Intranasal Vaccination with Murine Cytomegalovirus Expressing Respiratory Syncytial Virus Antigens Promotes Tissue-resident Memory CD8+ T cells
Graham, Barney S
Cytomegalovirus (CMV) vectors are a promising vaccine strategy aimed at eliciting effector CD8+ T cells. CMV-based vaccines have been shown to mediate protection against viral pathogens including simian immunodeficiency virus and Ebola virus, and produce responses that delay tumor growth in melanoma and prostate cancer in animal models. CMV infection generates robust cellular and humoral immune responses. In addition to conventional CD8+ T cell memory responses that contract following acute T cell expansion resulting in a low-level stable memory population, CMV infection generates populations of CD8+ T cells that continue to accumulate throughout latent infection termed “inflationary memory.” These inflationary memory cells have high avidity T cell receptors, an effector phenotype, and remain functional throughout chronic infection providing the basis for highly effective and durable T cell-mediated immunity.For this dissertation, I engineered murine CMV (MCMV) to express the M and M2 proteins of respiratory syncytial virus (RSV). When expressed in MCMV, the M-specific CD8+ T cell population was inflationary and the M2-specific CD8+ T cell population was conventional. Intranasal vaccination generated a robust tissue-resident (TRM) effector and effector memory CD8+ T cell population that was absent in intraperitoneally vaccinated mice. This population of TRM was sustained at a high level through twenty-four weeks post-vaccination in mice vaccinated with the inflationary M epitope (MCMV-M). In contrast, mice vaccinated with MCMV expressing the conventional M2 epitope (MCMV-M2) generated a TRM population that waned over time. Co-administration of MCMV-M and MCMV-M2 had no impact on the M-specific CD8+ T cell response, but did decrease the M2-specific CD8+ T cell response during acute time points. All vaccinations led to decreased viral loads compared to RSV-naïve controls, but intranasal vaccination with MCMV-M elicited sustained TRM resulting in earlier T cell responses, viral clearance, and cytokine secretion after RSV challenge. Our findings using this novel approach of intranasal administration of MCMV emphasizes the importance of vaccination route for the generation of effective immune responses at sites of vulnerability, and the potential value of combining the local induction of TRM with inflationary properties as a general vaccination strategy for pathogens that require CD8+ T cell-mediated immunity.
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