Dirty mice better recapitulate key features of mRNA vaccine immunogenicity observed in humans

Although specific-pathogen-free (SPF) mice have traditionally been used to test candidate vaccines, recent work has demonstrated that "dirty" mice with broad microbial exposure more appropriately recapitulate human immune responses. Using a dirty mouse model in which lab mice are co-housed with pet store mice, we modeled SARS-CoV-2 mRNA vaccine responses in dirty and SPF mice. In this study, dirty mice showed reduced serum spike-binding antibody titers after prime vaccination and required a second booster dose to reach SPF-level spike antibody titers. Additionally, spike antibody titers waned faster in dirty mice in the 5 months following prime vaccination, while the neutralizing activity of these antibodies was reduced against Omicron variants, an effect that has also been observed in vaccinated humans. We further investigated the seasonality and consistency of pathogens in co-housed dirty mice, as well as the impact of serial microbial exposure on our animal model system. We found that pathogen exposure and T cell activation remained consistent over time and that a single co-housing event was sufficient to provide broad microbial exposure. This work demonstrates that the dirty mouse co-housing system is a promising, translationally representative approach to screen candidate mRNA vaccines for efficacy and durability prior to human clinical trials. IMPORTANCE: The development of mRNA vaccines during the COVID-19 pandemic dramatically reduced hospitalization and death rates for infected individuals. However, booster vaccinations were required to achieve high antibody titers, and protection waned over time. Our research leveraged a "dirty" mouse model to test whether SARS-CoV-2 mRNA vaccinations in animals with previous microbial exposure better modeled human immune responses. We found that, unlike standard SPF mice, dirty mice also require a booster vaccination to reach maximum antibody titers and experience waning serum antibody titers over time. We propose this platform as a future model for robust preclinical mRNA vaccine testing to improve immunogenicity and durability.