A Novel Strategy to Boost Antibody Production to EHV-1 in Neonates
Principal Investigator: Bettina Wagner
DESCRIPTION (provided by applicant):
Background: Early-in-life vaccination is desirable to protect neonates and young foals from infectious diseases. In particular for pathogens that are commonly transmitted early-in-life such as equine herpesvirus type 1 (EHV-1), successful early-in-life vaccination can make a substantial impact to decrease infection and clinical disease outbreaks in the horse population. Nevertheless, vaccination of neonates and young foals remains challenging because their immune system reacts differently than that of adults. It is thus not surprising that an effective neonatal vaccine needs to be composed differently. We and others have described that foals have decreased T-cell responses compared to adult horses. Our group has also shown that the T-helper 2 (Th2) response, which is the major initiator of long-lasting antibody production in adults, is impaired in foals until at least three months of age. Notably and despite the obvious T-cell immaturity, antibody production generally occurs in very young foals and reaches adult levels by 6-8 weeks of age suggesting that foals use alternative mechanisms to activate antibody production early in life. Recently, we identified another cell type, the basophil, which is the main producer of Th2-like responses in the
Hypothesis: Our hypothesis is that antigen-specific activation of basophils and production of the cytokine interleukin-4 by activated basophils is a major pathway to induce antibody production in foals after birth.
Specific Aims: Aim 1 is to generate antibody/EHV-1 antigen complexes to mimic activation of basophils in vitro. Five EHV-1 antigens known to induce antibody responses will be expressed and tested. Basophils will be isolated, loaded with antibody and activated with EHV-1 antigens. Basophil activation will be evaluated by cytokine induction. In this aim, we will also develop a sensitive EHV-1 antigen-specific assay with the goal to improve the evaluation of EHV-1 antibody responses in horses. Aim 2 is to test the potential of a novel neonatal vaccination strategy in foals after birth. The antibody will be administrated to foals from EHV-1 naïve mares within the first 6 hours after birth. At day 2, foals will obtain EHV-1 antigen to induce antibody production. After weaning, protective immunity will be evaluated by challenge infection with EHV-1. Clinical signs, viral loads and EHV-1 specific humoral and cellular immunity will be evaluated.
Relevancy: Various severe EHV-1 outbreaks in the US occurred recently despite widely used vaccination. This emphasizes the fact that currently available EHV-1 vaccines are not fully protective. Novel vaccination strategies are required to address the problem. This proposal will take advantage of a natural innate production pathway of interleukin-4, formerly known as B-cell stimulating factor, in neonatal foals to overcome the challenges of EHV-1 vaccination early in life. Our long-term goal is to prevent EHV-1 transmission to and infection of foals to reduce the number of latently infected horses and future EHV-1 outbreaks.