Risk considerations

The vaccine is based on the Ad26 vector platform. Clinical experience with this platform consists of the Ad26.ZEBOV/MVA-BN-Filo Ebola vaccine regimen, and vaccines against Zika, filovirus, HIV, HPV, malaria and respiratory syncytial virus. Almost 200,000 participants have used Ad26-based vaccines in clinical studies and vaccination programs with an acceptable clinical safety profile [WHO, 2021 ].

Efficacy of preclinical studies on the vaccine

Mercado et al [Mercado NB, 2020 ] conducted a study assessing the immunogenicity and protective efficacy of a single dose of the vaccine in 52 rhesus macaques. The animals were challenged with SARS-CoV-2 by the intranasal and intratracheal routes and the vaccine induced neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs. The vaccine elicited neutralizing antibody titers correlated with protective efficacy.

Tostanoski et al [Tostanoski LH, 2020 ] conducted a study in hamsters with severe clinical disease. A single immunization with the vaccine elicited binding and neutralizing antibody responses, and protected against SARS-CoV-2-induced weight loss, pneumonia and mortality.

Efficacy of the vaccine in clinical trials

Main immunogenicity outcomes

Immunogenicity was evaluated in the phase 1/2a randomized trial COV1001 [Sadoff J, 2021 ]. The trial included healthy adults older than 18 years, that received the vaccine at a dose of 5×10^10 viral particles (low dose) or 1×10^11 viral particles (high dose) per milliliter, or placebo, in a single-dose or two-dose schedule. Neutralizing-antibody titers were detected in 90% or more of all participants on day 29 after the first vaccine dose, and reached 100% by day 57, with a further increase in titers, regardless of vaccine dose or age group. A second dose provided an increase in the titer. Spike-binding antibody responses were similar to neutralizing-antibody responses. CD4+ T-cell responses were detected in 60 to 83% of the participants in different age groups with different cell response profiles in each group.

Key messages

Janssen COVID-19 vaccine reduces the risk of contracting any symptomatic COVID-19

Janssen COVID-19 vaccine reduces the risk of contracting moderate to severe COVID-19

Main efficacy outcomes of Janssen COVID-19 vaccine

Contracting symptomatic COVID-19 (measured at least 14 days after the injection)

The relative risk of contracting any symptomatic COVID-19 in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.36 (95% CI 0.2 to 0.65). This means Janssen COVID-19 vaccine reduced the risk of contracting any symptomatic COVID-19 in 64%, compared with placebo vaccine.

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

In the available trial 1082 people not receiving Janssen COVID-19 vaccine out of 19398 presented this outcome (45 per 1000) versus 495 out of 19400 in the group that did receive it (16 per 1000). In other words, 29 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 2.9%, or that the intervention reduced the risk of contracting any symptomatic COVID-19 by 2.9 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 34. Which means that 34 people need to receive the vaccine for one of them to experienced contracting any symptomatic COVID-19.

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

Contracting moderate to severe/critical COVID-19 (measured at least 14 days after the injection)

The relative risk of contracting moderate to severe COVID-19 in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.36 (95% CI 0.21 to 0.64). This means Janssen COVID-19 vaccine reduced the risk of contracting moderate to severe COVID-19 in 64%, compared with the placebo vaccine.

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

In the trial identified in this review, 1067 people not receiving Janssen COVID-19 vaccine out of 19398 presented this outcome (45 per 1000) versus 484 out of 19400 in the group that did receive it (16 per 1000). In other words, 29 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 2.9%, or that the intervention reduced the risk of contracting moderate to severe COVID-19 by 2.9 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 34. Which means that 34 people need to receive the vaccine for one of them to experienced contracting moderate to severe 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/critical COVID-19 (measured at least 14 days after complete vaccination)

The relative risk of contracting severe/critical COVID-19 in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.23 (95% CI 0.09 to 0.59). This means Janssen COVID-19 vaccine reduced the risk of contracting severe/critical COVID-19 by 77%, compared with placebo vaccine.

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

In the trial identified in this review, 205 people not receiving Janssen COVID-19 vaccine out of 19398 presented this outcome (9 per 1000) versus 56 out of 19400 in the group that did receive it (2 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/critical 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 experienced contracting severe/critical 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 Janssen COVID-19 vaccine on the risk of mortality. The information provided by randomized trials was not adequately powered to estimate a difference in this outcome. Deaths can occur in the intervention and control group for reasons unrelated to COVID-19 or the vaccine. Establishing that there is a reduction (or increase) in the risk of death attributable to Janssen COVID-19 vaccine would require trials with a higher statistical power.

Efficacy of the vaccine in subgroups

Contracting COVID-19 (≥60y) (measured at least 14 days after complete vaccination)

The relative risk of contracting COVID-19 (≥60y) in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.46 (95% CI 0.37 to 0.58). This means Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 (≥60y) by 54%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (≥60y). Comparison: Janssen COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 220 people not receiving Janssen COVID-19 vaccine out of 6724 presented this outcome (19 per 1000) versus 103 out of 6734 in the group that did receive it (9 per 1000). In other words, 10 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%, or that the intervention reduced the risk of contracting COVID-19 (≥60y) by 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 100. Which means that 100 people need to receive the vaccine for one of them to experienced contracting COVID-19 (≥60y).

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

Contracting COVID-19 (Male) (measured at least 14 days after complete vaccination)

The relative risk of contracting COVID-19 for men in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.46 (95% CI 0.4 to 0.53). This means Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 (Male) by 54%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (Male). Comparison: Janssen COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 581 people not receiving Janssen COVID-19 vaccine out of 10742 presented this outcome (54 per 1000) versus 267 out of 10798 in the group that did receive it (25 per 1000). In other words, 29 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 2.9%, or that the intervention reduced the risk of contracting COVID-19 (Male) by 2.9 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 34. Which means that 34 people need to receive the vaccine for one of them to experienced contracting COVID-19 (Male).

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

Contracting COVID-19 (Female) (measured at least 14 days after complete vaccination)

The relative risk of contracting COVID-19 for women in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.45 (95% CI 0.38 to 0.53). This means Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 (Female) by 55%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (Female). Comparison: Janssen COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 486 people not receiving Janssen COVID-19 vaccine out of 8652 presented this outcome (56 per 1000) versus 217 out of 8599 in the group that did receive it (25 per 1000). In other words, 31 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 3.1%, or that the intervention reduced the risk of contracting COVID-19 (Female) by 3.1 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 32. Which means that 32 people need to receive the vaccine for one of them to experienced contracting COVID-19 (Female)

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)

Efficacy and effectiveness of the vaccine in subgroups

Sex
Randomized trials
The proportion of women in the ENSEMBLE trial was 45% (19722 out of 43783 participants) [Sadoff J, 2021 ].

Among women, the relative risk of contracting moderate to severe COVID-19 with onset at least 14 days or 28 days after vaccination, when comparing with the group that received placebo vaccine, was 0.37 (95% CI 0.29 to 0.47). This means that, in relative terms, Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 in 63%, compared with the placebo vaccine. This estimate is not importantly different from the one in males and in the overall population of the trial, for this outcome.

Age
Randomized trials
The proportion of participants 65 years of age and more in the ENSEMBLE trial was 19.6% (8561 out of 43783 participants) [Sadoff J, 2021 ].

