AIDS and Immunosuppression Program, Integrative Biology and Infectious Diseases Branch, DER, NIDCR
Objective
This initiative will support research projects that will develop and test novel HIV vaccines for direct administration into oral lymphoid tissues to trigger protective, local and systemic immunity. Specifically, this initiative will seek projects to: 1) define the mechanisms by which direct HIV vaccination of oral lymphoid tissues induce oral innate as well as local and systemic adaptive immune responses; 2) determine the mechanisms by which novel adjuvants used together with oral HIV vaccines enhance local and systemic immunity; 3) test novel, oral vaccine vectors that express HIV vaccine antigens to trigger protective immunity; 4) compare different HIV vaccine immunization strategies and schemes for the oral mucosa to maximize protection; and 5) delineate the role of dynamic changes in oral and immune cell subsets and their interactions that enhance immunity upon oral HIV vaccination. This initiative will support projects that develop HIV vaccine formulations with or without adjuvants for direct oral lymphoid tissue inoculation and preclinical testing in animal models.
Background
Substantial progress has been made worldwide in improving life expectancy and quality of life for millions of people infected with HIV by introducing antiretroviral therapy. However, the foremost goal still is to prevent HIV infections. One of the most cost effective and safe strategies to prevent HIV/AIDS globally is through the development and application of a prophylactic HIV vaccine. This is especially valid for the developing world where this pandemic has caused devastating effects.
Historically, two institutes of the National Institutes of Health have supported HIV vaccine research. The National Institute of Allergy and Infectious Diseases (NIAID) has led the field of antigen discovery and HIV vaccine development and clinical testing. NIDCR has complemented the NIAID efforts by focusing on oral mucosal prophylactic HIV vaccines for two reasons. First, the oral cavity is an excellent model to understand innate and mucosal immunity against disease. Second, the oral lymphoid tissue is an effective and easily accessible immunization route against HIV. The ultimate goal in prevention efforts is to use an oral mucosal prophylactic HIV vaccine injected directly into the oral lymphoid tissue in combination with other HIV vaccinations administered through other immunization routes to confer protective immunity.
During vaccination, the immune system is optimally primed and boosted with an immunogen or combination of immunogens in the presence or absence of adjuvants that serve as immune enhancers. Then, upon an infectious challenge, a quick and effective immune response is generated that clears the infection with no permanent health effects. There are many considerations when developing and using a vaccine, including: the nature and composition of the immunogen or mix of immunogens, adjuvant use, immunization route, vaccination scheme, and the age, gender, and genetic makeup of cohorts (Haynes and McElrath, 2013). Currently, the HIV vaccine pipeline is complex and includes developing and testing strategies that differ in the following: vaccine vectors, multiple combinations of HIV antigens from different subtypes, adjuvants, routes of immunizations, vaccination schemes and geographical areas reflecting different genetic makeup (Excler et al, 2014). Results from a phase III clinical trial called RV144 or the Thai trial provided encouraging results for HIV vaccine development (Rerks-Ngarmm et al., 2009). This trial showed for the first time that the rate of HIV acquisition in participants who received the vaccine was 31% lower than that of in participants who received the placebo. Other HIV vaccine candidates are being tested in early and advanced phases of clinical trials. For instance, in addition to the canarypox vaccine vector, which was used in the Thai trial, other vectors being tested include recombinant adenovirus, which is being tested in humans and cytomegalovirus, which has shown encouraging results in non-human primates and may be tested in humans.
Other vaccine strategies are testing candidates that stimulate immune responses in the mucosal surfaces such as the gut and the oral cavity. The development of an effective mucosal HIV vaccine, unlike systemic immunization, offers the advantage of inducing protective immunity at the first line of defense. As most HIV infections begin at mucosal surfaces, induction of innate as well as mucosal humoral and cellular immunity post-vaccination is essential to arrest and clear HIV infections before their systemic dissemination. The richness of the lymphoid tissue in the oral cavity offers an easily accessible vaccination site that, in combination with other immunization routes, may confer effective immune protection against HIV infection, especially via breastfeeding and oral sex. Recent findings support this strategy. For instance, it has been shown through NIDCR sponsored research that oral and systemic immunity was induced upon oral SIV vaccination of monkeys. These oral mucosal prophylactic SIV vaccines were shown to be safe and immunogenic (Vagenas, P. et al., 2009; Jensen, K. et al., 2012, 2013; and Manrique, M. et al., 2013, 2014). Despite the progress made in NIAID and NIDCR sponsored research, many aspects of HIV vaccine development, testing and immune response remain unclear and require further investigation. For instance, it is critical to confirm initial findings about oral mucosal prophylactic HIV vaccines and to expand the development and testing of these vaccines to elicit protective immunity against HIV.
