Effects of natural killer cell depletion on innate and adaptive immune responses to COVID mRNA vaccination

This study assessed the role that natural killer (NK) cells play in a murine model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike mRNA vaccination. Flow cytometric analyses revealed that mRNA vaccination results in recruitment and maturation of NK cells in the spleen. Primed (CD27+ CD11b+) NK cells increased from 0.35% of all CD45+ cells pre-vaccination to 2.44% at 4 d post-vaccination, while terminally mature (CD27- CD11b+) NK cells increased from 0.85% of all CD45+ cells pre-vaccination to 3.91% at 7 d post-vaccination. We next evaluated Spike mRNA and protein expression, circulating cytokines, and Spike-specific antibody and T cell responses in mice depleted of NK cells before primary or booster vaccination. Depleting NK cells prior to mRNA vaccination resulted in decreased serum levels of IL-1β and IL-6 at 6 and 24 h, respectively, after vaccination. NK depletion also caused a significant reduction in Spike mRNA expression in draining lymph nodes, with greater than 5-fold reductions in Spike mRNA copies/μL, as measured by digital droplet PCR. Three weeks post-vaccination with 1 μg mRNA LNP, Spike-specific CD25+ CD4 T cells were also significantly decreased. Despite these decreases in early pro-inflammatory cytokines, Spike mRNA expression, and Spike-specific CD4 T cells, NK depletion had little impact on Spike-specific antibody levels at 1 and 6 mo following single vaccination, as well as at 3 wk after booster vaccination. Together, these data suggest that NK cells contribute to early inflammatory responses induced by mRNA vaccination, yet their depletion does not impair the magnitude of long-term adaptive immune responses induced by this platform.