AIDS and Immunosuppression Program, Integrative Biology and Infectious Diseases Branch, DER, NIDCR
This concept will encourage basic, translational and pre-clinical research to: 1) characterize the breadth, magnitude and immunological properties of oral anti-HIV immunoglobulins induced after direct prophylactic HIV vaccination of the oral lymphoid tissue; 2) use new HIV vaccine immunogens, adjuvants and delivery systems designed for direct oral mucosal immunization to trigger an HIV specific, protective, and long-lasting humoral immunity; 3) address genetic and immunological mechanisms that govern HIV vaccine-driven B cell ontogeny for the induction of protective anti-HIV antibodies in the oral mucosa; and 4) study oral innate and cellular immunity as well as immune interactions that enhance the production oral anti-HIV neutralizing antibodies after vaccination. The ultimate goal of this concept is to support research to realize ways of inducing oral mucosal, protective, humoral immune responses against HIV.
After 30 year of the HIV pandemic, a protective HIV vaccine is yet to be developed and only one vaccination regimen has shown limited efficacy in a human clinical trial. However, the induction of neutralizing and non-neutralizing, but partially protective anti-HIV antibodies upon HIV immunization raises hope for the development of an efficacious HIV vaccine. The latter may require multi-pronged approaches and delivery systems, including direct immunization of oral mucosal lymphoid tissue to yield protective humoral and cellular immunity against HIV.
Preclinical data in non-human primates have shown that sublingual and tonsillar immunizations trigger anti-HIV/SIV specific IgA, IgG immunoglobulins and virus specific cellular responses in the oral mucosa and at other body sites. However, limited information is known on the quality, quantity, biological function and protective effect of viral humoral immune responses. HIV humoral immunity is predicated by oral B cell ontogeny. The latter is modulated by partially known genetic and immunological pathways as well as by multiple levels of complex interactions with diverse cell types and factors present in the oral mucosa, which are still to be well characterized.
Despite the immunogenicity of new formulations for oral HIV vaccine candidates, success has not been achieved in inducing broadly reactive neutralizing antibodies. The protective role of HIV vaccine-induced, non-neutralizing and neutralizing, oral anti-HIV antibodies needs further investigation. Hence, it is critical to continue testing new HIV vaccine immunogens, adjuvants and immunization methods to optimize and enhance the induction of neutralizing antibodies in the oral mucosa.
A better understanding is necessary regarding genetic and immunological pathways governing oral B cell development, activation, proliferation and differentiation to yield repertoires of protective anti-HIV antibodies upon oral vaccination. Knowledge regarding the interactions between oral innate and cellular immunity to enhance humoral, neutralizing immunity upon vaccination is missing. Hence, it is important to understand the breadth, magnitude, and immunological function of oral HIV neutralizing antibodies produced upon vaccination as well as the contributions of oral innate and cellular immunity.
The current state-of-the-science in the HIV vaccine development field allows knowledge gaps described above to be addressed, representing an excellent opportunity to improve prophylactic HIV vaccine design and the induction of protective oral humoral immunity.
Also, a well-developed HIV vaccine field comprised of multiple expertise and sophisticated technologies makes it feasible to enhance our understanding of oral HIV humoral immunity upon vaccination of the oral lymphoid tissue. This is a critical requirement to develop a safe and efficacious vaccine. Findings from studies supported by this concept will be of great impact to improve the induction of protective oral HIV humoral immunity upon oral prophylactic HIV vaccination.
Examples of research topics supported by this concept include but are not limited to:
- Test new SHIV/SIV immunogens, multivalent vaccines, mucosal adjuvants and immunization strategies in non-human primates to induce oral neutralizing antibodies
- Elucidate genetic and immune mechanisms that govern the induction of oral neutralizing and non-neutralizing anti-HIV immunoglobulins
- Determine the impact of B cell ontogeny on HIV-vaccine induced, protective, oral humoral immunity
- Delineate the mechanisms by which oral innate and cellular immunity influence neutralizing and non-neutralizing anti-HIV immunoglobulins upon vaccination
- Define new correlates of oral mucosal protection linked to oral prophylactic HIV vaccination
- Use of single cell analyses and omics approaches to assess oral innate and protective adaptive immunity after oral HIV vaccination and viral challenge
Current Portfolio Overview
NIDCR has supported HIV vaccine research through six Funding Opportunity Announcements (FOAs) in the past twelve years. These FOAs have supported 19 grants, which have yielded 158 scientific publications that have enhanced our knowledge on oral mucosal prophylactic HIV vaccines. Currently, the portfolio has 7 active grants. Investigators are exploring diverse aspects of vaccine research and the pathogenesis of HIV/SIV after vaccination. Nevertheless, the portfolio has research gaps as described in this concept that are not covered by the active grants. A central and immediate aspect is to exploit recent encouraging findings that direct immunization of the oral lymphoid tissue induces local and systemic immunity against SIV in non-human primates, including the induction of oral humoral immunity. These promising results may yield high impact in the HIV vaccine field. The state-of-the-science in the HIV vaccine field is robust and requires new research, approaches and technologies continuously to advance and develop prophylactic, safe and efficacious oral and systemic HIV vaccines.
Alignment with Institute Goals, Strategies and Implementation Plan
This initiative is aligned with the NIDCR’s Strategic Plan 2014-2019, Goal I, Objective 1 (enable basic research to advance knowledge of dental, oral, and craniofacial health) and with the FY2016 Trans-NIH Plan for HIV-Related Research on vaccine development.
- Oral Immunization with a Recombinant Lactococcus lactis-Expressing HIV-1 Antigen on Group A Streptococcus Pilus Induces Strong Mucosal Immunity in the Gut. Chamcha, V., Jones, A., Quigley, B.R., Scott, J.R., and Amara, R.R. J Immunol. 2015 Nov 15; 195(10):5025-34.
- Inhibition of HIV Entry by Targeting the Envelope Transmembrane Subunit gp41. Yi, H.A., Fochtman, B.C., Rizzo, R.C., and Jacobs, A. Curr HIV Res. 2016; 14(3): 283-94.
- Oral Immunization with Recombinant Vaccinia Virus Prime and Intramuscular Protein Boost Provides Protection against Intrarectal Simian-Human Immunodeficiency Virus Challenge in Macaques. Thippeshappa, R., Tian, B., Cleveland, B, Guo, W., Polacino, P., and Hu, S.L. Clin Vaccine Immunol. 2015 Dec 30; 23(3): 204-12.
- Oral Delivery of a Novel Recombinant Streptococcus mitis Vector Elicits Robust Vaccine Antigen-Specific Oral Mucosal and Systemic Antibody Responses and T Cell Tolerance. Xie, E., Kotha, A., Biaco, T., Sedani, N., Zou, J., Stashenko, P., Duncan, M.J., Campos-Neto, A., Cayabyab, M.J. PLoS One. 2015 Nov 30; 10(11): e0143422.
- Vaccine delivery to the oral cavity using coated microneedles induces systemic and mucosal immunity. Ma, Y., Tao, W., Krebs, S.J., Sutton, W.F., Haigwood, N.L., and Gil,l H.S. Pharm Res. 2014 Sep; 31(9): 2393-403 .