T Cell Immunity To Enterovirus 71 Infection In Humans And Implications For Vaccine Development

Abstract

Enterovirus 71 (EV-A71) is one of the major pathogens causing hand, foot and mouth disease (HFMD). Some strains can lead to neurological disease and fatality in children. Up to date, there is no FDA-approved vaccine to prevent severe HFMD and mortality. Although the inactivated vaccine has advanced to production in China, lack of long-term protection and the requirement of multiple boosters have necessitated the development of other types of vaccines. Recent studies indicate that cellular and not humoral immunity determines the clinical outcome of EV-A71 infections. High levels of cytokines such as IL-1β, IL-6, IL-10 and IFN-γ tend to correlate with clinical severity in patients with pulmonary edema and encephalitis. The live attenuated vaccine may serve as the preferred choice as it can induce excellent humoral and cellular immunity as well as live-long immunity. Expression of certain HLA alleles such as TNF-α promoter type II (-308 allele), HLA-A33 and HLA-DR17 responses have been linked to severe HFMD. However, the high variability of MHC genes could restrict T cell recognition and be a major obstacle in the design of peptide vaccines. Hence, the development of a T cell universal vaccine (incorporating both CD4⁺ and CD8⁺ T cell epitopes) that induces broad, multifunctional and cross-reactive CD8⁺ T cell responses maybe desirable.

Keywords: Hand, foot and mouth disease; cellular immunity; enterovirus 71; immunogenicity..

Figure 1

Routes of presentation of viral peptides on APCs . Some viruses can infect cells and replicate prior to being degraded into peptide fragments. Some fragments will be presented on MHC class I molecules to naïve CD8⁺ T cells. Binding of the TCR to the MHC class I-peptide complex activates the CD8⁺ T cells and releases cytotoxic granules and cytokines (TNF-α and IFN-γ). Some viral peptides can be presented on MHC class II molecules in parallel by APCs. The TCR of naïve CD4⁺ T cells can recognize MHC class II-peptide complexes on APCs and differentiate into Th1 and Th2 cells. Copyright 2014. Frontiers Media SA. Permission attained on May 25, 2017 by author Rosendahl Huber and Frontiers in Immunology, in accordance with the Creative Common Attribution licence (https://creativecommons.org/licenses/by/4.0/). Disclaimer: All software used on the site, and the copyright in the code constituting such software, is the property of or is licensed to Frontiers and its use is restricted in accordance with the Frontiers Terms and Conditions. All copyright, and all rights therein, are protected by national and international copyright laws.

Figure 2

Diverse distribution of VP2-specific T cell immunogenic regions . The T cell responses were specified to a region of 40-50 aa for VP1 (A), VP2 (B), VP3 (C), and VP4 (D). The y-axis displays the strength of responses as represented by SFCs per 10⁵ PBMCs. The x- and z-axes show the peptide spanning region and subjects, respectively. The magnitude of responses to VP2 were more diversely distributed along the Ag (B), whereas there was an intensely focused distribution of responses to the central region in VP1, VP3, and VP4. Copyright 2013. The American Association of Immunologists, Inc. Permission obtained on April 12, 2017 from the American Association of Immunologists, Inc.