Risk considerations

Risk of insertional mutagenesis
Unlike DNA vaccines, which might carry a small risk of insertional mutagenesis and integration, mRNA does not have the potential to integrate into the host genome and is degraded naturally during the process of antigen expression [Stenler S, 2014 ].

Risk of infection
Moderna COVID-19 vaccine is a non-replicating platform. This means the delivered mRNA does not carry an intrinsic risk for infection [GAVI,2020 ]. Additionally, contaminating microorganisms in mRNA vaccines are unlikely because the manufacturer does not need bacterial cell culture [Pardi N, 2018 ].

Inflammatory reactions
mRNA vaccines have a more pronounced proinflammatory nature. This feature might provide a self-adjuvant property but also can result in local and systemic reactions
[Liu MA, 2019 ]. However, a proposed mechanism for possible autoimmune responses is via the induction of type I interferon, which has been observed in preclinical studies [Pepini T, 2017 ].

Allergic reactions
Most immediate allergic reactions associated with vaccines are related with excipients
[Stone CA, 2019 ]. Polyethylene glycols (PEG) are frequently used as excipients in many liquid and solid formulations of medications and are also used to stabilize the lipid nanoparticle containing the mRNA of Moderna COVID-19 vaccine. Therefore, PEG constitutes the main candidate for explaining the cause of allergic reactions to this vaccine [Stone CA, 2019 ].
PEG itself has not previously used in other vaccines but polysorbate, a closely related compound, has been implicated in allergic reactions to other vaccines [Stone CA, 2019 ].

Efficacy of preclinical studies on the vaccine

The immunogenicity of the Moderna COVID-19 vaccine was tested in non-human primates that received 10 or 100 µg of mRNA-1273 or no vaccine. The mRNA-1273 vaccine candidate induced robust antibody responses with ID50 GMTs higher in the 100 μg dose group (3481) compared to the 10 μg dose group (501). Peak subgenomic RNA levels during days 2 through 7 were significantly lower in both the 100 μg dose group and the 10 μg dose group than the control group, in both bronchoalveolar fluid specimens (BAL) and nasal swab samples. Furthermore, total RNA levels were significantly lower in BAL fluid in both dose groups than in the control group [Corbett KS, 2020 ].

Efficacy of the vaccine in clinical trials

Main immunogenicity outcomes

mRNA-1273-P201 (NCT04405076) was a phase 2 trial sponsored by ModernaTX, Inc. and conducted in the United States. The trial included healthy participants ≥18 years of age. The sample size was 600 (2 cohorts of 300). Participants were randomized 1: 1 to receive Moderna COVID-19 vaccine in doses of 50 µg, 100 µg or placebo. The results showed that in both vaccination schemes of mRNA-1273 vaccine, the geometric mean titers increased 28 days after the first dose. Furthermore, 14 days after the second dose (day 43), the geometric mean titers improved significantly, 1733 (1611-1865) µg/ml in the 50 µg group and 1909 (1849-1971) µg/ml in 100 µg group in young adults, while in older adults, mean titers were 1827 (1722 -1938) µg/ml in the 50 µg group and 1686 [1521-1869] µg/ml in the 100 µg group of mRNA-1273 vaccine [Chu L, 2021 ].

In the preliminary report of the phase 1 study [Jackson LA, 2020 ], it was reported that the vaccine induced anti-SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. In this dose-escalation trial, in 45 adults 18 to 55 years of age antibody responses were higher with higher doses after a first vaccination, and serum neutralizing activity was detected after second vaccination.

Main efficacy outcomes of Moderna COVID-19 vaccine

Key messages

Moderna COVID-19 vaccine reduces the risk of contracting COVID-19

Moderna COVID-19 vaccine reduces the risk of contracting severe COVID-19

Contracting COVID-19 (measured at least 14 days after the second injection, with a median follow-up of 5.3 months after 2nd dose)

The relative risk of contracting COVID-19 in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.07 (95% CI 0.06 to 0.1). This means Moderna COVID-19 vaccine reduced the risk of contracting COVID-19 by 93%, compared with placebo vaccine.

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

In the trial identified in this review, 751 people not receiving Moderna COVID-19 vaccine out of 14164 presented this outcome (49 per 1000) versus 55 out of 14287 in the group that did receive it (4 per 1000). In other words, 45 less people per 1000 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 4.5%, or that the intervention reduced the risk of contracting COVID-19 by 4.5 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 22. Which means that 22 people need to receive the vaccine for one of them to not contract COVID-19.

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

Contracting severe COVID-19 (measured at least 14 days after the second injection, with a median follow-up of 5.3 months after 2nd dose)

The relative risk of contracting severe COVID-19 in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.02 (95% CI 0 to 0.08). This means Moderna COVID-19 vaccine reduced the risk of contracting severe COVID-19 by 98%, compared with placebo vaccine.

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

In the trial identified in this review, 106 people not receiving Moderna COVID-19 vaccine out of 14164 presented this outcome (7 per 1000) versus 2 out of 14287 in the group that did receive it (0 per 1000). In other words, 7 less people per 1000 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 0.7%, or that the intervention reduced the risk of contracting severe COVID-19 by 0.7 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 143. Which means that 143 people need to receive the vaccine for one of them to not contract severe COVID-19.

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

Mortality

The existing evidence does not allow to assess the impact of Moderna COVID-19 vaccine on the risk of death attributable to COVID-19. 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 Moderna COVID-19 vaccine would require trials with a higher statistical power.

Efficacy of the vaccine in subgroups

Contracting COVID-19 (6-11y) (measured at least 14 days after the first injection)

The relative risk of contracting COVID-19 (6-11y) in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.12 (95% CI 0.05 to 0.28). This means Moderna COVID-19 vaccine reduced the risk of contracting COVID-19 (6-11y) by 88%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (6-11y). Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 7 people not receiving Moderna COVID-19 vaccine out of 2887 presented this outcome (20 per 1000) versus 18 out of 880 in the group that did receive it (2 per 1000). In other words, 18 less people per 1000 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 1.8%, or that the intervention reduced the risk of contracting COVID-19 (6-11y) by 1.8 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 NNT is 56. Which means that 250 people need to receive the vaccine for one of them to not contract COVID-19.

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

Contracting COVID-19 after second dose (12-17y) (measured at least 14 days after the second injection)

The relative risk of Contracting COVID-19 after second dose (12-17y) in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.06 (95% CI 0 to 1.03). This means Moderna COVID-19 vaccine reduced the risk of Contracting COVID-19 after second dose (12-17y) by 94%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: Contracting COVID-19 after second dose (12-17y). Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, people not receiving Moderna COVID-19 vaccine out of presented this outcome (3 per 1000) versus out of in the group that did receive it (0 per 1000). In other words, 3 less people per 1000 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 0.3%, or that the intervention reduced the risk of Contracting COVID-19 after second dose (12-17y) by 0.3 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 333. Which means that 250 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: the information provides from a small sample; Publication bias: no concerns.

Contracting COVID-19 (>65y) (measured at least 14 days after the second injection)

The relative risk of Contracting COVID-19 (>65y) in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.11 (95% CI 0.05 to 0.21). This means Moderna COVID-19 vaccine reduced the risk of Contracting COVID-19 (>65y) by 89%, compared with placebo vaccine.

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

In the trial identified in this review, 81 people not receiving Moderna COVID-19 vaccine out of 2898 presented this outcome (8 per 1000) versus 9 out of 2990 in the group that did receive it (1 per 1000). In other words, 7 less people per 1000 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 0.7%, or that the intervention reduced the risk of Contracting COVID-19 (>65y) by 0.7 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 143. Which means that 143 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: the information provides from a small sample; Publication bias: no concerns.

Contracting COVID-19 (>75y) (measured at least 14 days after the second injection)

The relative risk of Contracting COVID-19 (>75y) in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.03 (95% CI 0 to 0.46). This means Moderna COVID-19 vaccine reduced the risk of Contracting COVID-19 (>75y) by 97%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: Contracting COVID-19 (>75y). Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 19 people not receiving Moderna COVID-19 vaccine out of 697 presented this outcome (8 per 1000) versus 0 out of 636 in the group that did receive it (0 per 1000). In other words, 8 less people per 1000 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 0.8%, or that the intervention reduced the risk of Contracting COVID-19 (>75y) by 0.8 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 125. Which means that 125 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: the information provides from a small sample; Publication bias: no concerns.

Contracting COVID-19 (men subgroup) (measured at least 14 days after the second injection)

The relative risk of contracting COVID-19 in men in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.08 (95% CI 0.06 to 0.12). This means Moderna COVID-19 vaccine reduced the risk of contracting COVID-19 in men by 92%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 in men. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 378 people not receiving Moderna COVID-19 vaccine out of 7494 presented this outcome (50 per 1000) versus 30 out of 7439 in the group that did receive it (4 per 1000). In other words, 46 less people per 1000 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 4.6%, or that the intervention reduced the risk of contracting COVID-19 in men by 4.6 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 22. Which means that 22 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: the information provides from a small sample; Publication bias: no concerns.

Contracting COVID-19 (women subgroup) (measured at least 14 days after the second injection)

The relative risk of contracting COVID-19 in women in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.07 (95% CI 0.04 to 0.1). This means Moderna COVID-19 vaccine reduced the risk of contracting COVID-19 in women by 93%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 in women. Comparison: Moderna COVID-19 vaccine versus

In the trial identified in this review, 366 people not receiving Moderna COVID-19 vaccine out of 6670 presented this outcome (55 per 1000) versus 25 out of 6848 in the group that did receive it (4 per 1000). In other words, 51 less people per 1000 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 5.1%, or that the intervention reduced the risk of contracting COVID-19 in women by 5.1 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 20. Which means that 20 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: the information provides from a small sample; Publication bias: no concerns.

Summary of findings (iSoF) Table

Efficacy and effectiveness of the vaccine in subgroups

Sex
Randomized trials
The proportion of females in the COVE trial was 43% (14372 out of 30346 participants) [El Sahly HM, 2021 ].
The relative risk of contracting COVID-19 in men in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.08 (95% CI 0.06 to 0.12). This means Moderna COVID-19 vaccine reduced the risk of contracting COVID-19 in men by 92%, compared with placebo vaccine.
The relative risk of contracting COVID-19 in women in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.07 (95% CI 0.04 to 0.1). This means Moderna COVID-19 vaccine reduced the risk of contracting COVID-19 in women by 93%, compared with placebo vaccine.
The magnitude of the effect was similar between the subgroups, and there was no statistical evidence of a subgroup effect by sex
   
Age
Randomized trials
The proportion of patients ≥65 years of age in the COVE trial was 25% (7512 out of 30351 participants) [El Sahly HM, 2021 ].
The relative risk of contracting COVID-19 (>65y) in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.11 (95% CI 0.05 to 0.21). This means Moderna COVID-19 vaccine reduced the risk of Contracting COVID-19 (>65y) by 89%, compared with placebo vaccine.
The relative risk of contracting COVID-19 (>75y) in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.03 (95% CI 0 to 0.46). This means Moderna COVID-19 vaccine reduced the risk of Contracting COVID-19 (>75y) by 97%, compared with placebo vaccine.
    
The phase 2, open-label study QHD00028 is currently evaluating the efficacy/safety of the vaccine in fully vaccinated adults with mRNA-1273 65 years of age and older [Sanofi Pasteur, a Sanofi Company, 2021 ].
The phase 4, randomized controlled trial mRNA-1273-D3-2021 is currently evaluating the efficacy/safety of the vaccine in vaccinated residents ≥65 years that received  [Mark Loeb, 2021 ].
           
Other comparative studies
The phase 1 study 20-0003 [Anderson EJ, 2020 ], NCT04283461 number, was expanded to include 40 older adults, who were stratified according to age (56 to 70 years or ≥71 years). This study showed that binding- and neutralizing-antibody responses appeared to be similar to those previously reported among vaccine recipients. A follow-up of this study at 119 days after the first vaccination [Widge AT, 2021 ] showed that despite a slight expected decline in titers of binding and neutralizing antibodies, the vaccine provided durable humoral immunity and elicited primarily CD4 type 1 helper T responses. There is no evidence that indicates a lower efficacy in older adults. It is important to notice that very few patients >80 years old were included.

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 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 or more compared with <64 years, even in the pre-Delta period. [Rane MS, 2022 ]
           
Children and adolescents
Randomized trials
The TeenCove or study P203 (NCT04649151) was a phase 2/3 trial sponsored by Moderna evaluating vaccine efficacy in adolescents from 12 to 17 years of age. Results of the study showed an efficacy of the vaccine of 95% after the second dose [Ali K, 2021 ].

The KidCOVE trial or study P204 (NCT04796896) is an ongoing phase 2/3 randomized trial sponsored by Moderna evaluating vaccine efficacy in children from 6 to 11 years of age. Preliminary results showed an efficacy of 88% after the second dose [Creech CB, 2022 ].

Other comparative studies
Levy M et al is a 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 Hazard ratio 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 results. The authors suggest that COVID-19 mRNA vaccination was associated with a lower incidence of multisystem inflammatory syndrome in adolescents [Levy M, 2021 ].

