The investigators broad objective is to develop methods for priming strong CTL and CD4 T cell responses to HIV using protein-based vaccines. The rationale for this focus is that these multiple immune responses should give the strongest protection. However, protein immunogens, which are desirable because they are in principle safer than live vaccines, fail to stimulate CTL immunity which may be one of the most important responses against HIV. Moreover, without strong adjuvants (which cannot be used in man) protein immunogens often elicit only weak and short-lived CD4-dependent immunity. In the previous funding period the investigators hypothesized that a novel antigen presenting pathway could be exploited to elicit CTL responses with protein immunogens. Their experimental approach was successful. In the present renewal, they will further develop this approach. They have 3 specific Aims:
Aim 1 : Develop methods to prime CTL immunity with non-living (protein) immunogens. The first objective of this Aim is to use our existing technology to develop a subunit vaccine with HIV antigens that elicits CTL immunity. The second objective is to further develop this technology so that it elicits the strongest possible immune response. The hypothesis underlying this second objective is that stronger antigen presentation will result in greater and longer lasting immunity. One experimental approach will increase antigenicity through modifications that enhance in antigen presenting cells that uptake of antigen and the rate of antigen processing. Another approach will attempt to increase immunogenicity through the formulation of antigen constructs with cytokines.
Aim 2 : Develop methods to prime concomitant MHC class I and II-restricted responses and mucosal immunity with protein immunogens. The hypothesis underlying this Aim is that optimal anti-viral vaccines will need to elicit not only CTL responses but also CD4 T cell responses and both systemic and mucosal immunity. The goal of this Aim is to engineer their antigen preparations from Aim 1 so that they elicit MHC class II- restricted responses (particularly Th1) and mucosal immunity. Important objectives will be oral bioavailability and systemic formulations that do not require inflammatory adjuvants.
Aim 3 : Evaluate vaccine strategies in primates. The goal of this Aim is to evaluate and adapt their methodologies for eliciting CTL and class II-restricted immunity in primates. Their experimental approach is to develop methodology to assay the activity of our antigen constructs in primate APCs. Once they identify active formulations and optimize their potency for primate cells, they will test their ability to elicit immune response in vivo in non-human primates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI031337-08
Application #
2667720
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Project Start
1991-03-01
Project End
2000-02-29
Budget Start
1998-03-01
Budget End
1999-02-28
Support Year
8
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pathology
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Vidard, L; Kovacsovics-Bankowski, M; Kraeft, S K et al. (1996) Analysis of MHC class II presentation of particulate antigens of B lymphocytes. J Immunol 156:2809-18
Falo Jr, L D; Kovacsovics-Bankowski, M; Thompson, K et al. (1995) Targeting antigen into the phagocytic pathway in vivo induces protective tumour immunity. Nat Med 1:649-53
Kovacsovics-Bankowski, M; Rock, K L (1995) A phagosome-to-cytosol pathway for exogenous antigens presented on MHC class I molecules. Science 267:243-6
Kovacsovics-Bankowski, M; Rock, K L (1994) Presentation of exogenous antigens by macrophages: analysis of major histocompatibility complex class I and II presentation and regulation by cytokines. Eur J Immunol 24:2421-8
Rock, K L; Rothstein, L; Gamble, S et al. (1993) Characterization of antigen-presenting cells that present exogenous antigens in association with class I MHC molecules. J Immunol 150:438-46
Kovacsovics-Bankowski, M; Clark, K; Benacerraf, B et al. (1993) Efficient major histocompatibility complex class I presentation of exogenous antigen upon phagocytosis by macrophages. Proc Natl Acad Sci U S A 90:4942-6
Rock, K L; Fleischacker, C; Gamble, S (1993) Peptide-priming of cytolytic T cell immunity in vivo using beta 2-microglobulin as an adjuvant. J Immunol 150:1244-52
Falo Jr, L D; Colarusso, L J; Benacerraf, B et al. (1992) Serum proteases alter the antigenicity of peptides presented by class I major histocompatibility complex molecules. Proc Natl Acad Sci U S A 89:8347-50
Grant, E P; Rock, K L (1992) MHC class I-restricted presentation of exogenous antigen by thymic antigen-presenting cells in vitro and in vivo. J Immunol 148:13-8