Mucosal Immunization of Cynomolgus Macaques with Adenoviral Vector Vaccine Elicits Neutralizing Nasal and Serum Antibody to Several SARS-CoV-2 Variants

Abstract

The emergence of SARS-CoV-2 variants continues to be a major obstacle for controlling the global pandemic. Despite the currently authorized SARS-CoV-2 vaccines ability to reduce severe disease and hospitalization, new immunization strategies are needed that enhance mucosal immune responses, inhibit community transmission, and provide protection against emerging variants. We have developed a mucosally delivered, non-replicating recombinant adenovirus vector (rAd5) vaccine, that has proven efficacy in the clinic against other respiratory viruses [1]. Here we evaluated the immunogenicity of three candidate SARS-CoV-2 vaccines in cynomolgus macaques that contained spike (S) and/or nucleocapsid (N) from either the Wuhan or the beta variant to select a candidate for future clinical development. Mucosal immunization with the Wuhan specific S vaccine (ED90) induced significant cross-reactive serum IgG responses against to Wuhan, beta, gamma and delta lineages, and generated substantial serum neutralizing activity. In nasal samples, ED90 immunization induced 1000-fold increases in IgA to all variants of concern tested and had neutralizing activity against Wuhan and delta. While immunization with the beta specific vaccine (ED94) enhanced IgG and IgA responses to homologous beta variant S and RBD, this approach resulted in less cross-reactive responses to other variants in the serum and nasal passages compared to ED90. As ED90 immunization induced the most robust cross-reactive systemic and mucosal antibody responses, this candidate was chosen for future clinical development.

Adenoviral-Based Vaccine Elicits Robust Systemic and Mucosal Cross-Reactive Responses in African Green Monkeys and Reduces Shedding after SARS-CoV-2 Challenge

“…Here we report rAd5 SARS-CoV-2 vaccines are highly immunogenic in AGMs and elicit cross-reactive functional antibody responses in the circulation and mucosal surfaces, confirming our previous immunogenicity results in Cynomolgus macaques [20]. We observed that all rAd5 vaccine candidates tested were able to generate cross-reactive antibody responses to mismatched antigens.…”

“…3B). This result confirmed our earlier findings in a Cynomolgus macaque model, that mucosal administration of ED90 generates cross-reactive functional antibody in the serum [20]. Furthermore, the neutralizing serum antibody responses observed were similar to what has been reported with other adenoviral and mRNA vaccines [21,22].…”

Adenovirus type 5 SARS-CoV-2 vaccines delivered orally or intranasally reduced disease severity and transmission in a hamster model

“…Furthermore, future work should include challenging mucosally vaccinated hamsters with the Delta and Omicron variants and other variants of concern. In terms of future human studies, a clinical trial with the vaccine construct used in this hamster study is predicted to improve the mucosal antibody response rate because studies in nonhuman primates have shown improved antibody responses compared to the original vaccine tested in humans (30).…”

Modeling the potential economic benefits of an oral SARS-CoV-2 vaccine during an outbreak of COVID-19

“…The first assumes that that the oral vaccine is equally effective as the existing mix of intramuscular vaccines and performs similarly against transmission, therefore isolating only uptake changes as translating to health impact. The second scenario, based upon clinical evidence, presents a scenario where the oral vaccine is an additional 50% effective against transmission and any infection compared with the existing mix of intramuscular vaccines in addition to the increased uptake rates observed in scenario 2 when compared with intramuscular vaccines [16,17].…”

“…Additionally, in the primary intervention scenario, we assume that an oral vaccine would offer the same protection against transmissibility of COVID-19 as the intramuscular vaccines. To take into account early clinical evidence, we also model a second intervention scenario where marginal oral vaccine cases exhibit a 50% reduction the relative risk of any infection compared with intramuscular vaccines [16,17].…”