Abstract

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.

Highlights

  • Human cytomegalovirus (HCMV) impacts 1 in 150 live born infants, making this pathogen the most common cause of congenital infection worldwide [1, 2]

  • The antigenic domain 3 (AD-3) immunodominant IgG response following human glycoprotein B (gB)/MF59 vaccination was closely mimicked in rabbits, with 78% of binding antibodies directed against this region in the full-length gB protein group compared to 1% and 46% in the ectodomain and mRNA-lipid nanoparticle (LNP)

  • After more than a half century of research and development, we remain without a clinically-licensed vaccine or therapeutic to reduce the burden of HCMV-associated disease

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Summary

Introduction

Human cytomegalovirus (HCMV) impacts 1 in 150 live born infants, making this pathogen the most common cause of congenital infection worldwide [1, 2]. HCMV is the most prevalent infection among solid organ and hematopoietic stem cell transplant recipients, causing end-organ disease such as gastroenteritis, pneumonitis, or hepatitis and potentially predisposing these individuals to allograft rejection and/or failure [5, 6]. We remain without a vaccine or immunotherapeutic intervention to reduce the burden of disease among newborn children and transplant recipients. A variety of vaccine platforms and formulations have been trialed for the prevention of both congenital (reviewed in [7]) and transplant-associated HCMV disease (reviewed in [8]), of which the most efficacious has been the glycoprotein B (gB) subunit vaccine administered with. GB is highly-expressed and an immune-dominant target following natural infection, making this protein an attractive target for vaccination. gB/MF59 subunit vaccination demonstrated moderate (~50%) efficacy in blocking

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