Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial
Shengli Xia, Yuntao Zhang, Yanxia Wang, Hui Wang, Yunkai Yang, George Fu Gao, Wenjie Tan, Guizhen Wu, Miao Xu, Zhiyong Lou, Weijin Huang, Wenbo Xu, Baoying Huang, Huijuan Wang, Wei Wang, Wei Zhang, Na Li, Zhiqiang Xie, Ling Ding, Wangyang You, Yuxiu Zhao, Xuqin Yang, Yang Liu, Qian Wang, Lili Huang, Yongli Yang, Guangxue Xu, Bojian Luo, Wenling Wang, Peipei Liu, Wanshen Guo, Xiaoming Yang, Shengli Xia, Yuntao Zhang, Yanxia Wang, Hui Wang, Yunkai Yang, George Fu Gao, Wenjie Tan, Guizhen Wu, Miao Xu, Zhiyong Lou, Weijin Huang, Wenbo Xu, Baoying Huang, Huijuan Wang, Wei Wang, Wei Zhang, Na Li, Zhiqiang Xie, Ling Ding, Wangyang You, Yuxiu Zhao, Xuqin Yang, Yang Liu, Qian Wang, Lili Huang, Yongli Yang, Guangxue Xu, Bojian Luo, Wenling Wang, Peipei Liu, Wanshen Guo, Xiaoming Yang
Abstract
Background: The ongoing COVID-19 pandemic warrants accelerated efforts to test vaccine candidates. We aimed to assess the safety and immunogenicity of an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine candidate, BBIBP-CorV, in humans.
Methods: We did a randomised, double-blind, placebo-controlled, phase 1/2 trial at Shangqiu City Liangyuan District Center for Disease Control and Prevention in Henan Province, China. In phase 1, healthy people aged 18-80 years, who were negative for serum-specific IgM/IgG antibodies against SARS-CoV-2 at the time of screening, were separated into two age groups (18-59 years and ≥60 years) and randomly assigned to receive vaccine or placebo in a two-dose schedule of 2 μg, 4 μg, or 8 μg on days 0 and 28. In phase 2, healthy adults (aged 18-59 years) were randomly assigned (1:1:1:1) to receive vaccine or placebo on a single-dose schedule of 8 μg on day 0 or on a two-dose schedule of 4 μg on days 0 and 14, 0 and 21, or 0 and 28. Participants within each cohort were randomly assigned by stratified block randomisation (block size eight) and allocated (3:1) to receive vaccine or placebo. Group allocation was concealed from participants, investigators, and outcome assessors. The primary outcomes were safety and tolerability. The secondary outcome was immunogenicity, assessed as the neutralising antibody responses against infectious SARS-CoV-2. This study is registered with www.chictr.org.cn, ChiCTR2000032459.
Findings: In phase 1, 192 participants were enrolled (mean age 53·7 years [SD 15·6]) and were randomly assigned to receive vaccine (2 μg [n=24], 4 μg [n=24], or 8 μg [n=24] for both age groups [18-59 years and ≥60 years]) or placebo (n=24). At least one adverse reaction was reported within the first 7 days of inoculation in 42 (29%) of 144 vaccine recipients. The most common systematic adverse reaction was fever (18-59 years, one [4%] in the 2 μg group, one [4%] in the 4 μg group, and two [8%] in the 8 μg group; ≥60 years, one [4%] in the 8 μg group). All adverse reactions were mild or moderate in severity. No serious adverse event was reported within 28 days post vaccination. Neutralising antibody geometric mean titres were higher at day 42 in the group aged 18-59 years (87·7 [95% CI 64·9-118·6], 2 μg group; 211·2 [158·9-280·6], 4 μg group; and 228·7 [186·1-281·1], 8 μg group) and the group aged 60 years and older (80·7 [65·4-99·6], 2 μg group; 131·5 [108·2-159·7], 4 μg group; and 170·87 [133·0-219·5], 8 μg group) compared with the placebo group (2·0 [2·0-2·0]). In phase 2, 448 participants were enrolled (mean age 41·7 years [SD 9·9]) and were randomly assigned to receive the vaccine (8 μg on day 0 [n=84] or 4 μg on days 0 and 14 [n=84], days 0 and 21 [n=84], or days 0 and 28 [n=84]) or placebo on the same schedules (n=112). At least one adverse reaction within the first 7 days was reported in 76 (23%) of 336 vaccine recipients (33 [39%], 8 μg day 0; 18 [21%], 4 μg days 0 and 14; 15 [18%], 4 μg days 0 and 21; and ten [12%], 4 μg days 0 and 28). One placebo recipient in the 4 μg days 0 and 21 group reported grade 3 fever, but was self-limited and recovered. All other adverse reactions were mild or moderate in severity. The most common systematic adverse reaction was fever (one [1%], 8 μg day 0; one [1%], 4 μg days 0 and 14; three [4%], 4 μg days 0 and 21; two [2%], 4 μg days 0 and 28). The vaccine-elicited neutralising antibody titres on day 28 were significantly greater in the 4 μg days 0 and 14 (169·5, 95% CI 132·2-217·1), days 0 and 21 (282·7, 221·2-361·4), and days 0 and 28 (218·0, 181·8-261·3) schedules than the 8 μg day 0 schedule (14·7, 11·6-18·8; all p<0·001).
