Polyfunctional antibody signature defines protection in Andes hantavirus survival

Background Andes orthohantavirus (ANDV) is a deadly pathogen that causes hantavirus cardiopulmonary syndrome (HCPS), which is a severe disease characterized by respiratory failure and high mortality rates (~30–40%). While previous studies have shown that neutralizing antibodies have a critical role in survival, the contribution of the Fc-mediated effector functions remains unexplored. Methods We performed a serological profiling of acute HCPS patients and survivors, analyzing antibody types, subtypes, and neutralization capacity targeting ANDV glycoproteins (Gn and GnGc). Fc-mediated effector functions, which are key to defining antibody-mediated correlates of protection, were analyzed using FcγR reporter signaling assays, antibody-dependent NK cell activation, and antibody-dependent complement deposition (ADCD). Results Acute HCPS patients who developed moderate disease exhibited significantly higher IgG levels against the Gn glycoprotein and stronger Fc-mediated effector functions, including antibody-dependent NK cell activation and ADCD against glycoproteins, compared to the more severe cases. Surviving acute patients showed elevated IgG and IgM responses against Gn. In survivors, polyfunctional non-neutralizing IgG activities persisted for years after infection and were more pronounced against the GnGc complex than Gn alone. Conclusion In summary, our study reveals the existence of functional diversity in the humoral immune response to ANDV glycoprotein during HCPS, which can be associated with protective responses and may contribute to a long-lasting immune response to restrict ANDV infection. These findings identify Fc effector functions as important correlates of protection and provide valuable insights for the design of next-generation vaccines and therapeutics against hantaviruses.