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

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.

SUBMITTER: Jenks JA

PROVIDER: S-EPMC8058742 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A vaccine to prevent maternal acquisition of human cytomegalovirus (HCMV) during pregnancy is a primary strategy to reduce the incidence of congenital disease. The MF59-adjuvanted glycoprotein B (gB) protein subunit vaccine (gB/MF59) is the most efficacious vaccine tested to date for this indication. We previously identified that gB/MF59 vaccination elicited poor neutralizing antibody responses and an immunodominant response against gB antigenic domain 3 (AD-3). Thus, we sought to test novel gB vaccines to improve functional antibody responses and reduce AD-3 immunodominance. Groups of juvenile New Zealand White rabbits were administered 3 sequential doses of the full-length gB protein with an MF59-like squalene-based adjuvant, the gB ectodomain protein (lacking AD-3) with squalene adjuvant, or lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA encoding full-length gB. All vaccines were highly immunogenic with similar kinetics and comparable peak gB-binding and functional antibody responses. The AD-3-immunodominant IgG response following human gB/MF59 vaccination was closely mimicked in rabbits. Though gB ectodomain subunit vaccination eliminated targeting of epitopes in AD-3, it did not improve vaccine-elicited neutralizing or nonneutralizing antibody functions. gB nucleoside-modified mRNA-LNP-immunized rabbits exhibited an enhanced durability of vaccine-elicited antibody responses. Furthermore, the gB mRNA-LNP vaccine enhanced the breadth of IgG binding responses against discrete gB peptides. Finally, low-magnitude gB-specific T cell activity was observed in the full-length gB protein and mRNA-LNP groups, though not in ectodomain-vaccinated rabbits. Altogether, these data suggest that the use of gB nucleoside-modified mRNA-LNP vaccines is a viable strategy for improving on the partial efficacy of gB/MF59 vaccination and should be further evaluated in preclinical models.IMPORTANCE Human cytomegalovirus (HCMV) is the most common infectious cause of infant birth defects, resulting in permanent neurological disability for one newborn child every hour in the United States. After more than a half century of research and development, we remain without a clinically licensed vaccine or immunotherapeutic to reduce the burden of HCMV-associated disease. In this study, we sought to improve upon the glycoprotein B protein vaccine (gB/MF59), the most efficacious HCMV vaccine evaluated in a clinical trial, via targeted modifications to either the protein structure or vaccine formulation. Utilization of a novel vaccine platform, nucleoside-modified mRNA formulated in lipid nanoparticles, increased the durability and breadth of vaccine-elicited antibody responses. We propose that an mRNA-based gB vaccine may ultimately prove more efficacious than the gB/MF59 vaccine and should be further evaluated for its ability to elicit antiviral immune factors that can prevent HCMV-associated disease.

Project description:BackgroundCytomegalovirus end-organ disease can be prevented by giving ganciclovir when viraemia is detected in allograft recipients. Values of viral load correlate with development of end-organ disease and are moderated by pre-existing natural immunity. Our aim was to determine whether vaccine-induced immunity could do likewise.MethodsWe undertook a phase-2 randomised placebo controlled trial in adults awaiting kidney or liver transplantation at the Royal Free Hospital, London, UK. Exclusion criteria were pregnancy, receipt of blood products (except albumin) in the previous 3 months, and simultaneous multiorgan transplantation. 70 patients seronegative and 70 seropositive for cytomegalovirus were randomly assigned from a scratch-off randomisation code in a 1:1 ratio to receive either cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant or placebo, each given at baseline, 1 month and 6 months later. If a patient was transplanted, no further vaccinations were given and serial blood samples were tested for cytomegalovirus DNA by real-time quantitative PCR (rtqPCR). Any patient with one blood sample containing more than 3000 cytomegalovirus genomes per mL received ganciclovir until two consecutive undetectable cytomegalovirus DNA measurements. Safety and immunogenicity were coprimary endpoints and were assessed by intention to treat in patients who received at least one dose of vaccine or placebo. This trial is registered with ClinicalTrials.gov, NCT00299260.Findings67 patients received vaccine and 73 placebo, all of whom were evaluable. Glycoprotein-B antibody titres were significantly increased in both seronegative (geometric mean titre 12,537 (95% CI 6593-23,840) versus 86 (63-118) in recipients of placebo recipients; p<0.0001) and seropositive (118,395; 64,503-217,272) versus 24,682 (17,909-34,017); p<0.0001) recipients of vaccine. In those who developed viraemia after transplantation, glycoprotein-B antibody titres correlated inversely with duration of viraemia (p=0.0022). In the seronegative patients with seropositive donors, the duration of viraemia (p=0.0480) and number of days of ganciclovir treatment (p=0.0287) were reduced in vaccine recipients.InterpretationAlthough cytomegalovirus disease occurs in the context of suppressed cell-mediated immunity post-transplantation, humoral immunity has a role in reduction of cytomegalovirus viraemia. Vaccines containing cytomegalovirus glycoprotein B merit further assessment in transplant recipients.FundingNational Institute of Allergy and Infectious Diseases, Grant R01AI051355 and Wellcome Trust, Grant 078332.SponsorUniversity College London (UCL).

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

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