Safety and Immunogenicity of Heterologous Boost Immunisation With an Aerosolized Ad5-nCoV After Two-Dose Priming With an Inactivated SARS-CoV-2 Vaccine CoronaVac in Adults: A Randomised, Open-Label, Parallel-Control Trial

Background: A third dose of homologous or heterologous COVID-19 vaccine is suggested to use in individuals who were previously primed with two doses of inactivated COVID-19 vaccine.Methods: We conducted a randomised, open-label, parallel-controlled trial to evaluate the safety and immunogenicity of heterologous boost immunisation with an aerosolized adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) after two-dose priming with an inactivated SARS-CoV-2 vaccine CoronaVac in adults aged ≥18 years. Eligible participants were randomly assigned at a ratio of 1:1:1 to receive a heterologous boost vaccination with low-dose aerosolized Ad5-nCoV, or high-dose aerosolized Ad5-nCoV, or a homologous intramuscular vaccination with CoronaVac. Only laboratory staff were masked to group assignment. The primary endpoint for safety was the incidence of adverse reactions within 14 days after the booster dose. The primary endpoint for immunogenicity was the geometric mean titres (GMTs) of neutralising antibodies against live SARS-CoV-2 virus at 14 days after the booster dose. This study was registered with Clinicaltrials.gov, number NCT05043259.Findings: A total of 420 participants were involved, with 140 per group. Participants receiving low-dose or high-dose aerosolized Ad5-nCoV reported significantly lower occurrences of adverse reactions than those receiving CoronaVac did within 14 days after the vaccination (p<0·0001). The low-dose and high-dose aerosolized Ad5-nCoV elicited GMTs of SARS-CoV-2 neutralising antibodies of 744·4(95%CI 520·1, 1065·6) and 714·1(479·4, 1063·7), respectively, at days 14, and 1937·3(1466·9, 2558·4) and 1350·8(952·6, 1915·3), respectively, at days 28, which were significantly higher than those (78·5[60·5, 101·7] at days 14 and 73·5[52·3, 103·3] at days 28) elicited by homologous boosting with CoronaVac, with p values<0·0001. GMTs of neutralising antibody titres against the SARS-CoV-2 B.1.617.2 (delta) variant among the aerosolized Ad5-nCoV recipients were also higher than that observed in the CoronaVac recipients. Th1-skewed cellular immune responses were found in the aerosolized Ad5-nCoV groups. The dose-response relationships of immune responses associated with the dosage of aerosolized Ad5-nCoV as a booster were not identified.Interpretation: We found that a heterologous boost immunisation with an aerosolized Ad5-nCoV is safe and highly immunogenic in adults who have received two-dose inactivated COVID-19 vaccine CoronaVac as the primary series vaccination.Trial Registration Details: This study was registered with Clinicaltrials.gov, number NCT05043259.Funding Information: This work is funded by National Natural Science Foundation of China, and Jiangsu Provincial Key Research and Development Program. CanSino Biologics Inc. contributed in providing investigational vaccines and Continuous Vapouring System for this study.Declaration of Interests: Hai-Tao Huang, Jin-Bo Gou, Wei-Xue Si, Xue Wang, Xiao-Long Zhao, and Tao Zhu are 494 employees of CanSino Biologics. All the other authors declare no competing interests.Ethics Approval Statement: The trial protocol and informed consent were reviewed and approved by Research Ethics Committee of Jiangsu Provincial Center for Disease Control and Prevention. The written informed consent was obtained from each participant before inclusion. This trial was conducted following the principles of the Declaration of Helsinki, ICH-Good Clinical Practice guideline and local guidelines.