Development of a therapeutic antibody cocktail against New World Arenaviruses

PROJECT SUMMARY/ABSTRACT The Mammarenavirus genus of the Arenaviridae family, encompasses several severe human pathogens, including Old World arenaviruses (OWAs) like Lassa virus and New World arenaviruses (NWAs) such as Machupo and Junín viruses, each of which cause hemorrhagic fever. Currently, the only available vaccine, the live-attenuated Candid #1 for JUNV, is not FDA-approved and provides limited neutralization breadth, leaving populations vulnerable to diverse arenaviruses. Monoclonal antibody (mAb) therapies represent one of the most important treatment opportunities in modern medicine. They are being used to treat and cure numerous diseases, including different types of cancer and autoimmune diseases. Since the 1980s, mAbs like Synagis against RSV, and Ebanga™ and Inmazeb™ against Ebola virus disease have been used to treat viral health threats. However, there remains no licensed therapies for treatment of any arenavirus infection. As such, development, especially of broadly applicable therapeutics, is an urgent need. Pioneering discoveries from our group illuminated the "Achilles Heels" on the Lassa virus surface glycoprotein and led to a first-in-class pre- clinical therapeutic for Lassa virus infection. Here, we extend this cutting-edge work to New World arenaviruses. Employing a novel panel of prefusion-stabilized NWA GPCs, we will elucidate the structural and functional properties of these proteins, providing essential templates to interpret antibody responses. Our approach includes advanced methods such as high-resolution cryo-electron microscopy to visualize nAb interactions at a molecular level. We will isolate a diverse array of broadly protective nAbs from immunized animal models and humans vaccinated with Candid #1, assessing their breadth and potency to identify candidates for therapeutic development. Furthermore, we will conduct comprehensive structural and biochemical analyses to delineate the antigenic landscape of NWA GPCs and establish mechanistic rules underlying their neutralization. This multifaceted investigation promises to yield groundbreaking insights into the immune response to NWAs, paving the way for the development of effective vaccines and immunotherapeutics to combat these unpredictable and often fatal infections.