Sci Transl Med. 2020 Nov 4;12(568):eabb3611. doi: 10.1126/scitranslmed.abb3611. | PubMed

Jennifer A Jenks¹, Cody S Nelson^1,2, Hunter K Roark¹, Matthew L Goodwin¹, Robert F Pass³, David I Bernstein⁴, Emmanuel B Walter¹, Kathryn M Edwards⁵, Dai Wang⁶, Tong-Ming Fu⁷, Zhiqiang An⁷, Cliburn Chan⁸, Sallie R Permar^9,10

1. Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27705, USA.
2. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
3. Department of Pediatrics, University of Alabama of Birmingham, Birmingham, AL 35233, USA.
4. Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA.
5. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
6. Merck & Co. Inc., Kenilworth, NJ 07033, USA.
7. Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA.
8. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC 27705, USA.
9. Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27705, USA. sallie.permar@duke.edu.
10. Department of Pediatrics, Duke University Medical Center, Durham, NC 27705, USA.

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.

Presented By Jennifer Jenks | ORCID iD