Heterosubtypic, cross-reactive immunity to human Cytomegalovirus glycoprotein B

Abstract

Cytomegalovirus (CMV) genome is highly variable and heterosubtypic immunity should be considered in vaccine development since it can enhance protection in a cross-reactive manner. Here, we developed a protein array to evaluate heterosubtypic immunity to CMV glycoprotein B (gB) in natural infection and vaccination. DNA sequences of four antigenic domains (AD1, AD2, AD4/5 and AD5) of gB were amplified from six reference and 12 clinical CMV strains, and the most divergent genotypes were determined by phylogenetic analysis. Assigned genotypes were in vitro translated and immobilized on protein array. Then, we tested immune response of variable serum groups (primarily infected patients, reactivated CMV infections and healthy individuals with latent CMV infection, as well gB-vaccinated rabbits) with protein in situ array (PISA). Serum antibodies of all patient cohorts and gB-vaccinated rabbits recognized many genetic variants of ADs on protein array, including but not limited to the subtype of infecting strain. High-grade cross-reactivity was observed. In several patients, we observed none or neglectable immune response to AD1 and AD2, while the same patients showed high antibody response to AD4/5 and AD5. Among the primary infected patients, AD5 was the predominant antigenic domain, in antibody response. The most successful CMV vaccine to date contains gB and demonstrates only 50% efficacy. In this study, we showed that heterosubtypic and cross-reactive immunity to CMV gB is extensive. Therefore, the failure of CMV gB vaccines cannot be explained by a highly, strain-specific immunity. Our observations suggest that other CMV antigens should be addressed in vaccine design.

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

“…We determined the total vaccine dosage by giving New Zealand White rabbits 50 µg mRNA-LNP vaccines based on previous studies 24,27 . Since multivalent vaccines were usually designed by equally distributing the total dosage for each antigen at a 1:1 ratio [30][31][32][33] , we applied a similar strategy to design the bivalent and pentavalent gB mRNA vaccines in our study.…”

“…Lipid nanoparticles-encapsulated nucleoside-modified mRNA (mRNA-LNP) is a novel vaccine platform that was translated for safe and effective human use in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic 23 and has had success in other vaccine pursuits, including human immunodeficiency virus type 1 (HIV-1) 24,25 , Zika virus 26 , influenza virus 27 , and herpes simplex virus type 2 (HSV-2) 28 . Additionally 29 , multivalent mRNA-LNP vaccines have proved to be a promising strategy for the development of broadly protective SARS-COV-2 and influenza virus vaccines [30][31][32][33] . Recently, ModernaTX, Inc. has launched a phase III trial of an mRNA-LNP including HCMV Merlin strain gB and the pentameric glycoprotein complex.…”

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

“…Additionally, the mRNA-LNP vaccine possesses multiple advantages, including a favorable safety profile, presentation of immunogens on the cell surface, rapid and cost-effective manufacturing process, and the ease of combining multiple antigens into a single vaccine 34 . Indeed, the generation of multivalent mRNA-LNP vaccines proved to be a promising strategy for the development of broadly protective influenza virus vaccines 35, 36 . Our lab previously compared the immunogenicity of the mRNA-LNP delivery platform to the protein-based full-length or ectodomain platform with squalene-like adjuvants encoding full-length HCMV gB genotype 1 (gB-1, sequence from Towne strain, GenBank accessioning number: FJ616285.1) in a rabbit model.…”

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

“…Additionally, the mRNA-LNP vaccine possesses multiple advantages, including a favorable safety profile, presentation of immunogens on the cell surface , rapid and costeffective manufacturing process, and the ease of combining multiple antigens into a single vaccine 34 . Indeed, the generation of multivalent mRNA-LNP vaccines proved to be a promising strategy for the development of broadly protective influenza virus vaccines 35,36 .…”