Therapeutic vaccination against shingles broadens the VZV-specific CD4+ T cell response (VAC7P.994)

Abstract Life-long latent neuronal infection with varicella zoster virus (VZV) is a legacy of childhood chickenpox. VZV reactivation occurs in about 1/3 of persons to cause shingles. Live, attenuated VZV (vOka)—the only licensed therapeutic vaccine—moderately reduces both the incidence and the severity of shingles. The partial level of protection is poorly understood but may plausibly derive from variation in T cell boosting. Twelve subjects (>50 years old) were vaccinated with vOka and blood obtained on days 0, 14, and 28. Ex vivo ICC analyses confirmed boosting of vOka-reactive T cells: the mean increase in frequency of IFNγ+IL2+ CD4+ T cells was 74% by day 14 (p=0.02). We enriched and expanded VZV-specific CD4+ T cells in an unbiased manner and defined the specificity and breadth of the resulting polyclonal CD4+ T cell lines using each of the 70 known VZV proteins. Prior to boosting, the median number of detectable responses was 9 ORFs (range 3-10). Vaccination increased the median breadth to 17 ORFs (range 9-20) at day 28. Prevalent targets before and after boosting were glycoproteins gE, gI, and gH, and the tegument proteins encoded by ORF12 and ORF44. While new responses were noted post-vaccination, baseline responses rarely disappeared. T cell breadth was well-maintained during VZV latency and further increased by therapeutic vaccination. In addition to CD4+ T cell magnitude, specificity and breadth are now accessible as candidate immune correlates of vaccine efficacy.