Research Project
8981911
? DESCRIPTION (provided by applicant): Several arenaviruses, chiefly Lassa virus (LASV) in West Africa and Junín virus (JUNV) in the Pampas region of Argentina, cause hemorrhagic fever (HF) disease in humans and pose a serious public health concern in their endemic regions. Thus, LASV is estimated to infect several hundred thousand individuals yearly in its endemic regions of West Africa, resulting in a high number of Lassa fever (LF) cases associated with high morbidity and mortality. Likewise, JUNV causes Argentine HF (AHF), a disease associated with hemorrhagic and neurological manifestations and fatality rates of 15-30%. On the other hand, although the worldwide- distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) does not cause HF, evidence indicates that LCMV is a neglected important human pathogen. Thus, LCMV has been shown to cause a significant number of cases of congenital neurological and ophthalmological diseases. Moreover, LCMV poses a serious threat to immunocompromised individuals as tragically documented recently by fatal cases of LCMV infection associated with patients undergoing transplant procedures. In addition, epidemiological studies have shown a high seroprevalence of LCMV in the United States and other populations tested, raising the question of whether LCMV may contribute to the many cases of undiagnosed aseptic meningitis reported yearly. Besides a public health risk, LCMV poses also a credible biodefense threat and is classified as a Category A priority pathogen by the NIAID. Public health concerns posed by LCMV infection of humans are aggravated by the lack of Food and Drug Administration (FDA)-licensed vaccines and current anti-arenaviral therapy being limited to the off-label use of ribavirin, which is only partially effective and associated with side effects. The significance of LCMV in human health and biodefense readiness, together with the limited existing armamentarium to combat LCMV infections, highlight the importance of developing therapies to treat human LCMV infections resulted from an accidental virus exposure, a potential intentional virus release and/or LCMV infections of immunocompromised individuals. To this end we propose to combine the use of our state-of-the- art LCMV reverse genetics with the access to a unique collection of 120 LASV glycoprotein (GP)-specific human monoclonal antibodies (hMAbs) derived from 17 different LF survivors to identify and characterize hMAbs with broadly neutralizing activity (BNhMAbs) in vivo against GPs of different isolates related to human cases of LCMV-induced disease.
