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Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial.
Lancet Microbe. 2022 Mar; 3(3):e193-e202.LM

Abstract

BACKGROUND

Safe and effective vaccines are urgently needed to end the COVID-19 pandemic caused by SARS-CoV-2 infection. We aimed to assess the preliminary safety, tolerability, and immunogenicity of an mRNA vaccine ARCoV, which encodes the SARS-CoV-2 spike protein receptor-binding domain (RBD).

METHODS

This single centre, double-blind, randomised, placebo-controlled, dose-escalation, phase 1 trial of ARCoV was conducted at Shulan (Hangzhou) hospital in Hangzhou, Zhejiang province, China. Healthy adults aged 18-59 years negative for SARS-CoV-2 infection were enrolled and randomly assigned using block randomisation to receive an intramuscular injection of vaccine or placebo. Vaccine doses were 5 μg, 10 μg, 15 μg, 20 μg, and 25 μg. The first six participants in each block were sentinels and along with the remaining 18 participants, were randomly assigned to groups (5:1). In block 1 sentinels were given the lowest vaccine dose and after a 4-day observation with confirmed safety analyses, the remaining 18 participants in the same dose group proceeded and sentinels in block 2 were given their first administration on a two-dose schedule, 28 days apart. All participants, investigators, and staff doing laboratory analyses were masked to treatment allocation. Humoral responses were assessed by measuring anti-SARS-CoV-2 RBD IgG using a standardised ELISA and neutralising antibodies using pseudovirus-based and live SARS-CoV-2 neutralisation assays. SARS-CoV-2 RBD-specific T-cell responses, including IFN-γ and IL-2 production, were assessed using an enzyme-linked immunospot (ELISpot) assay. The primary outcome for safety was incidence of adverse events or adverse reactions within 60 min, and at days 7, 14, and 28 after each vaccine dose. The secondary safety outcome was abnormal changes detected by laboratory tests at days 1, 4, 7, and 28 after each vaccine dose. For immunogenicity, the secondary outcome was humoral immune responses: titres of neutralising antibodies to live SARS-CoV-2, neutralising antibodies to pseudovirus, and RBD-specific IgG at baseline and 28 days after first vaccination and at days 7, 15, and 28 after second vaccination. The exploratory outcome was SARS-CoV-2-specific T-cell responses at 7 days after the first vaccination and at days 7 and 15 after the second vaccination. This trial is registered with www.chictr.org.cn (ChiCTR2000039212).

FINDINGS

Between Oct 30 and Dec 2, 2020, 230 individuals were screened and 120 eligible participants were randomly assigned to receive five-dose levels of ARCoV or a placebo (20 per group). All participants received the first vaccination and 118 received the second dose. No serious adverse events were reported within 56 days after vaccination and the majority of adverse events were mild or moderate. Fever was the most common systemic adverse reaction (one [5%] of 20 in the 5 μg group, 13 [65%] of 20 in the 10 μg group, 17 [85%] of 20 in the 15 μg group, 19 [95%] of 20 in the 20 μg group, 16 [100%] of 16 in the 25 μg group; p<0·0001). The incidence of grade 3 systemic adverse events were none (0%) of 20 in the 5 μg group, three (15%) of 20 in the 10 μg group, six (30%) of 20 in the 15 μg group, seven (35%) of 20 in the 20 μg group, five (31%) of 16 in the 25 μg group, and none (0%) of 20 in the placebo group (p=0·0013). As expected, the majority of fever resolved in the first 2 days after vaccination for all groups. The incidence of solicited systemic adverse events was similar after administration of ARCoV as a first or second vaccination. Humoral immune responses including anti-RBD IgG and neutralising antibodies increased significantly 7 days after the second dose and peaked between 14 and 28 days thereafter. Specific T-cell response peaked between 7 and 14 days after full vaccination. 15 μg induced the highest titre of neutralising antibodies, which was about twofold more than the antibody titre of convalescent patients with COVID-19.

INTERPRETATION

ARCoV was safe and well tolerated at all five doses. The acceptable safety profile, together with the induction of strong humoral and cellular immune responses, support further clinical testing of ARCoV at a large scale.

FUNDING

National Key Research and Development Project of China, Academy of Medical Sciences China, National Natural Science Foundation China, and Chinese Academy of Medical Sciences.

