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Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials.
JAMA. 2020 Aug 13 [Online ahead of print]JAMA

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.

Authors+Show Affiliations

Henan Center for Disease Control and Prevention, Zhengzhou, Henan, China.National Engineering Technology Research Center for Combined Vaccines, Wuhan Institute of Biological Products Co Ltd, Wuhan, Hubei, China.China National Biotec Group Company Limited, Beijing, China.Henan Center for Disease Control and Prevention, Zhengzhou, Henan, China.Chinese Academy of Sciences Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China.Henan Center for Disease Control and Prevention, Zhengzhou, Henan, China.National Engineering Technology Research Center for Combined Vaccines, Wuhan Institute of Biological Products Co Ltd, Wuhan, Hubei, China.Chinese Academy of Sciences Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China.Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health and State Key Laboratory of Environmental Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.Henan Center for Disease Control and Prevention, Zhengzhou, Henan, China.China National Biotec Group Company Limited, Beijing, China.National Engineering Technology Research Center for Combined Vaccines, Wuhan Institute of Biological Products Co Ltd, Wuhan, Hubei, China.Chinese Academy of Sciences Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China.Henan Center for Disease Control and Prevention, Zhengzhou, Henan, China.China National Biotec Group Company Limited, Beijing, China.National Engineering Technology Research Center for Combined Vaccines, Wuhan Institute of Biological Products Co Ltd, Wuhan, Hubei, China.Chinese Academy of Sciences Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China.Henan Center for Disease Control and Prevention, Zhengzhou, Henan, China.China National Biotec Group Company Limited, Beijing, China.National Engineering Technology Research Center for Combined Vaccines, Wuhan Institute of Biological Products Co Ltd, Wuhan, Hubei, China.Henan Center for Disease Control and Prevention, Zhengzhou, Henan, China.China National Biotec Group Company Limited, Beijing, China.National Engineering Technology Research Center for Combined Vaccines, Wuhan Institute of Biological Products Co Ltd, Wuhan, Hubei, China.Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China.National Engineering Technology Research Center for Combined Vaccines, Wuhan Institute of Biological Products Co Ltd, Wuhan, Hubei, China.National Engineering Technology Research Center for Combined Vaccines, Wuhan Institute of Biological Products Co Ltd, Wuhan, Hubei, China.National Engineering Technology Research Center for Combined Vaccines, Wuhan Institute of Biological Products Co Ltd, Wuhan, Hubei, China.National Engineering Technology Research Center for Combined Vaccines, Wuhan Institute of Biological Products Co Ltd, Wuhan, Hubei, China.National Engineering Technology Research Center for Combined Vaccines, Wuhan Institute of Biological Products Co Ltd, Wuhan, Hubei, China.National Engineering Technology Research Center for Combined Vaccines, Wuhan Institute of Biological Products Co Ltd, Wuhan, Hubei, China.National Engineering Technology Research Center for Combined Vaccines, Wuhan Institute of Biological Products Co Ltd, Wuhan, Hubei, China.National Engineering Technology Research Center for Combined Vaccines, Wuhan Institute of Biological Products Co Ltd, Wuhan, Hubei, China.Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health and State Key Laboratory of Environmental Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. National Medical Center for Major Public Health Events, Huazhong University of Science and Technology, Wuhan, Hubei, China.Chinese Academy of Sciences Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China.National Engineering Technology Research Center for Combined Vaccines, Wuhan Institute of Biological Products Co Ltd, Wuhan, Hubei, China.Henan Center for Disease Control and Prevention, Zhengzhou, Henan, China.National Engineering Technology Research Center for Combined Vaccines, Wuhan Institute of Biological Products Co Ltd, Wuhan, Hubei, China. China National Biotec Group Company Limited, Beijing, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32789505

Citation

Xia, Shengli, et al. "Effect of an Inactivated Vaccine Against SARS-CoV-2 On Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials." JAMA, 2020.
Xia S, Duan K, Zhang Y, et al. Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials. JAMA. 2020.
Xia, S., Duan, K., Zhang, Y., Zhao, D., Zhang, H., Xie, Z., Li, X., Peng, C., Zhang, Y., Zhang, W., Yang, Y., Chen, W., Gao, X., You, W., Wang, X., Wang, Z., Shi, Z., Wang, Y., Yang, X., ... Yang, X. (2020). Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials. JAMA. https://doi.org/10.1001/jama.2020.15543
Xia S, et al. Effect of an Inactivated Vaccine Against SARS-CoV-2 On Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials. JAMA. 2020 Aug 13; PubMed PMID: 32789505.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials. AU - Xia,Shengli, AU - Duan,Kai, AU - Zhang,Yuntao, AU - Zhao,Dongyang, AU - Zhang,Huajun, AU - Xie,Zhiqiang, AU - Li,Xinguo, AU - Peng,Cheng, AU - Zhang,Yanbo, AU - Zhang,Wei, AU - Yang,Yunkai, AU - Chen,Wei, AU - Gao,Xiaoxiao, AU - You,Wangyang, AU - Wang,Xuewei, AU - Wang,Zejun, AU - Shi,Zhengli, AU - Wang,Yanxia, AU - Yang,Xuqin, AU - Zhang,Lianghao, AU - Huang,Lili, AU - Wang,Qian, AU - Lu,Jia, AU - Yang,Yongli, AU - Guo,Jing, AU - Zhou,Wei, AU - Wan,Xin, AU - Wu,Cong, AU - Wang,Wenhui, AU - Huang,Shihe, AU - Du,Jianhui, AU - Meng,Ziyan, AU - Pan,An, AU - Yuan,Zhiming, AU - Shen,Shuo, AU - Guo,Wanshen, AU - Yang,Xiaoming, Y1 - 2020/08/13/ PY - 2021/02/13/pmc-release PY - 2020/8/14/entrez PY - 2020/8/14/pubmed PY - 2020/8/14/medline JF - JAMA JO - JAMA N2 - 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. SN - 1538-3598 UR - https://www.unboundmedicine.com/medline/citation/32789505/full_citation L2 - https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2020.15543 DB - PRIME DP - Unbound Medicine ER -
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