Identification of Protective Lassa Virus Epitopes That Are Restricted by HLA-A2

Abstract

Recovery from Lassa virus (LASV) infection usually precedes the appearance of neutralizing antibodies, indicating that cellular immunity plays a primary role in viral clearance. To date, the role of LASV-specific CD8 ؉ T cells has not been evaluated in humans. To facilitate such studies, we utilized a predictive algorithm to identify candidate HLA-A2 supertype epitopes from the LASV nucleoprotein and glycoprotein precursor (GPC) genes. We identified three peptides (GPC 42-50 , GLVGLVTFL; GPC 60-68 , SLYKGVYEL; and GPC 441-449 , YLISIFLHL) that displayed high-affinity binding (<98 nM) to HLA-A*0201, induced CD8؉ T-cell responses of high functional avidity in HLA-A*0201 transgenic mice, and were naturally processed from native LASV GPC in human HLA-A*0201-positive target cells. HLA-A*0201 mice immunized with either GPC 42-50 or GPC 60-68 were protected against challenge with a recombinant vaccinia virus that expressed LASV GPC. The epitopes identified in this study represent potential diagnostic reagents and candidates for inclusion in epitope-based vaccine constructs. Our approach is applicable to any pathogen with existing sequence data, does not require manipulation of the actual pathogen or access to immune human donors, and should therefore be generally applicable to category A through C agents and other emerging pathogens.

Vaccinia Virus-Specific CD4+ T Cell Responses Target a Set of Antigens Largely Distinct from Those Targeted by CD8+ T Cell Responses

“…That binding beyond a certain threshold often does not correlate strongly with immunodominance, in both class I and class II contexts, has been pointed out in several studies (17,(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47).…”

Coverage of Related Pathogenic Species by Multivalent and Cross-Protective Vaccine Design: Arenaviruses as a Model System

“…Likewise, the studies conducted by Botten et al demonstrated that infection of human HLA-A*0201-positive target cells with an rVACV could be used to detect naturally processed LASV-and LCMV-derived CD8 ϩ T cell epitopes (13,14).…”

“…ϩ and CD4 ϩ T cell responses have clearly been associated with reduced pathology and protection against Old World arenaviruses in animal models of infection (13,14,50,56,99,101). Previous studies demonstrated that mice lacking CD8 ϩ T cells or the cytolytic protein perforin are incapable of resolving a primary LCMV infection (49,101).…”

“…A primary study, examining LASV-specific CD8 ϩ T cell responses, identified three novel LASV GPC-derived epitopes following peptide immunization of HLA-A*0201 transgenic mice (Table 4) (13). These three CD8 ϩ T cell epitopes displayed high binding affinity to HLA-A*0201 and were naturally processed from native LASV GPC in human HLA-A*0201-positive target cells.…”

“…Studies have also shown that CD4 ϩ T cell-deficient mice were unable to mount an effective memory CD8 ϩ T cell response and control viremia following infection with highly virulent LCMV strains (50,99). Furthermore, vaccine strategies aimed at generating a CD8 ϩ T cell-mediated response confer protection against virus challenge in murine (13,14,56), guinea pig (5, 69), and NHP (36) models of LCMV and LASV infection. In humans, cell-mediated immunity also seems to be critical for protection against LASV infection, as neutralizing antibodies appear several weeks or months after viral clearance (28,37), and treatment of infected patients with immune plasma does not protect against disease (65).…”