Fever Temperatures Differentially Alter Ebola-Antibody Functionality Depending on Affinity Maturation 2306819

Abstract Introduction In 2013-16, Western Africa experienced the largest known outbreak of the highly lethal virus, Ebolavirus (EBOV) and ongoing sporadic outbreaks have occurred since. EBOV is the causative agent of EBOV hemorrhagic fever, characterized by a high-grade fever. Antibody responses to EBOV have been correlated with protection against EBOV disease. However, it is unclear how antibody functions result in protection from repeat exposure. Understanding antibody-mediated mechanisms of protection against Ebola infection is critical to maximize long-term protection against infection. Methods We utilize a systems serology approach to analyze a cohort of 60 survivors of the 2013-16 Ebola epidemic in Guinea and 81 individuals of pygmy ancestry in the Republic of Congo who did not have documented EBOV infection, but do experience frequent zoonotic exposures to characterize the impact of fever conditions on affinity matured EBOV-directed antibody responses. Antibody binding and cellular activation were measured at both physiologic (37C) and high grade fever (40C) temperatures. Results We show that neutralization of EBOV is impaired under fever temperatures, both for affinity-matured and non-specific antibody responses. In contrast, effector-mediated functions, particularly against the EBOV soluble glycoprotein (sGP, a signature previously linked to enhanced protection in animal vaccine challenge models), are enhanced at febrile temperatures. This temperature-sensitive enhancement of effector function correlates with full length GP and sGP-directed IgG subclasses, IgA, FcγR-binding- and FcαR-binding antibodies, demonstrating a highly associated network of humoral features that are maintained during periods of febrile temperatures. Conclusion Collectively, our findings suggest that although neutralization plays a key role in surveillance in a non-fever state, fever modulates affinity-matured antibody responses to the hemorrhagic fever-inducing EBOV, moving antibody profiles to a pro-effector function phenotype. Funding Source NIH NIAID U19 AI135995 Topic Categories Viral Immunology (VIR)