Multivalent Human Cytomegalovirus Glycoprotein B Nucleoside-Modified mRNA Vaccines Demonstrate a Greater Breadth in T cell but not Antibody Responses

Permar, S. R.; Wang, H.-Y.; Li, L.; Nelson, C. S.; Barfield, R.; Valencia, S.; Chan, C.; Muramatsu, H.; Lin, P. J. C.; Pardi, N.; An, Z.; Weissman, D.

doi:10.1101/2022.11.23.517695

bioRxiv · 10.1101/2022.11.23.517695

Multivalent Human Cytomegalovirus Glycoprotein B Nucleoside-Modified mRNA Vaccines Demonstrate a Greater Breadth in T cell but not Antibody Responses

Permar, S. R.·Wang, H.-Y.·Li, L.·Nelson, C. S.·Barfield, R.·Valencia, S.·Chan, C.·Muramatsu, H.·Lin, P. J. C.·Pardi, N.·An, Z.·Weissman, D.

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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 higher magnitude or breadth of the IgG response to the gB ectodomain or cell-associated gB compared to that of 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. Yet, peripheral blood mononuclear cell-derived 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. Our data suggests that inclusion of multivalent gB antigens is beneficial to increase the magnitude of T cell response but not an effective strategy to increase the breadth of anti-HCMV gB antibody responses. Further studies are required to validate whether the multivalent gB mRNA vaccines could effectively increase the T cell response breadth.

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Permar, S. R., Wang, H.-Y., Li, L., Nelson, C. S., Barfield, R., Valencia, S., Chan, C., Muramatsu, H., Lin, P. J. C., Pardi, N., An, Z., Weissman, D.. 2022-11-29. Multivalent Human Cytomegalovirus Glycoprotein B Nucleoside-Modified mRNA Vaccines Demonstrate a Greater Breadth in T cell but not Antibody Responses. https://doi.org/10.1101/2022.11.23.517695

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