Safety and Immunogenicity of Heterologous and Homologous Boosting with Orally Aerosolized or Intramuscular Ad5-nCoV and Inactivated Vaccines in Children and Adolescents: A Randomized, Open-Label, Parallel Controlled, Single-Center Study

Background: Heterologous booster immunization with orally administered aerosolized Ad5-nCoV has been proven to be safe and highly immunogenic in adults. Here, we aimed to assess the safety and immunogenicity of heterologous booster immunization with orally administered aerosolized Ad5-nCoV in children and adolescents aged 6–17 years who had received two doses of inactivated vaccine.Methods: We performed a randomized, open-label, parallel-controlled study to assess the safety and immunogenicity of heterologous booster immunization with aerosolized (0.1 ml) or intramuscular Ad5-nCoV (0.3 ml) and homologous booster immunization with inactivated vaccines (ICVs) in children 6–12 years of age and adolescents 13–17 years of age who received two doses of inactivated vaccines (ICVs) > 3 months earlier. Adverse events within 28 days after the booster vaccination were used as the primary outcome for safety evaluation. Plasma neutralizing antibodies (NAbs) on day 28 after the booster were used as the primary endpoint for immunogenicity. This study was registered at ClinicalTrial.gov, NCT05330871.Findings: Between April 17 and May 28, 436 participants were screened and 360 were enrolled. Of them, 180 were children, and 180 were adolescents. Overall vaccine-related adverse events (VRAEs) were reported in 19.55% (43/220) of aerosolized Ad5-nCoV, 51.43% (36/70) of intramuscular Ad5-nCoV, and 21.43% (15/70) of ICV within 28 days after immunization. Heterologous and homologous booster vaccination elicited a significantly increased neutralizing antibody (NAb) response compared to the antibody response before vaccination on day 28 after booster vaccination. The GMTs of NAb in aerosolized or intramuscular Ad5-nCoV participants were significantly higher than the GMTs in ICV-boosted participants. Heterologous and homologous booster vaccination elicited a limited IFN-γ-secreting T-cell response in children. Heterologous aerosolized Ad5-nCoV boosted the IFN-γ-secreting T-cell response in adolescents.Interpretation: Our study shows that a heterologous booster with aerosolized Ad5-nCoV is safe and highly immunogenic in children and adolescents.Trial Registration Details: ClinicalTrial.gov, NCT05330871.Funding Information: This work was funded by National Key R&D Program of China, No.2021YFC0866200. CanSino Biologics provided investigational vaccines and Continuous Vapouring System for this study. We would like to thank Maijuan Ma of the Beijing Institute of Microbiology and Epidemiology for his useful feedback that improved this paper.Declaration of Interests: J-BG, H-TH, XW and HL are employees of CanSino Biologics. All the other authors declare no competing interests.Ethics Considerations: The study protocol and informed consent were reviewed and approved by the Ethical Committee of PLA Army General Hospital and Hunan Provincial Center for Disease Control and Prevention, China (S2021-001-03). Written informed consent was obtained from the children's and adolescents' parents or guardians.