Identification and characterization of CD4+ T cell epitopes after Shingrix vaccination

Abstract

Infections with varicella zoster virus (VZV), a member of the Herpesviridae family, are associated with a range of clinical manifestations. Primary infection with VZV causes chicken pox, and due to the virus’s capacity to remain latent in neurons, it can reactivate later in life causing herpes zoster (HZ), also known as shingles. Two different licensed vaccines are available to prevent HZ, either based on a live attenuated VZV strain (Zostavax) or on adjuvanted gE recombinant protein (Shingrix). While Zostavax efficacy wanes with age, Shingrix protection retains its efficacy in elderly subjects (80 years of age and beyond). In this context, studies to evaluate the potential role of T cell immunity as a correlate of protection and Shingrix efficacy are of interest. In this study, we characterized Shingrix specific ex vivo CD4 T cell responses in the context of natural exposure and HZ vaccination using pools of predicted epitopes. We show that T cell reactivity following natural infection and Zostavax vaccination dominantly targets non-structural proteins, while Shingrix vaccination redirects dominant reactivity to target gE. We mapped the gE-specific responses following Shingrix vaccination to 89 different gE epitopes, 34 of which accounted for 80% of the response. Using antigen presentation assays and single HLA molecule transfected lines, we experimentally determined HLA restrictions for 94 different donor/peptide combinations. Finally, we used our results as a training set to assess strategies to predict restrictions based on measured or predicted HLA binding and the corresponding HLA types of responding subjects.ImportanceUnderstanding the T cell profile associated with the protection observed in elderly vaccines following Shingrix vaccination is relevant to the general definition of correlates of vaccine efficacy. Our study enables these future studies by clarifying patterns of immunodominance associated with Shingrix vaccination, as opposed to natural infection or Zostavax vaccination. Identification of epitopes recognized by Shingrix-induced CD4 T cells vaccinees, and their associated HLA restrictions, enables the generation of tetrameric staining reagents, and more broadly the capability to characterize specificity, magnitude and phenotype of VZV specific T cells.

Targets and cross-reactivity of human T cell recognition of Common Cold Coronaviruses

“…Bioinformatic analysis of sequence conservation in panels of different viral species was shown to be effective in informing selection of potential cross-reactive T cell epitopes 33,36,70 . Crossreactive epitopes were associated with overall 67% or greater sequence conservation, in agreement with previous studies in the context of SARS-CoV-2 and other viral infections such as ZIKV and VZV 36,58,74,75 . Our results provide the largest data set available to address this issue, with cross-reactivity data involving 18 different epitopes and 37 TCLs, testing a total of 594 different viral variant epitope sequences.…”

Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans

“…A total of 142 SARS-CoV-2 epitopes were identified, 66 from the spike protein (CD4-S) and 76 from the remainder of the genome (CD4-R) (table S1). For each combination of epitope and responding donor, potential human leukocyte antigen (HLA) restrictions were inferred on the basis of the predicted HLA-binding capacity of the particular epitope for the specific HLA alleles present in the responding donor (22). Each donor recognized an average of 11.4 epitopes (range 1 to 33, median 6.5; fig.…”