Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18–59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial

Abstract

Background With the unprecedented morbidity and mortality associated with the COVID-19 pandemic, a vaccine against COVID-19 is urgently needed. We investigated CoronaVac (Sinovac Life Sciences, Beijing, China), an inactivated vaccine candidate against COVID-19, containing inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for its safety, tolerability and immunogenicity. Methods In this randomised, double-blind, placebo-controlled, phase 1/2 clinical trial, healthy adults aged 18-59 years were recruited from the community in Suining County of Jiangsu province, China. Adults with SARS-CoV-2 exposure or infection history, with axillary temperature above 37•0°C, or an allergic reaction to any vaccine component were excluded. The experimental vaccine for the phase 1 trial was manufactured using a cell factory process (CellSTACK Cell Culture Chamber 10, Corning, Wujiang, China) , whereas those for the phase 2 trial were produced through a bioreactor process (ReadyToProcess WAVE 25, GE, Umea, Sweden). The phase 1 trial was done in a dose-escalating manner. At screening, participants were initially separated (1:1), with no specific randomisation, into two vaccination schedule cohorts, the days 0 and 14 vaccination cohort and the days 0 and 28 vaccination cohort, and within each cohort the first 36 participants were assigned to block 1 (low dose CoronaVac [3 μg per 0•5 mL of aluminium hydroxide diluent per dose) then another 36 were assigned to block 2 (high-dose Coronavc [6 μg per 0•5 mL of aluminium hydroxide diluent per dse]). Within each block, participants were randomly assigned (2:1), using block randomisation with a block size of six, to either two doses of CoronaVac or two doses of placebo. In the phase 2 trial, at screening, participants were initially separated (1:1), with no specific randomisation, into the days 0 and 14 vaccination cohort and the days 0 and 28 vaccination cohort, and participants were randomly assigned (2:2:1), using block randomisation with a block size of five, to receive two doses of either low-dose CoronaVac, high-dose CoronaVac, or placebo. Participants, investigators, and laboratory staff were masked to treatment allocation. The primary safety endpoint was adverse reactions within 28 days after injection in all participants who were given at least one dose of study drug (safety population). The primary immunogenic outcome was seroconversion rates of neutralising antibodies to live SARS-CoV-2 at day 14 after the last dose in the days 0 and 14 cohort, and at day 28 after the last dose in the days 0 and 28 cohort in participants who completed their allocated two-dose vaccination schedule (per-protocol population). This trial is registered with ClinicalTrials.gov, NCT04352608, and is closed to accrual. Findings Between April 16 and April 25, 2020, 144 participants were enrolled in the phase 1 trial, and between May 3 and May 5, 2020, 600 participants were enrolled in the phase 2 trial. 743 participants received at least one dose of investigational product (n=143 for ph...

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“…Furthermore, they protected NHPs against challenge by SARS-CoV-2, suggesting an important role for humoral responses as the immune correlates of protection. Initial clinical trial studies of these two inactivated vaccine candidates showed that, similar to in NHPs, these vaccines elicited substantial nAbs in humans 145,146 . These inactivated vaccine candidates did not induce either T H 1 or T H 2 cell-associated cytokines in those vaccinated.…”

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“…Results from measles virus and vesicular stomatitis virus (VSV) based vaccine candidates in animal models were also reported (Horner et al, 2020;. Three studies reported preliminary results on the safety and immunogenicity of inactivated COVID-19 vaccines from phase I/II clinical trials (Che et al, 2020;Zhang et al, 2020g). The inactivated vaccines demonstrated acceptable safety profiles and were effective in inducing neutralizing antibodies.…”

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“…The participant remained in the study and did not report a similar reaction after the booster dose. Overall, there was no significant difference in AEs among study groups [ 237 ].…”

“…Higher nAb and binding IgG titers in the Phase II trial (compared to Phase I) was due to a different vaccine production process for the Phase II study which inadvertently increased the content of spike protein in the vaccine used for Phase II studies by almost two-fold. T cell responses were determined by measuring IFN-γ in an ELISpot assay wherein PBMCs were cultured with overlapping peptides from the S protein or controls peptides [ 237 ].…”