Ongoing neurological EHV-1 outbreaks in the US support the increase in morbidity and mortality of disease induced by current EHV-1 strains despite widely used vaccination. EHV-1 is frequently transmitted early in life. Once infected, foals or weanlings remain latently infected and can act as virus reservoirs. Currently, neonatal vaccines to prevent early-in-life infection are unavailable. Neonatal vaccination, in general, is a challenging task because the immune system of young foals reacts differently than that of adult horses. Our preliminary data support the use of a neonatal EHV-1 vaccine targeting memory B-cell activation at birth. A previous trial using our novel neonatal EHV-1 vaccine was supported by the Harry M. Zweig Memorial Fund for Equine Research. The project ended in 2015. The results have recently been published and show proof-of-principle that our neonatal EHV-1 vaccine induces partial protection from disease, a faster and stronger antibody responses against EHV-1 and B-cell memory against the pathogen. Our hypothesis is that vaccination of neonatal foals with IL-4/EHV-1 antigens will induce EHV-1 specific B-cell memory thereby priming the immune system of young foals to an earlier onset of systemic antibody responses after EHV-1 challenge or vaccination Aim 1 is to further improve the concept of neonatal vaccination and to test if IL-4 is essential for neonatal memory B-cell activation. We will analyze if neonatal vaccination with IL-4/EHV-1 antigen primes the immune system of the young vaccinated foal to respond effectively to conventional vaccination at 3 months of age, a time when foals typically mount poor antibody responses to these vaccines. Aim 2 is to evaluate neonatal memory B-cell induction, expression profiles, and possible differences from adult horse memory B-cells. We will also further analyze the influence of IL-4 on EHV-1 specific memory B-cells. The goal of this project is to optimize neonatal vaccination and to achieve full protection from infection using the newly discovered neonatal memory B-cell induction pathway in combination with conventional vaccination early in life. We also aim to further explore the underlying mechanism of neonatal memory B-cell activation. Overall, the project is relevant to prevent transmission of EHV-1 and the development of latency, to achieve protection from disease by increasing immunity the equine population including young foals, and thereby reducing severe neurological and abortion outbreaks in the US.