Examples of research topics supported by this initiative include but are not limited to:
- HIV-specific immunity induced by direct immunization of the oral mucosa
- Mucosal adjuvants to enhance vaccine immunogenicity and efficacy
- Immune control of HIV infection, replication and spread upon oral vaccination
- HIV/SIV/SHIV antigens expressed in novel vectors for oral vaccine testing in animals
- Cross-talk between oral and systemic immunity upon vaccination
- Responses in oral cell types post-vaccination and interactions to trigger immunity
- Oral vaccines that induce sustained high levels of broadly reactive neutralizing antibodies
- Oral vaccine-enhanced immunologic memory and long term protection against HIV
- Immune correlates of oral and systemic protection against HIV defined with new tools
Current Portfolio Overview
NIDCR has supported HIV vaccine research through five Funding Opportunity Announcements (FOAs) in the past ten years. These FOAs have supported 16 grants, which have yielded 153 scientific publications that have enhanced our knowledge on oral mucosal prophylactic HIV vaccines. Currently, the portfolio has 13 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. 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 Strategic Plan 2014-2019: Goal I, Objective 1-1: Enable basic research to advance knowledge of dental, oral, and craniofacial health; and Goal 3, Objective 3-1: Support multidisciplinary, multilevel research and research training to overcome oral health disparities; as well as with the FY2014 Trans-NIH Plan for HIV-Related Research on FY2014 Trans-NIH Plan for HIV-Related Research on vaccine development.
References
de Souza MS, Ratto-Kim S, Chuenarom W, Schuetz A, Chantakulkij S, Nuntapinit B, Valencia- Micolta A, Thelian D, Nitayaphan S, Pitisuttithum P, Paris RM, Kaewkungwal J, Michael NL, Rerks-Ngarm S, Mathieson B, Marovich M, Currier JR, Kim JH; Ministry of Public Health– Thai AIDS Vaccine Evaluation Group Collaborators. The Thai phase III trial (RV144) vaccine regimen induces T cell responses that preferentially target epitopes within the V2 region of HIV-1 envelope. J Immunol. 2012 May 15; 188(10): 5166-76.
Excler JL, Robb ML, Kim JH. HIV-1 vaccines: Challenges and new perspectives. Hum Vaccin Immunother. 2014 Mar 17; 10(6): 1-13.
Haynes BF, McElrath MJ. Progress in HIV-1 vaccine development. Curr Opin HIV AIDS. 2013 Jul; 8(4): 326-32.
Jensen K, Pena MG, Wilson RL, Ranganathan UD, Jacobs WR Jr, Fennelly G, Larsen M, Van Rompay KK, Kozlowski PA, Abel K. A neonatal oral Mycobacterium tuberculosis-SIV prime / intramuscular MVA-SIV boost combination vaccine induces both SIV and Mtb-specific immune responses in infant macaques. Trials Vaccinol. 2013 Nov 1; 2: 53-63.
Jensen K, Ranganathan UD, Van Rompay KK, Canfield DR, Khan I, Ravindran R, Luciw PA, Jacobs WR Jr, Fennelly G, Larsen MH, Abel K. A recombinant attenuated Mycobacterium tuberculosis vaccine strain is safe in immunosuppressed simian immunodeficiency virus- infected infant macaques. Clin Vaccine Immunol. 2012 Aug; 19(8): 1170-81.
Manrique M, Kozlowski PA, Cobo-Molinos A, Wang SW, Wilson RL, Martinez-Viedma Mdel P, Montefiori DC, Carville A, Aldovini A. Resistance to infection, early and persistent suppression of simian immunodeficiency virus SIVmac251 viremia, and significant reduction of tissue viral burden after mucosal vaccination in female rhesus macaques. J Virol 2014 Jan; 88(1): 212-24.
J Virol. 2013 Apr; 87(8): 4738-50.
Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, Premsri N, Namwat C, de Souza M, Adams E, Benenson M, Gurunathan S, Tartaglia J, McNeil JG, Francis DP, Stablein D, Birx DL, Chunsuttiwat S, Khamboonruang C, Thongcharoen P, Robb ML, Michael NL, Kunasol P, Kim JH; MOPH-TAVEG Investigators. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009 Dec 3361(23): 2209-20.
Vagenas P, Williams VG, Piatak M Jr, Bess JW Jr, Lifson JD, Blanchard JL, Gettie A, Robbiani M. Tonsillar application of AT-2 SIV affords partial protection against rectal challenge with SIVmac239. J Acquir Immune Defic Syndr. 2009 Dec 1; 52(4): 433-42.
Zolla-Pazner S, deCamp AC, Cardozo T, Karasavvas N, Gottardo R, Williams C, Morris DE, Tomaras G, Rao M, Billings E, Berman P, Shen X, Andrews C, O'Connell RJ, Ngauy V, Nitayaphan S, de Souza M, Korber B, Koup R, Bailer RT, Mascola JR, Pinter A, Montefiori D, Haynes BF, Robb ML, Rerks-Ngarm S, Michael NL, Gilbert PB, Kim JH. Analysis of V2 antibody responses induced in vaccinees in the ALVAC/AIDSVAX HIV-1 vaccine efficacy trial. PLoS One. 2013; 8(1): e53629.