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 ]

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) for the Pfizer/Moderna heterologous 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. VE for the Moderna primary schedule was 70.2% (95% CI, 66.8 to 73.1) during the Delta predominance period, and 17.9% (95% CI, 14.0 to 21.5) during the Omicron predominance period. [Castelli JM, 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 pre-Delta period and 79% (95% CI, 77% to 81%) in 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 more compared with <64 years, even in the pre-Delta period. [Rane MS, 2022 ]

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 (VE) of the second Moderna dose against symptomatic infection was 60% (95% CI, 49% to 68%). VE of monovalent Pfizer-BioNTech doses (complete primary series) against symptomatic infection was 31% (95% CI, 7% to 49%). [Fleming-Dutra KE, 2023 ]

Pregnancy
Randomized trials
The available data are insufficient to assess vaccine efficacy since no clinical trial has included this group.

Other comparative studies
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 ]
    
Breast-feeding
Randomized trials
The available data are insufficient to assess vaccine efficacy since no clinical trial has included this group.

Other comparative studies
Golan et al. was a prospective cohort study that enrolled 50 lactating women 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 ].
    
Alisa Fox et al. was a cohort study that enrolled 50 lactating women (23 participants had received Pfizer vaccine, 14 had received Moderna vaccine, and 13 had received Janssen Vaccine). 50 pairs of milk samples were obtained from vaccine recipients within 1 week before vaccination and 14 days (Pfizer/Moderna) or 28 days (Janssen) after completion of the vaccine regimen. Results showed that Moderna milk samples exhibited significantly greater relative IgA than Pfizer and Janssen recipients. It was found that 100% and 87% of Moderna and Pfizer recipient post-vaccine milk samples contained positive levels of Spike-specific IgG [ ].

Immunocompromised persons 
Randomized trials
The proportion of participants with HIV in the COVE trial was 0.6% (179 out of 30351 participants) [Baden LR, 2021 ].
In a post hoc analysis, the relative risk of contracting COVID-19 in participants living with HIV that received Moderna COVID-19 vaccine versus those that received placebo vaccine was 0.32 (95% CI 0.01 to 7.67) [FDA, 2020 ].
           
COVERALL was a phase 3 randomized trial conducted in Switzerland. The study enrolled 430 patients (412 included in the intention to treat analysis): 341 patients living with HIV and 71 solid organ transplant recipients. Patients were randomized to Moderna or Pfizer–BioNTech. The primary endpoint was antibody response to the SARS-CoV-2 spike (S1) protein receptor binding domain 8 weeks after the second vaccination. The percentage of patients showing an immune response to Moderna was 92.1%  (95% CI 88.4 to 95.8)  and 94.3% (95% CI 91.2 to 97.4) for Pfizer–BioNTech fulfilling the non-inferiority of Moderna. With the ABCORA 2 test, 89.1% (95% CI 84.8 to 93.4) had an immune response to mRNA-1273 and 89.5% (95% CI 85.4 to 93.7) to BNT162b2. Based on the Elecsys test, all patients living with HIV had an antibody response while for solid organ transplant recipients only 60.6% (95% CI 49.2 to 71.9%) had titres above the cut-off [Speich B, 2022 ].
           
The Hall VG et al was a phase 4, randomized, placebo-controlled trial evaluating vaccine efficacy in organ-transplant recipients. Results showed that at month 4 post-vaccination, an anti-RBD antibody level of at least 100 U per milliliter was present in 33 of 60 patients (55%) in the mRNA-1273 group and in 10 of 57 patients (18%) in the placebo group (relative risk, 3.1; 95% CI: 1.7 to 5.8; P<0.001) [Hall VG, 2021 ]. 
           
Heinzel et al was a secondary analysis of the phase 2 randomized trial BOOST-TX 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 third dose of the same mRNA vaccine (the mRNA group) or a dose of the vector vaccine (Janssen, 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 ]

RECOVAC was a randomized trial conducted in the Netherlands that enrolled 333 kidney transplant recipients (KTR) who did not seroconvert after an initial mRNA vaccine schedule: 230 KTRs were randomly assigned in a 1:1:1 manner to receive 100 μg mRNA-1273, 2 × 100 μg mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTRs receiving 100 μg mRNA-1273, were randomly assigned 1:1 to continue (mycophenolate mofetil+) or discontinue (mycophenolate mofetil-) mycophenolate mofetil or mycophenolic acid treatment for 2 weeks. The primary outcome was the percentage of participants with a spike protein (S1)-specific IgG concentration of at least 10 binding antibody units per mL at 28 days after vaccination. The seroreponse rates were 68% (95% CI, 56% to 79%) for the 2 × mRNA-1273 group, 63% (95% CI, 51% to 74%) for the Ad26.COV2-S group and 68% (95% CI, 57% to 79%) for the single mRNA-1273 group. The seroresponse rate in mycophenolate mofetil- was 80% (95% CI, 66% to 91%) and 67% (95% CI, 52% to 80%) in mycophenolate mofetil+. [Kho MML, 2022 ]

Bonelli et al was a randomized controlled trial in Austria that 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 ]
           
Other comparative studies
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 infections 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 it was 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, and the rate of severe infections was significantly reduced in all the disease-modifying therapies excluding ocrelizumab [Irene Schiavetti, 2022 ].

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 ].

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 ].

Li LL et al. was a comparative cohort study conducted in United States [Li LL, 2022 ], evaluating impact of prior SARS-CoV-2 infection on incidence of hospitalization and adverse events after receiving Pfizer, Moderna or Janssen COVID-19 vaccines.

Aharon D et al. was a comparative cohort study conducted in United States [Aharon D, 2022 ], evaluating whether Pfizer or Moderna COVID-19 vaccine is associated with controlled ovarian hyperstimulation or early pregnancy outcomes in patients who undergo in vitro fertilization.
           
Lombardi A et al. was a cohort study conducted in Italy. The study enrolled 71 participants living with HIV, mostly male (84·5%), with a mean age of 47 years, a median CD4+ T cell count of 747·0 cells per µL and a median HIV viral load <50 copies/mL. The study results showed that inoculation with mRNA-1273 vaccine given 4 weeks apart produced detectable humoral immune response, similar to individuals without HIV infection [Lombardi A, 2021 ].

Lin et al conducted a sub-analysis of a previous study [Sheng WH, 2022 ] wich compare the immunogenicity of heterologous ChAdOx1/mRNA-1273 versus standar homologous ChAdOx1 and mRNA-1273m vaccination. 399 participants were enrolled, there were 100, 100, 100, and 99 participants undergoing ChAdOx1/ChAdOx1 8 weeks apart (Group 1), ChAdOx1/mRNA-1273 8 weeks apart (Group 2), ChAdOx1/mRNA-1273 4 weeks apart (Group 3), and mRNA-1273/mRNA-1273 4 weeks apart (Group 4), respectively. The majority of the enrolled participants were ≤50 years with 74.7% being women. Among participants undergoing boost vaccination with mRNA-1273, compared with healthy participants aged ≤50 years, participants with immunocompromising conditions had similar anti-SARS-CoV-2 spike IgG titers 4 weeks after booster vaccination (geometric means, 1769.66 vs. 1946.41 BAU/mL; P = 0.255). Only participants with autoimmune diseases and receiving hydroxychloroquine, low-dose steroid, methotrexate, and/or sulfasalazine had numerically lower anti-SARS-CoV-2 spike IgG titers 4 weeks after booster vaccination compared to those without (geometric means, 1474.34 vs. 1923.23 and 1590.61 vs. 1918.38 BAU/mL; both P > 0.05). While anti-SARS-CoV-2 spike IgG titers 4 weeks after booster vaccination were comparable between participants receiving and not receiving NSAIDs (geometric means, 1894.94 vs. 1903.09 BAU/mL, P = 0.981), those receiving COX-2 selective NSAIDs had numerically lower titers (geometric means, 1362.55 vs. 1915.86 BAU/mL, P = 0.179). [Lin KY, 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 Moderna vaccine during the Omicron period in immunocompromised participants the effectiveness was 57% (95%CI 29 to 74) for two doses and 60% (95%CI 42 to 73) 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 Moderna vaccine was 69% (95% CI, 62% to 76%) for ED/UC events, and 76% (95% CI, 72% to 80%) for hospitalization, measured 14 days after the second dose. After a third dose, VE was 77% (95% CI, 58% to 87%), and 87% (95% CI, 79% to 92%) for ED/UC events and hospitalization, respectively. Preprint. [Peter J. Embi, 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 8% in the solid tumors group and 21,1% in the multiple myeloma group. [Furer V, 2022 ]

Smith JB was a retrospective cohort study 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 ]

Persons with recent COVID-19
Most guidelines recommend that individuals who have had COVID-19 should receive an identical vaccine regimen as those who have not had the infection. 
Randomized trials
Participants with a known history of COVID-19 were excluded from the COVE trial [Baden LR, 2021 ],[FDA, 2020 ] and there was only one case of COVID-19 among study participants with positive SARS-COV-2 infection status at baseline. Thus, this trial does not offer information to assess the benefit in individuals with recent infection.
           
Other comparative studies
Saadat S et al [Saman Saadat, 2021 ] assessed 59 health care workers with and without history of SARS-CoV-2 infection prior to vaccine. After a single dose of the SARS-CoV-2 vaccine (30/59 vaccinated with Moderna vaccine and the other half received Pfizer vaccine), individuals that had prior SARS-CoV-2 infection had higher titers of binding and functional antibodies than individuals that had no history of infection. 

Vaccine effectiveness (other comparative studies)

Contracting COVID-19
Chung H 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. The effectiveness of the vaccine in symptomatic infections, observed 14 days after the first dose, was 60%, and increases to 75% between 35-71 days. The effectiveness at 7 days of the second dose was 91%. The effectiveness of the vaccine against hospitalization or death was 70% with the first dose and 91% with the second dose. In adults ≥70 years, the effectiveness was comparable to that in younger people for all intervals after 28 days. [Chung H, 2021 ]

Flacco M et al. conducted a retrospective cohort study conducted in Italy. The study enrolled 245,226 participants: 69,539 Vaccine; 175,687 Control. Based on data from an interim analysis of COVID-19 vaccines effectiveness in the entire population of an Italian Province between 2 January to 21 May 2021. Results showed vaccine effectiveness of 99 to 100% (n = 0 infections)[Flacco ME, 2021 ].

Pawlowski C et al. was a retrospective cohort study conducted in the United States. The study enrolled 136,532 participants: 68,266 vaccine (16,471 Moderna COVID-19 vaccine); 68,266 Control. Based on data from the Mayo Clinic health system between December 1 2020 and April 20, 2021. Results showed vaccine effectiveness of 92.3% (95% CI 82.4% to 9.3%) and infection rate 0.014%/ 0.19% (vaccinated/unvaccinated) [Pawlowski C, 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 7,368,289 receiving the Moderna 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 ].

Molani S et al. was a comparative cohort study conducted in the United States. The study included 7,620,084 records: 2,627,914 vaccine-induced immunity cohorts (Pfizer-BioNTech, Moderna or Janssen) and 191,722 infection-induced immunity cohorts. The study was based on data from Providence-St. Joseph Health electronic health records. The vaccine-induced cohort period data were collected from December 12, 2020, and the infection-induced cohort data were collected from the beginning of the pandemic. Data collection ended on May 11, 2021. Survival against breakthrough infection for Moderna was 99,7% in 180 days [Sevda Molani, 2022 ].

Chadeau-Hyam M et al. was a cohort study conducted in the 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 vaccine effectiveness of 75.1% (95%CI 22.7 to 92.0) against infection in vaccinated individuals [Chadeau-Hyam M, 2022 ].

Draws 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–BioNTech and 1,066,645 were fully vaccinated with Moderna. A Pfizer–BioNTech booster was administered to 609,153 individuals and a Moderna booster was administered to 395,634 individuals The 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 vaccine effectiveness after 26 weeks from the second dose was 65% (95% CI 65 to 66) for the Moderna COVID-19 Vaccine. [Drawz PE, 2022 ]

Roberts E et al. was a case-control study conducted in the United States. The study analyzed data from 170,487 positive COVID-19 adult patients: 74,060 fully vaccinated, 18,425 partially vaccinated and 7,187 fully vaccinated, and 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 vaccine effectiveness for contracting COVID-19 of 88.1% (95% CI 85.5 to 90.2). [Emily Roberts, 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 66% (95% CI 65 to 67) and 69% (95% CI 67 to 71) for adults ≥ 65 years [Winkelman TNA, 2022 ].

Oren Miron et al was a secondary analysis of a phase 3 randomized clinical trial conduct in United States. The study reunited data from 30,420 participants aged 18 to 95 years that were enrolled to receive two doses of Pfizer-BioNTech vaccine on days 0 and 28 (n= 15,181) or were enrolled to the placebo group (n= 15,170). 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 at day 111 of COVID-19 increased by 0.19% in the intervention group and 2.84% in the placebo group.The mRNA-1273 effectiveness at days 7, 14, and 21 was 33%, 62% and 90% respectively, followed by a mean of 95% effectiveness until day 112 [Oren Miron, 2021 ].

