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Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity OutcomesInterim Analysis of 2 Randomized Clinical Trials

Educational Objective
To understand the safety and immunogenicity outcomes of an inactivated vaccine against COVID-19
1 Credit CME
Key Points

Question  What are the safety and immunogenicity of an inactivated vaccine against coronavirus disease 2019 (COVID-19)?

Findings  This was an interim analysis of 2 randomized placebo-controlled trials. In 96 healthy adults in a phase 1 trial of patients randomized to aluminum hydroxide (alum) only and low, medium, and high vaccine doses on days 0, 28, and 56, 7-day adverse reactions occurred in 12.5%, 20.8%, 16.7%, and 25.0%, respectively; geometric mean titers of neutralizing antibodies at day 14 after the third injection were 316, 206 and 297 in the low-, medium-, and high-dose groups, respectively. In 224 healthy adults randomized to the medium dose, 7-day adverse reactions occurred in 6.0% and 14.3% of the participants who received injections on days 0 and 14 vs alum only, and 19.0% and 17.9% who received injections on days 0 and 21 vs alum only, respectively; geometric mean titers of neutralizing antibodies in the vaccine groups at day 14 after the second injection were 121 vs 247, respectively.

Meaning  This inactivated COVID-19 vaccine had a low rate of adverse reactions and demonstrated immunogenicity, but longer-term assessment of safety and efficacy will require phase 3 trials.

Abstract

Importance  A vaccine against coronavirus disease 2019 (COVID-19) is urgently needed.

Objective  To evaluate the safety and immunogenicity of an investigational inactivated whole-virus COVID-19 vaccine in China.

Interventions  In the phase 1 trial, 96 participants were assigned to 1 of the 3 dose groups (2.5, 5, and 10 μg/dose) and an aluminum hydroxide (alum) adjuvant–only group (n = 24 in each group), and received 3 intramuscular injections at days 0, 28, and 56. In the phase 2 trial, 224 adults were randomized to 5 μg/dose in 2 schedule groups (injections on days 0 and 14 [n = 84] vs alum only [n = 28], and days 0 and 21 [n = 84] vs alum only [n = 28]).

Design, Setting, and Participants  Interim analysis of ongoing randomized, double-blind, placebo-controlled, phase 1 and 2 clinical trials to assess an inactivated COVID-19 vaccine. The trials were conducted in Henan Province, China, among 96 (phase 1) and 224 (phase 2) healthy adults aged between 18 and 59 years. Study enrollment began on April 12, 2020. The interim analysis was conducted on June 16, 2020, and updated on July 27, 2020.

Main Outcomes and Measures  The primary safety outcome was the combined adverse reactions 7 days after each injection, and the primary immunogenicity outcome was neutralizing antibody response 14 days after the whole-course vaccination, which was measured by a 50% plaque reduction neutralization test against live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Results  Among 320 patients who were randomized (mean age, 42.8 years; 200 women [62.5%]), all completed the trial up to 28 days after the whole-course vaccination. The 7-day adverse reactions occurred in 3 (12.5%), 5 (20.8%), 4 (16.7%), and 6 (25.0%) patients in the alum only, low-dose, medium-dose, and high-dose groups, respectively, in the phase 1 trial; and in 5 (6.0%) and 4 (14.3%) patients who received injections on days 0 and 14 for vaccine and alum only, and 16 (19.0%) and 5 (17.9%) patients who received injections on days 0 and 21 for vaccine and alum only, respectively, in the phase 2 trial. The most common adverse reaction was injection site pain, followed by fever, which were mild and self-limiting; no serious adverse reactions were noted. The geometric mean titers of neutralizing antibodies in the low-, medium-, and high-dose groups at day 14 after 3 injections were 316 (95% CI, 218-457), 206 (95% CI, 123-343), and 297 (95% CI, 208-424), respectively, in the phase 1 trial, and were 121 (95% CI, 95-154) and 247 (95% CI, 176-345) at day 14 after 2 injections in participants receiving vaccine on days 0 and 14 and on days 0 and 21, respectively, in the phase 2 trial. There were no detectable antibody responses in all alum-only groups.

Conclusions and Relevance  In this interim report of the phase 1 and phase 2 trials of an inactivated COVID-19 vaccine, patients had a low rate of adverse reactions and demonstrated immunogenicity; the study is ongoing. Efficacy and longer-term adverse event assessment will require phase 3 trials.

Trial Registration  Chinese Clinical Trial Registry Identifier: ChiCTR2000031809

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Article Information

Corresponding Authors: Xiaoming Yang, MD, China National Biotec Group Company Limited, 4 Hui-Xin E St, Chaoyang District, Beijing, China (yangxiaoming@sinopharm.com); An Pan, PhD, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Qiaokou District, Wuhan, China (panan@hust.edu.cn).

