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Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.
Lancet. 2020 08 15; 396(10249):479-488.Lct

Abstract

BACKGROUND

This is the first randomised controlled trial for assessment of the immunogenicity and safety of a candidate non-replicating adenovirus type-5 (Ad5)-vectored COVID-19 vaccine, aiming to determine an appropriate dose of the candidate vaccine for an efficacy study.

METHODS

This randomised, double-blind, placebo-controlled, phase 2 trial of the Ad5-vectored COVID-19 vaccine was done in a single centre in Wuhan, China. Healthy adults aged 18 years or older, who were HIV-negative and previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-free, were eligible to participate and were randomly assigned to receive the vaccine at a dose of 1 × 1011 viral particles per mL or 5 × 1010 viral particles per mL, or placebo. Investigators allocated participants at a ratio of 2:1:1 to receive a single injection intramuscularly in the arm. The randomisation list (block size 4) was generated by an independent statistician. Participants, investigators, and staff undertaking laboratory analyses were masked to group allocation. The primary endpoints for immunogenicity were the geometric mean titres (GMTs) of specific ELISA antibody responses to the receptor binding domain (RBD) and neutralising antibody responses at day 28. The primary endpoint for safety evaluation was the incidence of adverse reactions within 14 days. All recruited participants who received at least one dose were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, NCT04341389.

FINDINGS

603 volunteers were recruited and screened for eligibility between April 11 and 16, 2020. 508 eligible participants (50% male; mean age 39·7 years, SD 12·5) consented to participate in the trial and were randomly assigned to receive the vaccine (1 × 1011 viral particles n=253; 5 × 1010 viral particles n=129) or placebo (n=126). In the 1 × 1011 and 5 × 1010 viral particles dose groups, the RBD-specific ELISA antibodies peaked at 656·5 (95% CI 575·2-749·2) and 571·0 (467·6-697·3), with seroconversion rates at 96% (95% CI 93-98) and 97% (92-99), respectively, at day 28. Both doses of the vaccine induced significant neutralising antibody responses to live SARS-CoV-2, with GMTs of 19·5 (95% CI 16·8-22·7) and 18·3 (14·4-23·3) in participants receiving 1 × 1011 and 5 × 1010 viral particles, respectively. Specific interferon γ enzyme-linked immunospot assay responses post vaccination were observed in 227 (90%, 95% CI 85-93) of 253 and 113 (88%, 81-92) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Solicited adverse reactions were reported by 183 (72%) of 253 and 96 (74%) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Severe adverse reactions were reported by 24 (9%) participants in the 1 × 1011 viral particles dose group and one (1%) participant in the 5 × 1010 viral particles dose group. No serious adverse reactions were documented.

INTERPRETATION

The Ad5-vectored COVID-19 vaccine at 5 × 1010 viral particles is safe, and induced significant immune responses in the majority of recipients after a single immunisation.

FUNDING

National Key R&D Programme of China, National Science and Technology Major Project, and CanSino Biologics.

Authors+Show Affiliations

NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China. Electronic address: jszfc@vip.sina.com.Hubei Provincial Center for Diseases Control and Prevention, Wuhan, China.National Institute for Food and Drug Control, Dongcheng, Beijing, China.Clinical Trial Center, Zhongnan Hospital of Wuhan University, Wuhan, China.Beijing Institute of Microbiology and Epidemiology, State Key Laboratory of Pathogen and Biosecurity, Beijing, China.Beijing Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China.NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China.Hubei Provincial Center for Diseases Control and Prevention, Wuhan, China.National Institute for Food and Drug Control, Dongcheng, Beijing, China.NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China.Beijing Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China.Hubei Provincial Center for Diseases Control and Prevention, Wuhan, China.National Institute for Food and Drug Control, Dongcheng, Beijing, China.Beijing Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China.Beijing Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China.NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China.Beijing Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China.Beijing Institute of Microbiology and Epidemiology, State Key Laboratory of Pathogen and Biosecurity, Beijing, China.National Institute for Food and Drug Control, Dongcheng, Beijing, China.Beijing Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China.Hubei Provincial Center for Diseases Control and Prevention, Wuhan, China.Hubei Provincial Center for Diseases Control and Prevention, Wuhan, China.NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China.NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China.Hubei Provincial Center for Diseases Control and Prevention, Wuhan, China.CanSino Biologics, Tianjin, China.Shanghai Canming Medical Technology, Shanghai, China.Clinical Trial Center, Zhongnan Hospital of Wuhan University, Wuhan, China. Electronic address: wangxinghuan@whu.edu.cn.Beijing Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China. Electronic address: cw0226@foxmail.com.

