Current progress towards vaccines for arenavirus-caused diseases

Alexander²,

Pasquetto

et al. 2006

J Virol

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.

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confidence: 98%

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confidence: 99%

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confidence: 99%

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

Alexander²,

Pasquetto

et al. 2006

J Virol

“…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).…”

Section: Cd8mentioning

confidence: 99%

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

Sidney

Mothé

et al. 2010

Microbiol Mol Biol Rev

SUMMARY The arenaviruses are a family of negative-sense RNA viruses that cause severe human disease ranging from aseptic meningitis to hemorrhagic fever syndromes. There are currently no FDA-approved vaccines for the prevention of arenavirus disease, and therapeutic treatment is limited to the use of ribavirin and/or immune plasma for a subset of the pathogenic arenaviruses. The considerable genetic variability observed among the seven arenaviruses that are pathogenic for humans illustrates one of the major challenges for vaccine development today, namely, to overcome pathogen heterogeneity. Over the past 5 years, our group has tested several strategies to overcome pathogen heterogeneity, utilizing the pathogenic arenaviruses as a model system. Because T cells play a prominent role in protective immunity following arenavirus infection, we specifically focused on the development of human vaccines that would induce multivalent and cross-protective cell-mediated immune responses. To facilitate our vaccine development and testing, we conducted large-scale major histocompatibility complex (MHC) class I and class II epitope discovery on murine, nonhuman primate, and human backgrounds for each of the pathogenic arenaviruses, including the identification of protective HLA-restricted epitopes. Finally, using the murine model of lymphocytic choriomeningitis virus infection, we studied the phenotypic characteristics associated with immunodominant and protective T cell epitopes. This review summarizes the findings from our studies and discusses their application to future vaccine design.

“…This is particularly true for the pathogenic Old World arenaviruses LCMV and LASV, as high-quality antiviral nAbs typically do not form following infection with these viruses; low-titer nAbs, if formed, usually appear weeks to months following clearance of the primary infection (11,14,18,21,34). In the case of LCMV, it was recently shown that the GPC itself, not the viral backbone, is responsible for this poor nAb response (40).…”

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confidence: 99%

A Multivalent Vaccination Strategy for the Prevention of Old World Arenavirus Infection in Humans

Whitton

Barrowman³

et al. 2010

J Virol

Arenaviruses cause severe human disease ranging from aseptic meningitis following lymphocytic choriomeningitis virus (LCMV) infection to hemorrhagic fever syndromes following infection with Guanarito virus (GTOV), Junin virus (JUNV), Lassa virus (LASV), Machupo virus (MACV), Sabia virus (SABV), or Whitewater Arroyo virus (WWAV). Cellular immunity, chiefly the CD8؉ T-cell response, plays a critical role in providing protective immunity following infection with the Old World arenaviruses LASV and LCMV. In the current study, we evaluated whether HLA class I-restricted epitopes that are cross-reactive among pathogenic arenaviruses could be identified for the purpose of developing an epitope-based vaccination approach that would cross-protect against multiple arenaviruses. We were able to identify a