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 Moderna against infection was 76.5% (95% CI 75.7 to 77.2) and 48.4% (95% CI 47.5 to 49.3), 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 21st 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 a homologous mRNA-1273 schedule 7 to 59 days after the second dose was 92% (95% CI, 91% to 92%) against any infection and 95% (95% CI, 94% to 96%) against symptomatic infection. VE >240 days after the second dose was 80% (95% CI, 71% to 86%) against any infection and 87% (95% CI, 78% to 92%) 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 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 ]

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 Moderna was 97.5% (95% CI, 82.5% to 99.7%). Adjusted VE against Omicron (2 doses of Moderna) was 25.6% (95% CI, 10.7% to 39.0%). Adjusted VE against Omicron (3 doses of Moderna) was 71.2% (95% CI, 24.0% to 90.8%). [Weng CH, 2023 ]

Puranik A et al was a case control study conducted in United States that included data from 15,313 participants: 2,364 cases and 12,949 controls. The aim was to assess the durability of protection against symptomatic infection after vaccination with the Moderna vaccine. Odds of symptomatic infection at 250 days after full vaccination compared to the date of full vaccination was 2.24 (95% CI, 1.19-5.13). [Puranik A, 2022 ]

Bello-Chavolla OY et al was 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 3,764 participants vaccinated with Moderna, VE against infection was 91.45% (95% CI, 90.34% to 92.43%), and VE against hospitalization was 78% (95% CI, 69% to 84.38%). [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 the Pfizer vaccine and RR 0.90 (95% CI, 0.87-0.92) for the Moderna vaccine. [Kayoko Shioda, 2023 ]

Contracting severe COVID-19
Pawlowski C et al. was a retrospective cohort study conducted in the United States. The study enrolled 136,532 participants: 68,266 vaccine (16 471 Moderna COVID-19 vaccine); 68,266 Control. Based on data from the Mayo Clinic health system between December 1,2020 and April 20, 2021. Results showed vaccine effectiveness 90.6% (95% CI 76.5% to 97.1%) infection rate 0.006%/0.064% (vaccinated/unvaccinated) [Pawlowski C, 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 7,368,289 receiving the Moderna vaccine. Based on claims and laboratory data from vaccinated individuals between January 1 and September 7, 2021. Odds ratios (OR) for developing an 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 ].

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 ].

Draws 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–BioNTech and 1,066,645 were fully vaccinated with Moderna. A Pfizer–BioNTech booster was administered to 609,153 individuals and a Moderna booster was administered to 395,634 individuals The 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 vaccine effectiveness after 26 weeks from the second dose was 65% (95% CI 65 to 66) for the Moderna COVID-19 Vaccine. [Drawz PE, 2022 ]

Roberts E et al. was a case-control study conducted in the United States. The study analyzed data from 170,487 positive COVID-19 adult patients: 74,060 fully vaccinated, 18,425 partially vaccinated and 7,187 fully vaccinated, and 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 vaccine effectiveness for contracting COVID-19 of 88.1% (95% CI 85.5 to 90.2). [Emily Roberts, 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 69% (95% CI 65 to 72) [Winkelman TNA, 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. IBased 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 Moderna against hospitalization was 77.2% (95% CI 63.8  to 72.2) and 72.7% (95% CI 67.8 to 77), 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). IRR = Incidence Rate Ratio. [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. They included 261,360 test-positive cases (of any SARS-CoV-2 lineage) and 2,783,699 individuals as test-negative controls. VE for a homologous mRNA-1273 schedule 7 to 59 days after the second dose was 96% (95% CI, 95% to 97%) against severe outcomes (hospitalization or death) and 98% (95% CI, 88% to 100%), >240 days after the second dose. [Chung H, 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 against COVID-19-related death was 46.22% (95% CI, 44.47% to 47.93%) for a Moderna primary schedule. [Yuanyuan Fu, 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 3,764 participants vaccinated with Moderna, VE against infection was 91.45% (95% CI, 90.34% to 92.43%), and VE against hospitalization was 78% (95% CI, 69% to 84.38%). [Bello-Chavolla OY, 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 cohorts 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 ].

Efficacy and effectiveness against SARS-CoV-2 variants

Immunogenicity outcomes
Alpha (B.1.1.7) 
Lafon et al. used data from samples of 116 patients who had been vaccinated with AstraZeneca, Pfizer, or Moderna COVID-19 vaccines or had recovered from COVID-19. The study found that all the vaccines induced a neutralizing response against the Alpha variant that was higher than the wild-type virus. The mRNA vaccines generated an 82% increase in neutralizing activity, while the AstraZeneca vaccine induced a 13% increase.  Responses against the Beta and Delta variants were lower for all vaccines than for wild-type viruses. Neutralizing activity against the Beta variant was 42 and 47% lower in AstraZeneca and Pfizer recipients while only 25% lower for Moderna recipients. The AstraZeneca vaccine had an 82% reduction in neutralizing activity against the Delta variant, and the Pfizer and Moderna vaccines had a decrease of 2% and 14% respectively [Lafon E, 2022 ].

Chuang et al. was a randomized controlled study made in Taiwan. It included data from samples of 340 health care workers (HCW) with prior Oxford-AstraZeneca homologous vaccination and that received one of the four vaccines as booster doses: Pfizer–BioNTech, half-dose Moderna, full dose Moderna or MVC-COV1901.The primary outcomes were humoral and cellular immunogenicity and the secondary outcomes safety and reactogenicity 28 days post-booster. The study found that the neutralizing activity increased significantly post boost (P < 0.0001) and the fold-rise ranged from 23.0 in MCV-COV1901 to 118.1 in mRNA1273 against the Alpha variant. After each booster vaccine, the neutralization titers against the Alpha variant were compatible with those of the wild type [Chih-Hsien Chuang, 2022 ].

ARNCOMBI was a randomized controlled trial conducted in France. The study included 414 individuals who received an mRNA vaccine first dose and a second dose of Pfizer-BioNTech or Moderna after 28 days. Measurement of neutralizing antibodies against the specific variants (Alpha, Beta, Delta) was performed on a representative population of 30 subjects randomly selected after stratification on vaccine schedule group, age (<40 years, ≥40 years, and <55 years, ≥55 years), and level of anti-spike IgG against the wild-type viral strains at D28 (<1000 BAU/mL, ≥1000 BAU/mL, and <5000 BAU/ml, ≥ 5000 BAU/mL). The study showed that the neutralizing antibodies titers against SARS-CoV-2 variants were not different between the homologous and heterologous vaccine groups [Janssen C, 2022 ].

Beta (B.1.351) 
Lafon et al. used data from samples of 116 patients who had been vaccinated with AstraZeneca, Pfizer, or Moderna COVID-19 vaccines or had recovered from COVID-19. The study found that all the vaccines induced a neutralizing response against the Alpha variant that was higher than the wild-type virus. The mRNA vaccines generated an 82% increase in neutralizing activity, while the AstraZeneca vaccine induced a 13% increase.  Responses against the Beta and Delta variants were lower for all vaccines than for wild-type viruses. Neutralizing activity against the Beta variant was 42 and 47% lower in AstraZeneca and Pfizer recipients while only 25% lower for Moderna recipients. The AstraZeneca vaccine had an 82% reduction in neutralizing activity against the Delta variant, and the Pfizer and Moderna vaccines had a decrease of 2% and 14% respectively [Lafon E, 2022 ].

ARNCOMBI was a randomized controlled trial conducted in France. The study included 414 individuals who received an mRNA vaccine first dose and a second dose of Pfizer-BioNTech or Moderna after 28 days. Measurement of neutralizing antibodies against the specific variants (Alpha, Beta, Delta) was performed on a representative population of 30 subjects randomly selected after stratification on vaccine schedule group, age (<40 years, ≥40 years, and <55 years, ≥55 years), and level of anti-spike IgG against the wild-type viral strains at D28 (<1000 BAU/mL, ≥1000 BAU/mL, and <5000 BAU/ml, ≥ 5000 BAU/mL). The study showed that the neutralizing antibodies titers against SARS-CoV-2 variants were not different between the homologous and heterologous vaccine groups [Janssen C, 2022 ].

Anderson et al. was a phase 2 randomized controlled trial conducted in the United States that included 96 participants with a primary schedule of Moderna: 48 with Monovalent prototype boost (100 mcg) of mRNA-1273, 25 with Monovalent variant boost of mRNA-1273.351 (50 mcg) and 23 with a bivalent boost of mRNA1273.351 (25 mcg ) and bivalent mRNA-1273 (25 mcg). This study assessed the immunogenicity after a third mRNA vaccination in adults who received the mRNA-1273 primary schedule approximately 9 to 10 months earlier. The booster vaccine formulations included 100 mcg of mRNA-1273, 50 mcg of mRNA1273.351 that encodes Beta variant spike protein, and a bivalent vaccine of 25 mcg each mRNA-1273 and mRNA-1273.351. The results showed that following booster vaccination, a robust response to similar titers was observed in all three groups to 614D S-2P at Day 15 [monovalent prototype 62,272 AUC (95% CI 59,973, 64,659); monovalent variant 61,373 (95% CI 58,622, 64,254); bivalent 62,025 (95% CI 59,468, 64,691). In all groups, the third dose of mRNA vaccine induced similar responses against B.1.351 [monovalent prototype 47,733 AUC (95% CI 44,932, 50,710); monovalent variant 49,768 (95% CI 46,282, 53,517); bivalent 48,126 (95% 44,728, 51,781)] that were only 20% lower than the Day 15 responses to 614D . Spike-specific CD4+ and CD8+ T cells increased to similar levels to that after the second dose.

Chalkias et al. was a phase 2/3 non-randomized trial conducted in the United States as part of a larger study registered as NCT04927065. Its aim was to evaluate the safety, reactogenicity and immunogenicity of a single booster dose of the bivalent beta-containing mRNA candidate vaccine mRNA-1273.211, in adults who received a primary schedule of mRNA-1273. The study included 300 participants who received 50 µg of mRNA-1273.211 booster, 595 participants who received 100 µg of mRNA-1273.211 booster, a historical cohort of 584 participants who received the 100 µg primary schedule and 171 participants who received a mRNA-1273 50 µg booster dose. Geometric Mean Titers (GMT) of neutralizing antibodies against the Beta variant were 953.9 (95% CI, 844.1–1,078.0) for the mRNA-1273.211 (50 µg) group and 1,574.6 (95% CI, 1,439.4–1,722.5) for the mRNA-1273.211 (100 µg) group. [Chalkias S, 2022 ]

Delta (B.1.617.2) 
Lafon et al. used data from samples of 116 patients who had been vaccinated with AstraZeneca, Pfizer, or Moderna COVID-19 vaccines or had recovered from COVID-19. The study found that all the vaccines induced a neutralizing response against the Alpha variant that was higher than the wild-type virus. The mRNA vaccines generated an 82% increase in neutralizing activity, while the AstraZeneca vaccine induced a 13% increase.  Responses against the Beta and Delta variants were lower for all vaccines than for wild-type viruses. Neutralizing activity against the Beta variant was 42 and 47% lower in AstraZeneca and Pfizer recipients while only 25% lower for Moderna recipients. The AstraZeneca vaccine had an 82% reduction in neutralizing activity against the Delta variant, and the Pfizer and Moderna vaccines had a decrease of 2% and 14% respectively [Lafon E, 2022 ].

Kanokudom S et al. recruited 222 adults with a complete CoronaVac regimen 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 booster dose induced a neutralizing response against the Delta and Omicron variants in previously seronegative participants that were not affected by dosage. On day 28 the GMT of neutralizing antibodies against the Delta variant increased to 1,505 and 2,088 in the reduced dose Pfizer-BioNTech and Moderna vaccine groups. [Kanokudom S, 2022 ].

Chuang et al. was a randomized controlled study made in Taiwan. It included data from samples of 340 health care workers (HCW) with prior Oxford-AstraZeneca homologous vaccination and that received one of the four vaccines as booster doses: Pfizer–BioNTech, half-dose Moderna, full dose Moderna or MVC-COV1901.The primary outcomes were humoral and cellular immunogenicity and the secondary outcomes safety and reactogenicity 28 days post-booster. The study found that the neutralizing activity increased significantly post boost (P < 0.0001) and the fold-rise ranged from 23.8 in MCV-COV1901 to 97.8 in mRNA1273 against the Delta variant. After each booster vaccine, the neutralization titers against the Delta variant were compatible with those of the wild type [Chih-Hsien Chuang, 2022 ].

ARNCOMBI was a randomized controlled trial conducted in France. The study included 414 individuals who received an mRNA vaccine first dose and a second dose of Pfizer-BioNTech or Moderna after 28 days. Measurement of neutralizing antibodies against the specific variants (Alpha, Beta, Delta) was performed on a representative population of 30 subjects randomly selected after stratification on vaccine schedule group, age (<40 years, ≥40 years, and <55 years, ≥55 years), and level of anti-spike IgG against the wild-type viral strains at D28 (<1000 BAU/mL, ≥1000 BAU/mL, and <5000 BAU/ml, ≥ 5000 BAU/mL). The study showed that the neutralizing antibodies titers against SARS-CoV-2 variants were not different between the homologous and heterologous vaccine groups [Janssen C, 2022 ].

