| dc.description.abstract | Hantaviruses are high-priority emerging pathogens carried by rodents and transmitted to humans by aerosolized excreta or, in rare cases, person-to-person contact. While sporadic in North and South America, many infections occur in Europe and Asia, with mortality ranging from 1 to 40% depending on the hantavirus species. There are currently no FDA-approved vaccines or therapeutics for hantaviruses, and the only treatment for infection is supportive care for respiratory or renal failure. Additionally, the humoral immune response to hantavirus infection is incompletely understood, especially the location of major antigenic sites on the viral glycoproteins, Gn and Gc, and conserved neutralizing epitopes. This work describes human monoclonal antibodies isolated from individuals previously infected with Sin Nombre virus or Andes virus. Most SNV-reactive antibodies show broad recognition and cross-clade neutralizing activity, while many ANDV-reactive antibodies show activity for ANDV only. Four mAbs show therapeutic efficacy at clinically relevant doses in hamsters. We performed antigenic mapping and functional characterization of four neutralizing hantavirus antibodies to investigate further the antibodies isolated in this dissertation. A broadly neutralizing antibody, SNV-53, targets the interface between Gn/Gc, neutralizes through fusion inhibition, and can cross-protect against an Old World hantavirus species, Hantaan, when administered pre-or post-exposure. Another broad antibody, SNV-24, also neutralizes through fusion inhibition but targets Gc and demonstrates weak neutralizing activity across hantavirus
species. ANDV-specific, neutralizing antibodies (ANDV-5 and ANDV-34) neutralize through attachment blocking, protect hamsters from lethal ANDV challenge, and target two different faces on the head domain of Gn. Finally, we evaluated the molecular level rationale for the function of a potently neutralizing, SNV-specific antibody, termed SNV-42. Interestingly, SNV-42 targets the membrane distal region of the virus, and critical interacting residues within the SNV-42 paratope exhibit a high sequence conservation level with that of the originating germline. These studies reveal a convergent and potently neutralizing human antibody response to New World hantaviruses and suggest therapeutic potential for human antibodies against HCPS. Determining the antigenic sites for broadly neutralizing antibodies will contribute to further therapeutic development for hantavirus-related diseases and inform the design of new broadly protective hantavirus vaccines. | |
