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Multivalent cytomegalovirus glycoprotein B nucleoside modified mRNA vaccines did not demonstrate a greater antibody
Hsuan-Yuan Wang1,2, Leike Li3,4, Cody S Nelson5
1Department of Pediatrics, Weill Cornell Medicine, New York, NY, 10065, USA.
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.
Insights
Multivalent human cytomegalovirus (HCMV) glycoprotein B (gB) mRNA vaccines did not broaden antibody or T-cell responses compared to monovalent vaccines. This suggests that including multiple gB genotypes is not an effective strategy for improving HCMV vaccine breadth and efficacy.
Area of Science:
- Virology
- Vaccinology
- Immunology
Background:
- Human cytomegalovirus (HCMV) is a common congenital infection and complication in immunocompromised individuals.
- Current HCMV glycoprotein B (gB) subunit vaccines show limited efficacy, potentially due to strain-specific immunity.
- Previous vaccine trials suggest that immunity may be biased towards vaccine-matched HCMV gB genotypes.
Purpose of the Study:
- To investigate if vaccinating with multiple HCMV gB genotypes can enhance the breadth of humoral and cellular immune responses.
- To evaluate the efficacy of monovalent, bivalent, and pentavalent gB mRNA-lipid nanoparticle (mRNA-LNP) vaccines in rabbits.
Main Methods:
- Rabbits were immunized with monovalent (gB-1), bivalent (gB-1+gB-3), or pentavalent (gB-1 through gB-5) gB mRNA-LNP vaccines.
- Humoral responses were assessed by measuring IgG to gB ectodomain and cell-associated gB.
- Neutralization activity, antibody-dependent cellular phagocytosis (ADCP), and T-cell responses were evaluated against various HCMV gB genotypes.
Main Results:
- Multivalent vaccines did not increase the magnitude or breadth of IgG responses compared to monovalent vaccines.
- No enhanced neutralization or ADCP breadth was observed with multivalent vaccines against diverse HCMV gB genotypes.
- While some gB-2 specific T-cell responses were higher in multivalent groups, no overall increase in T-cell breadth was detected across genotypes.
Conclusions:
- The inclusion of multiple HCMV gB genotypes in mRNA-LNP vaccines does not effectively broaden antibody or T-cell responses.
- This strategy is unlikely to improve the protective breadth of HCMV vaccines.
- Further research is needed to identify effective strategies for increasing HCMV vaccine protection breadth.
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