Interpretation: The inactivated SARS-CoV-2 vaccine, BBIBP-CorV, is safe and well tolerated at all tested doses in two age groups. Humoral responses against SARS-CoV-2 were induced in all vaccine recipients on day 42. Two-dose immunisation with 4 μg vaccine on days 0 and 21 or days 0 and 28 achieved higher neutralising antibody titres than the single 8 μg dose or 4 μg dose on days 0 and 14.
Funding: National Program on Key Research Project of China, National Mega projects of China for Major Infectious Diseases, National Mega Projects of China for New Drug Creation, and Beijing Science and Technology Plan.
Copyright © 2020 Elsevier Ltd. All rights reserved.
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References
- Chan JF, Yuan S, Kok KH. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020;395:514–523.
- Chen N, Zhou M, Dong X. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395:507–513.
- Li Q, Guan X, Wu P. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. 2020;382:1199–1207.
- Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. Lancet. 2020;395:470–473.
- Zhu N, Zhang D, Wang W. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382:727–733.
- Tan WJ, Zhao X, Ma XJ. A novel coronavirus genome identified in a cluster of pneumonia cases—Wuhan, China 2019–2020. China CDC Weekly. 2020;2:61–62.
- Weiss P, Murdoch DR. Clinical course and mortality risk of severe COVID-19. Lancet. 2020;395:1014–1015.
- WHO DRAFT landscape of COVID-19 candidate vaccines–7. July 2020.
- Gao Q, Bao L, Mao H. Development of an inactivated vaccine candidate for SARS-CoV-2. Science. 2020;369:77–81.
- Yu J, Tostanoski LH, Peter L. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science. 2020;369:806–811.
- van Doremalen N, Lambe T, Spencer A. ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques. bioRxiv. 2020 doi: 10.1101/2020.05.13.093195. published online May 13. (preprint)
- Lurie N, Saville M, Hatchett R, Halton J. Developing COVID-19 vaccines at pandemic speed. N Engl J Med. 2020;382:1969–1973.
- Wang H, Zhang Y, Huang B. Development of an inactivated vaccine candidate, BBIBP-CorV, with potent protection against SARS-CoV-2. Cell. 2020;182:713–721.
- Corbett KS, Flynn B, Foulds KE. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. N Engl J Med. 2020 doi: 10.1056/NEJMoa2024671. published online July 28.
- Jackson LA, Anderson EJ, Rouphael NG. An mRNA vaccine against SARS-CoV-2—preliminary report. N Engl J Med. 2020 doi: 10.1056/NEJMoa2022483. published online July 15.
- Chi X, Yan R, Zhang J. A neutralizing human antibody binds to the N-terminal domain of the spike protein of SARS-CoV-2. 2020;369:650–655.
- Yang ZY, Werner HC, Kong WP. Evasion of antibody neutralization in emerging severe acute respiratory syndrome coronaviruses. Proc Natl Acad Sci USA. 2005;102:797–801.
- Wang Q, Zhang L, Kuwahara K. Immunodominant SARS coronavirus epitopes in humans elicited both enhancing and neutralizing effects on infection in non-human primates. ACS Infect Dis. 2016;2:361–376.
- Xia S, Duan K, Zhang Y. Effect of an inactivated vaccine against SARS-CoV-2 on safety and immunogenicity outcomes: interim analysis of 2 randomized clinical trials. JAMA. 2020;324:951–960.
Source: PubMed