Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19

Abstract

Background: The Ad26.COV2.S vaccine is a recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein in a prefusion-stabilized conformation.

Methods: In an international, randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned adult participants in a 1:1 ratio to receive a single dose of Ad26.COV2.S (5×10¹⁰ viral particles) or placebo. The primary end points were vaccine efficacy against moderate to severe-critical coronavirus disease 2019 (Covid-19) with an onset at least 14 days and at least 28 days after administration among participants in the per-protocol population who had tested negative for SARS-CoV-2. Safety was also assessed.

Results: The per-protocol population included 19,630 SARS-CoV-2-negative participants who received Ad26.COV2.S and 19,691 who received placebo. Ad26.COV2.S protected against moderate to severe-critical Covid-19 with onset at least 14 days after administration (116 cases in the vaccine group vs. 348 in the placebo group; efficacy, 66.9%; adjusted 95% confidence interval [CI], 59.0 to 73.4) and at least 28 days after administration (66 vs. 193 cases; efficacy, 66.1%; adjusted 95% CI, 55.0 to 74.8). Vaccine efficacy was higher against severe-critical Covid-19 (76.7% [adjusted 95% CI, 54.6 to 89.1] for onset at ≥14 days and 85.4% [adjusted 95% CI, 54.2 to 96.9] for onset at ≥28 days). Despite 86 of 91 cases (94.5%) in South Africa with sequenced virus having the 20H/501Y.V2 variant, vaccine efficacy was 52.0% and 64.0% against moderate to severe-critical Covid-19 with onset at least 14 days and at least 28 days after administration, respectively, and efficacy against severe-critical Covid-19 was 73.1% and 81.7%, respectively. Reactogenicity was higher with Ad26.COV2.S than with placebo but was generally mild to moderate and transient. The incidence of serious adverse events was balanced between the two groups. Three deaths occurred in the vaccine group (none were Covid-19-related), and 16 in the placebo group (5 were Covid-19-related).

Conclusions: A single dose of Ad26.COV2.S protected against symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection and was effective against severe-critical disease, including hospitalization and death. Safety appeared to be similar to that in other phase 3 trials of Covid-19 vaccines. (Funded by Janssen Research and Development and others; ENSEMBLE ClinicalTrials.gov number, NCT04505722.).

Figure 1. Solicited Local and Systemic Adverse Events Reported within 7 days after the Administration of Vaccine or Placebo (Safety Subpopulation).

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).

Figure 2. Cumulative Incidence of Covid-19 with Onset at Least 1 Day after Vaccination and Vaccine Efficacy over Time.

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.