AIDS and Immunosuppression Program
Center for Integrative Biology and Infectious Diseases
OBJECTIVE
The purpose of this initiative is to encourage research that will focus on harnessing mucosal immune responses in order to facilitate the development of effective HIV vaccines that utilize the oropharyngeal mucosal tissues as the route of inoculation. Specifically we are seeking applications that will further develop already characterized target vaccine antigens and formulations and relevant model antigens for oral delivery, target validation and early preclinical evaluation in relevant animal models. This initiative will not support basic vaccine antigen discovery or therapeutic vaccine research.
BACKGROUND
Despite the resources and extensive efforts that have been channeled to achieve a protective vaccine for AIDS, major challenges surrounding vaccine design and immunization regimen still exist. The debate is ongoing on the correlates of protection against HIV infection and the role innate immunity, humoral and/or cell mediated immunity play in such protection. To date, several investigational vaccines have been evaluated in clinical trials, but efficacy has not yet been demonstrated. These approaches have largely relied on parenteral delivery of vaccine antigens.
The oral mucosal route for vaccine delivery to achieve local and systemic protection against HIV infection is largely unexplored. The majority of infections associated with HIV disease are initiated at mucosal surfaces, occurring as a result of the adherence to and passage of the pathogens across mucosal membranes. This warrants the exploration of induction and characterization of protective immune responses through and at oral and pharyngeal mucosal tissues which are rich in immune cells and provide easy access for delivery of vaccines against oral, respiratory, gut and systemic pathogens.
While parenteral immunization with non-replicating antigens induces mostly systemic immune responses, mucosal delivery of antigens is able to trigger both mucosal and systemic immune responses. This has been shown for antigen delivery for HIV and other human viruses using the intranasal, rectal and intra-oral delivery systems. The inability of current vaccine approaches to generate a suitable vaccine for HIV prompts the search for better adjuvants, formulations and novel delivery systems and a better understanding of the immune parameters required for vaccine-elicited protection to achieve this goal.
Scientific areas of interest that might be included under this initiative are: development of broadly reactive antibodies to primary isolates at oral and other mucosal sites of infection; harnessing innate and regulatory T cell responses for the development of oral mucosal vaccines; development and validation of adjuvants (e.g. TLR ligands, cytokines) for oral mucosal vaccines; methodologies to increase and mobilize antigen presenting cells to oral mucosal vaccination sites; and comparison of parenteral and oral mucosal routes of vaccine delivery in humans and/or non human primate models of AIDS.
RECOMMENDATIONS FROM WORKSHOPS
The development and validation of prophylactic AIDS vaccines is a high priority for the NIH and as recommended by the Office of AIDS Research Advisory Council.