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Safety and Immunogenicity of Aerosolised Ad5-nCoV or Intramuscular Ad5-nCoV or Inactivated COVID-19 Vaccine Coronavac Given as the Second Booster Following Three Doses of CoronaVac: A Multicentre, Open-Label, Phase 4, Randomized Trial

24 Pages Posted: 30 Dec 2022

See all articles by Rong Tang

Rong Tang

Jiangsu Provincial Center for Disease Control and Prevention - NHC Key Laboratory of Enteric Pathogenic Microbiology

Hui Zheng

Southeast University - School of Public Health

Bu-Sen Wang

Academy of Military Medical Sciences - Institute of Biotechnology

Jin-Bo Gou

CanSino Biologics Inc.

Xi-Ling Guo

Jiangsu Provincial Center for Disease Control and Prevention - NHC Key Laboratory of Enteric Pathogenic Microbiology

Xiao-Qin Chen

Donghai County Center for Disease Control and Prevention

Hai-Tao Huang

CanSino Biologics Inc.

Yin Chen

Jiangsu Provincial Center for Disease Control and Prevention - NHC Key Laboratory of Enteric Pathogenic Microbiology

Shi-Po Wu

Academy of Military Medical Sciences - Institute of Biotechnology

Xiaolong Li

CanSino Biologics Inc.

Jin Zhong

Donghai County Center for Disease Control and Prevention

Xue Wang

CanSino Biologics Inc.

Hong-Xing Pan

Jiangsu Provincial Center for Disease Control and Prevention - NHC Key Laboratory of Enteric Pathogenic Microbiology

Jiahong Zhu

Lianshui Center for Disease Control and Prevention

Peng Wan

CanSino Biologics Inc.

Xiao-Yu Xu

Nanjing Vazyme Biotech Co., Ltd.

Feng-Juan Shi

Jiangsu Provincial Center for Disease Control and Prevention - NHC Key Laboratory of Enteric Pathogenic Microbiology

Zhuo-Pei Li

Nanjing Medical University - School of Public Health

Jing-Xian Liu

Jiangsu Provincial Center for Disease Control and Prevention - NHC Key Laboratory of Enteric Pathogenic Microbiology

Xiao-Yin Zhang

Southeast University - School of Public Health

Lun-Biao Cui

Jiangsu Provincial Center for Disease Control and Prevention - NHC Key Laboratory of Enteric Pathogenic Microbiology

Zhizhou Song

Lianshui Center for Disease Control and Prevention

Tao Zhu

CanSino Biologics Inc.

Li-Hua Hou

Academy of Military Medical Sciences - Institute of Biotechnology

Feng-Cai Zhu

Jiangsu Provincial Center for Disease Control and Prevention - NHC Key Laboratory of Enteric Pathogenic Microbiology

Jing-Xin Li

Jiangsu Provincial Center for Disease Control and Prevention - NHC Key Laboratory of Enteric Pathogenic Microbiology

More...

Abstract

Background: This study aimed to evaluate the safety and immunogenicity of aerosolised Ad5-nCoV or intramuscular Ad5-nCoV or inactivated COVID-19 vaccine CoronaVac given as the second booster.

Methods: This is an ongoing, randomized, open-label, parallel-controlled phase 4 trial involving healthy participants who have completed the two-dose primary immunisation and a booster immunisation with inactivated COVID-19 vaccines for at least 6 months. We recruited eligible participants from previous trials (NCT04892459, NCT04952727, and NCT05043259) as cohort 1 (with the serum before and after the first booster dose available), and eligible volunteers as cohort 2 in Lianshui and Donghai counties, Jiangsu Province. Participants were randomised at a ratio of 1:1:1 and allocated to receive the fourth dose (second booster) of aerosolised Ad5-nCoV (0.1 mL of 1.0 × 1011 viral particles per mL) or intramuscular Ad5-nCoV (0.5 mL of 1.0 × 1011 viral particles per mL) or inactivated COVID-19 vaccine CoronaVac (0.5 mL), respectively. The coprimary outcomes were safety and immunogenicity of geometric mean titres (GMTs) of serum neutralising antibodies against prototype live SARS-CoV-2 virus 28 days after the vaccination. This study was registered with ClinicalTrials.gov, NCT05303584.

Findings: Between April 23 and May 23, 2022, 356 participants met eligibility criteria, and received either a dose of aerosolised Ad5-nCoV (n=117), or intramuscular Ad5-nCoV (n=120) or CoronaVac (n=119). Within 28 days of booster vaccination, participants in the intramuscular Ad5-nCoV group reported a significantly higher frequency of adverse reactions than those in the aerosolised Ad5-nCoV and intramuscular CoronaVac groups (30.0% vs. 9.4% and 14.3%, p values<0.0001, respectively). No serious adverse events related to the vaccination were reported. The heterologous boosting with aerosolised Ad5-nCoV triggered a GMT of 672.4 (539.7-837.7) and intramuscular Ad5-nCoV triggered a serum neutralizing antibody GMT of 582.6 (505.0-672.2) 28 days after booster dose, significantly higher than the GMT in the CoronaVac group (58.5 [48.0-71.4]; p<0.0001). While, the serum pseudovirus neutralizing antibody GMTs against the Omicron variant BA 4/5 in participants receiving aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, and CoronaVac group were 108.2 (84.3-138.9), 79.9 (65.4-97.6), and 18.7 (17.1-20.5), at day 28 after booster dose.

Interpretation: The heterologous fourth dose (second booster) with either the aerosolised Ad5-nCoV or intramuscular Ad5-nCoV was safe and highly immunogenic, with robust humoral and cellular immune responses in healthy adults who have been immunized with three doses of CoronaVac.

