title: Innate and adaptive immune control of genetically engineered live-attenuated arenavirus vaccine prototypes.
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.
authors.affiliation: Department of Pathology and Immunology, WHO Collaborating Center for Neonatal Vaccinology, University of Geneva, 1 rue Michel Servet, 1211 Geneva 4, Switzerland.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Pinschewer
authors.forename: Lukas
authors.initials: L
authors.lastname: Flatz
authors.forename: Ralf
authors.initials: R
authors.lastname: Steinborn
authors.forename: Edit
authors.initials: E
authors.lastname: Horvath
authors.forename: Marylise
authors.initials: M
authors.lastname: Fernandez
authors.forename: Hans
authors.initials: H
authors.lastname: Lutz
authors.forename: Mark
authors.initials: M
authors.lastname: Suter
authors.forename: Andreas
authors.initials: A
authors.lastname: Bergthaler
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016654:Genes, RAG-1 / Q000235:genetics; D007113:Immunity, Innate; D007156:Immunologic Memory; D007835:Lassa Fever / Q000276:immunology / Q000517:prevention & control; D007836:Lassa virus / Q000276:immunology* / Q000472:pathogenicity; D051379:Mice; D008810:Mice, Inbred C57BL; D030781:Organisms, Genetically Modified; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014613:Vaccines, Attenuated; D014765:Viral Vaccines; D000096743:Interferon gamma Receptor
chemical_list: D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon; D014613:Vaccines, Attenuated; D014765:Viral Vaccines; D000096743:Interferon gamma Receptor