Safety and Immunogenicity of aerosolized adenovirus-vectored COVID-19 vaccine and intramuscular mRNA vaccine bivalent boosters: a randomized open-label clinical trial

Shipo Wu, Jianying Huang, Busen Wang, Jianhua Li, Jianyuan Wu, Zhe Zhang, Lin Luo, Jinlong Zhang, Nan Huo, Jianglan Long, He Huang, Zhengshan Chen, Mengyao Zhang, Zhenghao Zhao, Junyan Dan, Xiaohong Song, Haiyan Mao, Shengyuan Huo, Hao Yan, Yanjun Zhang (), Xinghuan Wang () and Lihua Hou ()
Additional contact information
Shipo Wu: Beijing Institute of Biotechnology
Jianying Huang: Zhongnan Hospital of Wuhan University
Busen Wang: Beijing Institute of Biotechnology
Jianhua Li: Zhejiang Provincial Center for Disease Control and Prevention
Jianyuan Wu: Zhongnan Hospital of Wuhan University
Zhe Zhang: Beijing Institute of Biotechnology
Lin Luo: Zhongnan Hospital of Wuhan University
Jinlong Zhang: Beijing Institute of Biotechnology
Nan Huo: Beijing Institute of Biotechnology
Jianglan Long: Beijing Institute of Biotechnology
He Huang: Beijing Institute of Biotechnology
Zhengshan Chen: Beijing Institute of Biotechnology
Mengyao Zhang: Beijing Institute of Biotechnology
Zhenghao Zhao: Beijing Institute of Biotechnology
Junyan Dan: Beijing Institute of Biotechnology
Xiaohong Song: Beijing Institute of Biotechnology
Haiyan Mao: Zhejiang Provincial Center for Disease Control and Prevention
Shengyuan Huo: Beijing Institute of Biotechnology
Hao Yan: Zhejiang Provincial Center for Disease Control and Prevention
Yanjun Zhang: Zhejiang Provincial Center for Disease Control and Prevention
Xinghuan Wang: Zhongnan Hospital of Wuhan University
Lihua Hou: Beijing Institute of Biotechnology

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Both SARS-CoV-2 mRNA and mucosal vaccines induce protective immunity against COVID-19 but showed different immune profiles. We conducted a longitudinal head-to-head analysis of the safety and immunogenicity of the aerosolized adenovirus-vectored and mRNA COVID-19 vaccines. 450 participants were enrolled and randomly assigned into three groups to be vaccinated with an aerosolized Ad5-vectored bivalent vaccine (wild-type and BA.5, Ad5-CoV5T), an intramuscular bivalent mRNA vaccine (mbO5), and an aerosolized wild-type Ad5-vectored vaccine (Ad5-nCoV). The primary outcomes were adverse reactions within 28 days and anti-XBB.1.5-specific neutralizing antibody titers at day 28 after vaccination. The secondary outcome assessed safety within 30 min, serious adverse event within 6 months, and the persistence of anti-XBB.1.5/BA.5-specific neutralizing antibodies during the 6 months. Both the vaccines were well tolerated, but participants vaccinated with mbO5 reported more adverse reactions (73.3% mbO5 vaccinees vs. 28.7% aerosol vaccinees). No serious adverse events were recorded. The Ad5-CoV5T vaccine induced a superior anti-XBB.1.5-specific neutralizing titer than Ad5-nCoV at day 28 (geometric mean titer ratio of 1.48, 95% CI 1.12–1.97), while the mbO5 vaccine induced the highest antibody titer. The neutralizing antibodies were declined at month 6 and were similar across the three groups. In the pre-specified exploratory analysis, the mbO5 and the aerosolized vaccines induced comparable antigen-specific memory B cells but the latter stimulated higher frequency of IgA isotype and higher expression of CXCR3. This trial met the main hypothesis; the findings may provide insights for the development of the next-generation COVID-19 vaccines. Clinical Trials.gov identifier: NCT05886790.

Date: 2025
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DOI: 10.1038/s41467-025-62698-7

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