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.