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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.
Lancet Infect Dis. 2021 02; 21(2):181-192.LI

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.

Authors+Show Affiliations

Department of Microbiology, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China.Sinovac Biotech, Beijing, China.Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China.National Institutes for Food and Drug Control, Beijing, China.Sinovac Biotech, Beijing, China.Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China.Sinovac Biotech, Beijing, China.National Institutes for Food and Drug Control, Beijing, China.Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China.Sinovac Biotech, Beijing, China.Suining County Center for Disease Control and Prevention, Suining, Jiangsu Province, China.Sinovac Biotech, Beijing, China.Suining County Center for Disease Control and Prevention, Suining, Jiangsu Province, China.Suining County Center for Disease Control and Prevention, Suining, Jiangsu Province, China.Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China.CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.Suining County Center for Disease Control and Prevention, Suining, Jiangsu Province, China.CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.Sinovac Life Sciences, Beijing, China. Electronic address: gaoq@sinovac.com.Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China. Electronic address: jszfc@vip.sina.com.

Pub Type(s)

Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33217362

Citation

Zhang, Yanjun, et al. "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." The Lancet. Infectious Diseases, vol. 21, no. 2, 2021, pp. 181-192.
Zhang Y, Zeng G, Pan H, et al. 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. Lancet Infect Dis. 2021;21(2):181-192.
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. (2021). 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. The Lancet. Infectious Diseases, 21(2), 181-192. https://doi.org/10.1016/S1473-3099(20)30843-4
Zhang Y, et al. 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. Lancet Infect Dis. 2021;21(2):181-192. PubMed PMID: 33217362.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Zhang,Yanjun, AU - Zeng,Gang, AU - Pan,Hongxing, AU - Li,Changgui, AU - Hu,Yaling, AU - Chu,Kai, AU - Han,Weixiao, AU - Chen,Zhen, AU - Tang,Rong, AU - Yin,Weidong, AU - Chen,Xin, AU - Hu,Yuansheng, AU - Liu,Xiaoyong, AU - Jiang,Congbing, AU - Li,Jingxin, AU - Yang,Minnan, AU - Song,Yan, AU - Wang,Xiangxi, AU - Gao,Qiang, AU - Zhu,Fengcai, Y1 - 2020/11/17/ PY - 2020/09/14/received PY - 2020/10/10/revised PY - 2020/10/14/accepted PY - 2020/11/21/pubmed PY - 2021/2/16/medline PY - 2020/11/20/entrez SP - 181 EP - 192 JF - The Lancet. Infectious diseases JO - Lancet Infect Dis VL - 21 IS - 2 N2 - 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. SN - 1474-4457 UR - https://www.unboundmedicine.com/medline/citation/33217362/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1473-3099(20)30843-4 DB - PRIME DP - Unbound Medicine ER -