Elite neutralizers of human cytomegalovirus are characterized by high magnitude plasma IgG responses against multiple glycoprotein complexes

Abstract

Background. Human cytomegalovirus (HCMV) is the most common infectious complication of organ transplantation and cause of birth defects worldwide. There are limited therapeutic options and no licensed vaccine to prevent HCMV infection or disease. To inform development of HCMV antibody-based interventions, a previous study identified individuals with potent and broad plasma HCMV-neutralizing activity, termed elite neutralizers (EN), from a cohort of HCMV-seropositive (SP) blood donors. Yet, the specificities and functions of plasma antibodies associated with EN status remained undefined. Methods. We sought to determine the plasma antibody specificities, breadth, and Fc-mediated antibody effector functions associated with the most potent HCMV-neutralizing responses in plasma from EN (n=25) relative to SP (n=19). We measured antibody binding against various HCMV strains and glycoprotein targets, and evaluated Fc-mediated effector functions, antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). Results. We demonstrate that elite HCMV neutralizers have elevated IgG binding responses against multiple viral glycoproteins, relative to SP. Our study also revealed potent HCMV-specific ADCC and ADCP activity of EN plasma, Conclusions. We conclude that antibody responses against multiple glycoprotein specificities may be needed to achieve potent plasma neutralization and that potently HCMV elite-neutralizing plasma antibodies can also mediate polyfunctional responses.

Multivalent Human Cytomegalovirus Glycoprotein B Nucleoside-Modified mRNA Vaccines Demonstrate a Greater Breadth in T cell but not Antibody Responses

“…Future HCMV vaccine design should consider several perspectives. We recently demonstrated that elite neutralizers of HCMV have potent neutralizing antibody responses that target multiple glycoprotein specificities 69 , including pentameric and trimeric glycoprotein complexes on the HCMV virion surface. However, there was no difference in gB-specific binding breadth comparing the HCMV-seropositive elite neutralizers to non-elite neutralizing individuals.…”

ADCC-activating antibodies correlate with protection against congenital human cytomegalovirus infection

“…Natural killer (NK) cell-mediated ADCC. NK cell degranulation was quantified by cell-surface expression of CD107a as previously described (47). MRC-5 fibroblasts (target cells; ATCC) were infected with HCMV strain AD169r (a AD169 derivative with repaired UL128-131 expression named BadrUL131-Y4-GFP ( 48)) at an MOI of 1.0 or mock-infected.…”