Cross-binding antibodies capable of neutralizing diverse orthohantaviruses are produced in response to Puumala virus infection

BackgroundOrthohantaviruses (hantaviruses) are emerging rodent-borne pathogens that can cause severe human disease. They are present on multiple continents and are responsible for thousands of human cases per year, predominantly in China. Despite this, no vaccines or licensed therapeutics are available, and the immunological response to infection is poorly characterized. This study aimed to analyze the humoral response to PUUV infection to inform future studies focusing on the production of therapeutic monoclonal antibodies and vaccination strategies. MethodsSerum was obtained from a cohort of 23 patients hospitalized with Puumala virus (PUUV) infection at four time points, covering the early acute, late acute, early convalescent, and late convalescent stages of the disease. The humoral responses at each time point were quantified, and cross-binding, cross-neutralizing antibody responses were investigated. Serum cytokine levels were also interrogated, and expression was correlated with humoral outputs. FindingsPUUV infection elicited a robust anti-PUUV neutralizing antibody response. However, cross-reactive antibodies that were capable of binding diverse hantaviruses were also induced in late convalescence. Modulations in the abundance of IgG subclasses were also evident following infection, with significant differences present months after infection. InterpretationThis study demonstrates that broadly reactive anti-hantavirus antibodies are produced in response to Old-World hantavirus infection, but predominantly months after recovery. As this is concomitant with changes in IgG subtypes, our results suggest that PUUV antigen persists in humans post-infection, which promotes prolonged class-switching and somatic hypermutation, favoring conserved epitopes.