Pub Type(s)

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

Language

eng

PubMed ID

32702299

Citation

Zhu, Feng-Cai, et al. "Immunogenicity and Safety of a Recombinant Adenovirus Type-5-vectored COVID-19 Vaccine in Healthy Adults Aged 18 Years or Older: a Randomised, Double-blind, Placebo-controlled, Phase 2 Trial." Lancet (London, England), vol. 396, no. 10249, 2020, pp. 479-488.
Zhu FC, Guan XH, Li YH, et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020;396(10249):479-488.
Zhu, F. C., Guan, X. H., Li, Y. H., Huang, J. Y., Jiang, T., Hou, L. H., Li, J. X., Yang, B. F., Wang, L., Wang, W. J., Wu, S. P., Wang, Z., Wu, X. H., Xu, J. J., Zhang, Z., Jia, S. Y., Wang, B. S., Hu, Y., Liu, J. J., ... Chen, W. (2020). Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet (London, England), 396(10249), 479-488. https://doi.org/10.1016/S0140-6736(20)31605-6
Zhu FC, et al. Immunogenicity and Safety of a Recombinant Adenovirus Type-5-vectored COVID-19 Vaccine in Healthy Adults Aged 18 Years or Older: a Randomised, Double-blind, Placebo-controlled, Phase 2 Trial. Lancet. 2020 08 15;396(10249):479-488. PubMed PMID: 32702299.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. AU - Zhu,Feng-Cai, AU - Guan,Xu-Hua, AU - Li,Yu-Hua, AU - Huang,Jian-Ying, AU - Jiang,Tao, AU - Hou,Li-Hua, AU - Li,Jing-Xin, AU - Yang,Bei-Fang, AU - Wang,Ling, AU - Wang,Wen-Juan, AU - Wu,Shi-Po, AU - Wang,Zhao, AU - Wu,Xiao-Hong, AU - Xu,Jun-Jie, AU - Zhang,Zhe, AU - Jia,Si-Yue, AU - Wang,Bu-Sen, AU - Hu,Yi, AU - Liu,Jing-Jing, AU - Zhang,Jun, AU - Qian,Xiao-Ai, AU - Li,Qiong, AU - Pan,Hong-Xing, AU - Jiang,Hu-Dachuan, AU - Deng,Peng, AU - Gou,Jin-Bo, AU - Wang,Xue-Wen, AU - Wang,Xing-Huan, AU - Chen,Wei, Y1 - 2020/07/20/ PY - 2020/06/15/received PY - 2020/07/13/revised PY - 2020/07/14/accepted PY - 2020/7/24/pubmed PY - 2020/8/25/medline PY - 2020/7/24/entrez SP - 479 EP - 488 JF - Lancet (London, England) JO - Lancet VL - 396 IS - 10249 N2 - BACKGROUND: This is the first randomised controlled trial for assessment of the immunogenicity and safety of a candidate non-replicating adenovirus type-5 (Ad5)-vectored COVID-19 vaccine, aiming to determine an appropriate dose of the candidate vaccine for an efficacy study. METHODS: This randomised, double-blind, placebo-controlled, phase 2 trial of the Ad5-vectored COVID-19 vaccine was done in a single centre in Wuhan, China. Healthy adults aged 18 years or older, who were HIV-negative and previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-free, were eligible to participate and were randomly assigned to receive the vaccine at a dose of 1 × 1011 viral particles per mL or 5 × 1010 viral particles per mL, or placebo. Investigators allocated participants at a ratio of 2:1:1 to receive a single injection intramuscularly in the arm. The randomisation list (block size 4) was generated by an independent statistician. Participants, investigators, and staff undertaking laboratory analyses were masked to group allocation. The primary endpoints for immunogenicity were the geometric mean titres (GMTs) of specific ELISA antibody responses to the receptor binding domain (RBD) and neutralising antibody responses at day 28. The primary endpoint for safety evaluation was the incidence of adverse reactions within 14 days. All recruited participants who received at least one dose were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, NCT04341389. FINDINGS: 603 volunteers were recruited and screened for eligibility between April 11 and 16, 2020. 508 eligible participants (50% male; mean age 39·7 years, SD 12·5) consented to participate in the trial and were randomly assigned to receive the vaccine (1 × 1011 viral particles n=253; 5 × 1010 viral particles n=129) or placebo (n=126). In the 1 × 1011 and 5 × 1010 viral particles dose groups, the RBD-specific ELISA antibodies peaked at 656·5 (95% CI 575·2-749·2) and 571·0 (467·6-697·3), with seroconversion rates at 96% (95% CI 93-98) and 97% (92-99), respectively, at day 28. Both doses of the vaccine induced significant neutralising antibody responses to live SARS-CoV-2, with GMTs of 19·5 (95% CI 16·8-22·7) and 18·3 (14·4-23·3) in participants receiving 1 × 1011 and 5 × 1010 viral particles, respectively. Specific interferon γ enzyme-linked immunospot assay responses post vaccination were observed in 227 (90%, 95% CI 85-93) of 253 and 113 (88%, 81-92) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Solicited adverse reactions were reported by 183 (72%) of 253 and 96 (74%) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Severe adverse reactions were reported by 24 (9%) participants in the 1 × 1011 viral particles dose group and one (1%) participant in the 5 × 1010 viral particles dose group. No serious adverse reactions were documented. INTERPRETATION: The Ad5-vectored COVID-19 vaccine at 5 × 1010 viral particles is safe, and induced significant immune responses in the majority of recipients after a single immunisation. FUNDING: National Key R&D Programme of China, National Science and Technology Major Project, and CanSino Biologics. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/32702299/full_citation L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(20)31605-6 DB - PRIME DP - Unbound Medicine ER -