Innate and adaptive immune control of genetically engineered live-attenuated arenavirus vaccine prototypes

Int Immunol. 2010 Sep;22(9):749-56. doi: 10.1093/intimm/dxq061. Epub 2010 Jun 28.

Abstract

Arenaviruses such as Lassa virus (LASV) cause significant morbidity and mortality in endemic areas. Using a glycoprotein (GP) exchange strategy, we have recently developed live-attenuated arenavirus vaccine prototypes (rLCMV/VSVG) based on lymphocytic choriomeningitis virus (LCMV), a close relative of LASV. rLCMV/VSVG induced long-term CD8(+) T cell immunity against wild-type virus challenge and exhibited a stably attenuated phenotype in vivo. Here we elucidated the innate and adaptive immune requirements for the control of rLCMV/VSVG. Infection of RAG(-/-) mice resulted in persisting viral RNA in blood but not in overt viremia. The latter was only found in mice lacking both RAG and IFN type I receptor. Conversely, absence of IFN type II signaling or NK cells on an RAG-deficient background had only minor effects on vaccine virus load or none at all. rLCMV/VSVG infection of wild-type mice induced less type I IFN than did wild-type LCMV, and type I as well as type II IFNs were dispensable for the induction of virus-specific memory CD8 T cells and virus-neutralizing antibodies by rLCMV/VSVG. In conclusion, the adaptive immune systems are essential for elimination of rLCMV/VSVG, and type I but not type II IFN plays a major contributive role in lowering rLCMV/VSVG loads in vivo, attesting to the attenuation profile of the vaccine. Nevertheless, IFNs are not required for the induction of potent vaccine responses. These results provide a better understanding of the immunobiology of rLCMV/VSVG and will contribute to the further development of GP exchange vaccines for combating arenaviral hemorrhagic fevers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Genes, RAG-1 / genetics
  • Immunity, Innate
  • Immunologic Memory
  • Lassa Fever / immunology
  • Lassa Fever / prevention & control
  • Lassa virus / immunology*
  • Lassa virus / pathogenicity
  • Mice
  • Mice, Inbred C57BL
  • Organisms, Genetically Modified
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / immunology
  • Receptor, Interferon alpha-beta / metabolism*
  • Receptors, Interferon / genetics
  • Receptors, Interferon / immunology
  • Receptors, Interferon / metabolism*
  • Vaccines, Attenuated
  • Viral Vaccines*

Substances

  • Receptors, Interferon
  • Vaccines, Attenuated
  • Viral Vaccines
  • interferon gamma receptor
  • Receptor, Interferon alpha-beta