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• W4311762968 abstract "In this issue of Cell Host & Microbe, Grifoni et al. provide reassuring evidence that the majority of epitopes induced by vaccinia virus vaccines are conserved in monkeypox virus and can elicit memory T cell responses, while also providing an extensive list of potential T cell epitopes. In this issue of Cell Host & Microbe, Grifoni et al. provide reassuring evidence that the majority of epitopes induced by vaccinia virus vaccines are conserved in monkeypox virus and can elicit memory T cell responses, while also providing an extensive list of potential T cell epitopes. While the world’s focus was on SARS-CoV-2, another viral pathogen was gaining traction—monkeypox virus (MPXV). Since it was first identified in 1970, MPXV has become endemic in Africa but is rarely seen in other continents. The recent outbreak has now spread to more than 95 countries and infected more than 75,000 people. Despite this high prevalence of infections, the number of confirmed deaths remains low at 36 worldwide. Very few studies into the immune responses associated with natural infection exist. Vaccines based on vaccinia virus (VACV) or modified vaccinia virus Ankara, which were designed to protect against smallpox virus, have been successfully used to protect against MPXV, with efficacy rates of 85%.1Jezek Z. Marennikova S.S. Mutumbo M. Nakano J.H. Paluku K.M. Szczeniowski M. Human Monkeypox: A Study of 2, 510 Contacts of 214 Patients.J. Infect. Dis. 1986; 154: 551-555https://doi.org/10.1093/infdis/154.4.551Crossref PubMed Scopus (119) Google Scholar However, the immunity induced by these vaccines against MPXV has not been thoroughly characterized. This is largely due to their large viral genome sizes, ranging from 130 to 300 kb, with more than 200 open reading frames (ORFs).2Moutaftsi M. Tscharke D.C. Vaughan K. Koelle D.M. Stern L. Calvo-Calle M. Ennis F. Terajima M. Sutter G. Crotty S. et al.Uncovering the interplay between CD8, CD4 and antibody responses to complex pathogens.Future Microbiol. 2010; 5: 221-239https://doi.org/10.2217/fmb.09.110Crossref PubMed Scopus (59) Google Scholar T cell responses to infection are an integral part of the host’s ability to fight viruses. Most T cell studies have focused on responses to VACV, as these are the basis of vaccines against orthopoxviruses.3Kennedy R. Poland G.A. T-Cell epitope discovery for variola and vaccinia viruses.Rev. Med. Virol. 2007; 17: 93-113https://doi.org/10.1002/rmv.527Crossref PubMed Scopus (29) Google Scholar,4Shchelkunov S. Shchelkunova G.A. Genes that Control Vaccinia Virus Immunogenicity.Acta Naturae. 2020; 12: 33-41https://doi.org/10.32607/actanaturae.10935Crossref PubMed Scopus (14) Google Scholar While epitopes have been identified, understanding a hierarchy of immunodominance for these has been difficult, particularly due to the large number of antigens potentially available from the virus.5Terajima M. Orphin L. Leporati A.M. Pazoles P. Cruz J. Rothman A.L. Ennis F.A. Vaccinia virus-specific CD8(+) T-cell responses target a group of epitopes without a strong immunodominance hierarchy in humans.Hum. Immunol. 2008; 69: 815-825https://doi.org/10.1016/j.humimm.2008.09.009Crossref PubMed Scopus (23) Google Scholar In this issue, Grifoni et al.6Grifoni A. Zhang Y. Tarke A. Sidney J. Rubiro P. Reina-Campos M. Filaci G. Dan J. Scheuermann R.H. Sette A. Defining antigen targets to dissect vaccinia virus (VACV) and Monkeypox virus (MPXV)- specific T cell responses in humans.Cell Host Microbe. 2022; 30: 1662-1670https://doi.org/10.1016/j.chom.2022.11.003Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar present a timely and important study into the cross-reactivity of T cells to MPXV and VACV, which share 90% sequence homology. They created mega peptide pools based on publicly available data on confirmed orthopoxvirus epitopes and then compared how these epitope sequences related with MPXV regions, concluding that 94% of CD4 and 82% of CD8 epitopes were present in the MPXV sequence. This shared homology suggests that there will be strong cross-reactivity of T cells primed by VACV to MPXV. However, while there may be homology in the epitope sequence, the sequence of the epitope-flanking regions may also affect whether epitopes are actually presented at the cell surface.7Ranasinghe S.R.F. Kramer H.B. Wright C. Kessler B.M. di Gleria K. Zhang Y. Gillespie G.M. Blais M.-E. Culshaw A. Pichulik T. et al.The Antiviral Efficacy of HIV-Specific CD8+ T-Cells to a Conserved Epitope Is Heavily Dependent on the Infecting HIV-1 Isolate.PLoS Pathog. 