Intranasal unadjuvanted LcrV boosts parental Yersinia OMV primed lung immunity against pneumonic plague in mice

Pneumonic plague remains a high-consequence respiratory disease, highlighting the need for vaccines that induce durable lung-localized immunity. We show that intramuscular prime-boost vaccination with Alum-absorbed OMV₄₆-LcrV (OMV₄₆-LcrV/Alum) is safe but provides limited long-term protection against respiratory Yersinia pestis challenge in mice. To enhance lung immunity, we deliver an adjuvant-free intranasal LcrV "spike" following IM OMV₄₆-LcrV/Alum priming. This "prime-spike" regimen is well tolerated and confers complete short- and long-term protection against high-dose pulmonary Y. pestis challenge. The approach increases lung resident memory B cells, including antibody-secreting cells, and resident memory T cells with elevated Interferon-γ, Interleukin-17A, and Interleukin-4 production. These localized memory responses contribute to improved protection, demonstrating the promising potential of prime-spike immunization for combating pneumonic plague.