The trial began enrollment on September 21, 2020, and the data-cutoff date for the present analysis was January 22, 2021. A total of 44,325 participants underwent randomization, of whom 43,783 received vaccine or placebo; the per-protocol population included 39,321 SARS-CoV-2–negative participants, of whom 19,630 received Ad26.COV2.S and 19,691 received placebo (Fig. S3). The demographic characteristics and coexisting conditions of the participants at baseline were balanced across the two groups (Table 1 and S4). A total of 9.6% of the participants were SARS-CoV-2–seropositive at baseline. The median follow-up was 58 days (range, 1 to 124), and 55% of participants had at least 8 weeks of follow-up; later and slower recruitment of participants 60 years of age or older with coexisting conditions resulted in a shorter duration of follow-up in this subgroup (Table S5).
Most solicited local and systemic adverse events occurred within 1 to 2 days after the administration of vaccine or placebo and had a median duration of 1 to 2 days. No grade 4 local or systemic adverse events were reported. There were no local or systemic reactogenicity differences between participants who were seronegative at baseline and those who were seropositive (data not shown). Pain was categorized as grade 1 (mild; does not interfere with activity), grade 2 (moderate; requires modification of activity or involves discomfort with movement), grade 3 (severe; inability to perform usual activities), or grade 4 (potentially life-threatening; hospitalization or inability to perform basic self-care). Erythema and swelling were categorized as grade 1 (mild; 25 to 50 mm), grade 2 (moderate; 51 to 100 mm), grade 3 (severe; >100 mm), or grade 4 (potentially life-threatening; necrosis or leading to hospitalization). Systemic events were categorized as grade 1 (mild; minimal symptoms), grade 2 (moderate; notable symptoms not resulting in loss of work or school time), grade 3 (severe; incapacitating symptoms resulting in loss of work or school time), or grade 4 (life-threatening; hospitalization or inability to perform basic self-care). Fever was defined as grade 1 (mild; ≥38.0 to 38.4°C), grade 2 (moderate; ≥38.5 to 38.9°C), grade 3 (severe; ≥39.0 to 40.0°C), or grade 4 (potentially life-threatening; >40°C).
The safety subpopulation included 3356 participants in the vaccine group and 3380 in the placebo group. During the 7-day period after the administration of vaccine or placebo, more solicited adverse events were reported by Ad26.COV2.S recipients than by placebo recipients and by participants 18 to 59 years of age than by those 60 years of age or older (Figure 1). In the vaccine group, injection-site pain was the most common local reaction (in 48.6% of the participants); the most common systemic reactions were headache (in 38.9%), fatigue (in 38.2%), myalgia (in 33.2%), and nausea (in 14.2%).
The adverse events of at least grade 3 that were considered by the investigators to be possibly related to Ad26.COV2.S or placebo are listed in Table S6. Serious adverse events, excluding those related to Covid-19, were reported by 83 of 21,895 vaccine recipients (0.4%) and by 96 of 21,888 placebo recipients (0.4%). Seven serious adverse events were considered by the investigators to be related to vaccination in the Ad26.COV2.S group (Table S7).
A numeric imbalance was observed for venous thromboembolic events (11 in the vaccine group vs. 3 in the placebo group). Most of these participants had underlying medical conditions and predisposing factors that might have contributed to these events (Table S8). Imbalances were also observed with regard to seizure (which occurred in 4 participants in the vaccine group vs. 1 in the placebo group) and tinnitus (in 6 vs. 0). A causal relationship between these events and Ad26.COV2.S cannot be determined. These events will be monitored in the post-marketing setting.
Three deaths were reported in the vaccine group and 16 in the placebo group, all of which were considered by the investigators to be unrelated to the trial intervention (Table S7). No deaths related to Covid-19 were reported in the vaccine group, whereas 5 deaths related to Covid-19 were reported in the placebo group. Transverse sinus thrombosis with cerebral hemorrhage and a case of the Guillain–Barré syndrome were each seen in 1 vaccine recipient.
In the per-protocol at-risk population, 468 centrally confirmed cases of symptomatic Covid-19 with an onset at least 14 days after administration were observed, of which 464 were moderate to severe–critical (116 cases in the vaccine group vs. 348 in the placebo group), which indicated vaccine efficacy of 66.9% (adjusted 95% confidence interval [CI], 59.0 to 73.4) (Table 2). In terms of the primary end point of disease onset at least 28 days after administration, 66 cases of moderate to severe–critical Covid-19 in the vaccine group and 193 cases in the placebo group were observed, which indicated vaccine efficacy of 66.1% (adjusted 95% CI, 55.0 to 74.8) (Table 2).
Panel A shows the cumulative incidence of moderate to severe–critical cases of coronavirus disease 2019 (Covid-19); circles indicate severe–critical cases. Panel B shows the cumulative incidence of severe–critical cases. Cases included in the analyses in Panels A and B were centrally confirmed cases in the full analysis set among participants who were seronegative at baseline. Panel C shows the cumulative incidence of severe–critical cases in South Africa among participants who were seronegative at baseline; these cases were those that were positive on reverse-transcriptase–polymerase-chain-reaction (RT-PCR) testing from all sources, whether centrally confirmed or not.
