Pooled Analysis of the Effect of Pre-Existing Ad5 Neutralizing Antibodies on the Immunogenicity of Adenovirus Type 5 Vector-Based COVID-19 Vaccine from Eight Clinical Trials

<b>Background</b>: Pre-existing adenovirus immunity restricts the utilization of adenovirus-vectored vaccines. The current study aims to conduct a pooled analysis of eight clinical trials to evaluate the influence of pre-existing Ad5 neutralizing antibodies on immunogenicity of Ad5-nCoV. <b>Methods</b>: The primary outcome indicator of this pooled analysis is the geometric mean titers (GMTs) of live SARS-CoV-2 NAbs against the wild-type strain on day 28 post-vaccination. Participants were divided into two cohorts: an adolescent cohort comprising individuals aged 6-17 years and an adult cohort with individuals aged 18 years and older. Within each cohort, individuals were further categorized into three subgroups based on their Ad5-nCoV vaccination schedules: one subgroup received a single intramuscular dose as the primary regimen (Ad5-IM-prime), another received an intramuscular dose as the heterologous prime-boost regimen (Ad5-IM-boost), and the last subgroup received an aerosolized dose as the heterologous prime-boost regimen (Ad5-IH-boost). <b>Results</b>: A total of 3512 participants were included in this pooled analysis. In the Ad5-IM-prime subgroup, there were 1001 adolescents and 1450 adults; in the Ad5-IM-boost subgroup, there were 65 adolescents and 396 adults; and in the Ad5-IH-boost subgroup, there were 207 adolescents and 393 adults. In the adult cohort, the GMTs of NAbs against wild-type SARS-CoV-2 on day 28 post-vaccination for the Ad5-IM-prime, Ad5-IM-boost, and Ad5-IH-boost subgroups were 35.6 (95% CI: 32.0, 39.7), 358.3 (95% CI: 267.6, 479.6), and 2414.1 (95% CI: 2006.9, 2904.0), respectively, with negative (less than 1:12) pre-existing NAb titers compared to 10.7 (95% CI: 9.1, 12.6), 116.9 (95% CI: 84.9, 161.1), and 762.7 (95% CI: 596.2, 975.8), respectively, with high (greater than 1:1000) pre-existing NAb titers. A similar trend was observed in the adolescent cohort, where pre-existing immunity was found to reduce the peak of live SARS-CoV-2 Nabs post-vaccination. <b>Conclusions</b>: Regardless of whether Ad5-nCoV is administered as a primary vaccination regimen or as a heterologous prime-boost strategy, a negative impact on immunogenicity can still be observed in the presence of high pre-existing immunity. However, when primary immunization is achieved with inactivated COVID-19 vaccines, aerosol inhalation can significantly enhance the immunogenicity of Ad5-nCoV compared to intramuscular injections of Ad5-nCoV as a booster.