AIDS and Immunosuppression Program
Integrative Biology and Infectious Diseases Branch
OBJECTIVE
The primary goal of this reissued initiative is to further stimulate state-of-the-art research that will harness oral mucosal and innate immunity to develop protective HIV vaccines delivered through the oral mucosa. Reissuance of this expanded scope initiative will increase the critical mass of scientists and studies to more fully address the following areas: 1) mechanisms linking oral mucosal and innate immunity with systemic adaptive immunity; 2) development of HIV vaccine antigens in oral expression vectors that are stable in the oral cavity and have the ability to trigger anti-HIV protective immunity; 3) role of oral dendritic (DC) and natural killer (NK) cell subset changes during disease progression or upon oral mucosal HIV vaccination; 4) DC-NK cross-talk in the oral cavity and relationship to systemic adaptive immunity upon oral mucosal HIV vaccination; 5) similarities and differences between DC-NK cross-talk in the oral mucosal site compared with other mucosal sites of the body, and 6) characterization of soluble defense molecules produced in oral secretions upon oral mucosa HIV vaccination. Studies responsive to this initiative should greatly strengthen the knowledge base for developing safe and efficacious oral mucosal HIV vaccines. As initially described in the 2007 funding opportunity announcements (RFA-DE-08-003/004) this initiative will seek applications that will further develop already characterized target vaccine antigens, novel adjuvants, new 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
Transmission of HIV through mucosal surfaces of the body has guided comprehensive assessment of mucosal immunity against HIV, and has directed efforts to develop oral mucosal vaccines as effective prophylactic strategies capable of inducing broad humoral and cellular responses at both mucosal and systemic sites that are able to block viral infection at the portal of entry. The development of effective HIV vaccines for oral mucosal delivery represents one of the most cost-effective preventive approaches against HIV/AIDS. Yet, major challenges still exist in the development of oral mucosal HIV vaccines and immunization regimens partially due to a lack of a comprehensive understanding of oral mucosal and innate immunity. For example, it is not known how these immunological arms may contribute to the inhibition of early HIV replication and simultaneously stimulate adaptive immunity against HIV/AIDS.
Oral HIV transmission is a rare but possible event. The feasibility of HIV transmission is probably due to the tonsil Th2-dominant cytokine microenvironment along with tonsil epithelial factors, which may contribute to HIV susceptibility. Likewise, an increased expression of molecules in tonsil cells associated with HIV recognition, binding and entry (e.g., CXCR4, FcRγIII, complement receptor 2, and various complement components) coupled with decreased innate antiviral factors and the presence of heterogeneous lymphoid populations with increased expression of the viral co-receptor CXCR4 favor HIV susceptibility. Yet, it is uncommon for HIV to infect tonsil cells and to cause infection through the oral mucosa. To understand this phenomenon, three explanations have been proposed: the low concentration of HIV in saliva, the inhibiting role of anti-HIV saliva-soluble factors and the hypotonicity of saliva that lyses non-specifically HIV infected cells.
The low rate of HIV transmission through the oral cavity emphasizes the existence of protective oral innate immunity and of an effective oral mucosal barrier playing key roles to render HIV susceptible cells in the oral cavity less accessible. The physical barrier represented by the oral mucosa differs between micro-compartments represented by the salivary glands (parotid, submandibular and sublingual as principal glands and small minor glands of the oral cavity secreting anti-HIV soluble factors), the buccal mucosa (having a unique cellular structure) and the Waldeyer’s ring (containing the palatine tonsils and adenoids). Together, these oral mucosa micro-compartments form a specialized and compartmentalized mucosa-associated lymphoid tissue known as the oral MALT, which may contribute to the resistance to HIV infection of the oral mucosa. Examples of saliva-soluble factors of the oral MALT are defensins, secretory IgA antibodies, lysozyme, thrombospondin, secretory leucocyte protease inhibitor (SLPI), salivary lactoferrin, proline-rich proteins, mucinous glycoprotein 2, salivary agglutinin, and toll-like receptors that interact with HIV to block and control early infection. These saliva-soluble factors, and many other biomarkers associated with HIV resistance yet to be characterized, are produced by early oral innate and mucosal immune responses against HIV infection and may contribute to resistance.
Studies have shown that, in general, there are multiple immune effector mechanisms contributing to protection at mucosal surfaces. Examples of these mechanisms are the following: antigen-specific effector B and T cells in the bloodstream can recognize mucosal high endothelial venules and cross into mucosal sites. Mucosal plasma cells produce dimeric IgA, which is exported into secretions as secretory IgA to capture pathogens and prevent mucosal invasion. Neutralizing IgG present at mucosal sites (and produced by local plasma cells or diffused into mucosal sites from local fenestrated blood capillaries) can also intercept pathogens and prevent invasion at mucosal sites. Infected cells might be eradicated from mucosal tissues by specific cytotoxic T lymphocytes or by antibody-dependent cell-mediated cytotoxicity through a synchronized effort between NK cells and antibodies. Pathogens can also be confined by DCs and macrophages, and transported to draining lymph nodes for elimination. In spite of the current knowledge in mucosal immunity, the actual oral mucosal immune protection mechanisms that play a central role against HIV and that may be harnessed to trigger adaptive immunity need to be determined. Studies in this area are encouraged in this initiative.
In spite of the progress made in understanding HIV pathogenesis and early events of HIV infection, little is known about harnessing oral mucosal and innate immunity against HIV to enhance T and B cell oral and systemic immunity. Similarly, limited information is available regarding the interplay of innate and adaptive immune responses (e.g., NKs and DCs cross-talk and interactions between oral epithelial cells, antigen presenting cells, T cells and B cells) that lead to protective immunity at the oral mucosal surface and systemically. A better understanding of oral mucosal and innate immune mechanisms will improve HIV prevention, and will facilitate the development of novel and effective oral mucosal HIV vaccines.
In recent years, different oral vaccine candidates and immunization strategies have been tested as proof-of-concept in animal models and humans. These studies have shown that repeated oral immunizations alone, or as part of the prime-boost vaccination strategies, enhanced cellular and humoral immunity in mucosal and systemic tissues, thus providing evidence to support that oral HIV immunization is an effective prophylactic strategy as compared to the most commonly used HIV immunizations administered parenterally. These vaccine studies have also shown that the route of inoculation and the vaccine vector combination influences the magnitude and the antigen specificity of the immune responses produced. These recent breakthroughs present new and unique opportunities to enhance oral HIV vaccine development.
The lack of efficacy of parenterally delivered T- and B-cell based predominant HIV vaccines has made more urgent efforts to develop novel vaccine modalities such as oral mucosal HIV vaccines. The inability of current vaccine candidates and immunization strategies to generate mucosal and systemic protective immunity justifies the development of novel vaccine formulations, delivery systems, and mucosal adjuvants. Similarly, a better understanding is needed regarding the vaccine-induced correlates of immune protection, which will accelerate the development of protective HIV vaccines. This initiative will encourage applications from both individuals and groups interested in developing oral mucosal HIV vaccines.