Anderson et al. was a phase 2 randomized controlled trial conducted in the United States that included 96 participants with a primary schedule of Moderna: 48 with Monovalent prototype boost (100 mcg) of mRNA-1273, 25 with Monovalent variant boost of mRNA-1273.351 (50 mcg) and 23 with a bivalent boost of mRNA1273.351 (25 mcg ) and bivalent mRNA-1273 (25 mcg). This study assessed the immunogenicity after a third mRNA vaccination in adults who received the mRNA-1273 primary schedule approximately 9 to 10 months earlier. The booster vaccine formulations included 100 mcg of mRNA-1273, 50 mcg of mRNA1273.351 that encodes Beta variant spike protein, and a bivalent vaccine of 25 mcg each mRNA-1273 and mRNA-1273.351. The results showed that following booster vaccination, a robust response to similar titers was observed in all three groups to 614D S-2P at Day 15 [monovalent prototype 62,272 AUC (95% CI 59,973, 64,659); monovalent variant 61,373 (95% CI 58,622, 64,254); bivalent 62,025 (95% CI 59,468, 64,691). In all groups, the third dose of mRNA vaccine induced similar responses against B.1.351 [monovalent prototype 47,733 AUC (95% CI 44,932, 50,710); monovalent variant 49,768 (95% CI 46,282, 53,517); bivalent 48,126 (95% 44,728, 51,781)] that were only 20% lower than the Day 15 responses to 614D . Spike-specific CD4+ and CD8+ T cells increased to similar levels to that after the second dose.

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. The study showed that, following the booster dose, individuals boosted with mRNA vaccines demonstrated a higher level of neutralizing activity than those boosted with Oxford-AstraZeneca [Suntronwong N, 2022 ].

Omicron (B.1.1.529.1) 
Kanokudom S et al. recruited 222 adults with a complete CoronaVac regimen 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 booster dose induced a neutralizing response against the Delta and Omicron variants in previously seronegative participants that were not affected by dosage. On day 28 the GMTs against the Omicron variant reached 343.3 and 541.2 in the reduced dose Pfizer-BioNTech and Moderna vaccine groups. [Kanokudom S, 2022 ].

Branche A et al. recruited 602 adults with primary schedules and a single homologous or heterologous boost. The participants were randomized to six Moderna vaccine arms (50µg dose): 99 received prototype Moderna vaccine, 100 received 1 dose of Beta and Omicron BA.1 bivalent vaccine, 102 received 2 doses of Beta and Omicron BA.1 bivalent vaccine, 101 received 1 dose of Delta and Omicron BA.1 bivalent vaccine, 100 received 1 dose of Omicron BA.1 monovalent vaccine and 100 received 1 dose of Omicron BA.1 Moderna bivalent vaccine. Neutralization antibody titers (ID50) were assessed for D614G, Delta, Beta, and Omicron BA.1 variants and Omicron BA.2.12.1 and BA.4/BA.5 subvariants 15 days after vaccination. The study found that the Omicron BA.1 monovalent and Omicron BA.1+Prototype vaccines induced a geometric mean ratio (GMR) to Prototype for Omicron BA.1 of 2.03 (97.5%CI:1.37-3.00) and 1.56 (97.5%CI:1.06-2.31), respectively. Omicron BA.4/BA.5 GMTs were approximately one third BA.1 GMTs (Prototype 517 [95%CI:324-826] vs. 1503 [95%CI:949-2381]; Omicron BA.1+Beta 628 [95%CI:367-1,074] vs. 2125 [95%CI:1139-3965]; Omicron BA.1+Delta 765 [95%CI:443-1,322] vs. 2242 [95%CI:1218- 4128] and Omicron BA.1+Prototype 635 [95%CI:447-903] vs. 1972 [95%CI:1337-2907) [Angela R Branche, 2022 ].

Chuang et al. was a randomized controlled study made in Taiwan. It included data from samples of 340 health care workers (HCW) with prior Oxford-AstraZeneca homologous vaccination and that received one of the four vaccines as booster doses: Pfizer–BioNTech, half-dose Moderna, full dose Moderna or MVC-COV1901. The primary outcomes were humoral and cellular immunogenicity and the secondary outcomes safety and reactogenicity 28 days post-booster. The study found that the neutralizing activity increased significantly post boost (P < 0.0001) and the fold-rise ranged from 2.1 in MCV-COV1901 to 14.4 in Pfizer against the omicron variant. The neutralization titers against the omicron variant were 6.4 to 13.5 times lower than those against the wild type. All except one participant who received mRNA vaccines as a booster had detectable neutralizing antibodies against the Omicron variant [Chih-Hsien Chuang, 2022 ].

mRNA-1273-P205 was an open-label, phase 2/3 study conducted in the United States that included 819 participants with a primary schedule of Moderna: 377 included in the mRNA-1273 (50 µg) booster group, and 437 included in the mRNA-1273.24 (50 µg) Omicron BA,.1-containing bivalent vaccine group. Geometric mean titers (GMT) of neutralizing antibodies against ancestral SARS-CoV-2 (D614G) were 5977.3 (95% CI, 5321.9 -6713.3) in the mRNA-1273.214 (50 µg) group and 5649.3 (95% CI, 5056.8-6311.2) in the mRNA-1273 (50 µg) group. The adjusted GMT ratio against the ancestral strain was 1.22 (97.5% CI, 1.08-1.37) which met the prespecified criterion for noninferiority. GMT of neutralizing antibodies against Omicron were 2372.4 (95% CI, 2070.6-2718.2) in the mRNA-1273.214 (50 µg) group and 1473.5 (95% CI, 1270.8-1708.4) in the mRNA-1273 (50 µg) group. Adjusted GMT ratio against Omicron was 1.75 (97.5% CI, 1.49-2.04) which met the prespecified criterion for noninferiority. The percentages of participants with a seroresponse against ancestral SARS-CoV-2 (D614G) were 100% (95% CI, 98.9% to 100%) for mRNA1273.214 and 100% (95% CI, 98.6% to 100%) for mRNA-1273 at 28 days after the booster doses, with an estimated difference of 0, which met the noninferiority criterion. [Chalkias S, 2022 ]

mRNA-1273-P205 was an open-label, phase 2/3 study conducted in the United States that included 887 participants with a primary schedule of Moderna and a first homologous booster: 176 received a second booster dose of mRNA-1273 (50 µg)  and 511 received a second booster dose of the omicron BA.4/BA.5-containing mRNA-1273.222 (50 µg) vaccine. ​​Geometric mean titers (GMT) of neutralizing antibodies against the ancestral SARS-CoV-2 (D614G) strain were 7322.4 (95% CI, 6386.2-8395.7), and 5651.4 (95% CI, 5055.7-6317.3) for mRNA-1273.222 (50 µg) and mRNA-1273 (50 µg), respectively. GMT of neutralizing antibodies against Omicron were 2324.6 (95% CI, 1921.2-2812.7), and 488.5 (95% CI, 427.4-558.4) for mRNA-1273.222 (50 µg), and mRNA-1273 (50 µg), respectively. [Spyros Chalkias, 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 ].

Lee I et al was a phase 3 randomized trial conducted in the United Kingdom that assessed the immunogenicity and safety of 50 µg doses of Omicron BA.1- monovalent mRNA1273.529 and bivalent mRNA-1273.214 booster vaccines compared with 50 µg mRNA-1273. Neutralizing antibody geometric mean concentrations against Omicron BA.1 were 537.7 (95% CI, 478.2−604.6) for mRNA-1273.529 booster and 307.4 (95% CI, 279.5−338.2) for mRNA-1273 booster [Lee, I. T., 2023 ].

Effectiveness outcomes
Alpha (B.1.1.7) 
Nasreen et al. was a case-control study (test-negative) conducted in Canada. The study included 421,073 SARS-CoV-2-positive symptomatic cases (707 with Alpha variant receive 1 or 2 doses of Moderna) and 351,540 SARS-CoV-2-negative symptomatic controls. The study evaluates the effectiveness of mRNA-1273 vaccines against symptomatic SARS-CoV-2 infection and severe outcomes caused by the Alpha (B.1.1.7) variant, from December 2020 to May 2021. Effectiveness against symptomatic infection was 92% (95% CI, 86–96%) and effectiveness against hospitalization or death was 94% (95% CI, 89–97%). [Nasreen, S., 2021 ].

Fabiani M et al conducted a comparative cohort study in Italy that included 33,250,344 individuals aged ≥16 years who received the 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 vaccine effectiveness against infection during the 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 ].

Delta (B.1.617.2) 
Nasreen et al. was a case-control study (test-negative) conducted in Canada. The study included 421,073 SARS-CoV-2 positive symptomatic cases (participants ≤61 years of age with Delta variant infection receive 1 or 2 doses of Moderna) and 351,540 SARS-CoV- 2 negative symptomatic controls. The study evaluates the efficacy of the Moderna COVID-19 vaccine against the symptomatic infection of SARS-CoV-2 and the serious outcomes caused by the Delta variant (B.1.617.2) during December 2020 to May 2021. Effectiveness against symptomatic infection was 72% (95% CI, 57–82%) and effectiveness against hospitalization or death was 96% (95% CI, 72 to 99%) [Nasreen, S., 2021 ].

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 Moderna COVID-19 vaccine compared to not receiving any or 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 0.28 (95% CI 0.26 to 0.31) and for Delta variant OR 0.045 (95% CI 0.038 to 0.053). Comparison of 3 doses versus 2 doses showed for Omicron variant OR 0.31 (95% CI 0.28 to 0.34) and for Delta variant OR 0.13 (95% CI 0.11 to 0.15) [Accorsi EK, 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 (Canadá) to estimate the vaccine effectiveness (VE) against symptomatic infections and severe outcomes associates with these infections. Of 134,435, 4261 were Delta-positive cases, and 114 087 were test-negative controls. VE against Delta symptomatic infection: 97% (95% CI 95-98). VE against Delta severe outcome:100% (95% CI 98-100). [Buchan SA, 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. Data were collected between April  4, 2021, and 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 4.6 (95% CI 4.2 to 5.1)  for the group without a booster and IRR 17.4 (95% CI 14.5 to 21.1) for the booster group.[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 2021 to and 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 ]

Fabiani M et al conducted a comparative cohort study in Italy that included 33,250,344 individuals aged ≥16 years who received the 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 vaccine effectiveness against infection during the 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 ].

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 or Moderna. Based on data from RT-PCR SARS-CoV-2 positive cases were 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 ].

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.  Moderna effectiveness against Delta variant for symptomatic infection was 57.4% (95% CI 52.6 to 61.8) 4 weeks after the first dose, 80.4% (95% CI 67.3 to 88.2) 25 weeks after the second dose, 94.7% (95% CI 89.3 to 97.3) 2-4 weeks after a Pfizer-BioNTech booster and 96.4% (95% CI 91.4 to 98.5) 2-4 weeks after  Moderna booster [Andrews N, 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 ].

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 (Canadá) to estimate the vaccine effectiveness (VE) against symptomatic infections and severe outcomes associates with these infections. Of 134,435 total participants (> 18 years older), 4261 were Delta-positive cases (mean [SD] age, 44.2 [16.8] years; 2199 [51.6%] female), and 114 087 were test-negative controls (mean [SD] age, 42.0 [16.5] years; 7 884 [59.5%] female). Symptomatic Infection DELTA (VE %, 95% CI) BNT16b2: 97 (96-98) and mRNA-1273: 97 (95-98). Severe Outcome DELTA (VE %, 95% CI) BNT16b2: 99 (98-99) and mRNA-1273: 100 (98-100). [Buchan SA, 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 Moderna vaccine was 98% (95% CI, 97-99) (less than two months after the second dose) and 97% (95% CI, 96-98) with the third booster dose. [Ferdinands JM, 2022 ]

Rennert L. was an observational study conducted in the United States that included 21,261 university students undergoing repeated surveillance testing during which Delta was the dominant SARS-CoV-2 variant. The estimated Moderna vaccine effectiveness against any SARS-CoV-2 infection was 75.4% (95% CI, 70.5-79.5). Between 0 and 6 months post-vaccination, the estimated protection decreased from 88.9% to 58.3% for mRNA-1273 vaccine. [Rennert L, 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) for the Pfizer/Moderna heterologous schedule was 88.9% (95% CI, 66.1% to 96.4%) during the Delta predominance period. VE for the Moderna primary schedule was 70.2% (95% CI, 66.8 to 73.1) during the Delta 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 (VE) against COVID-19 infection during the Delta predominance period was 47.64% (95% CI, 45.47% to 49.73%) for the Moderna/Moderna/Moderna 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 91.87% (95% CI, 84.88% to 95.63%) for the Pfizer/Pfizer/Moderna schedule, 81.09% (95% CI, 79.17% to 82.85%) for the Moderna/Moderna/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 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 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 ]

Huiberts A 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 15.8% (95% CI, -26.3% to 43.9%), 68.3% (95% CI, 63.1% to 72.8%) and 67.6% (95% CI, 60.1% to 73.7%) for Moderna primary schedule, mRNA primary schedule with Moderna booster and AstraZeneca primary schedule with Moderna booster, respectively. VE against contracting COVID-19 during the Delta period was 100% (95% CI, 0% to 100%) and 100% (95% CI, 0% to 100%) for Moderna primary schedule and mRNA primary schedule with Moderna booster, respectively. [Anne J. Huiberts, 2023 ]

Omicron (B.1.1.529.1) 
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 Moderna COVID-19 vaccine compared to not receiving any or 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 0.28 (95% CI 0.26 to 0.31) and for Delta variant OR 0.045 (95% CI 0.038 to 0.053). Comparison of 3 doses versus 2 doses showed for Omicron variant OR 0.31 (95% CI 0.28 to 0.34) and for Delta variant OR 0.13 (95% CI 0.11 to 0.15) [Accorsi EK, 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 (Canadá) to estimate the vaccine effectiveness (VE) against symptomatic infections and severe outcomes associates with these infections. Of 134,435 total participants (> 18 years older), 16,087 were Omicron-positive cases , and 114 087 were test-negative controls. VE against Omicron symptomatic infection: 65% (95% CI 55-72). VE against Omicron severe outcome: 93% (95% CI 74-98). [Buchan SA, 2022 ]

Chemaitelly H et al was a case-control study conducted in Qatar, based on data from a test-negative design study that seeks to assess the duration of protection of Pfizer-BioNTech after the 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.  Vaccine effectiveness was 53.1% (95% CI 40.7 to 62.8) 2 to 3 weeks after receiving the booster dose [Hiam Chemaitelly, 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. Data were collected between April  4, 2021, and 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 4.6 (95% CI 4.2 to 5.1)  for the group without a booster and IRR 17.4 (95% CI 14.5 to 21.1) for the booster group.[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 and 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 ].

