Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial

Abstract

Background: This is the first randomised controlled trial for assessment of the immunogenicity and safety of a candidate non-replicating adenovirus type-5 (Ad5)-vectored COVID-19 vaccine, aiming to determine an appropriate dose of the candidate vaccine for an efficacy study.

Methods: This randomised, double-blind, placebo-controlled, phase 2 trial of the Ad5-vectored COVID-19 vaccine was done in a single centre in Wuhan, China. Healthy adults aged 18 years or older, who were HIV-negative and previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-free, were eligible to participate and were randomly assigned to receive the vaccine at a dose of 1 × 10¹¹ viral particles per mL or 5 × 10¹⁰ viral particles per mL, or placebo. Investigators allocated participants at a ratio of 2:1:1 to receive a single injection intramuscularly in the arm. The randomisation list (block size 4) was generated by an independent statistician. Participants, investigators, and staff undertaking laboratory analyses were masked to group allocation. The primary endpoints for immunogenicity were the geometric mean titres (GMTs) of specific ELISA antibody responses to the receptor binding domain (RBD) and neutralising antibody responses at day 28. The primary endpoint for safety evaluation was the incidence of adverse reactions within 14 days. All recruited participants who received at least one dose were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, NCT04341389.

Findings: 603 volunteers were recruited and screened for eligibility between April 11 and 16, 2020. 508 eligible participants (50% male; mean age 39·7 years, SD 12·5) consented to participate in the trial and were randomly assigned to receive the vaccine (1 × 10¹¹ viral particles n=253; 5 × 10¹⁰ viral particles n=129) or placebo (n=126). In the 1 × 10¹¹ and 5 × 10¹⁰ viral particles dose groups, the RBD-specific ELISA antibodies peaked at 656·5 (95% CI 575·2-749·2) and 571·0 (467·6-697·3), with seroconversion rates at 96% (95% CI 93-98) and 97% (92-99), respectively, at day 28. Both doses of the vaccine induced significant neutralising antibody responses to live SARS-CoV-2, with GMTs of 19·5 (95% CI 16·8-22·7) and 18·3 (14·4-23·3) in participants receiving 1 × 10¹¹ and 5 × 10¹⁰ viral particles, respectively. Specific interferon γ enzyme-linked immunospot assay responses post vaccination were observed in 227 (90%, 95% CI 85-93) of 253 and 113 (88%, 81-92) of 129 participants in the 1 × 10¹¹ and 5 × 10¹⁰ viral particles dose groups, respectively. Solicited adverse reactions were reported by 183 (72%) of 253 and 96 (74%) of 129 participants in the 1 × 10¹¹ and 5 × 10¹⁰ viral particles dose groups, respectively. Severe adverse reactions were reported by 24 (9%) participants in the 1 × 10¹¹ viral particles dose group and one (1%) participant in the 5 × 10¹⁰ viral particles dose group. No serious adverse reactions were documented.

Interpretation: The Ad5-vectored COVID-19 vaccine at 5 × 10¹⁰ viral particles is safe, and induced significant immune responses in the majority of recipients after a single immunisation.

Funding: National Key R&D Programme of China, National Science and Technology Major Project, and CanSino Biologics.

Figure 1

Trial profile vp=viral particles. *26 did not meet the inclusion criteria of negative IgM/IgG to severe acute respiratory syndrome coronavirus 2.

Figure 2

Specific antibody responses to RBD, neutralising antibodies to live severe acute respiratory syndrome coronavirus 2 and pseudovirus post vaccination Seroconversion was defined as an increase in post-vaccination titre of at least four-times baseline. The baseline antibody titres are shown in the appendix (p 1). All comparisons across the three treatment groups are p<0·0001. Multiple comparisons showed no significant difference between the 1 × 10¹¹ vp and 5 × 10¹⁰ vp dose groups. GMT=geometric mean antibody titre. RBD=receptor binding domain. vp=viral particles.

Figure 3

Specific T-cell responses measured by ELISpot The number of specific T cells with secretion of IFNγ at days 0 and 28 in all participants (A), and stratified by pre-existing adenovirus type-5 neutralising antibody titres of less than or equal to 1:200 (B) and more than 1:200 (C). vp=viral particles. IFN=interferon. PBMC=peripheral blood mononuclear cell.