Development of Broadly Protective Vaccines against New World Arenaviruses - Abstract Mammarenaviruses, or arenaviruses, can cause a range of diseases in humans, including congenital disorders, encephalitis, meningitis, and severe hemorrhagic fevers (HFs). Arenaviruses are divided into Old World (OW) and New World (NW) groups. Several NW arenaviruses, such as Junín (JUNV), Machupo (MACV), Guanarito (GTOV), Chapare (CHAPV), and Sabiá (SABV), are endemic in South America and can cause HF infections in humans with fatality rates reaching up to 30%. Other uncharacterized or unknown NW arenaviruses may include potential pathogens. To date, there are no FDA-approved vaccines or therapeutics for arenaviruses. Candid#1, a live attenuated JUNV vaccine, is licensed for use in Argentina against JUNV-caused Argentine HF, but is unlikely to be approved by the FDA due to safety concerns. There is an urgent need for vaccines to prevent current and future arenavirus outbreaks. Our long-term goal is to create safe and effective vaccines against pathogenic arenaviruses. The objective of this R01 proposal is to leverage the unique properties of a viral vaccine vector rP18tri based on a non-pathogenic NW arenavirus, Pichinde virus (PICV), to develop safe and broadly protective vaccines against NW arenaviral pathogens. PICV has no to low seroprevalence in humans, even in endemic areas in Colombia, South America. The rP18tri-based live-attenuated vaccines show limited replication in the vaccinated animals, with no evidence of viremia or virus shedding. They induce a balanced level of antigen-specific antibody and T-cell responses, which can be further enhanced by homologous boosting. Our compelling preliminary data demonstrate that the rP18tri-based JUNV vaccines are safe and can provide complete protection against virulent JUNV challenges in guinea pigs. Furthermore, the rP18tri vector alone can confer partial protection against JUNV, underscoring its potential to elicit broadly protective immunity against diverse NW arenaviruses. We hypothesize that the non-pathogenic arenavirus vector (rP18tri)-based vaccines expressing multivalent antigens from JUNV and MACV will elicit robust and broadly protective immunity against various NW arenaviruses. We have assembled a multi-institutional team of investigators with complementing expertise in molecular virology, viral vector and vaccine development, guinea pig T cell immunology, and animal modeling of arenavirus HFs in the BSL3/4 facilities. We will produce a panel of rP18tri-based NW arenavirus vaccines expressing one or two antigens (glycoprotein GPC and nucleoprotein NP) from JUNV and MACV, evaluate their immunogenicity and protective efficacy against homologous (Aim 1) and heterologous (Aim 2) virus challenge in established guinea pig models, and characterize vaccine-induced protective immunity (Aim 3). Impact: The study will generate safe and broadly protective NW arenaviral vaccine candidates for subsequent preclinical and clinical evaluation, generate new knowledge about the protective antigen(s) and immunity to guide the design of next-generation arenavirus vaccines, and advance the rP18tri platform for developing vaccines and immune therapies against communicable and noncommunicable diseases, such as cancers, in humans.
