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

Abstract

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.

Differential T Cell Responses to Residual Viral Antigen Prolong CD4+ T Cell Contraction following the Resolution of Infection

“…Likewise, CD8+ T cells can detect a single foreign antigen, are cytolytic with 3 complexes, and require about 10 complexes to form a mature synapse and release calcium (59). Additionally, interactions between CD8+ T cells and peptide/MHC complexes should be more frequent and more stable than those between CD4+ T cells and peptide/MHC complexes: effector CD8+ T cells respond to lower concentrations of peptide than do CD4+ T cells (sub-nanomolar versus ~100 nanomolar) ((1, 60) & Figure 4); the affinity of GP 33 peptide for Db (Immune Epitope Database; ANN IC 50 =5nM) is greater than GP 61 for I-Ab (IC 50 =128nM)(61, 62); most cells express large amounts of MHC-I, whereas only a few cell types express MHC-II. Finally, we cannot exclude the possibility that CD4 T cells – but not CD8+ T cells – transit through an anatomical niche containing only MHCII-loaded antigen derived from long-lived immune complexes (49).…”

Arenavirus Coinfections Are Common in Snakes with Boid Inclusion Body Disease

“…In vitro studies with mammarenaviruses demonstrate that persistent arenavirus infection restricts the replication of a serologically similar but not more distant arenavirus (12). Some strains of lymphocytic choriomeningitis virus, the prototype arenavirus, induce acquired immunosuppression in their natural host (13), as also suggested for BIBD (14). We hypothesize that reptarenaviruses may establish a chronic infection in snakes.…”

Diseases of the central nervous system caused by lymphocytic choriomeningitis virus and other arenaviruses

“…In addition to the live attenuated vaccine utilizing the Candid 1 Junin virus strain, work is ongoing to develop more broadly acting vaccines to protect against arenavirus infection (Kotturi et al, 2009;Botten et al, 2010). With regard to antiviral treatments, the nucleoside analogue ribavirin does have efficacy against multiple arenaviruses and has reduced mortality from LF virus when administered early in infection (Stephen et al, 1977;McCormick et al, 1986;Kilgore et al, 1997).…”