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 ].

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 or Moderna. Based on data from RT-PCR SARS-CoV-2 positive cases were 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 ].

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 47.3% (95% CI 40.7  to 53.3) 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.  Moderna effectiveness against Delta variant for symptomatic infection was 57.4% (95% CI 52.6 to 61.8) 4 weeks after the first dose, 80.4% (95% CI 67.3 to 88.2) 25 weeks after the second dose, 94.7% (95% CI 89.3 to 97.3) 2-4 weeks after a Pfizer-BioNTech booster and 96.4% (95% CI 91.4 to 98.5) 2-4 weeks after  Moderna booster [Andrews N, 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 ].

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. Risk Infeccion (Incidence Rate Ratios) was 0.67% (95% CI 0.62 to 0.72) and 1.16% (95% CI 0.82 to 1.65) against Severe COVID Infeccion (Aggregated data from Moderna  and Pfizer COVID-19 vaccines). [Ng OT, 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 (Canadá) to estimate the vaccine effectiveness (VE) against symptomatic infections and severe outcomes associates with these infections. Of 134,435 total participants (> 18 years older), 16,087 were Omicron-positive cases (mean [SD] age, 36.0 [14.1] years; 8249 [51.3%] female), and 114 087 were test-negative controls (mean [SD] age, 42.0 [16.5] years; 7 884 [59.5%] female). Symptomatic Infection OMICRON (VE %, 95% CI) BNT16b2: 60 (55-65) and mRNA-1273: 65 (55-72). Severe Outcome OMICRON (VE %, 95% CI) BNT16b2: 95 (87-98) and mRNA-1273: 93 (74-98). [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. IBased 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 Moderna was 59% (95% CI 57.7% to 60.3%], when the Omicron variant emerged. [Lin DY, 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 ]

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 Moderna vaccine during the Omicron period in immunocompetent participants was 16% (95%CI 5 to 26) for two doses and 57% (95%CI 51 to 62) for three doses. In immunocompromised participants the effectiveness was 57% (95%CI 29 to 74) for two doses and 60% (95%CI 42 to 73) 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. Vaccine effectiveness with Moderna booster and AstraZeneca, JAnssen, Moderna or Pfizer primary schedule was 52,5% (95% CI, 51,3–53,7). Vaccine effectiveness of Moderna primary schedule and ARNm booster was 55.3% (95% CI, 52.3–58.2) (Moderna or Pfizer booster dose). [Monge S, 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 Moderna vaccine was 87% (95% CI, 75-93) (less than two months after the second dose) and 91% (95% CI, 89-92)
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. It included 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 the Moderna vaccine booster during the Omicron dominance period was 44.6% (95% CI, 42.5-46.6) against infection and 52.9% (95% CI, 45.6-59.2) against hospitalization. [Ioannou GN, 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 the 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 the Moderna vaccine against the Omicron variant to any infection was 44% (95% CI, 38% to 49%), against symptomatic infection was 61% (95% CI, 50% to 69%) and against severe outcomes 81% (95% CI, 74% to 86%). [Grewal R, 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 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 0.58 (95% CI, 0.46-0.73) for the Pfizer-BioNTech primary schedule and Moderna booster group, and 0.41 (95% CI, 0.33-0.50) for the ChAdOx1 primary schedule and Moderna booster group. [Agrawal U, 2022 ]

Hung FT et al was a case-control study conducted in the United States that included 123,236 participants, 30,809 cases and 92,427 controls. Based on data from KPSC electronic health records, California Immunizations Registry (CAIR) and Care Everywhere, during the Omicron predominance period (between January and June 2022). The study assessed the effectiveness of 3 and 4 doses of the mRNA-1273 vaccine against SARS-CoV-2 Omicron variants. The adjusted vaccine effectiveness against infection 14-30 days after the third dose against the BA.4 variant was 72.6% (95% CI, -54.7% to 96.6%) and against the BA.5 variant was 90.6% (95% CI, 30.6% to 98.7%). Vaccine effectiveness after the fourth dose against BA.4: 75.7% (95% CI, 44.7% to 91%) and 30.8% (95% CI, -9.2% to 56.5%) against BA.5. The adjusted effectiveness against hospitalization after the third dose against BA.4/BA.5 was 72.4% (95% CI, 23.9% to 90%), and 88.5% (95% CI, 51.8% to 97.2%) after the fourth dose. [Hung Fu Tseng, 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 79% (95% CI, 43% to 92%) for the primary schedule, 96% (95% CI, 91% to 98%) for the Moderna schedule+Moderna 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 94% (95% CI, 81% to 98%) for the AstraZeneca schedule + Moderna 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 a primary vaccination schedule. The aim was to assess the effectiveness of different combinations of mRNA vaccines in children and adolescents. Vaccine effectiveness (VE) for the Pfizer/Moderna heterologous schedule was 40.6% (95% CI, 29.4% to 50.0%) during the Omicron predominance period. VE for the Moderna primary schedule was 17.9% (95% CI, 14.0% to 21.5%) during the Omicron predominance period. [Castelli JM, 2022 ]

Intawong K et al was a test-negative case-control study conducted in Thailand that included 36,170 participants, 14,682 cases and 21,488 controls. Based on data from the Epid-CM platform, including participants aged 18 years and older, between October 2021 and April 2022.The aim was to assess the effectiveness of different booster doses. The adjusted vaccine effectiveness (VE) against infection during the Omicron predominance 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 ]

Grewal R was a case-control study conducted in Canada that included data from 3,736 Omicron positive cases and 77,695 SARS-CoV-2 negative controls. The aim was to estimate the effectiveness of a fourth dose of an mRNA vaccine against Omicron infections and severe outcomes over time. Vaccine effectiveness (VE) against symptomatic infection was 51% (95% CI, 42% to 60%), and 69% (95% CI, 61% to 75%) after the third and fourth doses, respectively. VE against severe outcomes was 77% (95% CI, 68% to 83%), and 79% (95% CI, 71% to 84%) after the third and fourth doses, respectively. [Grewal R, 2022 ]

Huiberts A 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 15.8% (95% CI, -26.3% to 43.9%), 68.3% (95% CI, 63.1% to 72.8%) and 67.6% (95% CI, 60.1% to 73.7%) for Moderna primary schedule, mRNA primary schedule with Moderna booster and AstraZeneca primary schedule with Moderna booster, respectively. VE against contracting COVID-19 during the Delta period was 100% (95% CI, 0% to 100%) and 100% (95% CI, 0% to 100%) for Moderna primary schedule and mRNA primary schedule with Moderna booster, respectively. [Anne J. Huiberts, 2023 ]

Tseng HF et al was a test negative case control study conducted in United States. This study included data from 123,236 participants: 30,809 with a SARS-CoV-2 positive test and 92,427 with SARS-CoV-2 negative test. This study assessed vaccine effectiveness  against infection and hospitalization with omicron sub-variants. Adjusted vaccine effectiveness against hospitalization for Omicron sub-variants for 3 doses was 97.5% (95% CI, 96.3% to 98.3%), 82% (95% CI, 64.5% to 90.8%) and 72.4% (95% CI, 23.9% to 90.0%) for BA.1, BA.2 and BA.4/BA.5 sub-variants, respectively. Adjusted vaccine effectiveness against hospitalization for Omicron sub-variants for 4 doses was 96.4% (95% CI, 88.4% to 98.9%) and 88.5% (95% CI, 51.8% to 97.2%) for BA.2 and BA.4/BA.5 sub-variants, respectively. [Tseng HF, 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 ]

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 Moderna was 97.5% (95% CI, 82.5% to 99.7%). Adjusted VE against Omicron (2 doses of Moderna) was 25.6% (95% CI, 10.7% to 39.0%). Adjusted VE against Omicron (3 doses of Moderna) was 71.2% (95% CI, 24.0% to 90.8%). [Weng CH, 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. The study included all residents in Sicily aged ≥ 18 years without previous SARS-CoV-2 infection and with a complete mRNA vaccine primary cycle. Vaccine effectiveness of the booster dose was 74.7% (95% CI, 72.7% to 76.7%) against infection, 79.7% (95% CI, 77.2% to 82.1%) against severe disease and 73.1% (95% CI, 70.6% to 75.7%) against intubation/death. [Vella G, 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 ]

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 ]

Vaccine efficacy and effectiveness for booster dose

Immunogenicity results
Benotmane I et al. was a non-comparative study conducted in France. The study included 159 participants (kidney transplant). This study found that a third dose of Moderna vaccine induced a serologic response in 49% of kidney transplant recipients who did not respond after 2 doses. ​Based on data from the French National Authority for Health that assesses the administration of a third vaccine dose in immunosuppressed patients who did not respond after two doses. [Benotmane I, 2021 ].
              
Hall VG et al was a phase 4, randomized, placebo-controlled trial sponsored by University Health Network, Toronto and conducted Canada May 2021 to August 2021. It was registered with trial registry number NCT04885907. The trial included organ-transplant recipients who had received two doses of mRNA-1273. The sample size was 120. The mean age of the participants was 66.6 years. The proportion of women in the mRNA-1273 group was 38.3% and in the placebo group was 30%. Participants were randomly assigned in a 1:1 ratio to receive a third dose of mRNA-1273 or a placebo. The intervention was administered as a third dose of mRNA-1273 vaccine or saline placebo 2 months after the second dose of mRNA-1273 (dosing schedule: 0, 1, and 3 months). [Hall VG, 2021 ]
          
Branche A et al. recruited 602 adults with primary schedules and a single homologous or heterologous boost. The participants were randomized to six Moderna vaccine arms (50µg dose): 99 received prototype Moderna vaccine, 100 received 1 dose of Beta and Omicron BA.1 bivalent vaccine, 102 received 2 doses of Beta and Omicron BA.1 bivalent vaccine, 101 received 1 dose of Delta and Omicron BA.1 bivalent vaccine, 100 received 1 dose of Omicron BA.1 monovalent vaccine and 100 received 1 dose of Omicron BA.1 Moderna bivalent vaccine. Neutralization antibody titers (ID50) were assessed for D614G, Delta, Beta, and Omicron BA.1 variants and Omicron BA.2.12.1 and BA.4/BA.5 subvariants 15 days after vaccination. The study found that the Omicron BA.1 monovalent and Omicron BA.1+Prototype vaccines induced a geometric mean ratio (GMR) to Prototype for Omicron BA.1 of 2.03 (97.5%CI:1.37-3.00) and 1.56 (97.5%CI:1.06-2.31), respectively. Omicron BA.4/BA.5 GMTs were approximately one third BA.1 GMTs (Prototype 517 [95%CI:324-826] vs. 1503 [95%CI:949-2381]; Omicron BA.1+Beta 628 [95%CI:367-1,074] vs. 2125 [95%CI:1139-3965]; Omicron BA.1+Delta 765 [95%CI:443-1,322] vs. 2242 [95%CI:1218- 4128] and Omicron BA.1+Prototype 635 [95%CI:447-903] vs. 1972 [95%CI:1337-2907) [Angela R Branche, 2022 ].

