Human Cytomegalovirus mRNA-1647 Vaccine Candidate Elicits Potent and Broad Neutralization and Higher Antibody-Dependent Cellular Cytotoxicity Responses than that of the Partially Effective gB/MF59 Vaccine

Abstract

BackgroundThe MF59-adjuvanted gB subunit (gB/MF59) vaccine demonstrated ~50% efficacy against human cytomegalovirus (HCMV) acquisition in multiple clinical trials, suggesting efforts to improve this vaccine design might yield a vaccine suitable for licensure. A vaccine candidate employing nucleoside-modified mRNAs encoding HCMV gB and pentameric complex (PC) encapsulated in lipid nanoparticle, mRNA-1647, is currently in late-stage efficacy trials. Yet, its immunogenicity has not been compared to the partially-effective gB/MF59 vaccine.MethodsWe assessed neutralizing and Fc-mediated IgG effector antibody responses induced by mRNA-1647, a vaccine comprising an equal mass of 6 mRNAs encoding gB and PC antigens, in both HCMV seropositive and seronegative vaccinees from a first-in-human clinical trial through 1-year following 3rdvaccination using a systems serology approach. Further, we compared peak anti-gB antibody responses in seronegative mRNA-1647 vaccinees to that of seronegative female adolescent gB/MF59 vaccine recipients.ResultsmRNA-1647 vaccination boosted pre-existing HCMV-specific IgG responses in seropositive vaccinees, including neutralizing and Fc-mediated effector antibody responses. In seronegative vaccinees, mRNA-1647 induced durable and functional HCMV-specific IgG responses. Elicited gB-specific IgG responses were lower than the PC-specific IgG responses. Additionally, gB-specific IgG and antibody-dependent cellular phagocytosis (ADCP) responses were lower than those elicited by gB/MF59. However, mRNA-1647 elicited robust neutralization and high antibody-dependent cellular cytotoxicity (ADCC) responses.ConclusionsmRNA-1647 vaccination induced polyfunctional and durable HCMV-specific antibody responses. mRNA-1647-elicited gB-specific IgG responses were lower than PC-specific IgG responses and lower than those elicited by the partially effective gB/MF59. However, higher neutralization and ADCC responses were elicited by mRNA-1647 than gB/MF59.Clinical Trials RegistrationClinicalTrials.gov(NCT03382405, mRNA-1647) and (NCT00133497, gB/MF59).SummarymRNA-1647 HCMV vaccine elicited polyfunctional and durable antibody responses in humans. While the mRNA-1647-elicited glycoprotein B (gB)-specific IgG responses were lower than that of the moderately-effective gB/MF59 vaccine, the pentameric complex (PC)-specific IgG responses were strong.

Induction of long-term tolerance to a specific antigen using anti-CD3 lipid nanoparticles following gene therapy

“… 21 , 37 , 38 , 39 , 40 , 41 , 42 , 43 To date, therapeutic mAbs encoded by mRNA LNPs have been used and reported in numerous preclinical and clinical studies. 16 , 18 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 An mRNA LNP-based therapeutic mAb expression system has several potential advantages over recombinant mAbs for the treatment of patients. The variation of recombinant products produced in different cell systems can be diminished.…”