The cumulative incidence of the first occurrence of moderate to severe–critical Covid-19 diverged between the two trial groups at approximately 14 days after the administration of vaccine or placebo, which indicates an early onset of protection with the vaccine (Figure 2A). Fewer cases in the vaccine group were observed after day 14 while cases continued to accrue in the placebo group, which led to increasing vaccine efficacy over time (Fig. S4A). Efficacy against disease with an onset at least 28 days after administration was similar across age groups, but efficacy against disease with an onset 14 days after administration was higher among older participants than among younger participants (Table 2). This discrepancy probably resulted from differences in follow-up duration or from smaller sample sizes in subgroups. The number of primary end-point cases was similar to the number of cases of symptomatic Covid-19 as defined according to the FDA harmonized definition (Table 2); thus, the primary end-point analyses captured most of the cases of symptomatic Covid-19. Estimates of vaccine efficacy in the analyses of the two primary end points and the secondary end points of centrally confirmed cases differed by less than 2 percentage points from the estimates in analyses of positive cases from all sources, and the confidence intervals were similar (Table 2 and Table 3). Vaccine-efficacy estimates in the full analysis set were generally lower than those in the per-protocol population because the estimates included cases that occurred at or after 1 day after administration, when immunity was building (Table S9).
With regard to severe–critical Covid-19, vaccine efficacy was 76.7% (adjusted 95% CI, 54.6 to 89.1) against disease with onset at least 14 days after administration and 85.4% (adjusted 95% CI, 54.2 to 96.9) against disease with onset at least 28 days after administration (Table 2). The cumulative-incidence curves began to separate approximately 7 days after administration; vaccine efficacy increased with longer follow-up and was 92.4% after day 42 (post hoc calculation) (Figures 2B and S4B).
The analysis of vaccine efficacy against asymptomatic infection included all the participants with a newly positive N-immunoassay result at day 71 (i.e., those who had been seronegative or had no result available at day 29 and who were seropositive at day 71). Only 2650 participants had an N-immunoassay result available at day 71, and therefore only a preliminary analysis could be performed. A total of 18 asymptomatic infections were identified in the vaccine group and 50 in the placebo group (vaccine efficacy, 65.5%; 95% CI, 39.9 to 81.1).
Vaccine efficacy against Covid-19 involving medical intervention ranged from 75.0 to 100.0% (Table S10). Two cases of Covid-19 with onset at least 14 days after administration in the Ad26.COV2.S group and 29 such cases in the placebo group led to hospitalization (vaccine efficacy, 93.1%; 95% CI, 72.7 to 99.2) (Fig. S5). No hospitalizations for cases with an onset at least 28 days after administration occurred in the vaccine group, as compared with 16 hospitalizations in the placebo group (vaccine efficacy, 100%; 95% CI, 74.3 to 100.0).
Participants with moderate Covid-19 who had received Ad26.COV2.S most frequently reported 4 to 6 symptoms, as compared with 7 to 9 symptoms in participants who had received placebo (Fig. S6). The total mean symptom-severity score as reported on the Symptoms of Infection with Coronavirus-19 questionnaire was 24% (95% CI, −1 to 46) lower among vaccine recipients than among placebo recipients at day 1 after symptom onset, 47% (95% CI, 23 to 66) lower at day 7 after symptom onset, and 53% (95% CI, 0 to 81) lower at day 14 after symptom onset among participants with an onset of moderate illness at least 28 days after administration (Fig. S1).
The estimates of vaccine efficacy against severe–critical disease were consistently high across countries that had sufficient cases for analysis (Table 3). On the basis of interim sequencing data from 512 unique RT-PCR–positive samples obtained from 714 participants (71.7%) with SARS-CoV-2 infection, the reference sequence (Wuhan-Hu-1 including the D614G mutation) was detected predominantly in the United States (190 of 197 sequences [96.4%]) and the 20H/501Y.V2 variant (also called B.1.351) was detected predominantly in South Africa (86 of 91 sequences [94.5%]), whereas in Brazil, the reference sequence was detected in 38 of 124 sequences (30.6%) and the reference sequence with the E484K mutation (P.2 lineage) was detected in 86 of 124 sequences (69.4%). Despite the high prevalence of the 20H/501Y.V2 variant in South Africa and in Covid-19 cases in the trial, vaccine efficacy was maintained (52.0% against moderate to severe–critical disease and 73.1% against severe–critical disease with onset ≥14 days after administration; 64.0% against moderate to severe–critical disease and 81.7% against severe–critical disease with onset at ≥28 days after administration) (Figure 2C and Table 3). In South Africa, no hospitalizations of participants with an onset of Covid-19 at least 28 days after administration occurred in the vaccine group, as compared with 6 hospitalizations in the placebo group. All five Covid-19–related deaths in the trial occurred in the placebo group in South Africa.
No meaningful differences in vaccine efficacy were observed among subgroups defined according to sex, race, or ethnic group (Fig. S7 and Table S11). A lower point estimate of vaccine efficacy was observed among participants 60 years of age or older with coexisting conditions in the analysis of cases with onset at least 28 days after administration (15 cases of moderate to severe–critical Covid-19 among vaccine recipients vs. 26 cases among placebo recipients) but not in the analysis of cases with onset at least 14 days after administration (22 vs. 63 cases) (Fig. S7). Estimates of efficacy over time that were based on Kaplan–Meier analysis were similar among participants 60 years of age or older with coexisting conditions and those without coexisting conditions (Figs. S4C and S8). Two participants 60 years of age or older with coexisting conditions in the vaccine group were hospitalized, as compared with 11 such participants in the placebo group (vaccine efficacy, 81.6%; 95% CI, 15.8 to 98.0).