Anderson et al was a phase 2 randomized controlled trial conducted in the United States that included 96 participants with a primary schedule of Moderna: 48 with Monovalent prototype boost (100 mcg) of mRNA-1273, 25 with Monovalent variant boost of mRNA-1273.351 (50 mcg) and 23 with a bivalent boost of mRNA1273.351 (25 mcg ) and bivalent mRNA-1273 (25 mcg). This study assessed the immunogenicity after a third mRNA vaccination in adults who received the mRNA-1273 primary schedule approximately 9 to 10 months earlier. The booster vaccine formulations included 100 mcg of mRNA-1273, 50 mcg of mRNA1273.351 that encodes Beta variant spike protein, and a bivalent vaccine of 25 mcg each mRNA-1273 and mRNA-1273.351. The results showed that following booster vaccination, a robust response to similar titers was observed in all three groups to 614D S-2P at Day 15 [monovalent prototype 62,272 AUC (95% CI 59,973, 64,659); monovalent variant 61,373 (95% CI 58,622, 64,254); bivalent 62,025 (95% CI 59,468, 64,691). In all groups, the third dose of mRNA vaccine induced similar responses against B.1.351 [monovalent prototype 47,733 AUC (95% CI 44,932, 50,710); monovalent variant 49,768 (95% CI 46,282, 53,517); bivalent 48,126 (95% 44,728, 51,781)] that were only 20% lower than the Day 15 responses to 614D . Spike-specific CD4+ and CD8+ T cells increased to similar levels to those after the second dose. [Anderson E, 2022 ]

Chalkias S et al was an open-label, ongoing phase 2–3 study conducted in United States. The study included 819 participants with primary schedule of Moderna: 377 included in the mRNA-1273 (50 µg) booster group and 437 included in the mRNA-1273.24 (50 µg) booster omicron-containing bivalent group. This study assessed the immunogenicity, safety, and reactogenicity of bivalent booster vaccine mRNA-1273.214 as compared with the previously authorized mRNA-1273 booster vaccine in adults who had received a two-dose primary series (100 μg) and first booster dose (50 μg) of mRNA-1273. Geometric mean titers of neutralizing antibodies against Ancestral SARS-CoV-2 (D614G) were 5977.3 (95% CI 5321.9 to 6713.3) in the mRNA-1273.214 (50 µg) group and 5649.3 (95% CI 5056.8 to 6311.2) in the mRNA-1273 (50 µg) group. Adjusted geometric mean titer ratio against wild type was 1.22 (97.5% CI 1.08 to 1.37) wich met the prespecified criterion for noninferiority. Geometric mean titers of neutralizing antibodies against Omicron were 2372.4 (95% CI 2070.6 to 2718.2) in the mRNA-1273.214 (50 µg) group and 1473.5 (95% CI 1270.8 to 1708.4) in the mRNA-1273 (50 µg) group. Adjusted geometric mean titer ratio against Omicron was 1.75 (97.5% CI 1.49 to 2.04) wich met the prespecified criterion for noninferiority. The percentages of participants with a seroresponse against ancestral SARS-CoV-2 (D614G) were 100% (95% CI, 98.9 to 100) for mRNA1273.214 and 100% (95% CI, 98.6 to 100) for mRNA-1273 at 28 days after the booster doses, with an estimated difference of 0, which met the noninferiority criterion. [Chalkias S, 2022 ]

Haggenburg S et al was a cohort study conducted in Netherlands. The study included 584  immunocompromised patients with hematologic cancers. The aim of this study was to assess whether a third mRNA-1273 vaccination is associated with increased neutralizing antibody concentrations in immunocompromised patients with hematologic cancers comparable to levels obtained in healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. A third mRNA-1273 vaccination was associated with a significant increase in S1-IgG concentration. Seroconversion rates improved from 68.9% (399 of 579) to 78.8% (443 of 562), and 378 of 562 (67.3%) patients obtained S1-IgG concentration of 300 BAU/mL or greater. The rise in S1-IgG concentration after the third vaccination was most pronounced in patients with a recovering immune system, but potent responses were also observed in patients with persistent immunodeficiencies. [Haggenburg S, 2022 ]

Chalkias et al, was a phase 2/3 non-randomized trial conducted in the United States as part of a larger study registered as NCT04927065. Its aim was to evaluate the safety, reactogenicity and immunogenicity of a single booster dose of the bivalent beta-containing mRNA candidate vaccine mRNA-1273.211, in adults who received a primary schedule of mRNA-1273. The study included 300 participants who received 50 µg of mRNA-1273.211 booster, 595 participants who received 100 µg of mRNA-1273.211 booster, a historical cohort of 584 participants who received the 100 µg primary schedule and 171 participants who received a mRNA-1273 50 µg booster dose. The Geometric Mean Titers (GMT) of neutralizing antibodies against the ancestral strain were 1,996.2 (95% CI, 1,777.9–2,241.4) for the mRNA-1273.211 (50 µg) group and 4,324.7 (95% CI, 3,974.6–4,705.6) for the mRNA-1273.211 (100 µg) group. The GMT of neutralizing antibodies against the Beta variant were 953.9 (95% CI, 844.1–1,078.0) for the mRNA-1273.211 (50 µg) group and 1,574.6 (95% CI, 1,439.4–1,722.5) for the mRNA-1273.211 (100 µg) group. [Chalkias S, 2022 ]

BOOST-TX was a randomized controlled trial conducted in Austria, of a third dose of SARS-CoV-2 vaccine in kidney transplant recipients who had not developed antibodies to SARS-CoV-2 spike protein after 2 dose of an mRNA vaccine. 197 patients were analyzed, 99 received a booster of a homologous vaccine (mRNA), 98 received a heterologous vaccine (Ad26COVS1). 39% developed SARS-CoV-2 antibodies after the third vaccination. There were no statistically significant differences 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, the IGRA-assessed T-cell response was low and only 17 patients showed 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), for doubling of years) and torque teno virus plasma (OR, 0.92 (95% CI, 0.88-0.96), for doubling of levels) were associated with response to vaccine. 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 ]

Heinzel et al was a secondary analysis of the randomized trial BOOST-TX 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 third dose of the same mRNA vaccine (the mRNA group) or a dose of the vector vaccine (Janssen, 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 ]

Effectiveness results
 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 doses of Moderna 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 50.8% (95% CI: 43.4-57.3%)[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 Moderna COVID-19 vaccine compared to not receiving any or 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 0.28 (95% CI 0.26 to 0.31) and for Delta variant OR 0.045 (95% CI 0.038 to 0.053). Comparison of 3 Doses vs 2 Doses showed for Omicron variant OR 0.31 (95% CI 0.28 to 0.34) and for Delta variant OR 0.13 (95% CI 0.11 to 0.15)[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 Pfizer or Moderna COVID-19 vaccine booster dose reduced infections by 50.4% (95% CI 29.4% to 64.7%) in nursing home 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 S et al. included 134,435 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 95 to 98) and 65% (95% CI 55 to 72) 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. Data were collected between April  4, 2021, and 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 4.6 (95% CI 4.2 to 5.1)  for the group without a booster and IRR 17.4 (95% CI 14.5 to 21.1) for the booster group.[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 and 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 ].

Chemaitelly H et al.was a case-control study conducted in Qatar based on data from a test-negative design study that seeks to assess the duration of protection of Pfizer-BioNTech after the second dose and after the third/booster dose against symptomatic Omicron infection and against COVID-19 hospitalization and death, between December 23, 2021, and February 2, 2022.  Vaccine effectiveness was 53.1% (95% CI 40.7 to 62.8) 2 to 3 weeks after receiving the booster dose. [Hiam Chemaitelly, 2022 ].

Draws 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–BioNTech and 1,066,645 were fully vaccinated with Moderna. A Pfizer–BioNTech booster was administered to 609,153 individuals and a Moderna booster was administered to 395,634 individuals The 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 vaccine effectiveness after 26 weeks from the second dose was 65% (95% CI 65 to 66) for the Moderna COVID-19 Vaccine. [Drawz PE, 2022 ]

Shrestha NK et al. was a cohort study conducted in the United States, Based on data from the Cleveland Clinic Health System in Ohio, United States, all employees vaccinated (with both Pfizer-BioNTech and Moderna) or who have a history of prior COVID-19 infection until November 26, 2021 were included, with a follow-up period of 90 days. Vaccine effectiveness during the Omicron variant boost was 57% (95% CI: 54% to 59%) for the full schedule and a boost with mRNA [Nabin K Shrestha, 2022 ] vaccines.

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 mRNA-1273) for individuals with PCR–confirmed infections was 0.198 (95% CI 0.144 to 0.271) [Tan SHX, 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 were 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 ].

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 47.3% (95% CI 40.7  to 53.3) 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.  Moderna effectiveness against Delta variant for symptomatic infection was 57.4% (95% CI 52.6 to 61.8) 4 weeks after the first dose, 80.4% (95% CI 67.3 to 88.2) 25 weeks after the second dose, 94.7% (95% CI 89.3 to 97.3) 2-4 weeks after a Pfizer-BioNTech booster and 96.4% (95% CI 91.4 to 98.5) 2-4 weeks after  Moderna booster [Andrews N, 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-19 Infeccion was 35.6% (95%CI 32.8-38.3) and 97.5% (95% CI 89.7 -  99.4) against Severe COVID Infeccion. [Ng OT, 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. IBased 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 homologous booster was 62.1% (95%CI 60.7 to 63.5) 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 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 Moderna vaccine during the Omicron period was 16% (95%CI 5 to 26) for two doses and 57% (95%CI 51 to 62) 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. Vaccine effectiveness with Moderna booster and AstraZeneca, JAnssen, Moderna or Pfizer primary schedule was 52,5% (95% CI, 51,3–53,7). Vaccine effectiveness of Moderna primary schedule and ARNm booster was 55.3% (95% CI, 52.3–58.2) (Moderna or Pfizer booster dose). [Monge S, 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 Moderna vaccine was 87% (95% CI, 75-93) (less than two months after the second dose) and 91% (95% CI, 89-92) with the third booster dose. Vaccine effectiveness (VE) against COVID-19-associated hospitalizations during the Delta-predominant period for Moderna vaccine was 98% (95% CI, 97-99) (less than two months after the second dose) and 97% (95% CI, 96-98) with the third booster dose.[Ferdinands JM, 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 Moderna vaccine against the Omicron variant to any infection was 44% (95% CI, 38% to 49%), against symptomatic infection was 61% (95% CI, 50% to 69%) and against severe outcomes 81% (95% CI, 74% to 86%).[Grewal R, 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 Pfizer or 2 doses of 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 a mRNA primary schedule was 81% (95% CI, 80% to 82%). [Mehta HB, 2022 ]

Hung FT et al fue un estudio de casos y controles conducido en Estados Unidos que incluyó 123.236 participantes, 30.809 casos y 92.427 controles. Basado en datos de KPSC, registros electrónicos, el registro de inmunización de California (CAIR) y el servicio Care Everywhere, durante el período de predominancia de Ómicron (entre enero y junio de 2022). El estudio evaluó la efectividad de una tercera y cuarta dosis de Moderna. La efectividad ajustada contra la infección 14-30 días después de la tercera dosis fue de 72,6% (IC 95%, -54,7% a 96,6%) contra BA.4 y 90,6% (IC 95%, 30,6% a 98,7%) contra BA.5. Luego de la cuarta dosis la efectividad de la vacuna fue de 75,7% (IC 95%, 44,7% a 91%) contra BA.4 y 30,8% (IC 95%, -9,2% a 56,5%) contra BA.5. La efectividad ajustada contra la hospitalización luego de la tercera dosis fue de 72,4% (IC 95%, 23,9% a 90%) contra BA.4/BA.5 y luego de la cuarta dosis fue de 88,5% (IC 95%, 51,8% a 97,2%). [Hung Fu Tseng, 2022 ]

Baum U et al was a cohort study conducted in Finland including 896,220 participants aged 70 years and over. The study was based on a nationwide register-based cohort, between December 27th 2020 and March 31st 2022. Vaccine effectiveness of the booster against hospital admission was 97% (95% CI, 93% to 98%). [Baum U, 2022 ]

Grewal R was a case-control study conducted in Canada that included data from 3,736 Omicron positive cases and 77,695 SARS-CoV-2 negative controls. The aim was to estimate the effectiveness of a fourth dose of an mRNA vaccine against Omicron infections and severe outcomes over time. Vaccine effectiveness (VE) against symptomatic infection was 51% (95% CI, 42% to 60%), and 69% (95% CI, 61% to 75%) after the third and fourth doses, respectively. VE against severe outcomes was 77% (95% CI, 68% to 83%), and 79% (95% CI, 71% to 84%) after the third and fourth doses, respectively. [Grewal R, 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 homologous booster dose was 47.59% (95% CI, 46.72% to 48.45%) against COVID-19 infection, and 81.09% (95% CI, 79.17% to 82.85%) against COVID-19-related death.  [Yuanyuan Fu, 2022 ]

Huiberts A 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 15.8% (95% CI, -26.3% to 43.9%), 68.3% (95% CI, 63.1% to 72.8%) and 67.6% (95% CI, 60.1% to 73.7%) for Moderna primary schedule, mRNA primary schedule with Moderna booster and AstraZeneca primary schedule with Moderna booster, respectively. VE against contracting COVID-19 during the Delta period was 100% (95% CI, 0% to 100%) and 100% (95% CI, 0% to 100%) for Moderna primary schedule and mRNA primary schedule with Moderna booster, respectively. [Anne J. Huiberts, 2023 ]

Tseng HF et al was a test negative case control study conducted in United States that included data from 123,236 participants: 30,809 with a SARS-CoV-2 positive test and 92,427 with SARS-CoV-2 negative test. This study assessed vaccine effectiveness against infection and hospitalization with Omicron sub-variants. Adjusted vaccine effectiveness against hospitalization for Omicron sub-variants for 3 doses was 97.5% (95% CI, 96.3% to 98.3%), 82% (95% CI, 64.5% to 90.8%) and 72.4% (95% CI, 23.9% to 90.0%) for BA.1, BA.2 and BA.4/BA.5 sub-variants, respectively. Adjusted vaccine effectiveness against hospitalization for Omicron sub-variants for 4 doses was 96.4% (95% CI, 88.4% to 98.9%) and 88.5% (95% CI, 51.8% to 97.2%) for BA.2 and BA.4/BA.5 sub-variants, respectively. [Tseng HF, 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 Moderna was 97.5% (95% CI, 82.5% to 99.7%). Adjusted VE against Omicron (2 doses of Moderna) was 25.6% (95% CI, 10.7% to 39.0%). Adjusted VE against Omicron (3 doses of Moderna) was 71.2% (95% CI, 24.0% to 90.8%). [Weng CH, 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 ]

