The recent ability to map neutralizing B cell epitopes on protein antigens has created much interest in the potential use of these """"""""hapten-like"""""""" antigens in vaccine development. However, peptide antigens often require conjugation to an immunogenic carrier for efficient immunogenicity. An optimal protein carrier moiety suitable for human immunization is not available. The objective of the proposal is to exploit the potential of the hepatitis B nucleocapsid to function as a multi-valent carrier platform to enhance the immune response to weak peptide antigens. We recently used the HBcAg as a carrier for rodent (i.e., P. berghei, P. yoelii) and human (i.e., P. falciparum) malarial vaccine development. The rodent vaccines are 90-100% protective and the human candidate vaccine elicits unprecedented levels of sporozoite-neutralizing antibody in mice. A number of unique immunologic characteristics of the native HBCAG and the success achieved with the hybrid HBcAg-malaria candidate vaccines suggest that this particulate protein will be useful as a means of delivering a variety of antigens to the immune system. Three specific projects are proposed. (1) Examine basic immunologic mechanisms responsible for the enhanced immunogenicity of HBcAg- malaria hybrid particles. Understanding the cellular m4echanisms regulating the enhanced immune response to HBcAg-CS hybrid particles will enable future rational vaccine design. This will be accomplished in mice and involve examination of B cell recognition (i.e., T cell- independence, induction of co-stimulatory molecules) and Th cell recognition (i.e., fine specificity, genetic restriction, cytokine production, Th cell subset distribution) of HBcAg-hybrid particles as well as the antigen presentation and processing of hybrid particles. (2) Optimization of the HBcAg as a vaccine carrier platform. Variables to be examine: the optimal number of B cell/Th cell inserts, the insertion sites within HBcAg that best accommodate B cell as well as Th cell epitopes, the importance of particle stability, the effects of inclusion of unmethylated CpG dinucleotides, and the potential for multiple or combination vaccine design. Chemical conjugation of protein antigens to the HBCAG will also be explored. (3) Application of the HBcAg platform technology to other epitopes in addition to P. falciparum. We anticipate that the experience and information gained during the development of malaria candidate vaccines will be applicable to other vaccines which may benefit from the use of HBcAg as a platform. Specifically, selected epitopes (B and Th) cell from pathogens such as Influenza, P. vivax, FMDV, HCV and HIV-1 will be incorporated into hybrid HBcAg particles to determine the general applicability of the HBcAg carrier system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049730-02
Application #
6374724
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Hall, B Fenton
Project Start
2000-09-30
Project End
2003-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
2
Fiscal Year
2001
Total Cost
$320,000
Indirect Cost
Name
Vaccine Research Institute of San Diego
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92109
Lee, Byung O; Jones, Joyce E; Peters, Cory J et al. (2011) Identification of a unique double-negative regulatory T-cell population. Immunology 134:434-47
Frelin, Lars; Wahlstrom, Therese; Tucker, Amy E et al. (2009) A mechanism to explain the selection of the hepatitis e antigen-negative mutant during chronic hepatitis B virus infection. J Virol 83:1379-92
Whitacre, David C; Lee, Byung O; Milich, David R (2009) Use of hepadnavirus core proteins as vaccine platforms. Expert Rev Vaccines 8:1565-73
Lee, Byung O; Tucker, Amy; Frelin, Lars et al. (2009) Interaction of the hepatitis B core antigen and the innate immune system. J Immunol 182:6670-81
Billaud, Jean-Noel; Peterson, Darrell; Lee, Byung O et al. (2007) Advantages to the use of rodent hepadnavirus core proteins as vaccine platforms. Vaccine 25:1593-606
Chen, Margaret; Sallberg, Matti; Hughes, Janice et al. (2005) Immune tolerance split between hepatitis B virus precore and core proteins. J Virol 79:3016-27
Chen, Margaret T; Billaud, Jean-Noel; Sallberg, Matti et al. (2004) A function of the hepatitis B virus precore protein is to regulate the immune response to the core antigen. Proc Natl Acad Sci U S A 101:14913-8
Milich, David R; Leroux-Roels, Geert G (2003) Immunogenetics of the response to HBsAg vaccination. Autoimmun Rev 2:248-57