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Principal Investigator: ROBERT H CARNAHAN
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2024
Award: $7,023,024
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY - RP5
Arenaviruses, a family of viruses with pandemic potential, can cause hemorrhagic fever, meningitis, and other
clinical syndromes. These viruses include highly pathogenic strains such as Lassa virus (LASV) and Junín
virus (JUNV), as well as less pathogenic strains like lymphocytic choriomeningitis virus (LCMV). In this project,
we aim to focus on two major areas, active immunity induced by experimental vaccines and passive immunity
conferred by injection with human monoclonal antibodies. The later studies will include the study of extended
half-life protective antibodies bearing Fc mutations that cause ≥90-day half-life profiles in humans and thus
enable a vaccine-like prophylactic profile of a year or more. First, in studies in Aim 1, we will compare leading
vaccine platform technologies and define immune correlates of protection for LCMV in nonhuman primate
models of infection (macaques) as a virus prototype. Understanding the principles of immunity to this prototype
virus will allow us then to pivot and use those mechanistic insights to design and test vaccines for other
arenaviruses. This work will allow us to fully explore replicating attenuated LCMV vectors as a strategy for
developing candidate arenavirus vaccines. We also will explore the hypothesis that both antibodies and T cell
responses contribute to vaccine -induced protection against LCMV. Next, in studies in Aim 2, we will focus on
deploying optimal vaccine strategies for other arenaviruses of pandemic concerns, LASV and JUNV. Lastly, in
work in Aim 3, we will identify and characterize fully human neutralizing monoclonal antibodies and their
epitope targets, with initial work in LCMV antibody discovery providing a platform for further work on other
medically important arenaviruses. This project will be synergistic with other projects in the BP4 center focusing
on picornavirus and hantavirus vaccines and with the BP4 human monoclonal antibody projects to develop
candidate arenavirus, picornavirus, and hantavirus medical countermeasures.
Terms: <Active immunity><Ad vector><Adenoviral Vector><Adenovirus Vector><Antibodies><Antigenic Determinants><Area><Arenaviridae><Arenavirus><Arenavirus group><Argentine hemorrhagic fever virus><Argentinian Hemorrhagic Fever Virus><Attenuated><BBC1><BCL2-Interacting Killer Gene><BIK><BIK gene><BIP1><BP4><Bik/Nbk Gene><Binding Determinants><Blood Vessels><Bunyavirus><Clinical><Clinical Treatment Moab><Collaborations><Combined Modality Therapy><DNA delivery><Data><Development><Disease><Disorder><Epitopes><Extravasation><Family><Family Picornaviridae><Genes><Genetic Alteration><Genetic Change><Genetic defect><Half-Life><Hantavirus><Hu-mABs><Human><Immune><Immune response><Immunes><Immunity><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunological response><Immunosuppressed Host><Infection><Injections><Junin><Junin virus><LCM Viruses><LCMV><Lassa fever virus><Lassa virus><Lead><Leakage><Lymphocytic choriomeningitis virus><M mulatta><M. mulatta><Macaca><Macaca mulatta><Macaque><Medical><Meningitis><Messenger RNA><Modeling><Modern Man><Monoclonal Antibodies><Multimodal Therapy><Multimodal Treatment><Mutation><NBK><Orthobunyavirus><Passive Immunity><Pathogenesis><Pathogenicity><Pb element><Picornaviridae><Picornaviruses><Preparedness><Proteins><Readiness><Reagent><Resistance><Response Generalization><Rhesus Macaque><Rhesus Monkey><Role><Spillage><Syndrome><T cell response><T-Cells><T-Lymphocyte><Technology><Therapeutic><Therapeutic antibodies><Vaccination acquired immunity><Vaccination induced immunity><Vaccine Design><Vaccines><Viral Diseases><Viral Hemorrhagic Fevers><Virus><Virus Diseases><Work><adeno vector><adenovector><attenuate><attenuates><clinical development><combination therapy><combined modality treatment><combined treatment><data management><deliver DNA><design><designing><developmental><evaluate vaccines><experience><genome mutation><heavy metal Pb><heavy metal lead><hemorrhagic fever><host response><humAbs><human mAbs><human monoclonal antibodies><human monoclonals><immune system response><immunogenicity><immunoresponse><immunosuppressed patient><industrial partnership><industry partner><industry partnership><insight><lead candidate><mAbs><mRNA><manufacturing capabilities><manufacturing capacity><medical countermeasure><monoclonal Abs><multi-modal therapy><multi-modal treatment><neutralizing mAb><neutralizing monoclonal antibodies><non-human primate><nonhuman primate><pandemic concern><pandemic disease preparedness><pandemic pathogen><pandemic planning><pandemic potential><pandemic preparedness><pandemic readiness><pandemic risk><pandemic threat><pathogen><pathogenic virus><plasmid vaccine><pre-clinical><pre-clinical development><preclinical><preclinical development><prophylactic><protective efficacy><prototype><resistant><social role><synergism><technology platform><technology system><therapeutic agent development><therapeutic development><thymus derived lymphocyte><vaccine acquired immunity><vaccine associated immunity><vaccine candidate><vaccine evaluation><vaccine platform><vaccine screening><vaccine strategy><vaccine testing><vaccine-induced immunity><vaccine-induced protection><vascular><vector><vector vaccine><viral infection><viral pathogen><virus infection><virus pathogen><virus-induced disease>