Multivalent cytomegalovirus glycoprotein B nucleoside modified mRNA vaccines did not demonstrate a greater antibody breadth

Hsuan-Yuan Wang; Leike Li; Cody S Nelson; Richard Barfield; Sarah Valencia; Cliburn Chan; Hiromi Muramatsu; Paulo J C Lin; Norbert Pardi; Zhiqiang An; Drew Weissman; Sallie R Permar

doi:10.1038/s41541-024-00821-3

Multivalent cytomegalovirus glycoprotein B nucleoside modified mRNA vaccines did not demonstrate a greater antibody breadth

NPJ Vaccines. 2024 Feb 20;9(1):38. doi: 10.1038/s41541-024-00821-3.

Authors

Hsuan-Yuan Wang^{1

2}, Leike Li^{3

4}, Cody S Nelson⁵, Richard Barfield^{6

7}, Sarah Valencia², Cliburn Chan^{6

7}, Hiromi Muramatsu^{8

9}, Paulo J C Lin¹⁰, Norbert Pardi^{8

9}, Zhiqiang An³, Drew Weissman⁸, Sallie R Permar¹¹

Affiliations

¹ Department of Pediatrics, Weill Cornell Medicine, New York, NY, 10065, USA.
² Duke University Medical Center, Duke Human Vaccine Institute, Durham, NC, 27710, USA.
³ Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
⁴ Takeda Pharmaceutical, San Diego, CA, 92121, USA.
⁵ Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
⁶ Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, 27710, USA.
⁷ Center for Human Systems Immunology, Duke University Medical Center, Durham, NC, 27710, USA.
⁸ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁹ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
¹⁰ Acuitas Therapeutics, Vancouver, BC, V6T 1Z3, Canada.
¹¹ Department of Pediatrics, Weill Cornell Medicine, New York, NY, 10065, USA. sallie.permar@med.cornell.edu.

Abstract

Human cytomegalovirus (HCMV) remains the most common congenital infection and infectious complication in immunocompromised patients. The most successful HCMV vaccine to date, an HCMV glycoprotein B (gB) subunit vaccine adjuvanted with MF59, achieved 50% efficacy against primary HCMV infection. A previous study demonstrated that gB/MF59 vaccinees were less frequently infected with HCMV gB genotype strains most similar to the vaccine strain than strains encoding genetically distinct gB genotypes, suggesting strain-specific immunity accounted for the limited efficacy. To determine whether vaccination with multiple HCMV gB genotypes could increase the breadth of anti-HCMV gB humoral and cellular responses, we immunized 18 female rabbits with monovalent (gB-1), bivalent (gB-1+gB-3), or pentavalent (gB-1+gB-2+gB-3+gB-4+gB-5) gB lipid nanoparticle-encapsulated nucleoside-modified RNA (mRNA-LNP) vaccines. The multivalent vaccine groups did not demonstrate a higher magnitude or breadth of the IgG response to the gB ectodomain or cell-associated gB compared to that of the monovalent vaccine. Also, the multivalent vaccines did not show an increase in the breadth of neutralization activity and antibody-dependent cellular phagocytosis against HCMV strains encoding distinct gB genotypes. Interestingly, peripheral blood mononuclear cell-derived gB-2-specific T-cell responses elicited by multivalent vaccines were of a higher magnitude compared to that of monovalent vaccinated animals against a vaccine-mismatched gB genotype at peak immunogenicity. Yet, no statistical differences were observed in T cell response against gB-3 and gB-5 variable regions among the three vaccine groups. Our data suggests that the inclusion of multivalent gB antigens is not an effective strategy to increase the breadth of anti-HCMV gB antibody and T cell responses. Understanding how to increase the HCMV vaccine protection breadth will be essential to improve the vaccine efficacy.

Abstract

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