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
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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 phase 1 and n=600 for phase 2; safety population). In the phase 1 trial, the incidence of adverse reactions for the days 0 and 14 cohort was seven (29%) of 24 participants in the 3 ug group, nine (38%) of 24 in the 6 μg group, and two (8%) of 24 in the placebo group, and for the days 0 and 28 cohort was three (13%) of 24 in the 3 μg group, four (17%) of 24 in the 6 μg group, and three (13%) of 23 in the placebo group. The seroconversion of neutralising antibodies on day 14 after the days 0 and 14 vaccination schedule was seen in 11 (46%) of 24 participants in the 3 μg group, 12 (50%) of 24 in the 6 μg group, and none (0%) of 24 in the placebo group; whereas at day 28 after the days 0 and 28 vaccination schedule, seroconversion was seen in 20 (83%) of 24 in the 3 μg group, 19 (79%) of 24 in the 6 μg group, and one (4%) of 24 in the placebo group. In the phase 2 trial, the incidence of adverse reactions for the days 0 and 14 cohort was 40 (33%) of 120 participants in the 3 μg group, 42 (35%) of 120 in the 6 μg group, and 13 (22%) of 60 in the placebo group, and for the days 0 and 28 cohort was 23 (19%) of 120 in the 3 μg group, 23 (19%) of 120 in the 6 μg group, and 11 (18%) of 60 for the placebo group. Seroconversion of neutralising antibodies was seen for 109 (92%) of 118 participants in the 3 μg group, 117 (98%) of 119 in the 6 μg group, and two (3%) of 60 in the placebo group at day 14 after the days 0 and 14 schedule; whereas at day 28 after the days 0 and 28 schedule, seroconversion was seen in 114 (97%) of 117 in the 3 μg group, 118 (100%) of 118 in the 6 μg group, and none (0%) of 59 in the placebo group. Interpretation Taking safety, immunogenicity, and production capacity into account, the 3 μg dose of CoronaVac is the suggested dose for efficacy assessment in future phase 3 trials. Funding Chinese National Key Research and Development Program and Beijing Science and Technology Program.
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Phase 1/2 trials of CoronaVac in volunteers aged 18-59 years and older than 60 years showed that the vaccine doses and schedules investigated (3 μg or 6 μg, applied 14 days or 28 days apart) all had similar safety and immunogenicity profiles.
“Phase 1/2 trials of CoronaVac in volunteers aged 18–59 years and older than 60 years showed that the vaccine doses and schedules investigated (3 μg or 6 μg, applied 14 days or 28 days apart) all had similar safety and immunogenicity profiles.20, 21”
From Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): interim results of a double-blind, randomised, placebo-controlled, phase 3 trial in Turkey (2021) · cites this paper as [20]
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Experimental — accuracy not yet measuredConsidering the production capacity and emergent need for vaccines, the 3 μg dose of CoronaVac has been suggested for efficacy assessment.
“Considering the production capacity and emergent need for vaccines, the 3 μg dose of CoronaVac has been suggested for efficacy assessment.20”
Peak neutralizing antibody levels after licensed SARS-CoV-2 vaccination are about half to four times those observed in convalescent individuals.
“the currently licensed vaccines have been shown to produce peak neutralizing antibody responses that range from approximately half to four-times those seen in convalescent patients24,64–67 (preprint data, not yet peer reviewed)68.”
From Prospects for durable immune control of SARS-CoV-2 and prevention of reinfection (2021) · cites this paper as [64]
In different prime-boost regimens of CoronaVac, no more than 37% of participants reported any localized or systemic AE after the second dose, with fever reported by a maximum of 5% of participants.
“no more than 37% of the participants reported any (localized or systemic) AE after the second dose, with fever only reported by max. 5% of the participants (depending on the dosing and prime-boost schedule) [83].”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [83]
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“Proline mutations used in BNT162b2 vaccine to stabilize the spike protein in its pre-fusion state 35 and the serial passages in Vero cells and inactivation procedures used in the CoronaVac vaccine 36 contribute to the differences in neutralizing antibody responses elicited by the two vaccines.”
- Authors
- Zhang, Y., Zeng, G., Pan, H., Li, C., Hu, Y., Chu, K., Han, W., Chen, Z., Tang, R., Yin, W., Chen, X., Hu, Y., Liu, X., Jiang, C., Li, J., Yang, M., Song, Y., Wang, X., Gao, Q., & Zhu, F.
- Affiliations
- Zhejiang Center for Disease Control and Prevention (CN)
- Sinovac Biotech (CN)
- Jiangsu Provincial Center for Disease Control and Prevention (CN)
- National Institutes for Food and Drug Control (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Zhang, Yanjun
- Zeng, Gang
- Pan, Hongxing
- Li, Changgui
- Tang, Rong
- Hu, Yuansheng
- Liu, Xiaoyong
- Jiang, Congbing
- Li, Jingxin
- Yang, Minnan
- Song, Yan
- Wang, Xiangxi
- Gao, Qiang
- Zhu, Fengcai
- ORCID
- Venue
- The Lancet Infectious Diseases
- Publisher
- Elsevier BV
- Published
- 2021-02
- Volume
- 21
- Issue
- 2
- Pages
- 181-192
- ISSN
- 1473-3099 (ISSN-L)
- PMC
- PMC7832443
- OpenAlex
- W3102328262
- Cited by
- 1,504
- References
- 23
- Citations by year
- 2026: 18 · 2025: 61 · 2024: 109 · 2023: 238 · 2022: 450 · 2021: 584 · 2020: 36 · 2019: 1 · 2013: 4
- FWCI
- 42.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Lancet Infectious Diseases (publishedVersion)
- medRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Beijing Municipal Science and Technology Commission
- Ministry of Science and Technology of the People's Republic of China
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Keywords
- COVID-19 vaccines, inactivated SARS-CoV-2 vaccine, CoronaVac, vaccine safety, vaccine tolerability, immunogenicity, dose escalation, aluminum hydroxide adjuvant, vaccination schedule, healthy adults, SARS-CoV-2, cell culture production, bioreactor production, neutralizing antibodies, T cell response, vaccine manufacturing process
- MeSH terms
- Seroconversion, Immunogenicity, Vaccine, COVID-19, SARS-CoV-2, COVID-19 Vaccines, Adolescent, Adult, Antibodies, Viral, China, Female, Humans, Immunoglobulin G, Immunoglobulin M, Immunization Schedule, Male, Middle Aged, Vaccination, Vaccines, Inactivated, Young Adult, Antibodies, Neutralizing, Healthy Volunteers
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