Among participants 65 years or older, the relative risk of contracting moderate to severe COVID-19, with onset at least 14 or 28 days after vaccination, when comparing the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine, was 0.24 (95% CI 0.14 to 0.41). This means that, in relative terms, Janssen COVID-19 vaccine reduced the risk of contracting COVID-19 in 76%, compared with the placebo vaccine. This number is not importantly different from the estimate for this outcome in younger patients, and in the overall population of the trial
   
ENSEMBLE 2 was a randomized clinical trial that included 31 300 participants: 15 ,708 in vaccine group and 15, 592 in placebo group. This study aimed to investigate the efficacy, safety, and immunogenicity of the Ad26.COV2.S vaccine (Janssen) as primary vaccination plus a booster dose. Vaccine efficacy against moderate to severe-critical COVID-19 in people over 60 years of age was 66.2% (95 CI, -14.0- 92.2). [Hardt K, 2022 ]

Children and adolescents
Randomized trials
Children were excluded from the ENSEMBLE trial, therefore no efficacy data are available from participants aged 17 years and younger  [Sadoff J, 2021 ].

The randomized phase 2 ongoing trial COV2001 (CR108854 and VAC31518COV2001) is currently evaluating the efficacy/safety of the vaccine in adolescents (12-17 years) and adults (18 years or older) [Janssen Vaccines & Prevention B.V., 2020 ].

The randomized, double-blind, placebo-controlled, phase 2/3 ongoing trial HORIZON 2 (VAC31518COV3006) is currently evaluating the efficacy and safety of the vaccine in healthy children from birth to 17 years [Janssen Vaccines & Prevention B.V., 2021 ].

Pregnancy
Randomized trials
Pregnant women were excluded from the ENSEMBLE trial, so no efficacy data are available [Sadoff J, 2021 ].

The open-label, phase 2 ongoing trial HORIZON 1 (CR108962 and VAC31518COV2004) plans to recruit 240 pregnant women. Is currently evaluating the efficacy and safety of the vaccine in adult participants during the second and/or third trimester of pregnancy and post-partum [Janssen Vaccines & Prevention B.V., 2021 ].
   

Breastfeeding
Randomized trials
Breastfeeding women were excluded from the ENSEMBLE trial, therefore no efficacy data are available [Sadoff J, 2021 ]. 
    
Immunocompromised persons
Randomized trials
The proportion of individuals living with HIV in the ENSEMBLE trial was 2.8% (1218 out of 43783 participants) [Sadoff J, 2021 ].

The relative risk of contracting COVID-19 in participants with HIV that received the Janssen COVID-19 vaccine versus the group that received placebo vaccine was 1.07 (95% CI 0.31 to 3.66). This number is not importantly different from the estimate for this outcome in the overall population of the trial.

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

At the four-week follow-up of BOOST-TX, 197 kidney transplant recipients without detectable SARS-CoV-2 specific antibodies after two doses of an mRNA vaccine were included: 99 received a 3rd dose of the same RNA vaccine, and 98 received a 3rd dose of the Janssen COVID-19 vaccine. The primary endpoint was seroconversion after four weeks (29-42 days) following the third vaccine dose. Secondary endpoints included neutralizing antibodies and T-cell response assessed by interferon-γ release assays (IGRA). Four weeks after the third vaccination, 76 patients had developed antibodies against the SARS-CoV-2 spike protein(>0.8 U/mL) for an overall response rate of 39%. There was no statistically significant difference between the homologous and heterologous vaccination strategies, with a response rate of 35% vs 42% for mRNA vs Janssen vaccine (OR, 1.31; 95% CI, 0.71-2.44; P = 0.38) [Reindl-Schwaighofer R, 2021 ].

At the three-month follow-up of BOOST-TX, 201 kidney transplant recipients without detectable SARS-CoV-2 specific antibodies following two doses of an mRNA vaccine were included: 85 received the 3rd dose of the same RNA vaccine, and 84 received the 3rd dose of the Janssen COVID-19 vaccine. Study participants were followed up for antibody assessment at the outpatient transplant clinic of the Medical University of Vienna for a second follow-up between 60 and 120 days after the 3rd vaccine dose. Results showed that absolute antibody titers between the two groups were not significantly different (median mRNA: 0.2 U/ml and vector: 0.81 U/ml, p=0.104). However, when examining higher antibody cut-off levels at the 1-month follow up, a significantly higher number of patients in the Janssen group reached antibody levels above 141 and 264 BAU/ml (>141 BAU/ml: 4 vs. 15% OR: 4.96, 95%CI: 1.29 to 28.21, p = 0.009, and >264 BAU/ml: 1 vs. 10% OR = 8.75, 95% CI: 1.13 to 396.17, p =0.018, for mRNA vs. Janssen vaccine groups, 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 mRNA vaccination: 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, 63% (95% CI, 51% to 74%) for the Ad26.COV2-S group. [Kho MML, 2022 ]

Other comparative studies
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 people with HIV, 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 ]

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. Persons aged 18 years and older with ≥1 immunocompromising conditions were included and compared with non-immunocompromised individuals. 10,329 ED/UC events (5% immunocompromised) and 4,202 hospitalizations (23% immunocompromised) were among Janssen vaccine recipients. In the immunocompromised population, adjusted vaccine effectiveness (VE) for the Janssen vaccine was 7% (95% CI, -26-31) for ED/UC events, and 45% (95% CI, 29-57) for hospitalization, measured 14 days after the first dose. After a second dose of either Janssen or any mRNA vaccine, VE was 71% (CI 95%, 6-91), and 70% (CI 95% 25-88) for ED/UC encounters and hospitalization, respectively. Preprint [Peter J. Embi, 2022 ].

Vaccine effectiveness (other comparative studies)

Contracting COVID-19
Corchado Garcia J et al. was a comparative cohort study conducted in the USA. The study enrolled 23,945 participants (2,195 vaccine group; 21,950 Control group). Based on a leveraged large-scale longitudinal curation of electronic health records (EHRs) from the multi-state Mayo Clinic health system between February 27th and April 14th 2021. Outcome measured starting at ≥ 14 days after vaccination. The result of the study found a vaccine effectiveness of 76.7% (95%CI 30.3 to 95.3). [Juan Corchado-Garcia, 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 1,764,474 receiving the Janssen vaccine. Based on claims and laboratory data from vaccinated individuals between January 1 and September 7, 2021. The study showed evidence of waning protection against infections starting in month 2 from vaccination for 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 month 3 for mRNA-1273. There was no evidence of waning protection against hospitalization for Ad26.COV2.S [Amanda Zheutlin, 2022 ].

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

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 78% (95% CI 75 to 81) and 60% (95% CI 50 to 68) for adults ≥ 65 years  [Winkelman TNA, 2022 ].