Authors+Show Affiliations

Shulan (Hangzhou) Hospital, Hangzhou, China.State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China.Shulan (Hangzhou) Hospital, Hangzhou, China.Shulan (Hangzhou) Hospital, Hangzhou, China.State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China.Walvax Biotechnology, Kunming, China.State Key Laboratory for Diagnosis and Treatment of Infectious Diseases/National Clinical Research Center for Infectious Diseases/Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.Shulan (Hangzhou) Hospital, Hangzhou, China.Zhejiang Shuren University Shulan International Medical College, Hangzhou, China.State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China.Walvax Biotechnology, Kunming, China.State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China.State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China.State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China.Suzhou Abogen Biosciences, Suzhou, China.Shulan (Hangzhou) Hospital, Hangzhou, China.Shulan (Hangzhou) Hospital, Hangzhou, China.Shulan (Hangzhou) Hospital, Hangzhou, China.Shulan (Hangzhou) Hospital, Hangzhou, China.National Institutes for Food and Drug Control, Beijing, China.National Institutes for Food and Drug Control, Beijing, China.National Institutes for Food and Drug Control, Beijing, China.National Institutes for Food and Drug Control, Beijing, China.Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China. Center for Human Disease Immuno-monitoring, Beijing Friendship Hospital, Beijing, China.Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China. Center for Human Disease Immuno-monitoring, Beijing Friendship Hospital, Beijing, China.Suzhou Abogen Biosciences, Suzhou, China.Shulan (Hangzhou) Hospital, Hangzhou, China.State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China. Research Unit of Discovery and Tracing of Natural Focus Diseases, Chinese Academy of Medical Sciences, Beijing China.Shulan (Hangzhou) Hospital, Hangzhou, China.State Key Laboratory for Diagnosis and Treatment of Infectious Diseases/National Clinical Research Center for Infectious Diseases/Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Pub Type(s)

