Mucosal Adenoviral-vectored Vaccine Boosting Durably Prevents XBB.1.16 Infection in Nonhuman Primates
Authors: Gagne Matthew , Flynn Barbara J. , Andrew Shayne F. , Flebbe Dillon R. , Mychalowych Anna , Lamb Evan , Davis-Gardner Meredith E. , Burnett Matthew R. , Serebryannyy Leonid A. , Lin Bob C. , Pessaint Laurent , Todd John-Paul M. , Ziff Zohar E. , Maule Erin , Carroll Robin , Naisan Mursal , Jethmalani Yogita , Case James Brett , Dmitriev Igor P. , Kashentseva Elena A. , Ying Baoling , Dodson Alan , Kouneski Katelyn , Doria-Rose Nicole A. , O’Dell Sijy , Godbole Sucheta , Laboune Farida , Henry Amy R. , Marquez Josue , Teng I-Ting , Wang Lingshu , Zhou Qiong , Wali Bushra , Ellis Madison , Zouantchangadou Serge , Ry Alex Van , Lewis Mark G. , Andersen Hanne , Kwong Peter D. , Curiel David T. , Foulds Kathryn E. , Nason Martha C. , Suthar Mehul S. , Roederer Mario , Diamond Michael S. , Douek Daniel C. , Seder Robert A. 
Published: November 2023

Waning immunity and continued virus evolution have limited the durability of protection from symptomatic infection mediated by intramuscularly (IM)-delivered mRNA vaccines against COVID-19 although protection from severe disease remains high. Mucosal vaccination has been proposed as a strategy to increase protection at the site of SARS-CoV-2 infection by enhancing airway immunity, potentially reducing rates of infection and transmission. Here, we compared protection against XBB.1.16 virus challenge 5 months following IM or mucosal boosting in non-human primates (NHP) that had previously received a two-dose mRNA-1273 primary vaccine regimen. The mucosal boost was composed of a bivalent chimpanzee adenoviral-vectored vaccine encoding for both SARS-CoV-2 WA1 and BA.5 spike proteins (ChAd-SARS-CoV-2-S) and delivered either by an intranasal mist or an inhaled aerosol. An additional group of animals was boosted by the IM route with bivalent WA1/BA.5 spike-matched mRNA (mRNA-1273.222) as a benchmark control. NHP were challenged in the upper and lower airways 18 weeks after boosting with XBB.1.16, a heterologous Omicron lineage strain. Cohorts boosted with ChAd-SARS-CoV-2-S by an aerosolized or intranasal route had low to undetectable virus replication as assessed by levels of subgenomic SARS-CoV-2 RNA in the lungs and nose, respectively. In contrast, animals that received the mRNA-1273.222 boost by the IM route showed minimal protection against virus replication in the upper airway but substantial reduction of virus RNA levels in the lower airway. Immune analysis showed that the mucosal vaccines elicited more durable antibody and T cell responses than the IM vaccine. Protection elicited by the aerosolized vaccine was associated with mucosal IgG and IgA responses, whereas protection elicited by intranasal delivery was mediated primarily by mucosal IgA. Thus, durable immunity and effective protection against a highly transmissible heterologous variant in both the upper and lower airways can be achieved by mucosal delivery of a virus-vectored vaccine. Our study provides a template for the development of mucosal vaccines that limit infection and transmission against respiratory pathogens.

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