Mayr FB et al was a test-negative case-control design study conducted in the United States. The study included 4,805,942 participants: 1,289,639 with mRNA-1273, 971,750 with BNT162b2, 196,344 with Ad26.COV2.S and 2,348,209 Unvaccinated. The study used data from the US Department of Veterans Affairs COVID-19 Shared Data Resource to identify veterans who utilize VA health care and had no documented severe acute respiratory syndrome coronavirus 2 infections before December 11, 2020. This study estimated vaccine effectiveness (VE) over time for veterans who received 2 doses of mRNA vaccines or 1 dose of Ad26.Cov2.S. Vaccine effectiveness against symptomatic infection at one month since full vaccination was 25.4 (95% CI 2.9 to 42.6). Vaccine effectiveness against symptomatic infection at six months since full vaccination was 11.0 (95% CI -11.1 to 28.6). [Mayr FB, 2022 ]

Winkelman TNA was a test-negative design study conducted in the United States. The study included 4,431,190 individuals: 3 013 704 fully vaccinated with Pfizer, Moderna, or Janssen and 1 417 486 not fully vaccinated. This study 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 of Janssen vaccine for Medically Attended SARS-CoV-2 Infections was 33% (95 CI 30 to 37). [Winkelman TNA, 2022 ]

Reynolds M et al was a case-control study (test-negative design) conducted in the United States that included data from 2,481 participants who were tested and reported vaccination status (Pfizer–BioNTech, Moderna, or Janssen): 695 cases with a positive COVID-19 test and 1,786 controls with negative tests. Vaccine effectiveness was examined in two ways: considering cases who tested positive for COVID-19 and who tested positive with at least one moderate/severe COVID-19 symptom. Adjusted Odds of having a COVID-19 positive test was 0.04 (95% CI 0.02-0.09) [Reynolds MW, 2022 ].

Cerqueira-Silva et al was a case-control study (negative-test design) conducted in Brazil that included data from three national registries, including 22,566 participants as cases with positive RT-PCR test and 145,055 participants as controls with negative RT-PCR test. This study evaluated the effectiveness of four vaccines: CoronaVac, AstraZeneca, Janssen, and Pfizer–BioNTech. Demographic characteristics were similar among vaccine recipients, but recipients of AstraZeneca tended to be older and have more comorbidities. Vaccine effectiveness against symptomatic infection ≥ 14 days from vaccine series completion was: CoronaVac: 39.4% (95% CI 36.1-42.6), AstraZeneca: 56.0% (95% CI 51.4-60.2), Janssen 44.0% (95% CI 31.5-54.2), Pfizer–BioNTech: 64.8% (95% CI 54.9-72.4).  [Thiago Cerqueira-Silva, 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. Janssen effectiveness against infection was 70.6% (95% CI 68.8 to 72.3) and 48.8% (95% CI 47.2 to 50.4), 1 and 10 months after vaccination respectively. [Lin DY, 2022 ]

Monge S et al. was a retrospective cohort study conducted in Spain that recruited 1,897 individuals vaccinated with Janssen and 9,550 controls. The study was based on data from RENAVE and REGVACU including participants aged 50-59 years old during August 2021. The vaccine effectiveness of Janssen against the confirmed infection was 64% (95% CI, 62% to 66%) and against symptomatic infection was 56% (95% CI, 53% to 59%). [Monge, Susana, 2022 ]

Yuanyuan fu et al. conducted an observational study to analyze vaccination status and SARS-CoV-2 infection data from more tha 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 infection was 25.08% (95% CI, 22.39% to 27.68%) for the Ad26.COV2.S primary schedule. [Yuanyuan Fu, 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 14,870 participants vaccinated with Janssen, VE against infection was 82.18% (95% CI, 81.39% to 82.94%), and VE against hospitalization was 77.3% (95% CI, 72.91% to 81%).
[Bello-Chavolla OY, 2023 ].

Contracting severe COVID-19
Moline HL et al. was a comparative cohort study conducted in the USA. The study enrolled 7,280 participants, 1,819 Vaccine group (24 received Janssen vaccine) 5,461 Control group. Based on data from persons aged ≥65 years from the COVID-19–Associated Hospitalization Surveillance Network (COVID-NET) between February 1 and April 30, 2021. The outcome was measured 14 days after vaccination. The results of the study found vaccine effectiveness of  84% (95%CI 64 to 93) for people aged 65–74 years and 85% (95%CI 72 to 92) for people  ≥ 75 years. [Moline HL, 2021 ]

Corchado Garcia J et al. was a comparative cohort study conducted in the USA. The study enrolled 23,945 participants (2,195 vaccine group; 21,950 Control group). Based on a leveraged large-scale longitudinal curation of electronic health records (EHRs) from the multi-state Mayo Clinic health system between February 27th and April 14th, 2021. The outcome was measured starting at ≥ 14 days after vaccination. The result of the study found vaccine effectiveness of 76.7% (95%CI 30.3 to 95.3). [Juan Corchado-Garcia, 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 1,764,474 receiving the Janssen vaccine. Based on claims and laboratory data from vaccinated individuals between January 1 and September 7, 2021. The study 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 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=mRNA-1273 1,161,905; AstraZeneca=1,505,334; Janssen= 581,582). Data were collected between 11 January 2020 and 8 December 2021. The study showed that two doses of Pfizer, Moderna, or AstraZeneca COVID-19 vaccines offered vaccine effectiveness >90% against both intubation and death across all age groups. The effectiveness of the Janssen COVID-19 vaccine ranged between 61-81%. There was some waning over time, but vaccine effectiveness remained >80% at six months, and three doses increased vaccine effectiveness again to near 100%. Vaccination prevented an estimated 19,691 COVID-19 deaths (95% CI 18,890 to 20,788) over the study period [Theodore Lytras, 2022 ].

Wright BJ et al. was a case-control study conducted in the United States. It included data from 9,667 admissions for severe COVID-19 and 38,668 controls. Based on hospital admission registries from a large healthcare system (Providence). to analyze vaccine effectiveness against severe COVID-19 over time. Between April 1, 2021, and Oct 26, 2021. The effectiveness of the vaccine was 78.5% (95% CI 71.3 to 83.9) between 50 to 100 days after the 2nd dose, and it wanned to 72.6% (53.7 to 83.8)  between 200-250 days after the 2nd dose [Wright BJ, 2022 ].

Arregocés-Castillo et al was a retrospective cohort study conducted in Colombia. The study included 2,828,294 participants: 1,414,147 fully vaccinated (any vaccine) and 1,414,147 unvaccinated. The study evaluated the effectiveness of vaccines against COVID-19-related hospitalization and death in people aged 60 years and older. Participant follow-up was done between March 11, 2021, and Oct 26, 2021. It was estimated the overall effectiveness of being fully vaccinated and the effectiveness of each vaccine. The aim results showed that vaccine effectiveness against hospitalization without death was 60.9% (95% CI 36.8 to 75.8) in adults > 60 years. Effectiveness against death after hospitalization was 85.5% (95% CI 77.1 to 91.2) and against death without hospitalization was 95.5% (95% CI 82.0 to 98.9) in adults > 60 years [Arregocés-Castillo L, 2022 ].

Winkelman TNA et al. was a comparative cohort study conducted in the USA. The study included 4,431,190 individuals: 3,013,704 fully vaccinated and 1,417,486 not vaccinated. It used data from the Minnesota Immunization Information Connection from October 25, 2020, through October 30, 2021, that were linked with electronic health record (EHR) data from health systems collaborating as part of the Minnesota EHR Consortium (MNEHRC). Vaccine Effectiveness for SARS-CoV-2–Related Hospitalizations: was 78% (95% CI 75 to 81)and 60% (95% CI 50 to 68) [Winkelman TNA, 2022 ].

