Skin vaccination unravels novel intravascular CD8 memory T cell population which protects against influenza

Summary: Abstract Body: Respiratory viral pathogens like influenza A and SARS-CoV-2 pose significant global challenges, with vaccination efforts hindered by rapid viral evolution and a focus on antibody generation. We explored epidermal disruption (e.d.) as an alternative vaccination method, which generates protective CD8+ T memory cells in the lung vasculature. Unlike intramuscular (i.m.), e.d. vaccination generates CD8+ T cells that home to both the skin and lungs. Using a non-replicating poxvirus (MVANP) delivered via e.d., we tested its ability to protect against a lethal dose of PR8 (H1N1) influenza A. A single e.d. dose demonstrated superior protection, with 100% survival, compared to 40% survival of i.m animals. E.d. vaccinated mice showed lower viral loads in the lung and robust protection independent of antibodies, B cells, and CD4+ T cells, however this protection was abrogated upon CD8+ T cell depletion. Longitudinal analysis revealed these protective cells are not lung parenchyma resident but are lung-vasculature-residing memory cells, and they extravasate into parenchyma upon infection, initially involving CD8+ T cells already present in the vasculature (0-3 days). Depletion of CD8+ T cells before infection (day -1) abolished protection, while depletion at day 3 had a much less effect, highlighting the importance of the first wave, rapid acting, lung-vasculature-residing, CD8+ T cells. This population has a transcriptional profile distinct from central and effector memory cells and exhibits durable immune memory (up to 80 days post-immunization) and a robust protection against immune challenge up to 120 days post-immunization, compared to waning natural sublethal immunization. Our approach to immunization may offer lasting protection against respiratory pathogens and inform future vaccine strategies. Nicoletta Ninkovic¹, Jason B. Williams¹, Tian Tian¹, N P. Smith², Timothy Pan¹, Alexander Kley¹, Jiang Zhang¹, Bharat Rajmalani¹, Elizabeth Rotrosen¹, Alexandra C. Villani², Thomas S. Kupper¹ 1. Department of Dermatology, Brigham and Women's Hospital, Boston, MA, United States. 2. Department of Medicine, Massachusetts General Hospital, Boston, MA, United States. Translational Studies: Preclinical