Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults aged 60 years and older: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial

Background A vaccine against COVID-19 is urgently needed for older adults, in whom morbidity and mortality due to the disease are increased. We aimed to assess the safety, tolerability, and immunogenicity of a candidate COVID-19 vaccine, CoronaVac, containing inactivated SARS-CoV-2, in adults aged 60 years and older.Methods We did a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial of CoronaVac in healthy adults aged 60 years and older in Renqiu (Hebei, China). Vaccine or placebo was given by intramuscular injection in two doses (days 0 and 28). Phase 1 comprised a dose-escalation study, in which participants were allocated to two blocks: block 1 (3 mu g inactivated virus in 0 center dot 5 mL of aluminium hydroxide solution per injection) and block 2 (6 mu g per injection). Within each block, participants were randomly assigned (2:1) using block randomisation to receive CoronaVac or placebo (aluminium hydroxide solution only). In phase 2, participants were randomly assigned (2:2:2:1) using block randomisation to receive either CoronaVac at 1 center dot 5 mu g, 3 mu g, or 6 mu g per dose, or placebo. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary safety endpoint was adverse reactions within 28 days after each injection in all participants who received at least one dose. The primary immunogenicity endpoint was seroconversion rate at 28 days after the second injection (which was assessed in all participants who had received the two doses of vaccine according to their random assignment, had antibody results available, and did not violate the trial protocol). Seroconversion was defined as a change from seronegative at baseline to seropositive for neutralising antibodies to live SARS-CoV- 2 (positive cutoff titre 1/8), or a four-fold titre increase if the participant was seropositive at baseline. This study is ongoing and is registered with ClinicalTrials.gov (NCT04383574).Findings Between May 22 and June 1, 2020, 72 participants (24 in each intervention group and 24 in the placebo group; mean age 65 center dot 8 years [SD 4 center dot 8]) were enrolled in phase 1, and between June 12 and June 15, 2020, 350 participants were enrolled in phase 2 (100 in each intervention group and 50 in the placebo group; mean age 66 center dot 6 years [ SD 4 center dot 7] in 349 participants). In the safety populations from both phases, any adverse reaction within 28 days after injection occurred in 20 (20%) of 100 participants in the 1 center dot 5 mu g group, 25 (20%) of 125 in the 3 mu g group, 27 (22%) of 123 in the 6 mu g group, and 15 (21%) of 73 in the placebo group. All adverse reactions were mild or moderate in severity and injection site pain (39 [9%] of 421 participants) was the most frequently reported event. As of Aug 28, 2020, eight serious adverse events, considered unrelated to vaccination, have been reported by seven ( 2%) participants. In phase 1, seroconversion after the second dose was observed in 24 of 24 participants (100 center dot 0% [95% CI 85 center dot 8-100 center dot 0]) in the 3 mu g group and 22 of 23 (95 center dot 7% [78 center dot 1-99 center dot 9]) in the 6 mu g group. In phase 2, seroconversion was seen in 88 of 97 participants in the 1 center dot 5 mu g group (90 center dot 7% [83 center dot 1-95 center dot 7]), 96 of 98 in the 3 mu g group ( 98 center dot 0% [92 center dot 8-99 center dot 8]), and 97 of 98 (99 center dot 0% [94 center dot 5-100 center dot 0]) in the 6 mu g group. There were no detectable antibody responses in the placebo groups.Interpretation CoronaVac is safe and well tolerated in older adults. Neutralising antibody titres induced by the 3 mu g dose were similar to those of the 6 mu g dose, and higher than those of the 1 center dot 5 mu g dose, supporting the use of the 3 mu g dose CoronaVac in phase 3 trials to assess protection against COVID-19.Funding Chinese National Key Research and Development Program and Beijing Science and Technology Program.Copyright (c) 2021 Elsevier Ltd. All rights reserved.