Human Cytomegalovirus mRNA-1647 Vaccine Candidate Elicits Potent and Broad Neutralization and Higher Antibody-Dependent Cellular Cytotoxicity Responses Than the gB/MF59 Vaccine

Xintao Hu; Krithika P Karthigeyan; Savannah Herbek; Sarah M Valencia; Jennifer A Jenks; Helen Webster; Itzayana G Miller; Megan Connors; Justin Pollara; Caroline Andy; Linda M Gerber; Emmanuel B Walter; Kathryn M Edwards; David I Bernstein; Jacob Hou; Matthew Koch; Lori Panther; Andrea Carfi; Kai Wu; Sallie R Permar

doi:10.1093/infdis/jiad593

Human Cytomegalovirus mRNA-1647 Vaccine Candidate Elicits Potent and Broad Neutralization and Higher Antibody-Dependent Cellular Cytotoxicity Responses Than the gB/MF59 Vaccine

J Infect Dis. 2024 Feb 7:jiad593. doi: 10.1093/infdis/jiad593. Online ahead of print.

Authors

Xintao Hu¹, Krithika P Karthigeyan¹, Savannah Herbek¹, Sarah M Valencia², Jennifer A Jenks², Helen Webster², Itzayana G Miller¹, Megan Connors¹, Justin Pollara², Caroline Andy³, Linda M Gerber³, Emmanuel B Walter², Kathryn M Edwards⁴, David I Bernstein⁵, Jacob Hou⁶, Matthew Koch⁶, Lori Panther⁶, Andrea Carfi⁶, Kai Wu⁶, Sallie R Permar¹

Affiliations

¹ Department of Pediatrics, Weill Cornell Medicine, New York, New York.
² Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina.
³ Department of Population Health Sciences, Weill Cornell Medicine, New York, New York.
⁴ Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
⁵ Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
⁶ Moderna, Inc, Cambridge, Massachusetts.

PMID: 38324766
DOI: 10.1093/infdis/jiad593

Abstract

Background: MF59-adjuvanted gB subunit (gB/MF59) vaccine demonstrated approximately 50% efficacy against human cytomegalovirus (HCMV) acquisition in multiple clinical trials, suggesting that efforts to improve this vaccine design might yield a vaccine suitable for licensure.

Methods: A messenger RNA (mRNA)-based vaccine candidate encoding HCMV gB and pentameric complex (PC), mRNA-1647, is currently in late-stage efficacy trials. However, its immunogenicity has not been compared to the partially effective gB/MF59 vaccine. We assessed neutralizing and Fc-mediated immunoglobulin G (IgG) effector antibody responses induced by mRNA-1647 in both HCMV-seropositive and -seronegative vaccinees from a first-in-human clinical trial through 1 year following third vaccination using a systems serology approach. Furthermore, we compared peak anti-gB antibody responses in seronegative mRNA-1647 vaccinees to that of seronegative gB/MF59 vaccine recipients.

Results: mRNA-1647 vaccination elicited and boosted HCMV-specific IgG responses in seronegative and seropositive vaccinees, respectively, including neutralizing and Fc-mediated effector antibody responses. gB-specific IgG responses were lower than PC-specific IgG responses. gB-specific IgG and antibody-dependent cellular phagocytosis responses were lower than those elicited by gB/MF59. However, mRNA-1647 elicited higher neutralization and antibody-dependent cellular cytotoxicity (ADCC) responses.

Conclusions: Overall, mRNA-1647 vaccination induced polyfunctional and durable HCMV-specific antibody responses, with lower gB-specific IgG responses but higher neutralization and ADCC responses compared to the gB/MF59 vaccine.

Clinical trials registration: NCT03382405 (mRNA-1647) and NCT00133497 (gB/MF59).

Keywords: durability; gB/MF59 vaccine; human cytomegalovirus; mRNA-1647 vaccine; pentametric complex.

Associated data

ClinicalTrials.gov/NCT03382405
ClinicalTrials.gov/NCT00133497

Grants and funding

5R21 AI136556/NH/NIH HHS/United States