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

Flatz, Lukas
Steinborn, R.
Horvath, Edith
Lutz, H.
Suter, M.
Published in International Immunology. 2010
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.
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PMID: 20584765
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