Trial Registration Details: This study was registered with ClinicalTrials.gov, NCT05303584.

Funding Information: National Natural Science Foundation of China (number 82173584 and 82222062), Jiangsu Provincial Science Fund for Distinguished Young Scholars (number BK20220064), and Jiangsu Provincial Key Project of Science and Technology Plan (number BE2021738).

Declaration of Interests: Jin-Bo Gou, Haitao Huang, Xiaolong Li, Xue Wang, Peng Wan and Tao Zhu are employees of CanSino Biologics. Tao Zhu owns stock in CanSino Biologics. All other authors declare no competing interests.

Ethics Approval Statement: The trial protocol was reviewed and approved by the Research Ethics Committee of the Jiangsu Provincial Center of Disease Control and Prevention, and no changes to the protocol were made after the initiation of the study. The protocol is provided in appendix 2 (pp 22-27), with a full list of inclusion and exclusion criteria are reported (pp 28-29). Written informed consent was obtained from each participant before screening. This trial was conducted following the principles of the Declaration of Helsinki, Clinical Practice guidelines, and local guidelines.

Suggested Citation

Tang, Rong and Zheng, Hui and Wang, Bu-Sen and Gou, Jin-Bo and Guo, Xi-Ling and Chen, Xiao-Qin and Huang, Hai-Tao and Chen, Yin and Wu, Shi-Po and Li, Xiaolong and Zhong, Jin and Wang, Xue and Pan, Hong-Xing and Zhu, Jiahong and Wan, Peng and Xu, Xiao-Yu and Shi, Feng-Juan and Li, Zhuo-Pei and Liu, Jing-Xian and Zhang, Xiao-Yin and Cui, Lun-Biao and Song, Zhizhou and Zhu, Tao and Hou, Li-Hua and Zhu, Feng-Cai and Li, Jing-Xin, Safety and Immunogenicity of Aerosolised Ad5-nCoV or Intramuscular Ad5-nCoV or Inactivated COVID-19 Vaccine Coronavac Given as the Second Booster Following Three Doses of CoronaVac: A Multicentre, Open-Label, Phase 4, Randomized Trial. Available at SSRN: https://ssrn.com/abstract=4308756 or http://dx.doi.org/10.2139/ssrn.4308756

Rong Tang

Jiangsu Provincial Center for Disease Control and Prevention - NHC Key Laboratory of Enteric Pathogenic Microbiology ( email )

Nanjing
China

Hui Zheng

Southeast University - School of Public Health ( email )

Bu-Sen Wang

Academy of Military Medical Sciences - Institute of Biotechnology ( email )

Jin-Bo Gou

CanSino Biologics Inc. ( email )

Tianjin
China

Xi-Ling Guo

Jiangsu Provincial Center for Disease Control and Prevention - NHC Key Laboratory of Enteric Pathogenic Microbiology ( email )

Nanjing
China

Xiao-Qin Chen

Donghai County Center for Disease Control and Prevention ( email )

Donghai
China

Hai-Tao Huang

CanSino Biologics Inc. ( email )

Tianjin
China

Yin Chen

Jiangsu Provincial Center for Disease Control and Prevention - NHC Key Laboratory of Enteric Pathogenic Microbiology ( email )

Nanjing
China

Shi-Po Wu

Academy of Military Medical Sciences - Institute of Biotechnology ( email )

Beijing
China

Xiaolong Li

CanSino Biologics Inc. ( email )

Jin Zhong

Donghai County Center for Disease Control and Prevention ( email )

Donghai
China

Xue Wang

CanSino Biologics Inc. ( email )

Tianjin
China

Hong-Xing Pan

Jiangsu Provincial Center for Disease Control and Prevention - NHC Key Laboratory of Enteric Pathogenic Microbiology ( email )

Nanjing
China

Jiahong Zhu

Lianshui Center for Disease Control and Prevention ( email )

China

Peng Wan

CanSino Biologics Inc. ( email )

Xiao-Yu Xu

Nanjing Vazyme Biotech Co., Ltd. ( email )

Nanjing
China

Feng-Juan Shi

Jiangsu Provincial Center for Disease Control and Prevention - NHC Key Laboratory of Enteric Pathogenic Microbiology ( email )

Nanjing
China

Zhuo-Pei Li

Nanjing Medical University - School of Public Health ( email )

Nanjing
China

Jing-Xian Liu

Jiangsu Provincial Center for Disease Control and Prevention - NHC Key Laboratory of Enteric Pathogenic Microbiology ( email )

Nanjing
China

Xiao-Yin Zhang

Southeast University - School of Public Health ( email )

Nanjing, Jiangsu
China

Lun-Biao Cui

Jiangsu Provincial Center for Disease Control and Prevention - NHC Key Laboratory of Enteric Pathogenic Microbiology ( email )

Nanjing
China

Zhizhou Song

Lianshui Center for Disease Control and Prevention ( email )

Tao Zhu

CanSino Biologics Inc. ( email )

Tianjin
China

Li-Hua Hou

Academy of Military Medical Sciences - Institute of Biotechnology ( email )

Beijing
China

Feng-Cai Zhu (Contact Author)

Jiangsu Provincial Center for Disease Control and Prevention - NHC Key Laboratory of Enteric Pathogenic Microbiology ( email )

Nanjing
China

Jing-Xin Li

Jiangsu Provincial Center for Disease Control and Prevention - NHC Key Laboratory of Enteric Pathogenic Microbiology ( email )

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