Equine herpesvirus type 1 (EHV-1) outbreaks, including its neurological form equine herpesvirus myeloencephalopathy (EHM), continue to occur frequently in the US despite widely used vaccination. EHV-1 is often transmitted to foals early in life by their dams or herd mates. Once infected, foals remain latently infected and can act as virus reservoirs. Several EHV vaccines are available. Foals are typically first vaccinated against EHV-1 between 4-8 months of age. However, many foals have been latently infected by that time. Currently, neonatal vaccines to prevent early-in-life infection of the virus are unavailable. Neonatal vaccination is a challenging task because the immune system of young foals reacts differently than that of adult horses. In a previous Zweig project, we have used a novel neonatal EHV-1 vaccine developed in our group for vaccinating neonatal foals against EHV-1. Our neonatal vaccine targets innate immune pathways to induce B-cell activation, contrary to conventional EHV vaccine triggering T-cell immunity to induce antibodies. Our preliminary data support that our novel neonatal EHV-1 vaccine reduces fever, EHV-1 shedding and viremia after challenge infection. In addition to protection from severe disease, the vaccinated foals produced a faster and stronger antibody responses against EHV-1 and an early B-cell memory against the pathogen. We hypothesize that our recombinant EHV-1 glycoprotein-based vaccine (= neonatal vaccine) is essential for inducing B-memory cells in foals by triggering a ‘neonatal’ B-cell activation pathway and is therefore more efficacious than conventional vaccination. To test this hypothesize, we want to perform two aims. Aim 1 is to compare efficacy of our neonatal EHV-1 glycoprotein-based vaccine to a commercial vaccine (conventional vaccine. Neonatal foals (n=4 per group) will be vaccinated after birth and a non-vaccinated control group will be included. All three groups of foals will be vaccinated at 4 and 5 months of age with a conventional vaccine and will then be challenged by an experimental EHV-1 challenge infection at 7-8 months of age to compare the efficacy of the neonatal vaccination versus conventional vaccination at birth. Aim 2 will evaluate foal B-cell responses in foals by analyzing B-cell activation, proliferation, and maturation in response to vaccination and EHV-1 infection. We will measure IgM/IgD positive B-cells as a marker of B-cell activation, cell proliferation via CSFE staining, and IgG positive plasmablasts as markers for maturation to develop a better understanding of B-cell differentiation and development in foals during the first year of life. The long-term goal of this project is to prevent the transmission of EHV-1 to young foals through evidence-based vaccine design. Overall, the project is relevant to the prevention of disease induced by EHV-1 by increasing immunity and protection in the equine population and reducing severe neurological and abortion outbreaks in the US.