2011; 7e1001341https://doi.org/10.1371/journal.ppat.1001341Crossref PubMed Scopus (22) Google Scholar,8Wellington D. Yin Z. Yu Z. Heilig R. Davis S. Fischer R. Felce S.L. Hublitz P. Beveridge R. Dong D. et al.SARS-CoV-2 mutations affect proteasome processing to alter CD8+ T cell responses.Preprint at bioRxiv. 2022; https://doi.org/10.1101/2022.04.08.487623Crossref Scopus (0) Google Scholar The authors next confirmed that these mega peptide pools can stimulate memory T cell responses by investigating the responses of donors previously vaccinated with the Dryvax VACV vaccine. As orthopoxviruses generally have around 200 ORFs, Grifoni et al. further these studies by narrowing down the ORFs that generate the majority of epitopes (≥5). From the subsequent list of 19 CD4 and 40 CD8 candidates, and subsequent cross-referencing with only those epitopes homologous in MPXV, they created a second set of mega peptide pools of in silico predicted MPXV epitopes, which were subsequently shown to activate T cell responses. While this generated a large pool of potential immunodominant epitopes for MPXV that will be invaluable to the field moving forward, the use of only common HLA (human leukocyte antigen) alleles may result in the absence of additional key epitopes presented by non-common HLA alleles. Therefore, it is important that future studies include donors with less common HLA types, as there may be a whole raft of dominant epitopes that we have yet to identify. While this study is an excellent starting point, closer investigations are required to identify specific immunodominant MPXV epitopes that stimulate long-lasting T cell responses. In addition, the saturating concentration of exogenous pooled peptides may not be able to fully represent overall T cell responses to virus-infected cells and their anti-viral efficacy. The concentration of each epitope on the surface of infected cells may vary due to the efficiency of antigen processing and their presentation by individual HLA molecules. Future studies should consider combining exogenous peptides with systems such as vaccinia.9Ennis F. Cruz J. Demkowicz Jr W. Rothman A. McClain D. Primary Induction of Human CD8+ Cytotoxic T Lymphocytes and Interferon-γ-Producing T Cells after Smallpox Vaccination.J. Infect. Dis. 2002; 185: 1657-1659https://doi.org/10.1086/340517Crossref PubMed Scopus (92) Google Scholar,10Peng Y. Felce S.L. Dong D. Penkava F. Mentzer A.J. Yao X. Liu G. Yin Z. Chen J.-L. Lu Y. et al.An immunodominant NP105–113-B∗07:02 cytotoxic T cell response controls viral replication and is associated with less severe COVID-19 disease.Nat. Immunol. 2022; 23: 50-61https://doi.org/10.1038/s41590-021-01084-zCrossref PubMed Scopus (57) Google Scholar These systems allow epitopes to be naturally processed and presented, more accurately representing physiological conditions. However, due to the nature of these systems, the T cell responses seen may be lower or less sensitive due to the additional complications that virus infection brings. Although the correlates of protection are still being defined, what is reassuring about these results is that the use of VACV- or MVA-based vaccines should continue to be largely protective against MPXV disease. While this is positive, there is still the question of whether protection can be improved through the development of better vaccines. To do that, we need better understanding of the T cell responses, including those suggested here, as well as other elements of immunity. Considering the high homology of MPXV and VACV, we must still remember that even a 10% difference in sequence may be sufficient to alter the pool of peptides that actually induce robust and long-lasting T cell responses. Using the information provided here, we can now start to build a clear picture of T cell immune responses to MPXV (Figure 1). This work is supported by UKRI to the UK Monkeypox Research Consortium (T.D.), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences 2018-I2M-2-002 (T.D. and D.W.), and the UK Medical Research Council (T.D.). The authors declare no competing interests. Defining antigen targets to dissect vaccinia virus and monkeypox virus-specific T cell responses in humansGrifoni et al.Cell Host & MicrobeDecember 3, 2022In BriefGrifoni et al. developed orthopox- and monkeypox-specific epitope pools to measure monkeypox T cell responses in natural infection and vaccination. The pools were validated by detection of memory T cell responses in PBMCs from Dryvax vaccinees. A majority of the Dryvax-vaccinee CD4 responses were cytotoxic and produced granzyme B. Full-Text PDF" @default.
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• W4311762968 title "T cells are ready for the fight against monkeypox" @default.
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