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

Language

eng

PubMed ID

35098177

Citation

Chen, Gui-Ling, et al. "Safety and Immunogenicity of the SARS-CoV-2 ARCoV mRNA Vaccine in Chinese Adults: a Randomised, Double-blind, Placebo-controlled, Phase 1 Trial." The Lancet. Microbe, vol. 3, no. 3, 2022, pp. e193-e202.
Chen GL, Li XF, Dai XH, et al. Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Microbe. 2022;3(3):e193-e202.
Chen, G. L., Li, X. F., Dai, X. H., Li, N., Cheng, M. L., Huang, Z., Shen, J., Ge, Y. H., Shen, Z. W., Deng, Y. Q., Yang, S. Y., Zhao, H., Zhang, N. N., Zhang, Y. F., Wei, L., Wu, K. Q., Zhu, M. F., Peng, C. G., Jiang, Q., ... Li, L. J. (2022). Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial. The Lancet. Microbe, 3(3), e193-e202. https://doi.org/10.1016/S2666-5247(21)00280-9
Chen GL, et al. Safety and Immunogenicity of the SARS-CoV-2 ARCoV mRNA Vaccine in Chinese Adults: a Randomised, Double-blind, Placebo-controlled, Phase 1 Trial. Lancet Microbe. 2022;3(3):e193-e202. PubMed PMID: 35098177.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial. AU - Chen,Gui-Ling, AU - Li,Xiao-Feng, AU - Dai,Xia-Hong, AU - Li,Nan, AU - Cheng,Meng-Li, AU - Huang,Zhen, AU - Shen,Jian, AU - Ge,Yu-Hua, AU - Shen,Zhen-Wei, AU - Deng,Yong-Qiang, AU - Yang,Shu-Yuan, AU - Zhao,Hui, AU - Zhang,Na-Na, AU - Zhang,Yi-Fei, AU - Wei,Ling, AU - Wu,Kai-Qi, AU - Zhu,Meng-Fei, AU - Peng,Cong-Gao, AU - Jiang,Qi, AU - Cao,Shou-Chun, AU - Li,Yu-Hua, AU - Zhao,Dan-Hua, AU - Wu,Xiao-Hong, AU - Ni,Ling, AU - Shen,Hua-Hao, AU - Dong,Chen, AU - Ying,Bo, AU - Sheng,Guo-Ping, AU - Qin,Cheng-Feng, AU - Gao,Hai-Nv, AU - Li,Lan-Juan, Y1 - 2022/01/24/ PY - 2022/2/1/pubmed PY - 2022/2/1/medline PY - 2022/1/31/entrez SP - e193 EP - e202 JF - The Lancet. Microbe JO - Lancet Microbe VL - 3 IS - 3 N2 - BACKGROUND: Safe and effective vaccines are urgently needed to end the COVID-19 pandemic caused by SARS-CoV-2 infection. We aimed to assess the preliminary safety, tolerability, and immunogenicity of an mRNA vaccine ARCoV, which encodes the SARS-CoV-2 spike protein receptor-binding domain (RBD). METHODS: This single centre, double-blind, randomised, placebo-controlled, dose-escalation, phase 1 trial of ARCoV was conducted at Shulan (Hangzhou) hospital in Hangzhou, Zhejiang province, China. Healthy adults aged 18-59 years negative for SARS-CoV-2 infection were enrolled and randomly assigned using block randomisation to receive an intramuscular injection of vaccine or placebo. Vaccine doses were 5 μg, 10 μg, 15 μg, 20 μg, and 25 μg. The first six participants in each block were sentinels and along with the remaining 18 participants, were randomly assigned to groups (5:1). In block 1 sentinels were given the lowest vaccine dose and after a 4-day observation with confirmed safety analyses, the remaining 18 participants in the same dose group proceeded and sentinels in block 2 were given their first administration on a two-dose schedule, 28 days apart. All participants, investigators, and staff doing laboratory analyses were masked to treatment allocation. Humoral responses were assessed by measuring anti-SARS-CoV-2 RBD IgG using a standardised ELISA and neutralising antibodies using pseudovirus-based and live SARS-CoV-2 neutralisation assays. SARS-CoV-2 RBD-specific T-cell responses, including IFN-γ and IL-2 production, were assessed using an enzyme-linked immunospot (ELISpot) assay. The primary outcome for safety was incidence of adverse events or adverse reactions within 60 min, and at days 7, 14, and 28 after each vaccine dose. The secondary safety outcome was abnormal changes detected by laboratory tests at days 1, 4, 7, and 28 after each vaccine dose. For immunogenicity, the secondary outcome was humoral immune responses: titres of neutralising antibodies to live SARS-CoV-2, neutralising antibodies to pseudovirus, and RBD-specific IgG at baseline and 28 days after first vaccination and at days 7, 15, and 28 after second vaccination. The exploratory outcome was SARS-CoV-2-specific T-cell responses at 7 days after the first vaccination and at days 7 and 15 after the second vaccination. This trial is registered with www.chictr.org.cn (ChiCTR2000039212). FINDINGS: Between Oct 30 and Dec 2, 2020, 230 individuals were screened and 120 eligible participants were randomly assigned to receive five-dose levels of ARCoV or a placebo (20 per group). All participants received the first vaccination and 118 received the second dose. No serious adverse events were reported within 56 days after vaccination and the majority of adverse events were mild or moderate. Fever was the most common systemic adverse reaction (one [5%] of 20 in the 5 μg group, 13 [65%] of 20 in the 10 μg group, 17 [85%] of 20 in the 15 μg group, 19 [95%] of 20 in the 20 μg group, 16 [100%] of 16 in the 25 μg group; p<0·0001). The incidence of grade 3 systemic adverse events were none (0%) of 20 in the 5 μg group, three (15%) of 20 in the 10 μg group, six (30%) of 20 in the 15 μg group, seven (35%) of 20 in the 20 μg group, five (31%) of 16 in the 25 μg group, and none (0%) of 20 in the placebo group (p=0·0013). As expected, the majority of fever resolved in the first 2 days after vaccination for all groups. The incidence of solicited systemic adverse events was similar after administration of ARCoV as a first or second vaccination. Humoral immune responses including anti-RBD IgG and neutralising antibodies increased significantly 7 days after the second dose and peaked between 14 and 28 days thereafter. Specific T-cell response peaked between 7 and 14 days after full vaccination. 15 μg induced the highest titre of neutralising antibodies, which was about twofold more than the antibody titre of convalescent patients with COVID-19. INTERPRETATION: ARCoV was safe and well tolerated at all five doses. The acceptable safety profile, together with the induction of strong humoral and cellular immune responses, support further clinical testing of ARCoV at a large scale. FUNDING: National Key Research and Development Project of China, Academy of Medical Sciences China, National Natural Science Foundation China, and Chinese Academy of Medical Sciences. SN - 2666-5247 UR - https://www.unboundmedicine.com/medline/citation/35098177/Safety_and_immunogenicity_of_the_SARS_CoV_2_ARCoV_mRNA_vaccine_in_Chinese_adults:_a_randomised_double_blind_placebo_controlled_phase_1_trial_ DB - PRIME DP - Unbound Medicine ER -