Mayr FB et al was a test-negative case-control design study conducted in the United States. The study included 4,805,942 participants: 1,289,639 with mRNA-1273, 971,750 with BNT162b2, 196,344 with Ad26.COV2.S and 2,348,209 Unvaccinated. The study used data from the US Department of Veterans Affairs COVID-19 Shared Data Resource to identify veterans who utilize VA health care and had no documented severe acute respiratory syndrome coronavirus 2 infections before December 11, 2020. This study estimated vaccine effectiveness (VE) over time for veterans who received 2 doses of mRNA vaccines or 1 dose of Ad26.Cov2.S. Vaccine effectiveness against hospitalization at one month since full vaccination was 55.8 (95% CI 20.6 to 75.4). Vaccine effectiveness against hospitalization at six months since full vaccination was 41.0 (95% CI 2.1 to 64.4). [Mayr FB, 2022 ]

Winkelman TNA was a test-negative design study conducted in the United States. The study included 4,431,190 individuals: 3 013 704 fully vaccinated with Pfizer, Moderna, or Janssen and 1 417 486 not fully vaccinated. This study 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 against SARS-CoV-2–Related Hospitalizations was 78% (95% CI 75 to 81). [Winkelman TNA, 2022 ]

Reynolds M et al was a case-control study (test-negative design) conducted in the United States that included data from 2,481 participants who were tested and reported vaccination status (Pfizer–BioNTech, Moderna, or Janssen): 695 cases with a positive COVID-19 test and 1,786 controls with negative tests. Vaccine effectiveness was examined in two ways: considering cases who tested positive for COVID-19 and who tested positive with at least one moderate/severe COVID-19 symptom. Adjusted Odds of having a COVID-19 positive test with at least one moderate/severe symptom was 0.35 (95% CI 0.11-1.15) [Reynolds MW, 2022 ].

Cerqueira-Silva et al was a case-control study (negative-test design) conducted in Brazil that included data from three national registries, including 22,566 participants as cases with positive RT-PCR test and 145,055 participants as controls with negative RT-PCR test. This study evaluated the effectiveness of four vaccines: CoronaVac, AstraZeneca, Janssen, and Pfizer–BioNTech. Demographic characteristics were similar among vaccine recipients, but recipients of AstraZeneca tended to be older and have more comorbidities. Vaccine effectiveness against hospitalization or death ≥14 days after vaccine series completion was: CoronaVac: 81.3% (95% CI 75.3-85.8); AstraZeneca: 89.9% (95% CI 83.5-93.8); Janssen: 57.7% (95% CI -2.6-82.5); Pfizer–BioNTech : 89.7% (95% CI 54.3-97.7) [Thiago Cerqueira-Silva, 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. Janssen effectiveness against hospitalization was 67.9% (95% CI 56.5 to 76.3) and 65.3% (95% CI 58.3 to 71.1), 1 and 10 months after vaccination respectively. [Lin DY, 2022 ].

Chanda et al conducted a retrospective cohort study among admitted patients at eight COVID-19 treatment centers across Zambia between April 2021 and March 2022, when Delta and Omicron variants were circulating. 1821 patients had COVID-19 vaccination status documented. Adjusted effectiveness against progression to in-hospital mortality was 61.1% (95% CI 26.6-80.8) for the Janssen COVID-19 vaccine [Chanda D, 2022 ].

Lewis et al conducted a multicenter case-control analysis of US adults hospitalized March 11th - December 15th, 2021 to estimate Ad26.COV2.S vaccine effectiveness (VE). Among 3,979 COVID-19 case-patients (5% vaccinated with Ad26.COV2.S) and 2.229 controls (13% vaccinated with Ad26.COV2.S), Overall adjusted VE for a single dose Ad26.COV2.S vaccine against COVID-19 hospitalization was 70% (95% CI 63 to 75) and was lower in patients who were immunocompromised 55% (95% CI 31 to 72) than those who were immunocompetent 72% (95% CI 64 to 77). Among immunocompetent patients, VEs was higher 75% (95% CI 67 to 82) among patients aged 18-64 years than for those aged ≥65 years 66% (95% CI 50–77). VE was higher in patients without chronic medical conditions 86% (95% CI 74–93) than those with ≥1 chronic medical condition 64% (95% CI 54 to 73). Among hospitalized COVID-19 case-patients, VE against disease progression to death o invasive mechanical ventilation was 46% (95% CI 18–65) among immunocompetent patients. [Lewis NM, 2022 ]

Monge S et al. was a retrospective cohort study conducted in Spain that recruited 1,897 individuals vaccinated with Janssen and 9,550 controls. The study was based on data from RENAVE and REGVACU including participants aged 50-59 years old during August 2021. The vaccine effectiveness of Janssen against hospitalization was 86% (95% CI, 83% to 89%). [Monge, Susana, 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 during an 18-month-period (December 2020 to June 2022) in the United States. Vaccine Effectiveness against COVID-19-related death was 74.56% (95% CI, 68.95% to 79.44%) for the Ad26.COV2.S primary schedule. [Yuanyuan Fu, 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 14,870 participants vaccinated with Janssen, VE against infection was 82.18% (95% CI, 81.39% to 82.94%), and VE against hospitalization was 77.3% (95% CI, 72.91% to 81%). [Bello-Chavolla OY, 2023 ]

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
No studies reported or assessed this outcome.

Efficacy and effectiveness against SARS-CoV-2 variants

Immunogenicity outcomes
Alpha (B.1.1.7) 
Alter G et al., with data from the COV1001 phase 1/2 randomized trial, reported the immunogenicity of the Janssen vaccine against SARS-CoV-2 variants in humans. The randomized trial included 403 healthy adults ≥65 years within three groups: 161 participants with Low-Dose Vaccine (5×1010 vp); 161 participants with High-Dose Vaccine (1×1011 vp); and 81 participants with placebo. For the Alpha variant, Janssen induced a median psVNA titers response of 102 on day 57 and 121 on day 71; Also on day 57, median receptor binding domain (RBD)-specific binding antibody enzyme-linked immunosorbent assay (ELISA) titers were 1,364, and 1,682 on day 71. These data show a 1.2-fold reduction of ELISA titers against the Alpha variant as compared with WA1/2020 RBD on day 71. Similar to the ELISA titers, median RBD-specific ECLA responses were reduced 1.3-fold, and median spike-specific ECLA responses were reduced 1.6-fold, as compared with WA1/2020 on day 71. On the other hand, the CD8 and CD4 T cell responses, including central and effector memory responses, were comparable among the Alpha variant and the others evaluated (WA1/2020, B.1.3.5.1, P.1, and CAL.20C).  [Alter G, 2021 ]

Beta (B.1.351)
Alter G et al. with data from the COV1001 phase 1/2 randomized trial, reported the immunogenicity of the Janssen vaccine against SARS-CoV-2 variants in humans. The randomized trial included 403 healthy adults ≥65 years within three groups: 161 participants with Low-Dose Vaccine (5×1010 vp); 161 participants with High-Dose Vaccine (1×1011 vp); and 81 participants with placebo. For the Beta variant, Janssen induced a median pseudovirus neutralizing antibody titers that were 5.0-fold lower compared with WA1/2020 on day 71 following vaccination; a median binding antibody titer that was 2.9-fold lower, and preservation of the antibody-dependent cellular phagocytosis, complement deposition, and NK cell activation responses. On the other hand, CD8 and CD4 T cell responses, including central and effector memory responses, were comparable among the Beta variant and others (WA1/2020, B.1.1.7, P.1, and CAL.20C). These data show that neutralizing antibody responses induced by Janssen were reduced against the Beta variant, but functional non-neutralizing antibody responses and T cell responses were largely preserved against SARS-CoV-2 variants. [Alter G, 2021 ]

