Research ArticleVaccines

Antibody binding to native cytomegalovirus glycoprotein B predicts efficacy of the gB/MF59 vaccine in humans

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Science Translational Medicine  04 Nov 2020:
Vol. 12, Issue 568, eabb3611
DOI: 10.1126/scitranslmed.abb3611

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Vaccine protection profile

Cytomegalovirus (CMV) is a leading cause of posttransplant complications and congenital infections, but there are no CMV vaccines currently licensed. Jenks et al. characterized serum IgG responses in adolescent and postpartum women enrolled in phase 2 clinical trials with an experimental CMV subunit vaccine composed of glycoprotein B (gB) and MF59. Adolescent vaccinees developed CMV-specific IgG responses with binding and functional characteristics that were distinct from those of postpartum vaccinees. An immune correlate analysis further revealed that protection against primary CMV infection in both groups was associated with the magnitude of IgG binding to cell-associated gB and not soluble vaccine antigen. We also identified gB-specific monoclonal antibodies that specifically recognize cell-associated gB over soluble gB, providing valuable insight into protective immunity against CMV and immune targets for CMV vaccines.

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.

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