The development of a safe and effective HIV-1 vaccine is a global health priority. Plasmid DNA vaccines have elicited potent virus-specific cellular immune responses in animal models but have proven only marginally immunogenic in clinical trials to date. Strategies aimed at augmenting the immunogenicity of DNA vaccines are therefore an area of active investigation. We have recently demonstrated that co-administration of the combination of plasmid MIP-1alpha and plasmid GM-CSF with DNA vaccines resulted in the recruitment of large numbers of dendritic cells to the site of inoculation and a synergistic and durable augmentation of DNA vaccine-elicited immune responses in mice. We hypothesize that the immunogenicity of DNA vaccines is limited by the availability of professional antigen-presenting cells (APCs) at the site of inoculation. We further hypothesize that DNA vaccine-elicited immune responses in both mice and rhesus monkeys will be augmented by co-administration of plasmid-encoded chemoattractants that recruit APCs to the site of inoculation. To investigate these hypotheses, we propose: I. To investigate the immunogenicity, protective efficacy, and histopathology of a novel vaccine strategy consisting of GM-CSF/MIP-1alpha-augmented DNA vaccine priming followed by rAd5 boosting in rhesus monkeys; II. To construct plasmid chemokine/Ig fusions and to assess their ability to augment DNA vaccine-elicited immune responses in mice; III. To assess the ability of plasmid chemokines combined with plasmid costimulatory molecules to augment DNA vaccine-elicited immune responses in mice; and IV. To investigate the immunogenicity and protective efficacy of cytokine-augmented DNA vaccine priming followed by rAd5 boosting in rhesus monkeys with pre-existing anti-Ad5 immunity. The long-term objectives of these studies are to develop novel vaccine regimens that recruit APCs to the site of inoculation in animal models and to consider advancing the most promising strategies into clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058727-05
Application #
7344747
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Pensiero, Michael N
Project Start
2004-02-01
Project End
2010-01-31
Budget Start
2008-02-01
Budget End
2010-01-31
Support Year
5
Fiscal Year
2008
Total Cost
$369,208
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Barouch, Dan H; O'Brien, Kara L; Simmons, Nathaniel L et al. (2010) Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys. Nat Med 16:319-23
Nkolola, Joseph P; Peng, Hanqin; Settembre, Ethan C et al. (2010) Breadth of neutralizing antibodies elicited by stable, homogeneous clade A and clade C HIV-1 gp140 envelope trimers in guinea pigs. J Virol 84:3270-9
Barouch, Dan H; Korber, Bette (2010) HIV-1 vaccine development after STEP. Annu Rev Med 61:153-67
Rosenberg, Eric S; Graham, Barney S; Chan, Ellen S et al. (2010) Safety and immunogenicity of therapeutic DNA vaccination in individuals treated with antiretroviral therapy during acute/early HIV-1 infection. PLoS One 5:e10555
Barouch, Dan H; Liu, Jinyan; Lynch, Diana M et al. (2009) Protective efficacy of a single immunization of a chimeric adenovirus vector-based vaccine against simian immunodeficiency virus challenge in rhesus monkeys. J Virol 83:9584-90
Liu, Jinyan; O'Brien, Kara L; Lynch, Diana M et al. (2009) Immune control of an SIV challenge by a T-cell-based vaccine in rhesus monkeys. Nature 457:87-91
Kaufman, David R; Goudsmit, Jaap; Holterman, Lennart et al. (2008) Differential antigen requirements for protection against systemic and intranasal vaccinia virus challenges in mice. J Virol 82:6829-37
Liu, Jinyan; Kjeken, Rune; Mathiesen, Iacob et al. (2008) Recruitment of antigen-presenting cells to the site of inoculation and augmentation of human immunodeficiency virus type 1 DNA vaccine immunogenicity by in vivo electroporation. J Virol 82:5643-9
Barouch, Dan H (2008) Challenges in the development of an HIV-1 vaccine. Nature 455:613-9
Abbink, Peter; Lemckert, Angelique A C; Ewald, Bonnie A et al. (2007) Comparative seroprevalence and immunogenicity of six rare serotype recombinant adenovirus vaccine vectors from subgroups B and D. J Virol 81:4654-63

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