Omicron (B.1.1.529)
Roanne Keeton et al. was a non-comparative study conducted in South Africa. The study enrolled 138 participants: 40 in the Vaccine group (20 participants received the Janssen vaccine) and was based on data from peripheral blood mononuclear cells samples of vaccinated individuals and unvaccinated convalescent individuals. The study results showed that CD4 T cell frequencies to Omicron spike were consistently and significantly lower than ancestral spike, with a median decrease of 14-30% of the CD4 response to Omicron and a median reduction of 17-25% of the CD8 response to Omicron compared to the ancestral virus. 70-80% of the CD4 and CD8 T cell response to spike was maintained. [Roanne Keeton, 2021 ]

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 ]

Efficacy outcomes
Alpha (B.1.1.7) 
ENSEMBLE was a randomized clinical trial that included 39,183 participants: 19,577 in the vaccine group and 19,608 in the placebo group. This study was the final analysis of this randomized trial. The primary endpoints were vaccine efficacy against moderate to severe–critical Covid-19 with onset at least 14 days after administration and at least 28 days after administration in the per-protocol population. Vaccine efficacy against moderate to severe–critical Covid-19 (at least 14 days after the administration) for the alpha variant was 70.1% (95% CI 35.1 to 87.6) and 70.2% (95% CI 35.3 to 87.6) at least 28 days after administration of the vaccine or placebo. [Sadoff J, 2022 ]

Beta (B.1.351)
ENSEMBLE was a randomized clinical trial that included 39,183 participants: 19,577 in the vaccine group and 19,608 in the placebo group. This study was the final analysis of this randomized trial. The primary endpoints were vaccine efficacy against moderate to severe–critical Covid-19 with onset at least 14 days after administration and at least 28 days after administration in the per-protocol population. Vaccine efficacy against moderate to severe–critical Covid-19 (at least 14 days after the administration) for the beta variant was 38.1% (95% CI 4.2 to 60.4) and 51.9% (95% CI 19.1 to 72.2) at least 28 days after administration of the vaccine or placebo. [Sadoff J, 2022 ]

Gamma (P.1)
ENSEMBLE was a randomized clinical trial that included 39,183 participants: 19,577 in the vaccine group and 19,608 in the placebo group. This study was the final analysis of this randomized trial. The primary end points were vaccine efficacy against moderate to severe–critical Covid-19 with onset at least 14 days after administration and at least 28 days after administration in the per-protocol population. Vaccine efficacy  against moderate to severe–critical Covid-19 (at least 14 days after the administration) for the gamma variant was 36.4% (95% CI 13.9 to 53.2) and 36.5% (95%CI 14.1 to 53.3) at least 28 days after administration of the vaccine or placebo. [Sadoff J, 2022 ]

Effectiveness outcomes
Alpha (B.1.1.7) 
Toon Braeye et al was a study conducted in Belgium. The study estimated vaccine effectiveness (VE) against transmission of infection (VET) between January and November 2021 by two components: susceptibility of the contact (VEs) and infectiousness of breakthrough cases (VEi) for a complete schedule of Ad26.COV2.S, ChAdOx1, BNT162b2, mRNA-1273. In Covid-19-naïve persons, during the Alpha variant dominant period, VEs was 42% (95% CI 37 to 46) for Janssen. The infectiousness of breakthrough cases in Covid19-naïve persons was 35% (95% CI 24 to 43) for the Janssen COVID-19 vaccine. [Toon Braeye, 2022 ]

Lewis et al conducted a multicenter case-control analysis of US adults hospitalized between March 11th and December 15th 2021 to estimate Ad26.COV2.S vaccine effectiveness (VE). Among 3,979 COVID-19 case-patients (5% vaccinated with Ad26.COV2.S) and 2.229 controls (13% vaccinated with Ad26.COV2.S), VE for a single dose Ad26.COV2.S vaccine was similar between periods in which the Alpha variant 68% (95% CI 43 to 83) and Delta variant 72% (95% CI 64 to 78) predominated and remained similar 14–90 days 73% (95% CI 60 to 82), 91–180 days 71% (95% CI 59 to 80), and >180 days 70% (95% CI 53 to 81) post-vaccination. [Lewis NM, 2022 ]

Beta (B.1.351)
Graniss SJ et al. was a case-control (test-negative) study carried out in the United States, which included 7,418 participants (458 vaccine group and 6,960 unvaccinated group). The study seeks to evaluate the effectiveness of the vaccine against laboratory-confirmed COVID-19 among adults during SARS-CoV-2 B.1.617.2 (Delta) variant predominance June–August 2021. The results showed an effectiveness against severe COVID-19 of 60% (95% CI 31% to 77%). [Grannis SJ, 2021 ]

Delta (B.1.617.2)
Voko Z et al was a comparative cohort study conducted in Hungary that included data from 8,087,988 individuals. This study examined the effectiveness of primary immunization and single booster vaccinations in the prevention of SARS-CoV-2 infection and mortality during the Delta wave. Adjusted effectiveness against registered SARS-CoV-2 infection during the Delta wave (14 - 120 days) was 39.3% (95% CI 36.1 to 42.4). The Janssen booster provided 72.9%– 100.00% adjusted effectiveness depending on primary immunization type. [Vokó Z, 2022 ]

Rennert L et al was a comparative cohort study conducted in the United States. This study included data from 21,261 individuals: 4562 fully vaccinated with Moderna Vaccine, 7276 fully vaccinated with Pfizer vaccine, and 948 fully vaccinated with Janssen vaccine. It compared the rate of SARS-CoV-2 infection between vaccinated individuals, individuals previously infected with SARS-CoV-2, and those with no record of vaccination or previous SARS-CoV-2 infection between August 8th and December 4th, 2021.  The results showed effectiveness against infection with SARS-COV-2 during the period of delta variant predominance of 42.8% (95% CI 26.1 to 55.8) for the Janssen vaccine. [Rennert L, 2022 ]

Britton A et al. was a case-control study conducted in the United States. This study included 1 634 271 laboratory-based SARS-CoV-2 nucleic acid amplification tests (NAATs) from adults 20 years and older and 180 112 NAATs from adolescents 12 to 19 years old with COVID-19–like illness from March 13 to October 17, 2021. The analysis included 390 762 test-positive cases (21.5%) and 1 423 621 test-negative controls (78.5%). The Ad26.COV2.S initial OR was 0.42 (95% CI, 0.37-0.47) during the pre-Delta period and 0.62 (95% CI, 0.58-0.65) during the Delta period and did not significantly increase with time since vaccination (the OR for the association between symptomatic SARS-CoV-2 infection and COVID-19 vaccination (as an estimate of vaccine effectiveness) was higher during Delta variant predominance, suggesting lower protection). [Britton A, 2022 ]

Uschner D et al. was a Community-based cohort study conducted in North Carolina, United States. This study included 16.020 eligible participants, 310 with a positive test. The information used was self-reported by the participants via email or text surveys (COVID-19 symptoms, test results, vaccination status, and risk behavior). Vaccines evaluated were Pfizer, Moderna, and Janssen. The event rate was 7.3 breakthrough infections per 100,000 person-years. Infections were symptomatic in 286 (92%) cases. Participants vaccinated with Pfizer vs. Janssen had a higher risk of breakthrough infection HR 2.23 (95% CI 1.40 to 3.56); Moderna vs Janssen had a lower risk, HR 0.69 (95% CI 0.50 to 0.96). Participants from rural and suburban counties had a higher risk of breakthrough infections: Suburban vs. urban was HR 1.39 (95% CI 1.01 to 1.90); Rural vs. urban was HR 1.57 (95% CI 1.16 to 2.11). There was no association of breakthrough infection with sex, race/ethnicity, healthcare worker status, prior self-reported COVID-19 infection, general mask usage, or vaccination rate in the county of residence. [Diane Uschner, 2021 ]

