Safety, Immunogenicity and Efficacy of Heterologous Boost with an Aerosolized Ad5-nCoV after Two-Dose Priming with Inactivated COVID-19 Vaccines in Adults: A Multicenter, Open-Label Trial

Background: The aerosolized Ad5-nCoV is the first licensed mucosal respiratory vaccine against SARS-CoV-2 in the word. The safety and efficacy of the aerosolized Ad5-nCoV in large population has not been reported yet.Methods: This is a multicenter, open-label trial, aiming to evaluate the safety and immunogenicity with aerosolized Ad5-nCoV in health adults ≥18 years of age, who had received two priming doses of Inactivated COVID-19 vaccine. Of them, at least 30% were equal to or over 60 years of age. This study contains a non-randomized safety cohort, and a randomized, parallel-controlled immunogenicity sub-cohort. The primary endpoints were the incidence of adverse reactions following the booster vaccination with aerosolized Ad5-nCoV and the levels of neutralizing antibodies at day 28 post-boost.Findings: A total of 10059 participants who were boosted with the aerosolized Ad5-nCoV were involved in the safety analysis, while 416 participants were involved immunogenicity analysis. Adverse reactions were reported by 1299 (12.9%) participants within 28 days after receiving the booster vaccination with aerosolized Ad5-nCoV, but most of the adverse reactions reported were mild to moderate in severity. Participants receiving aerosolized Ad5-nCoV showed significantly higher level of the neutralizing antibodies against omicron BA.4/5 than those receiving inactivated vaccine at day 28 (107.7[95%CI 88.8-130.7] versus 17.2[95%CI 16.3-18.2]). The overall relative efficacy of the aerosolized Ad5-nCoV versus inactivated vaccine was 35.1% (95%CI 23.0-45.2) at about 12 months after the immunization.Interpretation: The heterologous booster regimen with aerosolized Ad5-nCoV is safe and highly immunogenic, and provided a long-term protection against Omicron variants (ClinicalTrials.gov, NCT05204589).Trial Registration: The study is registered at ClinicalTrials.gov, NCT05204589.Funding: This work is funded by National Natural Science Foundation of China (grant number 82173584 and 82222062), Jiangsu Provincial Science Fund for Distinguished Young Scholars (grant number BK20220064), and Jiangsu Provincial Key Project of Science and Technology Plan (grant number BE2021738). CanSino Biologics Inc. contributed in providing investigational vaccines and the vapouring unit (Aerogen, Galway, Ireland) integrated by Suzhou Weiqi Biological Technology (Suzhou City, China) were used for this study.Declaration of Interest: Jin-Bo Gou, and Tao Zhu are employees of CanSino Biologics. All the other authors declare no competing interests.Ethical Approval: The trial was reviewed and approved by the Scientific Review Committee and the Ethics Committee of Jiangsu Provincial Center for Disease Control and Prevention. All the participants provided written informed consent before enrollment. The trial adhered to the principles of the Declaration of Helsinki, International Council for Harmonisation-Good Clinical Practice guidelines, and local guidelines.