Inactivated influenza vaccines have struggled to provide consistent protection in older individuals. Circumventing immune senescence, an aging of the immune response characterized by weak humoral responses to vaccines, and unchecked inflammation during infection require novel immunization strategies. Plant-based virus-like particles (VLPs) bearing recombinant hemagglutinin proteins have been shown to provide protection in older animals in preclinical challenge studies, despite eliciting relatively low or absent humoral responses. The nature of the cellular response induced by these vaccines and its evolution during infection have not yet been fully characterized, however. Using a murine model that recapitulates features of human immune senescence, we assessed T cell responses to vaccination with a VLP bearing the hemagglutinin of H1N1/California 07/2009 (H1-VLP) before and after challenge in young and aged BALB/c mice (2 and 18 mo old, respectively). We report that two i.m. doses of H1-VLP (3 μg) vaccine 21 d apart generated H1-specific Th1 and Th2 cells associated with the prevention of prolonged pulmonary inflammation and mortality in both adult and aged mice. While investigating the regulation of cellular immunity, we identified a unique IL-1R1+ tissue-adapted regulatory T cell population in the lungs of both H1-VLP-vaccinated adult and aged mice, suggesting a novel regulatory T cell population associated with vaccine-mediated protection. Collectively, this study provides preclinical evidence that the plant-based H1-VLP vaccine may act, in part, by preventing exacerbated immune responses against influenza A.
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