While Epstein-Barr virus causes mostly asymptomatic infection, associated malignancies, and autoimmune and lymphoproliferative diseases occur. To dissect the evolution of humoral immune responses over the course of EBV infection and to gain a better understanding of the potential contribution of antibody (Ab) function to viral control, we comprehensively profiled Ab specificities and Fc-functionalities using systems serology and VirScan. Ab functions against two early (p18 and p47/54) and two latent (gp350/220 and EBNA-1) EBV proteins were overall modest and/or short-lived, differing from humoral responses induced during acute infection by other viruses such as HIV. In the first year post-infection, only p18 elicited robust IgM-driven complement deposition and IgG-driven neutrophil phagocytosis while responses against EBNA-1 were largely Fc-functionally silent and only matured during chronic infection to drive phagocytosis. In contrast, Abs against Influenza virus readily mediated broad Fc-activity in all participants. These data suggest that EBV evades the induction of robust Fc-functional Abs, potentially due to the virus’ life cycle, switching from lytic to latent stages during infection. 

SOI scoring was used to determine the severity of illness.

ELISAs were used to confirm EBV status, the titer, and class/subclass of EBV-specific antibodies.

qPCR was used to determine viral load.

High-throughput flow cytometry techniques of the systems serology pipeline were used to assess antibody-mediated immune functions.

Luminex assays were used to determine antibody binding to Fc receptors.

Antibody depletion experiments were used to test suspected causal associations between specific antibody classes and functions.

Virscan analysis was used to determine the breadth of existing and evolving antibody responses.

Prism, Excel.