Performing Department
Veterinary Medicine
Non Technical Summary
There are now estimated 33 million people infected with HIV-1 worldwide. Over 90% of them live in developing countries and are unable to afford currently existing antiretroviral therapies. Although there is a gratifying movement to provide these therapies in many developing nations, the long term costs and toxicities as well as the steady increase in viral resistance against anti-retroviral drugs mandate that major emphasis be placed on the development of a protective vaccine that can prevent acquisition of HIV infection. The major goal of this proposal is to develop novel vaccine delivery platforms that can enhance the human body's B-cell immune responses against HIV-1 with a long-term goal of developing a protective AIDS vaccine. Successful completion of the study will provide novel platforms for developing vaccines against not only HIV-1, but also against other pathogens. In addition to AIDS vaccine development, the proposed experiments also allow better understanding of basic B cell immunobiology in relation to multivalent antigens.
Animal Health Component
(N/A)
Research Effort Categories
Basic
10%
Applied
30%
Developmental
60%
Goals / Objectives
There is a global urgency to develop a protective vaccine against HIV-1. Although neutralizing antibodies (Nabs) can provide effective prophylaxis against HIV-1 infections, eliciting those that are broadly reactive against many antigenically diverse HIV-1 isolates has been the major challenge and it remains a critical roadblock to AIDS vaccine development. While generating the "right immunogen" that has the potential to elicit broadly reactive neutralizing antibodies (BR-Nabs) is of prime importance, it is also critical to have the "right vaccine delivery platform" that can (1) maintain the correct antigenic structure of the immunogen, (2) deliver it efficiently to appropriate cells of the immune system, and (3) promote induction of high titer antibodies that are long-lived. Successful completion of the study will provide novel platforms for developing vaccines against not only HIV-1, but also against other pathogens. In addition to AIDS vaccine development, the proposed experiments also allow better understanding of basic B cell immunobiology in relation to multivalent antigens.
Project Methods
The primary objective of this proposal is to explore a novel strategy to develop new vaccine delivery platforms, which will complement an ongoing research program in immunogen design. The central hypothesis behind this study is that a polymeric antigen containing many copies of the same target epitope in a repetitive, well-defined lattice (multivalent antigen) can elicit a better B cell immune response than a monomeric antigen (monovalent antigen), qualitatively and quantitatively, because of its potential to (1) induce both T cell-independent (TI) and -dependent (TD) B cell immunity; (2) enhance greater levels of B cell activation and maturation; and (3) activate a greater diversity of B cell subsets. Specifically, we propose to develop vaccine delivery platforms based on gold nanoparticles and a self-polymerizing DNA matrix that can present multivalent antigens based on the gp41 membrane-proximal external region (MPER). These platforms will be modular, which adds versatility and controllability, and will allow delivery of well-defined arrays of not only antigens, but also immune effector molecules. These two antigen delivery platforms will be complemented by a third platform based on nanoparticle encapsulation technology to enhance helper T cell response. Immunogenicity of multivalent vs. monovalent gp41 MPER antigens will be compared, and effects of antigen density and epitope periodicity on B cell immune responses will be characterized in detail. Specifically, We will examine germinal center development, B cell subset activation, and induction of TI and TD B cell immunity.