Abstract

The transmission of HIV-1 by both sexual and parenteral routes makes it likely that a successful preventative vaccine against this virus will need to induce protective immunity in both mucosal and systemic compartments. Moreover, aside from attenuated live virus vaccines, candidate HIV-1 vaccines usually require a prime-boost immunization strategy to elicit the broadest immune responses. The need to induce both mucosal and systemic immunity using a prime-boost protocol provides the rationale for our HIV-1 vaccine development program. The long-term objective of this program is to develop an HIV-1 vaccine that elicits protective immunity in both the mucosal and systemic compartments. This objective is pursued via two goals. The primary goal is to evaluate the safety and immunogenicity of an oral Salmonella HIV-1 gp120 DNA vaccine vector in health human volunteers. This goal stems from a long-standing collaboration of our group to develop Salmonella as a mucosal delivery system for HIV-1 antigens. To our knowledge, this will be the first study in volunteers to use an intracellular bacterium to deliver a DNA vaccine mucosally. The secondary goal is to develop an Env immunogen that elicits a broader spectrum of neutralizing antibodies than gp120 which can be delivered by Salmonella typhi as a DNA vaccine and as a soluble protein immunogen. Accordingly, we will evaluate the safety and immunogenicity of a new single chain chimeric protein, scgp120/Ba-L- CD4, that is predicted to elicit broadly neutralizing antibodies due to the constitutive exposure of conserved epitopes in the co-receptor binding domain of gp120. In this immunogen proves safe in preclinical studies in animals, it will be evaluated in human volunteers both as a soluble subunit protein and formulated as a DNA vaccine delivered by attenuated Salmonella as a vaccine vector for DNA vaccines encoding gp120Ba-L and scgp120Ba-L-CD4. Project 2 will carry out Phase I clinical trials in volunteers of these immunogens based on the preclinical data obtained in Projects 1 and 2. These projects will be supported by an Administrative Core.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI047490-03
Application #
6534251
Study Section
Special Emphasis Panel (ZAI1-ALR-A (J1))
Program Officer
Pensiero, Michael N
Project Start
2000-09-01
Project End
2005-06-30
Budget Start
2002-09-01
Budget End
2003-06-30
Support Year
3
Fiscal Year
2002
Total Cost
$1,220,773
Indirect Cost

  Institution

Name
University of MD Biotechnology Institute
Department
Type
Organized Research Units
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21202

  Publications

Gallo, Robert C (2015) Developing a Successful HIV Vaccine. J Infect Dis 212 Suppl 1:S40-1
Fouts, Timothy R; Bagley, Kenneth; Prado, Ilia J et al. (2015) Balance of cellular and humoral immunity determines the level of protection by HIV vaccines in rhesus macaque models of HIV infection. Proc Natl Acad Sci U S A 112:E992-9
DeVico, Anthony; Fouts, Timothy; Lewis, George K et al. (2007) Antibodies to CD4-induced sites in HIV gp120 correlate with the control of SHIV challenge in macaques vaccinated with subunit immunogens. Proc Natl Acad Sci U S A 104:17477-82
Vu, John R; Fouts, Timothy; Bobb, Katherine et al. (2006) An immunoglobulin fusion protein based on the gp120-CD4 receptor complex potently inhibits human immunodeficiency virus type 1 in vitro. AIDS Res Hum Retroviruses 22:477-90
Abdelwahab, Sayed F; Cocchi, Fiorenza; Bagley, Kenneth C et al. (2003) HIV-1-suppressive factors are secreted by CD4+ T cells during primary immune responses. Proc Natl Acad Sci U S A 100:15006-10
Fouts, T R; DeVico, A L; Onyabe, D Y et al. (2003) Progress toward the development of a bacterial vaccine vector that induces high-titer long-lived broadly neutralizing antibodies against HIV-1. FEMS Immunol Med Microbiol 37:129-34
Bagley, K C; Shata, M T; Onyabe, D Y et al. (2003) Immunogenicity of DNA vaccines that direct the coincident expression of the 120 kDa glycoprotein of human immunodeficiency virus and the catalytic domain of cholera toxin. Vaccine 21:3335-41
Hone, David M; DeVico, Anthony L; Fouts, Timothy R et al. (2002) Development of vaccination strategies that elicit broadly neutralizing antibodies against human immunodeficiency virus type 1 in both the mucosal and systemic immune compartments. J Hum Virol 5:17-23
Devico, Anthony L; Fouts, Timothy R; Shata, Mohamed T et al. (2002) Development of an oral prime-boost strategy to elicit broadly neutralizing antibodies against HIV-1. Vaccine 20:1968-74
Chow, Yen-Hung; Wei, Olivia L; Phogat, Sanjay et al. (2002) Conserved structures exposed in HIV-1 envelope glycoproteins stabilized by flexible linkers as potent entry inhibitors and potential immunogens. Biochemistry 41:7176-82

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