A DNA-based vaccine for the prevention of human cytomegalovirus-associated diseases.
Multiple lines of evidence indicate that in the transplant population human cytomegalovirus (HCMV) infection and its associated diseases are controlled by humoral and cellular immune responses similar to those that arise in asymptomatic, healthy individuals during a naturally-acquired infection. The dominant antibody response to HCMV is to the major surface glycoprotein B (gB) and the dominant cellular immune response is to the tegument phosphoprotein (pp65). We propose that an immunotherapeutic plasmid DNA (pDNA) vaccination approach that induces the requisite responses to major immunological targets of HCMV may provide relief from HCMV-associated diseases in the transplant setting. We have developed gene-based immunotherapeutic products consisting of pDNAs encoding gB and pp65 of HCMV. When tested individually in mice, both pDNAs were highly immunogenic. Relative to vaccination with either gB or pp65 pDNA delivered alone, vaccination with gB and pp65 pDNAs delivered together in phosphate-buffered saline (PBS) elicited reduced antibody and T cell responses to each antigen. Formulating this bivalent vaccine with a poloxamer-based delivery system (VF-P1205-02A), however, significantly increased the antigen-specific immune responses relative to those induced with the bivalent vaccine in PBS, and completely abrogated the decrease in pp65-specific T cell responses observed in mice covaccinated with the pDNAs in PBS. Based on these data, and a favorable safety and toxicity profile in preclinical studies, the bivalent HCMV vaccine consisting of gB and pp65 pDNAs delivered with VF-P1205-02A has advanced to human clinical trials.
Selinsky
C
C
Vical Incorporated, San Diego, California, USA. CSelinsky@vical.com
Luke
C
C
Wloch
M
M
Geall
A
A
Hermanson
G
G
Kaslow
D
D
Evans
T
T
D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D003586:Cytomegalovirus Infections / Q000150:complications* / Q000276:immunology / Q000517:prevention & control*; D022482:Cytomegalovirus Vaccines / Q000276:immunology / Q000627:therapeutic use*; D004279:DNA, Viral / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D015967:Gene Expression Regulation, Viral; D005814:Genes, Viral / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020442:Poloxamer; D013501:Surface-Active Agents; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology / Q000627:therapeutic use
D000914:Antibodies, Viral; D022482:Cytomegalovirus Vaccines; D004279:DNA, Viral; D013501:Surface-Active Agents; D019444:Vaccines, DNA; D020442:Poloxamer; D007371:Interferon-gamma