Identification and Characterization of CD4 ⁺ T Cell Epitopes after Shingrix Vaccination

Abstract

Infections with varicella zoster virus (VZV) are associated with a range of clinical manifestations. Primary infection with VZV causes chicken pox. The virus remains latent in neurons and it can reactivate later in life causing herpes zoster (HZ). Two different vaccines have been developed to prevent HZ, one based on a live attenuated VZV strain (Zostavax) and the other 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, it is of much interest to understand if there is a role for T cell immunity in differential clinical outcome, and if there is a correlate of protection between T cell immunity and Shingrix efficacy. 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 (NS), 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. Importance Understanding the T cell profile associated with the protection observed in elderly vaccinees 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 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.…”

Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases

“…We found that each donor responded to an average of 3.2 viral antigens (Figure 1D), and 5.9 CD4 + T cell epitopes were recognized per antigen for the top 80% most immunodominant antigens (data not shown). For each epitope/responding donor combination, potential HLA restrictions were also inferred based on the predicted HLA binding capacity of the epitope for the HLA alleles present in the respective responding donor (listed in Table S2), as previously described (Voic et al, 2020). 15,26 Table S6 provides the spectrum of distributions of the magnitudes of T cell responses to all peptides tested at the level of the individual donors.…”

“…org). 26 Typing was performed for the class I HLA A and B loci and class II DRBI, DQB1, and DPB1 loci.…”

Immunological memory to Common Cold Coronaviruses assessed longitudinally over a three-year period

“…CD4+ T cell responses to the four prototypical CCC viruses (NL63, 229E, HKU1 and OC43) were measured, using the Activation Induced Marker (AIM) and the OX40/4-1BB markers combination 26 , which has been previously utilized to characterize viral responses and particularly SARS-CoV-2 CD4+ T cell responses [36][37][38][39][40] . Responses to other respiratory viruses (influenza, RSV, and rhinovirus), chronically infectious viruses (EBV, CMV, and VZV), and ubiquitous bacterial vaccine antigens (TT and PT) were measured using specific peptide sets (Table 2 and methods section).…”