Professor of Clinical Pediatrics, Department of Pediatrics
Development of a Novel Combination HIV and TB Vaccine
The overall objective of our research is to develop a novel strategy to elicit protective T cells against both human immunodeficiency virus (HIV) and tuberculosis (TB) with recombinant attenuated M. tuberculosis (rAMtb) expressing HIV proteins. This approach would be safe for any population across the lifespan, including infants at high risk for HIV and TB in developing countries, and may rapidly generate protective T cell responses immediately after birth.
Rates of HIV and drug-resistant TB are rising in many developing countries. Despite advances in strategies to prevent mother to child HIV transmission, breast milk HIV transmission occurs in an estimated 200,000 infants annually. Whereas the results of the recent RV 144 vaccine trial, using a canarypox prime/protein boost, encourage the view that effective vaccination against HIV is feasible, there are two major shortcomings of this, and most other HIV vaccine development efforts to date. First, these approaches are being solely studied against sexual HIV transmission in adults. Secondly, they are not being tested for safety in infants and children, or for efficacy against breast milk HIV transmission. The treatment of TB, a major cause of death in HIV-infected individuals, is becoming more complicated due to the emergence of drug-resistance. BCG, the only approved vaccine against TB, has limited effectiveness against disseminated disease (yet is ineffective against primary pulmonary infection) and is an attractive vaccine vector candidate against HIV across the lifespan, as it is administered at birth to > 85% of the birth cohort in areas of high HIV prevalence. However, because BCG causes disseminated disease in infants with HIV infection, it is no longer indicated for use in infants at risk for HIV. We have shown recently that genetically a attenuated ΔpanCD ΔLeuCD Mtb strain expressing SIV antigens are safe in neonatal SIV-infected macaques that develop simian AIDS (unlike wild type BCG vaccine that causes disseminated disease in infants with AIDS) and induce T and B cells against SIV and TB in non-SIV-infected neonatal macaques The proposed strategy, if successful, will have a major impact on the control of HIV and TB across the lifespan in developing countries.
Fennelly GJ. Mycobacterium bovis versus Mycobacterium tuberculosis as a cause of acute cervical lymphadenitis without pulmonary disease. Pediatr Infect Dis J. 2004 Jun;23(6):590-1.
Vecino WH, Quanquin NM, Martinez-Sobrido L, Fernandez-Sesma A, García-Sastre A, Jacobs, WR, Jr., and Fennelly GJ. Mucosal immunization with attenuated Shigella flexneri harboring an influenza hemagglutinin DNA vaccine protects mice against a lethal influenza challenge. Virology 2004.August;325(2):192-9.
Legrand FA , Abadi J, Jordan KA, Davenport MP, Deeks SG, Fennelly GJ, Wiznia AA, Nixon DF, and Rosenberg MG. Partial treatment interruption of protease inhibitors augments HIV-specific immune responses in vertically infected pediatric patients. AIDS. 2005 Oct 14;19(15):1575-1585.
Abadi J, Sprecher E, Rosenberg MG, Dobroszycki J, Sansary J, Fennelly G and Wiznia A. Partial Treatment Interruption of PI-Based HAART Regimens In HIV-Infected Children. J Acquir Immune Defic Syndr 2006.
Cayabyab MJ, Hovav AV, HsuT, Krivulka GR, Lifton NA, Gorgone DA, Fennelly GJ, Haynes BF, Jacobs, WR Jr. and Letvin NL. Generation of CD8+ T cell Responses by a Recombinant Nonpathogenic Mycobacterium smegmatis Vaccine Vector Expressing HIV-1 Env. J Virol 2006 Feb;80(4):1645-1652.
Fennelly GJ., Mandala J., Suave F., Charles M, Opportunities to prevent mother-to-child transmission (PMTCT) of HIV: Lessons learned in Bronx (New York), Kijabe (Kenya) and Kericho (Kenya). PART I of II. Perspectives 20. From the International Center for Equal Healthcare Access. Medscape May 2006.
Mo Y, Quanquin NM, Vecino WH, Devi Ranganathan U, Tesfa L, Derbyshire, KM, Letvin NL, Jacobs, WR Jr, Fennelly GJ. Genetic Alteration of Mycobacterium smegmatis to Improve Mycobacterial Bactofection and DNA Immunization. Infect Immun 2007 Oct;75(10):4804-16.
Bueno SM, González PA, Cautivo KM, Mora JE, Leiva ED, Tobar HE, Fennelly GJ, Eugenin EA, Jacobs WR Jr, Riedel CA, Kalergis AM. Protective T cell immunity against respiratory syncytial virus is efficiently induced by recombinant BCG. Proc Natl Acad Sci U S A. 2008 Dec 15.
Recombinant Avirulent Proapoptotic M. tuberculosis Generates CD8+ T-cell Responses Against Human Immunodeficiency Virus Type 1 Env in Neonatal Mice. Devi Ranganathan U, Larsen MH, Kim J, Porcelli SA, William Jacobs WR Jr, Fennelly GJ. Vaccine 2009 Dec 10;28(1):152-61.
Jensen K, Ranganathan UD, Van Rompay KK, Canfield DR, Khan I, Ravindran R, Luciw PA, Jacobs WR Jr, Fennelly G, Larsen M, Abel K. A recombinant attenuated Mycobacterium tuberculosis vaccine strain is safe in immunosuppressed SIV-infected infant macaques. Clin Vaccine Immunol. Epub 2012 Jun 13.
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Jacobi Medical Center
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