Variable translatability represents a major criticism of the use of mouse models for preclinical research. Lack of exposure to most endogenous murine pathogens results in natural immune responses of specific pathogen free (SPF) lab mice to more closely resemble that of newborns rather than adult humans. Recently, the effects of prior infection exposure (PIE) on immune maturation and responses have been increasingly explored in mice. Here, we employed a PIE model where BALB/c mice underwent sequential subclinical infection with four pathogens at two-week intervals: 1) MHV-68, a gammaherpesvirus, 2) MCMV, a betaherpesvirus, 3) influenza virus, and 4) Heligmosomoides polygyrus, a murine intestinal nematode. Four-to-12 weeks following H. polygyrus infection, mice were sacrificed, spleens were collected for flow cytometric analysis, and lungs were collected for histological evaluation. Compared to SPF mice, PIE spleens demonstrated increased proportions of CD4+ and CD8+ T effector memory cells. In the lungs, PIE induced the formation of bronchus-associated lymphoid tissue and increased infiltration of CD4+ and CD8+ T cells. Following vaccination against SARS-CoV-2 with either a protein subunit-based (S2P) or inactivated (iCoV2) vaccine, iCoV2-, but not S2P-, vaccinated PIE mice demonstrated significantly reduced serum neutralizing antibodies compared to SPF mice. Following infection with SARS-CoV-2-MA10, PIE mice showed a mild reduction in mortality, weight loss, and lung titers, and a significant increase in lung T cell infiltration compared to SPF mice. These data indicate that PIE results in adaptive immune maturation but has a variable effect on SARS-CoV-2-specific vaccine responses and clinical outcomes in mice.

This work was supported by the NIH (K01OD026529, T32AI007151, U19AI100625, U19AI09680), an AAI Careers in Immunology Fellowship Award, an UNC School of Medicine Junior Investigator Development Award, and a NCTraCS and Emerging Challenges in Biomedical Research COVID Pilot Award.

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