Lewis et al conducted a multicenter case-control analysis of US adults hospitalized from March 11th to December 15th 2021 to estimate Ad26.COV2.S vaccine effectiveness (VE). Among 3,979 COVID-19 case patients (5% vaccinated with Ad26.COV2.S) and 2.229 controls (13% vaccinated with Ad26.COV2.S), VE for a single Ad26.COV2.S dose was similar between periods in which the Alpha variant and Delta variant predominated 68% (95% CI, 43% to 83%), and 72% (95% CI, 64% to 78%), respectively, and remained similar 14–90 days 73% (95% CI, 60–82), 91–180 days 71% (95% CI, 59–80), and >180 days 70% (95% CI, 53–81) post-vaccination. [Lewis NM, 2022 ]

Yuanyuan fu et al. was an observational study to analyze vaccination status and SARS-CoV-2 infection data from more tha 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 infection during the Delta predominance period was 32.95% (95% CI, 29.16% to 36.53%) for the Ad26.COV2.S primary schedule. [Yuanyuan Fu, 2022 ]

Omicron (B.1.1.529)
Simwanza J et al was a case–control study conducted in Zambia. In this study were included 328 male participantes (21-36 years), 180 cases and 21 controls, incarcerated at the prison facility during the outbreak from December 15th to 20th 2021. The study measured vaccine effectiveness against infection and symptomatic infection, when Omicron was the dominant circulating variant. 96.3% of participants were fully vaccinated (1 doses of Jansen vaccine, or two-dose AstraZeneca vaccines). Vaccination status was cross-referenced with the national registry. Effectiveness against COVID-19 infection was 63.6% (IC 95% 33.6% to 80.5%) and symptomatic COVID-19 infection was  73.0% (95%CI 41.6% to 87.7%). Effectiveness was higher for those vaccinated within the past 60 days 74.6% (95% CI, 50.3% to 87.4%) compared with 60 days before COVID-19 testing [Simwanza J, 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 Janssen was 37.3% (95% CI 32.9 to 41.5), when the Omicron variant emerged. [Lin DY, 2022 ]

Monge S et al was a nationwide cohort study conducted in Spain. This study included 7,036,433 participants older than 40 years: 3,111,159 in the booster group and 3,111,159 in the no-booster group. The aim of this study was to estimate the effectiveness of mRNA-based vaccine boosters against infection during the period of the predominance of the omicron variant in Spain. The vaccine effectiveness of Janssen primary schedule and an mRNA booster (Moderna or Pfizer) was 48.0% (95% CI, 42.5–53.7). [Monge S, 2022 ]

Vaccine efficacy and effectiveness for booster dose

Immunogenicity outcomes

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–BioNTech 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–BioNTech booster; both performed better than the homologous booster (response, 72.7%) [Sablerolles RSG, 2022 ].

The updated report of the randomized trials COV1001 (phase 1/2a) and COV2001 (phase 2) included a booster dose given 6 months after primary vaccination. Phase 1/2a study included 17 vaccinated people (18-55 years) with a homologous boosting dose (5×1010) and Phase 2 study included 44 vaccinated people (18–55 years) and 29 people ≥65 years with low-dose homologous boosting (1.25×1010). Results showed that both homologous booster doses at 6 months elicited rapid and robust increases in spike binding antibody levels in all age subgroups evaluated. In Phase 1/2a study GMC was 3779 (95% CI: 2741 to 4243) at day 7 post boost, while in Phase 2 study GMC was 1719 (95% CI: 1321 to 2236) at the same time. This was increased at day 28 post boost dose (GMC: 2444 (95% CI: 1855 to 3219) [Jerald Sadoff, 2021 ].

Effectiveness outcomes

Johnson AG et al. included 6,812,040 COVID-19 cases in unvaccinated persons and 2,866,517 cases in fully vaccinated persons. Data were collected between April 4, 2021, to December 25, 2021. The study showed that rates of COVID-19 cases were lowest among fully vaccinated persons with a booster dose of Janssen COVID-19 vaccine, compared with fully vaccinated persons without a booster dose, and much lower than rates among unvaccinated persons. During October - November (Delta predominance period), average weekly incidence rate ratios were 3.2 (95% CI 2.9 to 3.6) among fully vaccine persons without booster dose and 13.4 (95% CI 10.6 to16.9) among fully vaccinated persons with a booster dose. During December (Omicron Emergence period), average weekly incidence rate ratios were 2.9 (95% CI 1.8 to 4.8) among fully vaccine persons without booster dose and 5.5 (95% CI 3.2 to 9.4) among fully vaccinated persons with a booster dose. [Johnson AG, 2022 ]

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

Vaccine efficacy and effectiveness for heterologous schedule

No studies reported or assessed this outcome.

Vaccine efficacy and effectiveness for heterologous booster schedule

Immunogenicity outcomes
COV-BOOST was a clinical trial that evaluated the immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of Oxford–AstraZeneca or Pfizer/BioNTech COVID-19 vaccines. Efficacy was measured by neutralizing antibody titers at 84 days post-boost dose. The results indicated in general a significant drop between day 28 and day 84 was seen in all study arms for live virus neutralizing antibody and cellular responses. For cellular responses, Moderna (100 μg) had the highest cellular responses at D84 (75, 95%CI: 51–110), though not statistically significant compared with Pfizer–BioNTech. The cellular responses at D28 and D84, as well as the D84 to D28 ratio in the AOxford–AstraZeneca and Janssen arms were similar to the Pfizer–BioNTech arm. In the subgroup analysis, similar patterns of immunogenicity were observed in the two age groups (<70 years and >70 years) in both Oxford–AstraZeneca and Pfizer–BioNTech first doses populations. Pfizer–BioNTech-half induced similar humoral and cellular responses compared with Pfizer–BioNTech at D28 and D84. This was seen in populations primed with both Oxford–AstraZeneca/Oxford–AstraZeneca and Pfizer–BioNTech/Pfizer–BioNTech, and in both age groups. [Liu X, 2022 ]. 28-day follow-up study available from: [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 ].

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

At the four-week follow-up of the randomized trial BOOST-TX conducted in Austria, 197 kidney transplant recipients without detectable SARS-CoV-2 specific antibodies after two doses of an mRNA vaccine were included: 99 received a 3rd dose of the same RNA vaccine, and 98 received a 3rd dose of the Janssen COVID-19 vaccine. The primary endpoint was seroconversion after four weeks (29-42 days) following the third vaccine dose. Secondary endpoints included neutralizing antibodies and T-cell response assessed by interferon-γ release assays (IGRA). Four weeks after the third vaccination, 76 patients had developed antibodies against the SARS-CoV-2 spike protein(>0.8 U/mL) for an overall response rate of 39%. There was no statistically significant difference between the homologous and heterologous vaccination strategies, with a response rate of 35% vs 42% for mRNA vs Janssen vaccine (OR, 1.31; 95% CI, 0.71-2.44; P = 0.38) [Reindl-Schwaighofer R, 2021 ].

