Identification of protective T-cell antigens for smallpox vaccines

Abstract

Background aims: E3L is an immediate-early protein of vaccinia virus (VV) that is detected within 0.5 h of infection, potentially before the many immune evasion genes of vaccinia can exert their protective effects. E3L is highly conserved among orthopoxviruses and hence could provide important protective T-cell epitopes that should be retained in any subunit or attenuated vaccine. We have therefore evaluated the immunogenicity of E3L in healthy VV-vaccinated donors. Methods: Peripheral blood mononuclear cells from healthy volunteers (n = 13) who had previously received a smallpox vaccine (Dryvax) were activated and expanded using overlapping E3L peptides and their function, specificity and antiviral activity was analyzed. E3L-specific T cells were expanded from 7 of 12 (58.3%) vaccinated healthy donors. Twenty-five percent of these produced CD8+ T-cell responses and 87.5% produced CD4+ T cells. We identified epitopes restricted by HLA-B35 and HLA-DR15. Results: E3L-specific T cells killed peptide-loaded target cells as well as vaccinia-infected cells, but only CD8+ T cells could prevent the spread of infectious virus in virus inhibition assays. The epitopes recognized by E3Lspecific T cells were shared with monkeypox, and although there was a single amino acid change in the variola epitope homolog, it was recognized by vaccinia-specific T-cells. Conclusions: It might be important to include E3L in any deletion mutant or subunit vaccine and E3L could provide a useful antigen to monitor protective immunity in humans.

Monkeypox: disease epidemiology, host immunity and clinical interventions

“…Many are conserved among the major orthopoxviruses and bind to human MHC class I and class II molecules [126][127][128] . In particular, CD8 + T cells specific for two identified epitopes (MHC class II-restricted GRVFDKADGKSKRDA and MHC class I-restricted NPVTVINEY) in the immediateearly E3 protein of VACV were capable of killing infected cells and halting the spread of VACV 129 . Both epitopes are conserved in the MPXV homologue, which is encoded by the MPXV F3L gene 130 .…”

The prospective outcome of the monkeypox outbreak in 2022 and characterization of monkeypox disease immunobiology

“…Many are conserved among the most significant orthopoxviruses and attach to class I and II MHC molecules ( Calvo-Calle et al., 2007 ; Kennedy and Poland, 2010 ; Molero-Abraham et al., 2015 ). Specifically, CD8 + T lymphocytes precise for two discovered epitopes in the immediate-early E3 protein of VACV (class I-restricted MHC NPVTVINEY and class II-restricted MHC GRVFDKADGKSKRDA) were able to destroy infected cells and block the dissemination of VACV ( Ando et al., 2020 ). Both epitopes are expressed in the MPOX analogue, represented by the MPOX F3L gene ( Arndt et al., 2015 ).…”

Current Status of Epidemiology, Diagnosis, Therapeutics, and Vaccines for the Re-Emerging Human Monkeypox Virus

“…This is possible by boosting cellular immune responses. Since Mpox has highly similar amino acid sequences to vaccinia viruses, T cell-mediated cellular responses induced by VACV vaccines are cross-reactive to Mpox [ 112 ]. Optimization of adjuvants or the addition of peptides conserved between the VACV and Mpox can increase T cell-mediated cellular responses, allowing vaccines to target a broad range of viruses.…”