Rodent-borne viral outbreaks are increasing in both frequency and impact. Hantaviruses are transmitted through the excreta of infected rodents and, when aerosolized, infect humans. In the Americas, hantavirus infection leads to hantavirus cardiopulmonary syndrome (HCPS), a devastating condition that features rapid onset of pulmonary edema, respiratory failure and cardiogenic shock. Treatment is supportive, not pathogen-targeted, and accordingly, approximately 40% of patients do not survive. Because hantaviruses establish lifelong, asymptomatic infections in their rodent reservoirs, they are highly prevalent in nature and represent a constant threat to humans. For example, Sin Nombre virus (SNV), which causes greater than 95% of HCPS cases in North America, is carried by the most abundant mammal on the continent, the deer mouse, which has a near ubiquitous distribution throughout the US and Canada. Despite this large potential for infection and the high case fatality rate, there are no FDA-approved treatment options or vaccines available. Hantaviruses are thus classified as NIAID Priority Pathogens and considered potential bioterrorism threats. Our long term goal is to develop an effective therapeutic against SNV that can be used in the setting of natural exposure to infected rodents or during a bioterrorism attack. The only known correlate of protection against severe HCPS is the development of high titer, virus-specific neutralizing antibodies. Further, immune serum is protective against HCPS disease both animal models and humans. This proposal seeks to capitalize on this knowledge by developing human neutralizing antibodies for therapeutic and/or prophylactic treatment of HCPS caused by SNV. We have assembled a multidisciplinary team of molecular virologists, clinicians, B cell immunologists, and industry partners with experience developing antibody-based therapeutics. In this Phase I application, we will leverage our unique access to SNV patients to i) comprehensively map the antibody repertoire generated during acute SNV infection and ii) identify antibodies that potently neutralize SNV. The successful development of a potent neutralizing antibody against SNV has the potential to be a first-line antiviral for the treatment or prevention of HCPS.
Public Health Relevance Statement: Narrative Hantaviruses such as Sin Nombre (SNV) are rodent-borne viruses that cause highly lethal disease in humans. No approved drugs or vaccines exist to treat or prevent hantavirus infection. Antiviral neutralizing antibodies are protective against lethal SNV infection in both animals and humans. We will comprehensively map the antiviral antibodies made in humans during natural SNV infection and determine which of them strongly neutralize SNV. The successful development of a potent neutralizing antibody against SNV has the potential to be a first-line antiviral for the treatment or prevention of hantavirus cardiopulmonary syndrome in North America.
Project Terms: Acute; aerosolized; Aerosols; Affect; American; Americas; Animal Model; Animals; Anthrax disease; Antibodies; Antibody Repertoire; Antibody Therapy; Antiviral Agents; Area; authority; Authorization documentation; B-Lymphocytes; Bioterrorism; bioweapon; Canada; Cardiogenic Shock; Cardiopulmonary; Case Fatality Rates; Contracts; Deer Mouse; Dengue Virus; Development; Disease; Disease Outbreaks; Ebola virus; Emergency Situation; Event; experience; Exposure to; Fatality rate; FDA approved; Frequencies; Glycoproteins; Goals; Hamsters; Hantavirus; Hantavirus Infections; Human; human monoclonal antibodies; Immune Sera; immunogenicity; Immunologist; In Vitro; industry partner; infected vector rodent; Infection; Influenza A virus; Knowledge; Lassa Fever; Mammals; Maps; Medical; Medicine; Modeling; Molecular; Monoclonal Antibodies; mortality; multidisciplinary; National Institute of Allergy and Infectious Disease; Nature; neutralizing antibody; neutralizing monoclonal antibodies; North America; novel; pathogen; Patients; Pharmaceutical Preparations; pharmacokinetics and pharmacodynamics; Phase; Plasmablast; Population; Positioning Attribute; preclinical development; preclinical toxicity; prevent; Prevention; priority pathogen; Prophylactic treatment; Pulmonary Edema; research and development; Respiratory Failure; Rodent; Serum Immunologic; Sin Nombre virus; Staphylococcus aureus; Syndrome; Therapeutic; Therapeutic antibodies; Treatment Efficacy; Vaccines; Viral; Viral Antibodies; Virus; Virus Diseases; weapons of mass destruction; weather patterns; Western Africa; Work
