Long-term T cell memory to human leucocyte antigen-A2 supertype epitopes in humans vaccinated against smallpox

Abstract

SummaryIdentification of human leucocyte antigen (HLA) class I-restricted T cell epitopes is important to develop methods to track the evolution of T cell memory to new generation smallpox vaccines and allow comparison to older vaccinia virus preparations known to induce protection against smallpox. We evaluated the relative predictive values of four computational algorithms to identify candidate 9-mer HLA-A2 supertype epitopes that were confirmed to stimulate preferentially T cell interferon (IFN)-g responses by subjects last vaccinated with Dryvax 27-54 years previously. Six peptides encoded by I4L, G1L, A8R, I8R, D12L and H3L open reading frames that were identical for Vaccinia (Copenhagen), Variola major (Bangledesh 1975) and modified vaccinia Ankara strain preferentially stimulated IFN-g responses by healthy HLA-A2 supertype adults last given Dryvax 27-49 years earlier relative to remotely vaccinated non-HLA-A2 supertype and unvaccinated HLA-A2 supertype adults. Combining results from at least two computational algorithms that use different strategies to predict peptide binding to HLA-A2 supertype molecules was optimal for selection of candidate peptides that were confirmed to be epitopes by recall of T cell IFN-g responses. These data will facilitate evaluation of the immunogenicity of replication incompetent smallpox vaccines such as modified vaccinia Ankara and contribute to knowledge of poxvirus epitopes that are associated with long-lived T cell memory.

Discovery of naturally processed and HLA-presented class I peptides from vaccinia virus infection using mass spectrometry for vaccine development

“…Since there are approximately 230 ORFs in vaccinia, multiple viral proteins can be potentially targeted by human cellular (CTL) immune responses. In fact, some of these gene products have been demonstrated to be immunogenic in both humans and a mouse model, including A6L, A8R, A10L, A23R, D12L, E9L, J6R, and M1L [4, 6, 12, 14, 50]. …”

“…Antigen specificity of both CD8+ and CD4+ T cells is strongly controlled by HLA and other gene polymorphisms, and the immunogenicity (and ultimately the efficacy) of vaccines are dependent on particular HLA allelic polymorphisms [1] that restrict which peptides can be bound and hence presented [2, 3]. Both class I and class II HLA polymorphisms control antigen and peptide epitope specificity of T cell responses and have been associated with differences in smallpox vaccine response outcome [4-6]. Therefore, the immune response to smallpox vaccine is determined in large part by multigenic influences controlling the presentation of specific sets of peptides [7].…”

MHC-I-restricted epitopes conserved among variola and other related orthopoxviruses are recognized by T cells 30 years after vaccination

“…Most Danes were vaccinated > 30 years ago with the vaccine strain; vaccinia virus strain Copenhagen. Only one study has examined epitope recognition in long term vaccinia virus vaccinees without re-vaccination [33]. Ostrout and colleagues tested 46 HLA-A2 restricted peptides and found a positive IFN-γ response towards 6 of these [33].…”

“…Only one study has examined epitope recognition in long term vaccinia virus vaccinees without re-vaccination [33]. Ostrout and colleagues tested 46 HLA-A2 restricted peptides and found a positive IFN-γ response towards 6 of these [33]. In the present study we have screened peptides from 11 different HLA supertypes which have been calculated to have an average population coverage of more than 99% [39].…”

“…Most of the CTL responses described are observed shortly after vaccination, but long-term central memory responses associated with CD8+ T cells as well as CD4+ T cells have also been reported [10]. CD8+ T lymphocytes have been shown to be involved in controlling poxvirus infection, and this has prompted a search for potential CD8+ T cell epitopes [16, 27, 28, 31, 33, 35, 41, 45-47]. In recent years over 150 T cell epitopes from human and mouse have been identified (reviewed in Kennedy and Poland 2007)[22].…”