Lassa virus (LASV) is the causative agent of Lassa Fever (LF), a zoonotic viral hemorrhagic fever endemic in West Africa responsible for wide spread disease and significant morbidity and mortality. There currently exists no vaccine against LF, while the need for such a vaccine is ever increasing. Ribavirin, the only known treatment to be effective against LF early on after infection, is hard to come by in endemic areas while rodent reservoir control is an unfeasible strategy over the wide ranging areas of endemicity. Furthermore, with the classification of LASV as a Category A Priority agent the need for vaccine development research is even higher. However, LASV is a pathogen that requires the highest level of biocontainment for study and as such vaccine development is both difficult and costly. With the generation of a reassortant virus ML29 there exists the potential to develop a mouse model for the purpose of evaluating the LF vaccine candidates outside of a biosafety level 4 (BSL-4) environment. ML29 is a reassortant virus containing the replication machinery of the nonpathogenic Mopeia virus (MOPV), a genetic relative of LASV, and encodes the LASV major antigens, glycoprotein precursor (GPC) and the nucleoprotein (NP). It displays an attenuated phenotype both in vitro and in vivo as compared to wild type LASV. Furthermore, unlike past efforts to present LASV antigens using pseudotyped viruses, this reassortant virus is a replication competent complete arenavirus expressing wild type LASV immunogens GPC and NP making ML29 the ideal candidate to study the immunobiology involved in the protection against a LASV-like challenge. The proposed mouse model is a splenocyte adoptive transfer model. Inbred CBA/J mice have been shown to be susceptible to a lethal intracerebral (i.c.) challenge with ML29, but display no disease in response to an intraperitoneal (i.p.) immunization, similar to the closely related prototype arenavirus lymphocytic choriomeningitis virus (LCMV). ML29 immunized mice have been used to further characterize the immune response elicited by the reassortant virus by tracking non-specific and specific cell mediated immune responses. It is known that antibody responses play little role in viral clearance, while cell mediated responses to GPC and to NP seem to be the primary means of protection against LCMV and LASV. Once established, the model will provide an excellent tool for the study of a LASV-like immunity as well as an appropriate platform for the evaluation of potential LF vaccine candidates. ML29, a reassortant virus between Mopeia virus and Lassa virus will allow the study of the immune response elicited by a Lassa-like arenavirus in mice. The proposed mouse model will allow the evaluation of immunogenicity to a Lassa like-infection and the evaluation of Lassa fever vaccine candidates.
| Goicochea, Marco A; Zapata, Juan C; Bryant, Joseph et al. (2012) Evaluation of Lassa virus vaccine immunogenicity in a CBA/J-ML29 mouse model. Vaccine 30:1445-52 |
