The concentrations of antibodies to Epstein-Barr virus decrease during ocrelizumab treatment

•Antibodies to two major Epstein-Barr virus antigens, EBNA-1 and BFRF3, decrease in people treated with ocrevus.•Antibodies to two human proteins known to cross-react with Epstein-Barr virus had a trend towards decreasing on ocrevus treatment.•A treatment that removed only Epstein-Barr virus infected B lymphocytes might be effective and have less side effects. Epstein‐Barr Virus (EBV) is strongly associated with multiple sclerosis (MS). After initial infection, EBV maintains a life‐long latent infection in B lymphocytes. Depletion of B lymphocytes from the blood with the anti-CD20 antibody ocrelizumab (OCR) markedly reduces disease activity in MS. Our objective was to measure the effect of OCR treatment on the antibody response to EBV and human antigens that are cross-reactive with EBV. Blood was collected from MS patients before and during OCR treatment. Antibodies to three EBV antigens (EBNA-1, BFRF3, and gp350) and three human proteins that are cross-reactive with EBV (septin-9, DLST, and HNRNPL) were quantified with Western blots. Antibodies to EBNA-1 and BFRF3 were also quantified with ELISA. Antibodies to the EBV proteins BFRF3 and EBNA-1 measured on Western blot were significantly decreased after 12 months on OCR. Subsequent testing with ELISA confirmed the decrease for both BFRF3 and EBNA-1. With Western blots, there was a trend to decreased antibody response to septin-9 and DLST, but not HNRNPL. Total IgG concentration did not change. The antibody response to some EBV antigens decreases in OCR treated patients. The benefit of OCR for MS may be through removal of EBV antigenic stimulus.