Vaccine efficacy and effectiveness for heterologous schedule

Immunogenicity results
Macchia et al, was a randomized noninferiority clinical trial conducted in Argentina. The study compared the immune response generated by the homologous Sputnik V regimen to heterologous Sputnik V vaccine regimens with Moderna, Sinopharm BIBP, or AstraZeneca vaccines. The study showed that all but the Moderna regimen were statistically inferior to the standard Sputnik V regimen (rAd26/rAd5). The Moderna regimen showed a 3.53-fold increase in antibody concentrations compared to the standard Sputnik V regimen. [Macchia A, 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 study showed that the GMT antibodies were higher with the heterologous schedule compared to the Pfizer-BioNTech homologous regimen. [Janssen C, 2022 ]

Pascuale CA et al was a comparative cohort sutdy conducted in Argentina. The study enrolled 1,314 participants who had received the first dose of Sputnik V C1 (n = 669), AstraZeneca (n = 448), or BBIBPCorV (n = 197): 148 with Moderna second dose and Sputnik first dose, 67 Moderna second dose and AstraZeneca first dose, and 42 Moderna second dose and BBIBPCorV first dose. The study assessed the immunogenicity and reactogenicity by comparing homologous vaccination programs using either Sputnik V, ChAdOx1-S, or BBIBP-CorV with different heterologous schemes to define strategies to accelerate vaccination plans. A second dose of mRNA-1273 induced the highest antibody response in all cohorts. The levels of IgG anti-spike antibodies and the serum neutralizing capacity of the heterologous combinations with mRNA-1273 in all arms were similar to those obtained with the homologous two-dose schedule with mRNA1273, used as the reference. In all three cohorts, heterologous vaccination with mRNA-1273 resulted in a significant (p < 0.01) increase in the serum neutralizing titers compared with the homologous schemes. [Pascuale CA, 2022 ]

RECOVAC was a randomized trial conducted in the Netherlands that enrolled 333 kidney transplant recipients (KTR) who did not seroconvert after an initial mRNA vaccine schedule: 230 KTRs were randomly assigned in a 1:1:1 manner to receive 100 μg mRNA-1273, 2 × 100 μg mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTRs receiving 100 μg mRNA-1273, were randomly assigned 1:1 to continue (mycophenolate mofetil+) or discontinue (mycophenolate mofetil-) mycophenolate mofetil or mycophenolic acid treatment for 2 weeks. The primary outcome was the percentage of participants with a spike protein (S1)-specific IgG concentration of at least 10 binding antibody units per mL at 28 days after vaccination. The seroreponse rates were 68% (95% CI, 56% to 79%) for the 2 × mRNA-1273 group, 63% (95% CI, 51% to 74%) for the Ad26.COV2-S group and 68% (95% CI, 57% to 79%) for the single mRNA-1273 group. The seroresponse rate in mycophenolate mofetil- was 80% (95% CI, 66% to 91%) and 67% (95% CI, 52% to 80%) in mycophenolate mofetil+. [Kho MML, 2022 ]

Effectiveness results
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. 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 ChAdOx1/mRNA-1273 60-119 days after second dose was 87% (95% CI, 85% to 89%) against any infection, 93% (95% CI, 91% to 94%) against symptomatic infection and 99% (95% CI, 98% to 100%) against severe outcomes. [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 the Pfizer/Moderna heterologous 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 fu et al. was an observational study to analyzed vaccination status and SARS-CoV-2 infection data from more tha 10.4 million participants in the national COVID Cohort Collaborative (N3C) during an 18-month-period (December 2020 to June 2022) in the United States. Vaccine Effectiveness against COVID-19 infection was 35.17% (95% CI, 31.71% to 38.50%) for the Moderna/Pfizer schedule. [Yuanyuan Fu, 2022 ]

Vaccine efficacy and effectiveness for heterologous booster schedule

Immunogenicity results
Bonelli M 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 ].

COV-BOOST 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, hearafter 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 neutralising 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 the 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 ].

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 the 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 ].

Kanokudom S et al. recruited 222 adults with a complete CoronaVac regimen 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. 28 days after the booster dose binding antibody levels were 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. [Kanokudom S, 2022 ].

Poh X 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 on 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 titer 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 ].

Chuang et al. was a randomized controlled study made in Taiwan. It included data from samples of 340 health care workers (HCW) with prior Oxford-AstraZeneca homologous vaccination and that received one of the four vaccines as booster doses: Pfizer–BioNTech, half-dose Moderna, full dose Moderna or MVC-COV1901. The primary outcomes were humoral and cellular immunogenicity and the secondary outcomes safety and reactogenicity 28 days post-booster. The study found that, compared with pre-boost, all study vaccines elicited significantly higher anti-spike IgG at 28 days post-boost (P < 0.0001). The mRNA vaccines had more reactogenicity than the protein vaccine [Chih-Hsien Chuang, 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). It was compared immunogenicity 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 results showed a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25,317 ELU/mL, 95% CI 20,996–30,528) to 14 days after a fourth dose of Moderna (54 936 ELU/mL, 46,826–64,452), with a geometric mean fold change of 2,19 (1,90–2,52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12,19 (95% CI 10,37–14,32) and 15,90 (12,92–19,58) in the Pfizer–BioNTech and Moderna groups, respectively. T-cell responses were also boosted after the fourth dose (the fold changes for the wild-type variant from before to after the fourth dose were 7,32 [95% CI 3,24–16,54] in the Pfizer–BioNTech group and 6,22 [3,90–9,92] in the Moderna group). [Munro APS, 2022 ]

Suntronwong N et al. was a cohort study conducted in Thailand. One hundred and sixty-seven 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. The study showed that, following the booster dose, the anti-RBD IgG significantly increased and peaked at day 14 for all vaccines (p< 0.001). Comparing pre and post-boost, the Moderna vaccine induced an anti-RBD IgG 23-fold increase (126.9 vs. 2921 BAU/ml) and showed a higher level than the other vaccine groups. 90-97% of individuals boosted with Pfizer and Moderna induced IFN-γ responses at 14 days. [Suntronwong N, 2022 ]

BOOST-TX was a randomized controlled trial conducted in Austria, assessing a third vaccine dose 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 received an homologous booster (mRNA) vaccine, 98 received an heterologous (Ad26COVS1) vaccine. 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. Associated with vaccine response were cases 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). 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 ]

Bonelli et al was a randomized controlled trial in Austria that 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 ]

mRNA-1273-P205 was an open-label, phase 2/3 study conducted in the United States that included 819 participants with a primary schedule of Moderna: 377 included in the mRNA-1273 (50 µg) booster group, and 437 included in the mRNA-1273.24 (50 µg) Omicron BA,.1-containing bivalent vaccine group. Geometric mean titers (GMT) of neutralizing antibodies against ancestral SARS-CoV-2 (D614G) were 5977.3 (95% CI, 5321.9-6713.3) in the mRNA-1273.214 (50 µg) group and 5649.3 (95% CI, 5056.8-6311.2) in the mRNA-1273 (50 µg) group. The adjusted GMT ratio against the wild type was 1.22 (97.5% CI, 1.08-1.37) which met the prespecified criterion for noninferiority. GMT of neutralizing antibodies against Omicron were 2372.4 (95% CI, 2070.6-2718.2) in the mRNA-1273.214 (50 µg) group and 1473.5 (95% CI, 1270.8.1708.4) in the mRNA-1273 (50 µg) group. Adjusted GMT against Omicron was 1.75 (97.5% CI, 1.49-2.04) which met the prespecified criterion for noninferiority. The percentages of participants with a seroresponse against ancestral SARS-CoV-2 (D614G) were 100% (95% CI, 98.9% to 100%) for mRNA1273.214 and 100% (95% CI, 98.6% to 100%) for mRNA-1273 at 28 days after the booster doses, with an estimated difference of 0, which met the noninferiority criterion. [Chalkias S, 2022 ]

mRNA-1273-P205 was an open-label, phase 2/3 study conducted in the United States that included 887 participants with a primary schedule of Moderna and a first homologous booster: 176 received a second booster dose of mRNA-1273 (50 µg)  and 511 received a second booster dose of the Omicron BA.4/BA.5-containing mRNA-1273.222 (50 µg) vaccine. ​​Geometric mean titers (GMT) of neutralizing antibodies against the ancestral SARS-CoV-2 (D614G) strain were 7322.4 (95% CI, 6386.2-8395.7), and 5651.4 (95% CI, 5055.7-6317.3) for mRNA-1273.222 (50 µg) and mRNA-1273 (50 µg), respectively. GMT of neutralizing antibodies against Omicron were 2324.6 (95% CI, 1921.2-2812.7), and 488.5 (95% CI, 427.4-558.4) for mRNA-1273.222 (50 µg), and mRNA-1273 (50 µg), respectively. [Spyros Chalkias, 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 ].

Lee I et al was a phase 3 randomized trial conducted in the United Kingdom that assessed the immunogenicity and safety of 50 µg doses of Omicron-BA.1- monovalent mRNA-1273.529 and bivalent mRNA-1273.214 booster vaccines compared with 50 µg mRNA-1273. Neutralizing antibody geometric mean concentrations against Omicron BA.1 were 537.7 (95% CI, 478.2−604.6) for mRNA-1273.529 booster and 307.4 (95% CI, 279.5−338.2) for mRNA-1273 booster. [Lee, I. T., 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 titers 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 ]

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 results
Andrews N et al. was a case-control study (Test-negative) conducted in the 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 the 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 ].

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.  Moderna effectiveness against Delta variant for symptomatic infection was 57.4% (95% CI 52.6 to 61.8) 4 weeks after the first dose, 80.4% (95% CI 67.3 to 88.2) 25 weeks after the second dose, 94.7% (95% CI 89.3 to 97.3) 2-4 weeks after a Pfizer-BioNTech booster and 96.4% (95% CI 91.4 to 98.5) 2-4 weeks after  Moderna booster [Andrews N, 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 ].

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 ]

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 (Canadá) to estimate the vaccine effectiveness (VE) against symptomatic infections and severe outcomes associates with these infections. Of 134,435 total participants (> 18 years older), 16,087 were Omicron-positive cases , 4261 were Delta-positive cases, and 114 087 were test-negative controls. Symptomatic Infection against OMICRON BNT16b2: 60% (CI 95% 55-65). VE against Omicron severe outcome BNT16b2: 95% (95% CI 87-98).  VE  against Delta symptomatic infection BNT16b2: 97% (95% CI 96-98). VE against Delta severe outcome BNT16b2: 99% (95% CI 98-99). [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. IBased 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 to 70.5) after 1 month, the effectiveness of Pfizer-BioNTech vaccine booster after Moderna primary schedule was 66.1% (95%CI 61.9 to 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 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. We linked data from three nationwide population registries in Spain (Vaccination Registry, Laboratory Results Registry, and National Health System registry) . In this study were included 7, 036, 433 participantes ≥ 40 years . The aim of this study was to estimate the effectiveness of mRNA-based vaccine boosters against infection with the omicron variant. The estimated effectiveness from day 7 to 34 after a booster was 51.3% (95%CI 50.2-52.4), with Pfizer Booster was 46,2% (95% CI 43,5–48,7).  Estimated effectiveness was 43,6% (95% CI 40,0 –47,1) when the booster was administered between 151 days and 180 days after complete vaccination and 52,2% (95% CI 51,0–53,3) if administered more than 180 days after primary scheduled completion.[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.

VE 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:

Primary Schedule ChAd0x1-S Booster mRNA-1273
After 14-34 days: 88.3% (95% CI 84.3 to 91.3)
After 70+ days: 74.1% (95% CI 56.3 to 84.7)

Primary Schedule BNT162b2 Booster mRNA-1273
After 14-34 days: 87.3% (95% CI 81.2 to 91.3)
After 70+ days: 60.6% (95% CI 27.7 to 78.5)

VE 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:

Primary Schedule ChAd0x1-S Booster mRNA-1273
After 14-34 days: 98.1% (95% CI 92.1 to 99.5)
After 70+ days: 89.6% (95% CI 73.8 to 95.9)

Primary Schedule BNT162b2 Booster mRNA-1273
After 7-13 days: 89.0% (95% CI 17.2 to 98.5)
After 14-34 days: 91.2% (95% CI 75.5 to 96.9)

[Stowe J, 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 the 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 two doses of Pfizer and Moderna booster against the Omicron variant against any infection was 36% (95% CI, 28% to 44%), against symptomatic infection was 57% (95% CI, 40% to 69%) and against severe outcomes 81% (95% CI, 67% to 89%). [Grewal R, 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 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 0.58 (95% CI, 0.46-0.73) for the Pfizer-BioNTech primary schedule and Moderna booster group and 0.41 (95% CI, 0.33-0.50) for the ChAdOx1 primary schedule and Moderna booster group. [Agrawal U, 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) of the booster against hospital admission was 91% (95% CI, 87% to 94%) for the Pfizer schedule+Moderna booster, 91% (95% CI, 81% to 96%) for the Moderna schedule+Pfizer booster, and 94% (95% CI, 92% to 98%) for the AstraZeneca schedule+Moderna booster. 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+Moderna booster. [Baum U, 2022 ]

Intawong K et al was a test-negative case-control study conducted in Thailand that included 36,170 participants, 14,682 cases and 21,488 controls. Based on data from the Epid-CM platform, including participants aged 18 years and older, between October 2021 and April 2022. The aim was to assess the effectiveness of different booster doses. The adjusted vaccine effectiveness (VE) 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-related 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 ]

Nittayasoot et al., conducted 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: ChAdOx1 + ChAdOx1 + Moderna was 87.69% (95% CI, 46.60% to 97.16%), ChAdOx1 + Pfizer + Moderna was 100.00% (95% CI, 99.99% to 100.00%) and Coronavac + Coronavac + Moderna + Moderna was 100.00% (95% CI, 99.99% to 100.00%). [Nittayasoot N, 2022 ] 

Huiberts A 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 15.8% (95% CI, -26.3% to 43.9%), 68.3% (95% CI, 63.1% to 72.8%) and 67.6% (95% CI, 60.1% to 73.7%) for Moderna primary schedule, mRNA primary schedule with Moderna booster and AstraZeneca primary schedule with Moderna booster, respectively. VE against contracting COVID-19 during the Delta period was 100% (95% CI, 0% to 100%) and 100% (95% CI, 0% to 100%) for Moderna primary schedule and mRNA primary schedule with Moderna 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 ]

Kamal SM et al was a comparative cohort study conducted in Saudi Arabia that included data from 1,500 vaccinated participants: 503 AstraZeneca, 521 Pfizer, and 476 Moderna, and 1,500 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 0.015 (95% CI, 0.0049-0.047). [Kamal SM, 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% a 61%). [Tenforde MW, 2023 ]

Safety of the vaccine in preclinical studies

The Moderna COVID-19 vaccine was tested in non-human primates. There were no vaccine-related adverse events noted. No cases of death or pathological changes in the lung were noted [Corbett KS, 2020 ].

