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

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. ### Competing Interest Statement Dr. Permar is a consultant for Moderna, Merck, Pfizer, GSK, Dynavax, and Hoopika CMV vaccine programs and leads sponsored research programs with Moderna and Merck. She also serves on the board of the National CMV Foundation and as an educator on CMV for Medscape. ### Funding Statement We wish to acknowledge support from the Biostatistics, Epidemiology and Research Design (BERD) Methods Core at Duke University, funded through Grant Award Number UL1TR002553 from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH. This work was also supported by the Translating Duke Health Initiative (awarded to CC, RB), the Duke Center for Human Systems Immunology, the Else Kroener-Fresenius-Foundation (awarded to CS, 2016-A126), T32 Training Grant (awarded to MJH, 2T32AI052077-16A1), Medearis CMV Scholar Award (awarded to MJH), and NIH National Institute of Allergy and Infectious Disease P01 (awarded to SRP, 3P01AI129859). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Plasma samples were obtained from the German Red Cross Blood-Transfusion Service, with informed consent and approved by the Ethical Board of Ulm University vote number 53/14. Approval for this work was obtained from the Duke University School of Medicine Institutional Review Board (Pro00105640). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.