title: DNA/MVA vaccine for HIV type 1: effects of codon-optimization and the expression of aggregates or virus-like particles on the immunogenicity of the DNA prime.
abstract: Recently, a vaccine consisting of DNA priming followed by boosting with modified vaccinia Ankara (MVA) has provided long-term protection of rhesus macaques against a virulent challenge with a chimera of simian and human immunodeficiency viruses. Here, we report studies on the development of the DNA component for a DNA/MVA HIV vaccine for humans. Specifically, we assess the ability of a codon-optimized Gag-expressing DNA and two noncodon-optimized Gag-Pol-Env-expressing DNAs to prime the MVA booster dose. The codon-optimized DNA expressed virus-like particles (VLPs), whereas one of the noncodon-optimized DNAs expressed VLPs and the other expressed aggregates of HIV proteins. The MVA boost expressed Gag-Pol and Env and produced VLPs. Immunogenicity studies in macaques used one intramuscular prime with 600 microg of DNA and two intramuscular boosts with 1 x 10(8) pfu of MVA at weeks 8 and 30. The codon-optimized and noncodon-optimized DNAs proved similar in their ability to prime anti-Gag T cell responses. The aggregate and VLP-expressing Gag-Pol-Env DNAs also showed no significant differences in their ability to prime anti-Env Ab responses. The second MVA booster dose did not increase the peak CD4 and CD8 T cell responses, but increased anti-Env Ab titers by 40- to 90-fold. MVA-only immunizations elicited 10-100 times lower frequencies of T cells and 2-4 lower titers of anti-Env Ab than the Gag-Pol-Env DNA/MVA immunizations. Based on the breadth of the T cell response and a trend toward higher titers of anti-Env Ab, we are moving forward with human trials of the noncodon-optimized VLP-expressing DNA.
authors.affiliation: Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30329, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Smith
authors.forename: Rama Rao
authors.initials: RR
authors.lastname: Amara
authors.forename: David
authors.initials: D
authors.lastname: Campbell
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Milloni
authors.initials: M
authors.lastname: Patel
authors.forename: Sunita
authors.initials: S
authors.lastname: Sharma
authors.forename: Salvatore T
authors.initials: ST
authors.lastname: Butera
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Ellenberger
authors.forename: Hong
authors.initials: H
authors.lastname: Yi
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Chennareddi
authors.forename: James G
authors.initials: JG
authors.lastname: Herndon
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wyatt
authors.forename: David
authors.initials: D
authors.lastname: Montefiori
authors.forename: Bernard
authors.initials: B
authors.lastname: Moss
authors.forename: Harold M
authors.initials: HM
authors.lastname: McClure
authors.forename: Harriet L
authors.initials: HL
authors.lastname: Robinson
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D000818:Animals; D003062:Codon / Q000235:genetics*; D015752:Genes, env; D015750:Genes, gag; D015751:Genes, pol; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control; D015497:HIV-1; D008253:Macaca mulatta; D014611:Vaccination; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D003062:Codon; D019444:Vaccines, DNA