Improving herpes simplex virus vaccination efficacy and neonatal infection outcomes

Improving herpes simplex virus (HSV) vaccination efficacy and neonatal outcomes A successful Herpes Simplex Virus (HSV) immunization has remained elusive, despite over 80 years of research. Moving forward in murine studies with HSV immunizations it is imperative to consider overlooked biological factors that impact immune responses to immunization and therefore impact the overall efficacy. Age is a conserved biological variable across species that has been shown to impact both innate and adaptive immune functions. Clinical research has shown that age influences severity and outcomes of HSV infection in humans. Neonatal herpes simplex virus (nHSV) is observed in 1/10,000 live births, causing significant mortality and lifelong neurological morbidity. Early diagnosis and treatment with antiviral therapy ameliorates poor clinical outcomes but a lack of clinical suspicion leads to delayed treatment and so lifelong neurological morbidity remains prevalent, however longitudinal studies following neurological outcomes remain sparce. Our lab has published that neonatal infection with low-doses of HSV-1 leads to increased anxiety-like behaviors in mice. By utilizing a low-dose neonatal infection model, the relationship between viral infection and long-term neurologic morbidity can be studied. My overall goal is to determine if age impacts murine immunization efficacy and characterize the neonatal response to viral challenge. My central hypothesis is, therefore, that the type, and especially the timeline of neonatal, juvenile, adolescent, and maternal vaccinations are critical efficacy determinants of vaccines designed to prevent nHSV. In Aim 1, I will determine the extent of protection afforded to neonates via maternal immunization. I will utilize survival benchmarks during the acute phase of neonatal HSV infection and behavioral assays such as modified Barnes maze (MBM), and different paired associates learning (dPAL) to measure long-term behavioral changes following neonatal HSV infection. In Aim 2, I will establish and characterize murine neonatal, juvenile, and adolescent HSV immunization. I will utilize plaque neutralization assays and flow cytometry to characterize neutralizing and T cell responses following HSV immunization. Completion of these aims will form a foundation for human HSV vaccine clinical trials that take age and serostatus into account and will provide a comprehensive account of the long-term behavioral morbidities due to an early life clinical HSV infection.