Reproductive toxicity
A study performed in rats assessing postnatal reproductive toxicity of the Moderna COVID-19 vaccine was submitted to FDA on December 4, 2020. FDA review concluded that a dose of 100 μg given prior gestation periods did not have any adverse effects on female reproduction, fetal/embryonal development, or postnatal developmental [FDA, 2020 ]
Developmental and reproductive toxicology (DART) studies in rats concluded that the vaccine at a dose of 100 μg, given prior to mating and during gestation periods, did not have any adverse effects (including on female reproduction, fetal/embryonic development, or postnatal developmental). 

Safety of the vaccine in clinical trials

Main safety outcomes of Moderna COVID-19 vaccine

Key messages

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

Moderna COVID-19 vaccine did not increase the risk of serious adverse events.

Any adverse event after the 2nd dose (within 7 days after injection)

The relative risk of any adverse event after the 2nd dose in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 1.94 (95% CI 1.58 to 2.38). This means Moderna COVID-19 vaccine increased the risk of any adverse event after the 2nd dose by 94%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event after the 2nd dose. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 6255 people not receiving Moderna COVID-19 vaccine out of 14578 presented this outcome (439 per 1000) versus 13556 out of 14691 in the group that did receive it (851 per 1000). In other words, 412 more people per 1000 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 41.2%, or that the intervention increased the risk of any adverse event after the 2nd dose by 41.2 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 2. Which means that 2 people need to receive the vaccine for one of them to experienced any adverse event after the 2nd dose.

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

Local adverse events after the 2nd dose (within 7 days after injection)

The relative risk of local adverse events after the 2nd dose in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 3.67 (95% CI 2.26 to 5.95). This means Moderna COVID-19 vaccine increased the risk of local adverse events after the 2nd dose by 267%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: local adverse events after the 2nd dose. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 2757 people not receiving Moderna COVID-19 vaccine out of 14578 presented this outcome (200 per 1000) versus 13029 out of 14691 in the group that did receive it (734 per 1000). In other words, 534 more people per 1000 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 53.4%, or that the intervention increased the risk of local adverse events after the 2nd dose by 53.4 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 2. Which means that 2 people need to receive the vaccine for one of them to experienced local adverse events after the 2nd dose.

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

Systemic adverse events after the 2nd dose (within 7 days after injection)

The relative risk of systemic adverse events after the 2nd dose in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 2.98 (95% CI 1.56 to 5.67). This means Moderna COVID-19 vaccine increased the risk of systemic adverse events after the 2nd dose by 198%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: systemic adverse events after the 2nd dose. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 5343 people not receiving Moderna COVID-19 vaccine out of 14578 presented this outcome (342 per 1000) versus 11678 out of 14691 in the group that did receive it (1018 per 1000). In other words, 676 more people per 1000 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 67.6%, or that the intervention increased the risk of systemic adverse events after the 2nd dose by 67.6 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 1. Which means that 1 people need to receive the vaccine for one of them to experienced systemic adverse events after the 2nd dose.

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 non-serious adverse reactions associated with Moderna COVID-19 vaccine were pain at the injection site (91.6%), followed by fatigue (68.5%), headache (63.0%), muscle pain (59.6%), joint pain (44.8%), and chills (43.4%); local adverse reactions occurred more frequently after second dose, and were generally less frequent in younger participants (≥65 years of age).

Serious adverse events (within 28 days after any injection)

The relative risk of serious adverse events in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.95 (95% CI 0.73 to 1.25). No statistically significant differences between groups were found for serious adverse events.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event after the 2nd dose. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 104 people not receiving Moderna COVID-19 vaccine out of 104 presented this outcome (65 per 10000) versus 98 out of 15184 in the group that did receive it (62 per 10000). In other words, 3 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 of 0.03%, or that the intervention reduced the risk of serious adverse events by 0.03 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 3333. Which means that 3333 people need to receive the vaccine for one of them to experienced serious adverse events.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: the information provides from a small sample; Publication bias: no concerns.

Safety of the vaccine in subgroups

Any adverse event after the 2nd dose (Females subgroup) (within 7 days after 2nd injection)

The relative risk of any adverse event after the 2nd dose in the females subgroup in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 1.96 (95% CI 1.91 to 2.01). This means Moderna COVID-19 vaccine increased the risk of any adverse event after the 2nd dose in the females subgroup by 96%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event after the 2nd dose in the females subgroup. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 3292 people not receiving Moderna COVID-19 vaccine out of 6847 presented this outcome (428 per 1000) versus 6635 out of 7045 in the group that did receive it (838 per 1000). In other words, 410 more people per 1000 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 41%, or that the intervention increased the risk of any adverse event after the 2nd dose in the females subgroup by 41 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 2. Which means that 2 people need to receive the vaccine for one of them to experienced any adverse event after the 2nd dose in the females subgroup.

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

Any adverse event after the 2nd dose (Males subgroup) (within 7 days after 2nd injection)

The relative risk of any adverse event after the 2nd dose in the males subgroup in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 2.36 (95% CI 2.29 to 2.43). This means Moderna COVID-19 vaccine increased the risk of any adverse event after the 2nd dose in the males subgroup by 136%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event after the 2nd dose in the males subgroup. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 2963 people not receiving Moderna COVID-19 vaccine out of 7731 presented this outcome (428 per 1000) versus 6921 out of 7646 in the group that did receive it (1011 per 1000). In other words, 583 more people per 1000 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 58.3%, or that the intervention increased the risk of any adverse event after the 2nd dose in the males subgroup by 58.3 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 2. Which means that 2 people need to receive the vaccine for one of them to experienced any adverse event after the 2nd dose in the males subgroup.

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

Any adverse event after the 2nd dose (≥65 years) (within 7 days after 2nd injection)

The relative risk of any adverse event after the 2nd dose in the ≥65 year old participants in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 2.45 (95% CI 2.34 to 2.56). This means Moderna COVID-19 vaccine increased the risk of any adverse event after the 2nd dose in the ≥65 year old participants by 145%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event after the 2nd dose in the ≥65 year old participants . Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 1334 people not receiving Moderna COVID-19 vaccine out of 3649 presented this outcome (428 per 1000) versus 3304 out of 3691 in the group that did receive it (1048 per 1000). In other words, 620 more people per 1000 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 62%, or that the intervention increased the risk of any adverse event after the 2nd dose in the ≥65 year old participants by 62 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 2. Which means that 2 people need to receive the vaccine for one of them to experienced any adverse event after the 2nd dose in the ≥65 year old participants .

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

Any adverse event after the 2nd dose (12-17 years) (within 7 days after 2nd injection)

The relative risk of any adverse event after the 2nd dose in children between 12 to 17 years of age in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 1.74 (95% CI 1.66 to 1.83). This means Moderna COVID-19 vaccine increased the risk of any adverse event after the 2nd dose in children between 12 to 17 years of age by 74%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event after the 2nd dose in children between 12 to 17 years of age. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 680 people not receiving Moderna COVID-19 vaccine out of 1220 presented this outcome (428 per 1000) versus 2405 out of 2478 in the group that did receive it (745 per 1000). In other words, 317 more people per 1000 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 31.7%, or that the intervention increased the risk of any adverse event after the 2nd dose in children between 12 to 17 years of age by 31.7 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 3. Which means that 3 people need to receive the vaccine for one of them to experienced any adverse event after the 2nd dose in children between 12 to 17 years of age.

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

Summary of findings (iSoF)

Safety of the vaccine in subgroups

Sex
Randomized trials
The proportion of females in the COVE trial was 47.3% (14366 out of 30351 participants) [Baden LR, 2021 ].
Safety profile of Moderna COVID-19 vaccine was similar across sex groups.

Other comparative studies
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 ].

Age
Randomized trials
25% (7512/30351) of the participants in the COVE trial were aged 65 years or over (mean age: 70.6 years; range: 40-95 years) [Baden LR, 2021 ]. 
           
Severe adverse reactions were generally less frequent in participants ≥65 years of age as compared to younger participants [FDA, 2020 ].
Lymphadenopathy (axillary swelling and tenderness of the vaccination arm) was observed in 12.4% of vaccine recipients ≥65 years of age, as compared with 5.8% of placebo recipients [FDA, 2020 ]. 
           
The phase 2, open-label study QHD00028 is currently evaluating the efficacy/safety of the vaccine in fully vaccinated adults with mRNA-1273 65 years of age and older [Sanofi Pasteur, a Sanofi Company, 2021 ].
           
The phase 4, randomized controlled trial mRNA-1273-D3-2021 is currently evaluating the efficacy/safety of the vaccine in vaccinated residents ≥65 years that received  [Mark Loeb, 2021 ].
           
Children and adolescents
Randomized trials
The TeenCove or study P203 (NCT04649151) was a phase 2/3 trial sponsored by Moderna evaluating vaccine efficacy in adolescents from 12 to 17 years of age. Results of the study showed that in the mRNA-1273 group, the most common solicited adverse reactions after the first or second injections were injection-site pain (in 93.1% and 92.4%, respectively), headache (in 44.6% and 70.2%, respectively), and fatigue (in 47.9% and 67.8%, respectively); in the placebo group, the most common solicited adverse reactions after the first or second injections were injection-site pain (in 34.8% or 30.3%, respectively), headache (in 38.5% and 30.2%, respectively), and fatigue (in 36.6% and 28.9%, respectively). No serious adverse events related to mRNA-1273 or placebo were noted [Ali K, 2021 ]. 
   
P204 study (mRNA-1273-P204) is an ongoing phase 2/3, randomized trial sponsored by ModernaTX, Inc. It was first registered in March 15, 2021 and plans to enroll 6750 participants with children between 6 months of age and less than 12 years of age, finalizing in June 10, 2023. Participants will be randomized to receive intramuscular injections of the vaccine at different doses (defined in the different states of the study), 28 days apart, on Day 1 and Day 29. [ModernaTX, Inc., 2021 ].
           
Other comparative studies 
Cheng DR  et al was a population based study conducted in Australia. The study included 454,974 12 to17 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 immunisation reported following any COVID-19 mRNA vaccines in the adolescent population.  Confirmed myocarditis reporting rates were8.3 per 100 000 doses in this age group (aggregated data for both mRNA vaccines). [Cheng DR, 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 Moderna was 6,83 (95% CI, 2,14-21,85). [Cristina Morciano, 2023 ]

Pregnancy
Other comparative studies 
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 ].

Kachikis et al . analyzed a convenience sample of adults enrolled in the online prospective study who were pregnant, lactating, or neither pregnant nor lactating at the time of their booster or third dose was eligible for this follow-up survey; 17,014 (97.2%) completed the follow-up survey. 16, 989 individuals who 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 (adjusted odds ratio [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. [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 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 the 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 the Moderna vaccine were 1.99 (95% CI, 1.14-3.46) for skin and soft tissue or local allergic reactions, 4.65 (95% CI, 2.13-10.15) for fever, 2.88 (95% CI, 1.93-4.3) for malaise and 1.78 (95% CI, 0.93-3.4) for lymphadenopathy. [DeSilva M, 2022 ]

Mansour O et al was a prospective cohort study conducted in the United States including 2129 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 ]

Breast-feeding
Randomized trials
No clinical trial evaluating vaccines to prevent COVID-19 has included breast-feeding females.

Other comparative studies 
Kachikis et al . analyzed a convenience sample of adults enrolled in the online prospective study who were pregnant, lactating, or neither pregnant nor lactating at the time of their booster or third dose was eligible for this follow-up survey; 17,014 (97.2%) completed the follow-up survey. 16, 989 individuals who 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 (adjusted odds ratio [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. [Kachikis A, 2022 ]

Immunocompromised persons
Randomized trials
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 randomized, multi-site, adaptive, open-label clinical trial DAIT ACV01 is currently evaluating the efficacy/safety of the vaccine in participants with autoimmune disease requiring immunosuppressive medications [National Institute of Allergy and Infectious Diseases (NIAID), 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 ].