At the three-month follow-up of the randomized trial BOOST-TX conducted in Austria, 201 kidney transplant recipients without detectable SARS-CoV-2 specific antibodies following two doses of an mRNA vaccine were included: 85 received the 3rd dose of the same RNA vaccine, and 84 received the 3rd dose of the Janssen COVID-19 vaccine. Study participants were followed up for antibody assessment at the outpatient transplant clinic of the Medical University of Vienna for a second follow-up between 60 and 120 days after the 3rd vaccine dose. Results showed that absolute antibody titers between the two groups were not significantly different (median mRNA: 0.2 U/ml and vector: 0.81 U/ml, p=0.104). However, when examining higher antibody cut-off levels at the 1-month follow up, a significantly higher number of patients in the Janssen group reached antibody levels above 141 and 264 BAU/ml (>141 BAU/ml: 4 vs. 15% OR: 4.96, 95%CI: 1.29 to 28.21, p = 0.009, and >264 BAU/ml: 1 vs. 10% OR = 8.75, 95% CI: 1.13 to 396.17, p =0.018, for mRNA vs. Janssen vaccine groups, respectively) [Heinzel A, 2022 ].

Tan CS et al was a comparative cohort study conducted in the United States. The study included 68 participants vaccinated at least 6 months previously with 2 immunizations of BNT162b2: 41 boosted with Ad26.COV2.S and 27 boosted with BNT162b2. Humoral immune responses were assessed by neutralizing, binding, and functional antibody responses for 16 weeks following the boost. CD8+ and CD4+ T-cell responses were evaluated by intracellular cytokine staining assays. Ad26.COV2.S boosted median (IQR) Omicron BA.1 NAb titers from 21 (20-32) at week 0 to 591 (272-881) at week 2, a peak of 859 (467-1838) at week 4, and a decline of 2.1-fold to 403 (208-1130) at week 16 following the boost. Ad26.COV2.S boosted median Omicron BA.1 Spikespecific interferon (IFN)–γ CD8+ T-cell responses from medians (IQRs) of 0.017% (0.009%-0.030%) at week 0 to 0.093% (0.045%-0.181%) at week 2 and 0.081% (0.042%-0.200%) at week 16 and IFN-γ CD4+ T cell responses from medians (IQRs) of 0.030% (0.011%-0.047%) at week 0 to 0.092% (0.046%-0.123%) at week 2 and 0.065% (0.027%-0.110%) at week 16 [Tan CS, 2022 ].

Costa Clemens et al was a phase 4 randomized clinical trial conducted in Brazil. The study included 1205 vaccinated participants: 296 with AstraZeneca Vaccine, 281 with CoronaVac Vaccine, 295 with Janssen Vaccine, and 333 with Pfizer Vaccine. The study assessed the immunogenicity of a third heterologous booster dose of either AstraZeneca vaccine, Pfizer vaccine, or Janssen vaccine, compared with a third homologous booster dose of CoronaVac in Brazilian adults who had received two doses of CoronaVac 6 months previously. The geometric fold-rise (GMFR) from baseline to day 28 was 77 (95%CI 67 to 88) for the Janssen vaccine. All heterologous regimes had anti-spike IgG at Day 28 that were superior to those induced by the homologous boost. Geometric mean ratios (GMR) (heterologous vs homologous) was Geometric mean ratios (GMR) (heterologous vs homologous) was 6.7 (95% CI 5.8 to 7.7) for the Janssen vaccine. [Sue Ann Costa Clemens, 2021 ]

RECOVAC was a randomized trial conducted in the Netherlands that enrolled 333 kidney transplant recipients (KTR) who did not seroconvert after mRNA vaccination: 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 63% (95% CI, 51% to 74%) for the Ad26.COV2-S group. [Kho MML, 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 ]

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, respectively. [Dunkle, L. M., 2023 ]

Effectiveness outcomes
Voko Z et al was a comparative cohort study conducted in Hungary that included data from 8,087,988 individuals. The study examined the effectiveness of primary immunization and single booster vaccinations in the prevention of SARS-CoV-2 infection and mortality during the Delta wave. Adjusted effectiveness against registered SARS-CoV-2 infection during the Delta wave (14 - 120 days) was 39.3% (95% CI 36.1 to 42.4). The Janssen booster provided 72.9%– 100.00% adjusted effectiveness depending on primary immunization type.[Vokó Z, 2022 ]

Monge S et al was a nationwide Cohort study conducted in Spain. This study included 7,036,433 participants older than 40 years: 3,111,159 in the booster group and 3,111,159 in the no-booster group. The aim of this study was to estimate the effectiveness of mRNA-based vaccine boosters against infection during the period of the predominance of the omicron variant in Spain. The vaccine effectiveness of Janssen primary schedule and an mRNA booster (Moderna or Pfizer) was 48.0% (95% CI, 42.5–53.7). [Monge S, 2022 ]

Lin DY et al, was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. Based on data from the North Carolina COVID-19 Surveillance System and the Covid-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Vaccine effectiveness of Pfizer-BioNTech booster after Janssen schedule was 46.0% (95%CI 38.8 to  52.3) after 1 month, the effectiveness of Moderna vaccine booster after Janssen primary schedule was 60.4% (95%CI 54.9 to 65.2). [Lin DY, 2022 ]

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

Safety of the vaccine in preclinical studies

The Janssen COVID-19 vaccine was tested in Syrian hamsters and non-human primate SARS-CoV-2 infection models. There were no vaccine-related adverse events noted. There were no effects of Ad26.COV2.S on fertility, or embryo-fetal and postnatal development. No cases of death or obvious clinical signs were observed in any of the vaccinated groups [van der Lubbe JEM, 2021 ].

Genotoxicity and carcinogenicity

Janssen COVID-19 vaccine has not been evaluated for its genotoxic or carcinogenic potential but, according to the manufacturers, the components of the vaccine are not expected to have genotoxic or carcinogenic potential [EMA, 2021 ].

Risk of thrombosis

The causal relation between the Janssen COVID-19 vaccine or other adenoviral vector vaccines and thrombosis is not yet established. One hypothesis that would explain the rare occurrence of thrombotic events related to adenoviral vector vaccines is the generation of antibodies against platelet factor 4 (PF4). IgG antibodies would recognize PF4 and activate platelets through their Fcγ receptors. This condition would resemble autoimmune heparin-induced thrombocytopenia [Muir KL, 2021 ],[Warkentin TE., 2019 ].

Reproductive toxicity and fertility 

Female reproductive toxicity and fertility were assessed in a developmental study with rabbits. The vaccine was administered to female rabbits 7 days prior to mating, at a dose equivalent to 2-fold above the recommended human dose, followed by two vaccinations at the same dose during the gestation period. There were no vaccine-related effects on female fertility, pregnancy, or embryo-fetal or offspring development. Female rabbits as well as their offspring exhibited SARS-CoV-2 S protein-specific antibody titers, indicating that maternal antibodies were transferred to the fetuses during gestation. Additionally, a toxicity study was performed with repeated conventional doses in male rabbits. The vaccine did not show any effects on male sex organs that would impair male fertility [EMA, 2021 ].

Thrombocytopenia

Thrombocytopenia has been reported following the administration of adenoviral gene transfer vectors. The mechanism underlying this phenomenon is currently unknown. A study in mice showed thrombocytopenia occurred between 5 to 24 hours following adenovirus administration. Some changes induced by the virus were endothelial cell activation, platelet activation and accelerated platelet clearance [Othman M, 2007 ].

