Final Analysis of Efficacy and Safety of Single-Dose Ad26.COV2.S

Abstract

Background: The Ad26.COV2.S vaccine was highly effective against severe-critical coronavirus disease 2019 (Covid-19), hospitalization, and death in the primary phase 3 efficacy analysis.

Methods: We conducted the final analysis in the double-blind phase of our multinational, randomized, placebo-controlled trial, in which adults were assigned in a 1:1 ratio to receive single-dose Ad26.COV2.S (5×10¹⁰ viral particles) or placebo. 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. Safety and key secondary and exploratory end points were also assessed.

Results: Median follow-up in this analysis was 4 months; 8940 participants had at least 6 months of follow-up. In the per-protocol population (39,185 participants), vaccine efficacy against moderate to severe-critical Covid-19 at least 14 days after administration was 56.3% (95% confidence interval [CI], 51.3 to 60.8; 484 cases in the vaccine group vs. 1067 in the placebo group); at least 28 days after administration, vaccine efficacy was 52.9% (95% CI, 47.1 to 58.1; 433 cases in the vaccine group vs. 883 in the placebo group). Efficacy in the United States, primarily against the reference strain (B.1.D614G) and the B.1.1.7 (alpha) variant, was 69.7% (95% CI, 60.7 to 76.9); efficacy was reduced elsewhere against the P.1 (gamma), C.37 (lambda), and B.1.621 (mu) variants. Efficacy was 74.6% (95% CI, 64.7 to 82.1) against severe-critical Covid-19 (with only 4 severe-critical cases caused by the B.1.617.2 [delta] variant), 75.6% (95% CI, 54.3 to 88.0) against Covid-19 leading to medical intervention (including hospitalization), and 82.8% (95% CI, 40.5 to 96.8) against Covid-19-related death, with protection lasting 6 months or longer. Efficacy against any severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was 41.7% (95% CI, 36.3 to 46.7). Ad26.COV2.S was associated with mainly mild-to-moderate adverse events, and no new safety concerns were identified.

Conclusions: A single dose of Ad26.COV2.S provided 52.9% protection against moderate to severe-critical Covid-19. Protection varied according to variant; higher protection was observed against severe Covid-19, medical intervention, and death than against other end points and lasted for 6 months or longer. (Funded by Janssen Research and Development and others; ENSEMBLE ClinicalTrials.gov number, NCT04505722.).

Figure 1. Cases of Covid-19 According to SARS-CoV-2 Lineage (Full Analysis Population).

The distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages among cases of coronavirus disease 2019 (Covid-19) is shown for each country in the trial over time during the double-blind phase of the trial. The reference sequence is defined as the SARS-CoV-2 Wuhan-Hu-1 sequence but with the D614G amino acid variation. At the time of the trial, sequences categorized as “other” were those with substitutions not resulting in another SARS-CoV-2 lineage or variant. “Other+E484K” refers to sequences with E484K but no other substitutions resulting in another SARS-CoV-2 lineage or variant. Next-generation sequencing was performed with the use of the Swift Biosciences SNAP Assay, version 2. Amino acid variants are defined as changes from the reference sequence. The last available visit date across countries was July 1 through 9, 2021, and the last available date of onset for a primary end-point case was June 26 (Argentina), March 24 (Brazil), April 22 (Chile), June 23 (Colombia), May 27 (Mexico), July 1 (Peru), July 5 (South Africa), and April 16 (United States). None of the cases were caused by the eta, kappa, theta, or C.36.3 variant. The alpha, beta, gamma, and delta variants were variants of concern according to World Health Organization definitions at the time of the analysis.

Figure 2. Cumulative Incidence of Moderate to Severe–Critical Covid-19 and Vaccine Efficacy over Time (Per-Protocol Population).

Panel A shows the Kaplan–Meier cumulative incidence of molecularly confirmed moderate to severe–critical Covid-19 with onset at least 1 day after administration of vaccine or placebo. Shading indicates the 95% confidence interval. Panel B shows vaccine efficacy against moderate to severe–critical Covid-19 over time; dark gray shading indicates the 95% pointwise confidence interval, and light gray shading the 95% simultaneous confidence interval. The graph includes 95% of the events that occurred before day 189, with the hazard smoothed over 21 days. Participants were seronegative at baseline, as determined by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) and serologic tests.

Figure 3. Vaccine Efficacy against Moderate to Severe–Critical Covid-19 According to SARS-CoV-2 Lineage (Per-Protocol Population).

Shown is vaccine efficacy against moderate to severe–critical Covid-19 with onset at least 14 days after administration (Panel A) and at least 28 days after administration (Panel B). SARS-CoV-2 in the category of “Lineages other than the reference strain” were all variants of concern or interest, with “other” sequences excluded. At the time of the trial, sequences categorized as “other” were those with substitutions not resulting in another SARS-CoV-2 lineage or variant. “Other+E484K” refers to sequences with E484K but no other substitutions resulting in another SARS-CoV-2 lineage or variant. Vaccine efficacy was not calculated if fewer than 6 cases were observed for an end point. Confidence intervals have not been adjusted for multiplicity and should not be used to infer statistical significance.

Figure 4. Cumulative Incidence of Severe–Critical Covid-19 and Vaccine Efficacy over Time (Per-Protocol Population).

Panel A shows the Kaplan–Meier cumulative incidence of molecularly confirmed severe–critical Covid-19 with onset at least 1 day after administration of vaccine or placebo. Shading indicates the 95% confidence interval. Panel B shows vaccine efficacy against severe–critical Covid-19 over time; dark gray shading indicates the 95% pointwise confidence interval, and light gray shading the 95% simultaneous confidence interval. The graph includes 95% of the events that occurred before day 189, with the hazard smoothed over 21 days. Participants were seronegative at baseline, as determined by RT-PCR and serologic tests.