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.
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.
Smith
James M
JM
Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30329, USA.
Amara
Rama Rao
RR
Campbell
David
D
Xu
Yan
Y
Patel
Milloni
M
Sharma
Sunita
S
Butera
Salvatore T
ST
Ellenberger
Dennis L
DL
Yi
Hong
H
Chennareddi
Lakshmi
L
Herndon
James G
JG
Wyatt
Linda S
LS
Montefiori
David
D
Moss
Bernard
B
McClure
Harold M
HM
Robinson
Harriet L
HL
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*
D016915:AIDS Vaccines; D003062:Codon; D019444:Vaccines, DNA