A vaccine to prevent mother-to-child-transmission of HIV-1 via breast milk, to which vulnerable infants are repeatedly exposed, is urgently needed in resource-poor countries with limited access to antiretroviral therapy. Such a vaccine requires (1) a highly accelerated vaccine schedule and (2) the rapid induction of antiviral immunity in local tissues of the oral and intestinal mucosa and their draining lymph nodes. We hypothesize that live attenuated immunogens are optimal candidates because (i) they can induce innate and adaptive immune responses against a spectrum of antigens, (ii) continue to boost these responses, and, thus, (iii) would effectively stimulate the developing infant immune system. However, for obvious safety reasons, live attenuated HIV vaccination is not feasible. Mycobacterium bovis bacilli Calmette-Guerin (BCG) vaccination induces strong T helper 1 (Th1) responses in human infants. Given the large geographical overlap between Mycobacterium tuberculosis (Mtb) and HIV infection in Africa, BCG vaccination was formerly recommended for all infants at birth to protect against tuberculosis disease (TB). However, immunodeficiency resulting from HIV-1 infection clearly predisposes infants to disseminated BCGosis. A safer TB vaccine is urgently needed. We propose to address both the urgent needs for a pediatric HIV vaccine and for a novel, safer TB vaccine by developing a highly attenuated Mtb vaccine vector (AMtb) expressing HIV antigens as a prophylactic neonatal HIV vaccine. This immunogen may protect not only against breast-milk HIV transmission, but also against Mtb infection. Both HIV-1 and TB are major causes of infant mortality and morbidity in Africa, and the successful development of a combination vaccine effective against both infections would be a major advance in the global war against pediatric diseases in developing countries. We hypothesize that highly attenuated Mtb mc25226, or its derivatives, expressing HIV antigens (rAMtb-HIV) can be safely administered orally at birth, will elicit mucosal and systemic immune responses, and thus engender protection against oral HIV infection. We will test hypothesis in the rhesus macaque model of infant oral SIV infection.
AIM 1 will test the hypothesis that oral administration of mc25226- SIVgag is safe and superior to parental vaccination in eliciting local mucosal immune responses in newborn macaques.
In AIM 2, we will develop strategies to optimize the immunogenicity of rAMtb in newborn macaques through genetic manipulations of immune response genes in Mtb, and define the underlying immune mechanisms by which mc25226-SIVgag enhances mucosal and systemic immune responses, and how mucosal adjuvants and various prime-boost strategies influence dendritic cell activation, CD4+T cell priming, and enhance SIV-specific CD8+T and B cell responses in infant macaques. The efficacy of a rAMtb-SIV vaccine expressing multiple SIV antigens (Gag, Pol and Env) against oral SIV challenge in infant macaques will be tested in AIM 3.

Public Health Relevance

The goal of this project is to develop a novel oral pediatric combination vaccine that can potentially protect infants at birth against HIV infection via breast-milk transmission, and against Mycobacterium tuberculosis infection, two diseases with major impact on infant mortality and morbidity, especially in developing countries.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
3R01DE019064-06S1
Application #
8793889
Study Section
Special Emphasis Panel (ZDE1)
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Jensen, Kara; Nabi, Rafiq; Van Rompay, Koen K A et al. (2016) Vaccine-Elicited Mucosal and Systemic Antibody Responses Are Associated with Reduced Simian Immunodeficiency Viremia in Infant Rhesus Macaques. J Virol 90:7285-302
Jensen, Kara; Dela Pena-Ponce, Myra Grace; Piatak Jr, Michael et al. (2016) Balancing trained immunity with persistent immune activation and the risk of SIV infection in infant macaques vaccinated with attenuated Mycobacterium tuberculosis or BCG vaccines. Clin Vaccine Immunol :
Carryl, Heather; Swang, Melanie; Lawrence, Jerome et al. (2015) Of mice and monkeys: can animal models be utilized to study neurological consequences of pediatric HIV-1 infection? ACS Chem Neurosci 6:1276-89
Curtis, Kimberly; Rollins, Matthew; Carryl, Heather et al. (2014) Reduction of pyramidal and immature hippocampal neurons in pediatric simian immunodeficiency virus infection. Neuroreport 25:973-8
Jensen, Kara; Pena, Myra Grace Dela; Wilson, Robert L et al. (2013) 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 2:53-63
Jensen, Kara; Ranganathan, Uma Devi K; Van Rompay, Koen K A et al. (2012) A recombinant attenuated Mycobacterium tuberculosis vaccine strain is safe in immunosuppressed simian immunodeficiency virus-infected infant macaques. Clin Vaccine Immunol 19:1170-81
Van Rompay, Koen K A; Trott, Kristin A; Jayashankar, Kartika et al. (2012) Prolonged tenofovir treatment of macaques infected with K65R reverse transcriptase mutants of SIV results in the development of antiviral immune responses that control virus replication after drug withdrawal. Retrovirology 9:57
Marthas, Marta L; Van Rompay, Koen K A; Abbott, Zachary et al. (2011) Partial efficacy of a VSV-SIV/MVA-SIV vaccine regimen against oral SIV challenge in infant macaques. Vaccine 29:3124-37
Ranganathan, Uma Devi K; Larsen, Michelle H; Kim, John et al. (2009) Recombinant pro-apoptotic Mycobacterium tuberculosis generates CD8+ T cell responses against human immunodeficiency virus type 1 Env and M. tuberculosis in neonatal mice. Vaccine 28:152-61
Abel, Kristina (2009) The rhesus macaque pediatric SIV infection model - a valuable tool in understanding infant HIV-1 pathogenesis and for designing pediatric HIV-1 prevention strategies. Curr HIV Res 7:2-11