Balanced T and B cell responses are required for immune protection against Powassan virus in virus-like particle vaccination

Powassan virus (POWV) is a tick-borne pathogen for which humans are an incidental host. POWV infection can be fatal or result in long-term neurological sequelae; however, there are no approved vaccinations for POWV. Integral to efficacious vaccine development is the identification of correlates of protection, which we accomplished in this study by utilizing a murine model of POWV infection. Using POWV lethal and sub-lethal challenge models, we show that (1) robust B and T cell responses are necessary for immune protection, (2) POWV lethality can be attributed to both viral- and host-mediated drivers of disease, and (3) knowledge of the immune correlates of protection against POWV can be applied in a virus-like particle (VLP)-based vaccination approach that provides protection from lethal POWV challenge. Identification of these immune protection factors is significant as it will aid in the rational design of POWV vaccines. [Display omitted] •Robust B and T cell responses are necessary for protection against POWV•POWV lethality is comprised of both viral- and host-mediated mechanisms•A VLP-based vaccine protects against lethal POWV challenge Stone et al. describe Powassan virus (POWV) adaptive immune protection in a murine model of infection. This understanding culminates in a vaccination approach that elicits protective adaptive immune responses against POWV morbidity and mortality. These findings will aid in fulfilling the unmet need for rational design of POWV vaccinations.