Development of broadly protective Lassa vaccines using the Pichinde virus vector

Abstract Lassa virus (LASV) is a rodent-borne enveloped RNA virus within the Arenaviridae family and can cause Lassa fever, a lethal viral hemorrhagic fever (VHF) disease in humans, for which there are no approved vaccines and limited therapeutic options. Lassa fever is endemic in West Africa and, with an estimated 100,000 to 300,000 infections and ~ 5,000 deaths annually, has more cases than any other VHFs (including Ebola and Marburg) except for Dengue. The overall fatality rate of Lassa fever is estimated to be ~ 1 % but can be much higher in hospitalized patients (~18%) and during outbreaks (25%). LASV infection also results in severe disease sequelae including spontaneous abortion in nearly all infected mothers and permanent hearing loss in nearly a third of recovered patients. LASV's natural hosts are local rodents, in particular, the multimammate rats, which have a wide habitat in Africa. Together with an extremely high sequence variation among LASV lineages, rodent-borne LASV has the potential to cause large outbreaks and even pandemics. There are no FDA-approved vaccines or therapeutics against Lassa fever. Treatment mainly relies on supportive care. Given the severe disease burdens of LASV and its pandemic potential, effective and broadly protective vaccines against various LASV lineages are urgently needed. The objective of this R21 proposal is to explore the unique advantages of an arenavirus vector, Pichinde virus (PICV), to develop safe and broadly protective LASV vaccines. PICV is a non-pathogenic arenavirus with a bi-segmented RNA genome. The recombinant PICV vector (rP18tri) is engineered to consist of three RNA segments, which can accommodate two additional open-reading frames (ORFs) to express antigens in the targeted antigen-presenting cells. The live-attenuated rP18tri viral vaccine platform is safe and convenient and induces balanced antibody and T-cell responses. Built upon compelling preliminary data, the proposed research will test the hypothesis that non-pathogenic arenavirus vector (rP18tri)-based multivalent LASV antigens will induce robust and broadly protective immunity against diverse LASV isolates. In this exploratory R21 proposal, we will generate additional rP18tri vector-based multivalent LASV vaccine candidates (Aim 1 ), evaluate their antibody and T-cell responses (Aim 2), and assess the protective efficacy in an established LASV-guinea pig model in BSL4 facility (Aim 3). The study is highly significant in addressing an urgent unmet need for a LASV vaccine by producing at least one candidate with demonstrated safety and broad protection to be advanced to the next phases of preclinical and clinical testing, by generating new knowledge on the protective antigen(s) and correlates of protection to guide the design of next-generation vaccines against LASV and other arenavirus pathogens, and by advancing the development of the new PICV vector platform which holds promise for fighting infectious diseases and cancers.