Enveloped virus-like particle expression of human cytomegalovirus glycoprotein B antigen induces antibodies with potent and broad neutralizing activity.

Abstract

A prophylactic vaccine to prevent the congenital transmission of human cytomegalovirus (HCMV) in newborns and to reduce life-threatening disease in immunosuppressed recipients of HCMV-infected solid organ transplants is highly desirable. Neutralizing antibodies against HCMV confer significant protection against infection, and glycoprotein B (gB) is a major target of such neutralizing antibodies. However, one shortcoming of past HCMV vaccines may have been their failure to induce high-titer persistent neutralizing antibody responses that prevent the infection of epithelial cells. We used enveloped virus-like particles (eVLPs), in which particles were produced in cells after the expression of murine leukemia virus (MLV) viral matrix protein Gag, to express either full-length CMV gB (gB eVLPs) or the full extracellular domain of CMV gB fused with the transmembrane and cytoplasmic domains from vesicular stomatitis virus (VSV)-G protein (gB-G eVLPs). gB-G-expressing eVLPs induced potent neutralizing antibodies in mice with a much greater propensity toward epithelial cell-neutralizing activity than that induced with soluble recombinant gB protein. An analysis of gB antibody binding titers and T-helper cell responses demonstrated that high neutralizing antibody titers were not simply due to enhanced immunogenicity of the gB-G eVLPs. The cells transiently transfected with gB-G but not gB plasmid formed syncytia, consistent with a prefusion gB conformation like those of infected cells and viral particles. Two of the five gB-G eVLP-induced monoclonal antibodies we examined in detail had neutralizing activities, one of which possessed particularly potent epithelial cell-neutralizing activity. These data differentiate gB-G eVLPs from gB antigens used in the past and support their use in a CMV vaccine candidate with improved neutralizing activity against epithelial cell infection.

• Authors: Marc Kirchmeier, Anne-Catherine Fluckiger, Catalina Soare, Jasminka Bozic, Barthelemy Ontsouka, Tanvir Ahmed, Abebaw Diress, Lenore Pereira, Florian Schödel, Stanley Plotkin, Charlotte Dalba, David Klatzmann, David E Anderson
• Journal: Clinical and vaccine immunology : CVI (Clin Vaccine Immunol) Vol. 21 Issue 2 Pg. 174-80 (Feb 2014) ISSN: 1556-679X [Electronic] United States
• PMID: 24334684 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Neutralizing
• Antibodies, Viral
• Cytomegalovirus Vaccines
• Vaccines, Virus-Like Particle
• Viral Envelope Proteins
• glycoprotein B, Simplexvirus

Topics

• Animals
• Antibodies, Neutralizing (blood)
• Antibodies, Viral (blood)
• Cytomegalovirus (immunology)
• Cytomegalovirus Infections (immunology, prevention & control)
• Cytomegalovirus Vaccines (genetics, immunology, metabolism)
• Epithelial Cells (virology)
• Female
• Mice
• Mice, Inbred BALB C
• Vaccines, Virus-Like Particle (administration & dosage, genetics, immunology, metabolism)
• Viral Envelope Proteins (administration & dosage, genetics, immunology, metabolism)