Antibody binding to native cytomegalovirus glycoprotein B predicts efficacy of the gB/MF59 vaccine in humans
- 3 November 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 12 (568)
- https://doi.org/10.1126/scitranslmed.abb3611
Abstract
Human cytomegalovirus (CMV) is the most common infectious cause of infant brain damage and posttransplant complications worldwide. Despite the high global burden of disease, vaccine development to prevent infection remains hampered by challenges in generating protective immunity. The most efficacious CMV vaccine candidate tested to date is a soluble glycoprotein B (gB) subunit vaccine with MF59 adjuvant (gB/MF59), which achieved 50% protection in multiple historical phase 2 clinical trials. The vaccine-elicited immune responses that conferred this protection have remained unclear. We investigated the humoral immune correlates of protection from CMV acquisition in populations of CMV-seronegative adolescent and postpartum women who received the gB/MF59 vaccine. We found that gB/MF59 immunization elicited distinct CMV-specific immunoglobulin G (IgG)–binding profiles and IgG-mediated functional responses in adolescent and postpartum vaccinees, with heterologous CMV strain neutralization observed primarily in adolescent vaccinees. Using penalized multiple logistic regression analysis, we determined that protection against primary CMV infection in both cohorts was associated with serum IgG binding to gB present on a cell surface but not binding to the soluble vaccine antigen, suggesting that IgG binding to cell-associated gB is an immune correlate of vaccine efficacy. Supporting this, we identified gB-specific monoclonal antibodies that differentially recognized soluble or cell-associated gB, revealing that there are structural differences in cell-associated and soluble gB are relevant to the generation of protective immunity. Our results highlight the importance of the native, cell-associated gB conformation in future CMV vaccine design.Keywords
Funding Information
- National Institute of Allergy and Infectious Diseases (R21AI136556)
- National Institute of Allergy and Infectious Diseases (1P01AI129859)
- National Institute of Child Health and Human Development (F30HD089577)
This publication has 52 references indexed in Scilit:
- Prevention of Maternal and Congenital Cytomegalovirus InfectionClinical Obstetrics and Gynecology, 2012
- Immune-Correlates Analysis of an HIV-1 Vaccine Efficacy TrialThe New England Journal of Medicine, 2012
- Nomenclature for Immune Correlates of Protection After VaccinationClinical Infectious Diseases, 2012
- Congenital Cytomegalovirus Infection as a Cause of Sensorineural Hearing Loss in a Highly Immune PopulationThe Pediatric Infectious Disease Journal, 2011
- Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutatedThe Journal of Experimental Medicine, 2011
- Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trialThe Lancet, 2011
- Within-woman change in regulatory T cells from pregnancy to the postpartum periodJournal of Reproductive Immunology, 2011
- Detection of a Single Identical Cytomegalovirus (CMV) Strain in Recently Seroconverted Young WomenPLOS ONE, 2011
- Human Cytomegalovirus Glycoprotein B Is Required for Virus Entry and Cell-to-Cell Spread but Not for Virion Attachment, Assembly, or EgressJournal of Virology, 2009
- Vaccine Prevention of Maternal Cytomegalovirus InfectionThe New England Journal of Medicine, 2009