Safety of the vaccine in clinical trials

Key messages

Janssen COVID-19 vaccine increases the risk of local adverse events following vaccination

Janssen COVID-19 vaccine reduces the risk of serious adverse events

Main safety outcomes of Janssen COVID-19 vaccine

Any unsolicited adverse event (during 28 days post-vaccination)

The relative risk of any unsolicited adverse event in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 1.09 (95% CI 0.96 to 1.23). This means Janssen COVID-19 vaccine increased the risk of any unsolicited adverse event by 9%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any unsolicited adverse event. Comparison: Janssen COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 407 people not receiving Janssen COVID-19 vaccine out of 3380 presented this outcome (120 per 1000) versus 440 out of 3356 in the group that did receive it (131 per 1000). In other words, 11 more people per 1000 did develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk increase of 1.1%. 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). In this case, the NNTH is 91, which means that 91 people need to receive the vaccine for one of them to experience an unsolicited adverse event.

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

Local adverse events (7 days following vaccination)

The relative risk of local adverse events in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 2.95 (95% CI 2.47 to 3.52). This means that, in relative terms, Janssen COVID-19 vaccine increased the risk of local adverse events by 195%, compared with placebo vaccine.

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

In the trial identified in this review, 657 people not receiving Janssen COVID-19 vaccine out of 3380 presented this outcome (194 per 1000) versus 1685 out of 3356 in the group that did receive it (501 per 1000). In other words, the intervention led to an absolute risk increase of 30.7% of local adverse events following vaccination. Another way of presenting the same information about the absolute effects is the number of people needed to treat for an additional beneficial/harmful outcome (NNTB/H). In this case, the NNTH is 3, which means that 3 people need to receive the vaccine for one of them to experience a local adverse event.

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

Systemic adverse events (7 days following vaccination)

The relative risk of systemic adverse events in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 1.61 (95% CI 1.48 to 1.75). This means that, in relative terms, Janssen COVID-19 vaccine increased the risk of systemic adverse events by 61%, compared with placebo vaccine.

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

In the trial identified in this review, 1185 people not receiving Janssen COVID-19 vaccine out of 3380 presented this outcome (351 per 1000) versus 1850 out of 3356 in the group that did receive it (552 per 1000). In other words, 201 more people per 1000 did develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk increase of 20.1%. 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). In this case, the NNTH is 5, which means that 5 people need to receive the vaccine for one of them to experience a systemic adverse event.

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

Serious adverse events (during 28 days post-vaccination)

The relative risk of serious adverse events in the group that received Janssen COVID-19 vaccine versus the group that received placebo vaccine was 0.86 (95% CI 0.64 to 1.16). No statistically significant differences between groups were found for serious adverse events.

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

In the trial identified in this review, 96 people not receiving Janssen COVID-19 vaccine out of 21888 presented this outcome (4 per 1000) versus 83 out of 21895 in the group that did receive it (3 per 1000). In other words, 1 less people per 1000 did develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.1%, or that the intervention reduced the risk of serious adverse events by 0.1 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). In this case, the NNTB is 1000, which means that 1000 people need to receive the vaccine for one of them to not experience a severe adverse event

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: Low number of events; Publication bias: no concerns.

Summary of findings table (iSoF)

Safety of the vaccine in subgroups

Sex
Randomized trials
The ENSEMBLE trial showed no differences between sex regarding advers events  [Sadoff J, 2021 ].

Age
Randomized trials
The frequency of adverse effects in the vaccinated/not vaccinated population according to age was the following: 
Solicited local adverse reactions
· 59.8 vs 20.2 (RR 2.96; difference: 39.6 percentage points) in the group 18-59 years.
· 35.4 vs 18.3 (RR 1.93; difference: 17.1 percentage points) in the group ≥60 years.
Solicited systemic adverse reactions
· 61.5 vs 36.4 (RR 1.69; difference: 25.1 percentage points) in the group 18-59 years.
· 45.3 vs 33.1 (RR 1.37; difference: 12.2 percentage points) in the group ≥60 years.
Serious adverse events
· 0.3 vs 0.4 (RR 0.75; difference: -0.1 percentage points) in the group 18-59 years.
· 0.5 vs 0.5 (RR 1; difference: 0 percentage points) in the group ≥60 years.
In the Phase 1/2a study included 17 vaccinated people (18–55 years) with a homologous boosting dose (5×1010), the post-booster reactogenicity was similar compared to the reported in the primary vaccination. In the Phase 2 study, included 44 vaccinated people (18–55 years) and 29 people ≥65 years with low-dose homologous boosting (1.25×1010) in 81 participants, solicited AEs after the primary dose versus after the booster were 67.9% versus 54%, respectively, and for grade 3 solicited AEs, 1.2% versus 0%, for solicited local AEs, 51.9% versus 47%, for solicited local AEs of grade 3 or more 0% versus 0%, for solicited systemic AEs, 66.7% versus 28%, and for solicited systemic AEs of grade 3 or more, 1.2% vs 0%.  [Jerald Sadoff, 2021 ]

Children and adolescents
Randomized trials
Children were excluded from the ENSEMBLE trial, therefore no safety data are available from participants ages 17 years and younger  [Sadoff J, 2021 ].

The randomized phase 2 ongoing trial COV2001 (also known as CR108854 and VAC31518COV2001) is currently evaluating the efficacy/safety of the vaccine in adolescents (12-17 years) and adults (18 years or older) [Janssen Vaccines & Prevention B.V., 2020 ].

The randomized, double-blind, placebo-controlled, phase 2/3 ongoing trial HORIZON 2 (also known as VAC31518COV3006) is currently evaluating the efficacy/safety of the vaccine in healthy children from birth to 17 years [Janssen Vaccines & Prevention B.V., 2021 ].
   
Other comparatives studies
Morciano D et al was  a self-controlled case series study that included 15,986,009 participants who received at least one dose of a COVID-19 vaccine: 10,833,284 Pfizer, 1,706,979 Moderna, 2,863,950 AstraZeneca and 581,796 Janssen. 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 Janssen vaccine was 1.94 (95% CI, 0.32-11.69). [Cristina Morciano, 2023 ]

Pregnancy
Randomized trials
Pregnant females were excluded from the ENSEMBLE trial, therefore no safety data are available [Sadoff J, 2021 ].

Other comparatives studies
Covas D et al was a cross sectional study conducted in Brazil that included 2,486 pregnant and postpartum women vaccinated with: 187 Sinovac, 572 Pfizer, 1,712 AstraZeneca and 15 Janssen. The aim was to describe the adverse events of COVID-19 vaccines in pregnant and postpartum women in the early stage of the vaccination campaign in Brazil. Incidence of adverse events notified for pregnant women was 92.5 (95% CI, 78.95-106.04), 150.14 (95% CI, 137.72-162.57), 4463.3 (95% CI, 4,255.55-4,671.04) and 4,087.19 (95% CI, 2,061.54-6,112.85) for Sinovac, Pfizer, AstraZeneca and Janssen vaccine, respectively. Incidence of adverse events notified for postpartum women was 15.28 (95% CI, 5.3-25.26), 10.78 (95% CI, 4.68-16.88), 65.5 (95% CI, 35.25-95.75 and 0 (95% CI, 0-0) for Sinovac, Pfizer, AstraZeneca and Janssen vaccine, respectively. [Covas DT, 2023 ]

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

Breastfeeding
Randomized trials
Females who were breastfeeding were excluded from the ENSEMBLE trial, therefore no safety data are available [Sadoff J, 2021 ].