [Apaydin H, 2022 ].

Immunocompromised persons
Randomized trials
The phase 4, a single-center, open-label, investigator-initiated randomized controlled, superiority trial BECAME is currently evaluating the efficacy/safety of the vaccine in kidney transplant recipients [dafna yahav, 2021 ].

The phase 3, multicenter randomized controlled, open-label, 2-arm sub-study pilot trial COVERALL is currently evaluating the efficacy/safety of the vaccine in patients included in the Swiss HIV Cohort Study or the Swiss Transplant Cohort Study [University Hospital, Basel, Switzerland, 2021 ].

The phase 2, randomized, single-blinded study Boost-TX is currently evaluating the efficacy/safety of the vaccine in kidney transplant recipients [Medical University of Vienna, 2021 ].
           
Other comparative studies
The cohort study COVATRANS is currently evaluating the effectiveness/safety of the vaccine in kidney transplant recipients aged 15 years and older who receive Pfizer, Moderna and Astra-Zeneca vaccines [University Hospital, Strasbourg, France, 2021 ].

The non-randomized study COVAC-IC is currently evaluating the effectiveness/safety of the vaccine in immunocompromised and immunocompetent haematology patients aged 18 years and older [University Hospitals of North Midlands NHS Trust, 2021 ].

The monocentric observational study ANTICOV is currently evaluating the effectiveness/safety of the vaccine in cancer patients aged 18 years and older, to evaluate the effectiveness of BNT162b2 or mRNA-1273 vaccine [Azienda Socio Sanitaria Territoriale di Cremona, 2021 ].

The non-randomized study UNICO is currently evaluating the effectiveness/safety of the vaccine in cancer patients aged 18 years and older [Ente Ospedaliero Ospedali Galliera, 2021 ].

The non-randomized study COViNEPH-1 is currently evaluating the effectiveness/safety of the vaccine in patients on chronic dialysis vaccinated with BNT162b2 [Medical University of Gdansk, 2021 ].

The prospective, cohort, non-interventional, single-center clinical study ImmunoHaema-COVID-VAX-21 is currently evaluating the effectiveness/safety of the vaccine in patients with haematological malignancies 18 years of age and older [Ospedale di Circolo - Fondazione Macchi, 2021 ].

The phase 2, non-randomized study C4591024 is currently evaluating the effectiveness/safety of the vaccine in immunocompromised participants ≥2 Years Of Age [BioNTech SE, 2021 ].

The non-randomized study IROC is currently evaluating the effectiveness/safety of the vaccine in cancer patients 18 years of age and older [Indiana University, 2021 ].

The non-randomized study LymphVAX is currently evaluating the effectiveness/safety of the vaccine in women with a history of breast cancer [Massachusetts General Hospital, 2021 ].

The non-randomized study VIOLA is currently evaluating the effectiveness/safety of the vaccine in COVID-negative Multiple Sclerosis patients treated with ocrelizumab [NYU Langone Health, 2021 ].

The phase 4, non-randomized study Covid Vaccin Allo is currently evaluating the effectiveness/safety of the vaccine in patients allo-hematopoietic cell transplantation recipients [University of Liege, 2021 ].

The non-randomized study VAX4FRAIL is currently evaluating the effectiveness/safety of the vaccine in frail subjects with impaired immuno-competence, due to their underlying diseases or ongoing therapies that received SARS-CoV-2 with Pfizer-BioNTech or Moderna vaccines [Azienda Unità Sanitaria Locale Reggio Emilia, 2021 ].

The phase 4, non-randomized study EREVA is currently evaluating the effectiveness/safety of the vaccine in adults immunocompromised or non-immunocompromised volunteers [Centre Hospitalier Régional d'Orléans, 2021 ].

The phase 1 and 2, interventional, non-randomized study PACIFIC is currently evaluating the effectiveness/safety of the vaccine in children with acute leukemia (1 to 15 years old) and their siblings (≥12-15 years old) [Assistance Publique - Hôpitaux de Paris, 2021 ].

The non-randomized study CPAT is currently evaluating the effectiveness/safety of the vaccine in kidney transplant recipients [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ].

Shulman et al. was a comparative study conducted in the United States [Shulman RM, 2022 ], which recorded short-term adverse reactions to the COVID-19 vaccine in patients with cancer; it also compared the magnitude and duration of these reactions with those of patients without cancer and determined whether these adverse reactions are related to active cancer therapy. The study included patients with and without a history of cancer at an NCI-designated Comprehensive Cancer Center between February 16, 2021 and May 15, 2021. Post-vaccination symptoms were common and reported with similar frequencies by patients with and without cancer (73.3% vs 72.5%). There were no significant differences between patients with and without cancer in the frequency of adverse events when responses to the first and second vaccine dose were tabulated separately (dose 1: 61.3% vs 60.2%; dose 2: 64.2% vs 62.8%). The adverse event profile for patients with cancer receiving active treatment did not differ by treatment type for either dose 1 or dose 2. The authors suggest that the mRNA COVID-19 vaccine is well tolerated by patients with a history of cancer, including those receiving active treatment. Adverse events occurring shortly after vaccination closely resemble those seen in patients without cancer [Shulman RM, 2022 ].

Vinante L et al. was a comparative cohort that included 361 patients with 756 administered COVID-19 vaccinations (Pfizer:529 doses; Moderna: 194 doses; AstraZeneca: 28 doses; Janssen 5 doses). The study assessed the incidence of radiation recall dermatitis after COVID-19 vaccination in breast cancer patients previously treated with postoperative radiation therapy. Results showed that breast symptoms were reported by 7.5% of patients, while radiation recall dermatitis was considered for 5.5%. Radiation recall dermatitis was more common in the first dose compared to the second (4.4%) or third (1%), especially when administered within the first month after irradiation (12.5% vs 2.2%). Symptoms were generally self-limited, and anti-inflammatory medications were required in a few cases [Vinante L, 2022 ].

Persons living with HIV
Randomized trials
Available data are currently insufficient to assess safety in persons living with HIV.