Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia

Abstract

Background: A heterologous recombinant adenovirus (rAd)-based vaccine, Gam-COVID-Vac (Sputnik V), showed a good safety profile and induced strong humoral and cellular immune responses in participants in phase 1/2 clinical trials. Here, we report preliminary results on the efficacy and safety of Gam-COVID-Vac from the interim analysis of this phase 3 trial.

Methods: We did a randomised, double-blind, placebo-controlled, phase 3 trial at 25 hospitals and polyclinics in Moscow, Russia. We included participants aged at least 18 years, with negative SARS-CoV-2 PCR and IgG and IgM tests, no infectious diseases in the 14 days before enrolment, and no other vaccinations in the 30 days before enrolment. Participants were randomly assigned (3:1) to receive vaccine or placebo, with stratification by age group. Investigators, participants, and all study staff were masked to group assignment. The vaccine was administered (0·5 mL/dose) intramuscularly in a prime-boost regimen: a 21-day interval between the first dose (rAd26) and the second dose (rAd5), both vectors carrying the gene for the full-length SARS-CoV-2 glycoprotein S. The primary outcome was the proportion of participants with PCR-confirmed COVID-19 from day 21 after receiving the first dose. All analyses excluded participants with protocol violations: the primary outcome was assessed in participants who had received two doses of vaccine or placebo, serious adverse events were assessed in all participants who had received at least one dose at the time of database lock, and rare adverse events were assessed in all participants who had received two doses and for whom all available data were verified in the case report form at the time of database lock. The trial is registered at ClinicalTrials.gov (NCT04530396).

Findings: Between Sept 7 and Nov 24, 2020, 21 977 adults were randomly assigned to the vaccine group (n=16 501) or the placebo group (n=5476). 19 866 received two doses of vaccine or placebo and were included in the primary outcome analysis. From 21 days after the first dose of vaccine (the day of dose 2), 16 (0·1%) of 14 964 participants in the vaccine group and 62 (1·3%) of 4902 in the placebo group were confirmed to have COVID-19; vaccine efficacy was 91·6% (95% CI 85·6-95·2). Most reported adverse events were grade 1 (7485 [94·0%] of 7966 total events). 45 (0·3%) of 16 427 participants in the vaccine group and 23 (0·4%) of 5435 participants in the placebo group had serious adverse events; none were considered associated with vaccination, with confirmation from the independent data monitoring committee. Four deaths were reported during the study (three [<0·1%] of 16 427 participants in the vaccine group and one [<0·1%] of 5435 participants in the placebo group), none of which were considered related to the vaccine.

Interpretation: This interim analysis of the phase 3 trial of Gam-COVID-Vac showed 91·6% efficacy against COVID-19 and was well tolerated in a large cohort.

Funding: Moscow City Health Department, Russian Direct Investment Fund, and Sberbank.

Figure 1

Trial profile *At the time the database was locked, the data on adverse events in the case report form had not yet been verified in these participants; the data verification procedure can be done with a slight delay, thus, participants whose data were not verified were not included in this analysis.

Figure 2

Kaplan-Meier cumulative incidence curves for the first symptomatic, PCR-positive COVID-19 after dose 1, in participants who received at least one dose of vaccine or placebo

Figure 3

Humoral immune response (A) Receptor-binding domain-specific antibodies on day 42, as measured by ELISA, in participants administered with vaccine, by age group and overall, or placebo overall. Four participants are not included in the subgroup analysis by age because of missing date of birth on the case report form for this analysis. (B) Neutralising antibodies on day 42, as measured by neutralisation assay with 100 TCID₅₀, in participants administered with vaccine or placebo. Data are divided by age strata and by sex. Data of the overall vaccine group and placebo group are also presented. Dots show individual datapoints, bars show geometric mean titres, and whiskers show 95% CI. TCID₅₀=50% tissue culture infective dose.

Figure 4

IFN-γ response to SARS-CoV-2 glycoprotein S of peripheral blood mononuclear cells of participants who received two doses of vaccine (n=44) or placebo (n=14) Dots show individual datapoints of intact (unstimulated) cells and cells stimulated with SARS-CoV-2 glycoprotein S (antigen stimulated). Horizontal lines show median values, whiskers show 95% Cl. The threshold of detection (<2 pg/mL) is indicated with the grey shaded area. The grey lines connecting dots between unstimulated and antigen-stimulated cells show changes in IFN-γ response in some representative individuals. *p<0·0001 for day 28 antigen-stimulated cells versus day 1 antigen-stimulated cells, in the vaccine group.