Accepted for Publication: August 3, 2020.

Published Online: August 13, 2020. doi:10.1001/jama.2020.15543

Author Contributions: Dr Xiaoming Yang and Mr Xia had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Mr Xia and Drs Duan and Yuntao Zhang contributed equally and are joint first authors. Drs Shen and Yuan and Mr W Guo are joint last authors.

Concept and design: Xia, Shen, W. Guo, Duan, Yuan, Yuntao Zhang, Li, Yunkai Yang, Chen, L. Zhang, Wu, Xiaoming Yang.

Acquisition, analysis, or interpretation of data: Xia, Zhao, H. Zhang, Xie, Peng, Yanbo Zhang, W. Zhang, Gao, You, X. Wang, Z. Wang, Shi, Y. Wang, Xuqin Yang, L. Huang, Q. Wang, Lu, Yongli Yang, J. Guo, Zhou, Wan, W. Wang, S. Huang, Du, Meng, Pan.

Drafting of the manuscript: Xia, S. Huang, Du, Meng, Pan.

Critical revision of the manuscript for important intellectual content: Xia, Shen, W. Guo, Duan, Yuan, Yuntao Zhang, Zhao, H. Zhang, Xie, Li, Peng, Yanbo Zhang, W. Zhang, Yunkai Yang, Chen, Gao, You, X. Wang, Z. Wang, Shi, Y. Wang, Xuqin Yang, L. Zhang, L. Huang, Q. Wang, Lu, Yongli Yang, J. Guo, Zhou, Wan, Wu, W. Wang, Xiaoming Yang.

Statistical analysis: Yanbo Zhang, Z. Wang, Yongli Yang, Pan.

Obtained funding: Xia, Shen, W. Guo, Duan, Yuan, Yuntao Zhang, X. Wang, Z. Wang, Xiaoming Yang.

Administrative, technical, or material support: Xia, H. Zhang, Yunkai Yang, Chen, Z. Wang.

Supervision: Shen, W. Guo, Duan, Yuan, Yuntao Zhang, Xiaoming Yang.

Conflict of Interest Disclosures: Mr Xia, Mr W Gou, and Drs Duan, Yuntao Zhang, X. Wang, Z. Wang, Yuan, Shen, and Xiaoming Yang reported receiving grants from the Ministry of Science and Technology of the People’s Republic of China during the conduct of the study. Drs Yuntao Zhang, Yunkai Yang, X. Wang, Xuqin Yang, Q. Wang, and Xiaoming Yang reported being employees of the China National Biotec Group Co Ltd. Drs Duan, Li, Z. Wang, Lu, J. Guo, Zhou, Wan, Wu, W. Wang, S. Huang, Meng, and Shen; Mr Chen; and Mr L. Zhang reported being employees of the Wuhan Institute of Biological Products Co Ltd. Dr Du reported being a student of the Wuhan Institute of Biological Products Co Ltd. Dr Yongli Yang reported receiving personal fees from Wuhan Institute of Biological Products Co Ltd during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was supported by the National Program on Key Research Project of China (2020YFC0842100) and Major Science and Technology Project of the National New Drug Development of China (2018ZX09734-004). The vaccine was developed and the study was sponsored by the China National Biotec Group Co Ltd and the Wuhan Institute of Biological Products Co Ltd.

Role of the Funder/Sponsor: The China National Biotec Group Co Ltd and the Wuhan Institute of Biological Products Co Ltd were the study sponsors and designed the trial, provided the study product, and oversaw all trial operations. The sponsors used contract clinical research organizations to coordinate interactions with regulatory authorities and oversee clinical site operations. Data were collected by the clinical site research staff, managed by a blinded contract research organization data management team, monitored by a contract research organization, and overseen by the sponsor and an independent data and safety monitoring board. The interim analysis was performed by an independent statistician who was not involved in the trial after the data were collected, checked, and locked for the specific groups before unblinding. Manuscript preparation was performed by the study authors and the decision to submit the manuscript for publication was made by the study authors.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We are grateful for all investigators at the Henan provincial and Wuzhi county Center for Disease Control and Prevention who contributed to the site work of the trials. We appreciate the contributions of the members in the data and safety monitoring board, including Xiaoju Zhang, MD, and Qiuxing Zhang, MD, from the Henan Province People’s Hospital, and Guoli Yan, MD, from the Henan University of Chinese Medicine. They received remuneration for their work. We thank all the participants in the trial for their dedication to the trial.

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