Evaluation of the Safety and Effectiveness of TB Vaccines, Including DNA-Based, Viral Vectored and Live-Attenuated Products

Principal Investigator: Sheldon Morris, PhD
Office / Division / Lab: OVRR / DBPAP / LMDCI

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Overview

Public Health Issue: Tuberculosis remains the second leading cause of infectious disease mortality (2-3 million deaths per year) in the world. The convergence of the HIV and TB epidemics and the rapid emergence of multiple drug resistant TB strains has fueled the TB epidemic in recent years. Since the current TB vaccine (M. bovis BCG) is only modestly effective in preventing pulmonary TB, a safe and highly effective new TB vaccine is urgently needed to curb the global TB epidemic.

Regulatory Contribution: Pre-clinical characterization of the safety and effectiveness of new TB vaccine candidates in animal models is essential prior to testing these new candidate products in humans. For example, the use of specific TB vaccines in persons who have been previously exposed to TB may be problematic because injection of the new vaccine preparations may worsen pre-existing latent TB infections. Therefore, the development of better assays to evaluate vaccine safety in TB post-infection animal models is important for assessing the overall safety of these vaccine candidates. Additionally, the pre-clinical characterization of the highly immunogenic live, attenuated TB vaccines is essential because of safety concerns associated with clinical use of these M. tuberculosis mutants. Finally, since TB vaccines are being tested in regions of the world where malaria is endemic, it is important to evaluate whether concurrent malaria infections impact the safety and effectiveness of TB vaccines.

Research Approach: This research program reviews new DNA, viral-vectored, and live attenuated TB and malaria vaccine products. Using mouse models of pulmonary TB, the effectiveness of these vaccines in immunocompetent and immunocopromised animals is being evaluated and the capacity of these novel vaccines to boost waning BCG-induced immune responses is being monitored. Biomarkers such as protective correlates of immunity are being assessed using several immunological assays. Additionally, vaccine safety is being studied in normal and immunocompromised mouse disease models, including a novel assay which is under development to test the safety of these new vaccine candidates in animals that have been previously infected with TB. Recently, the activity of TB and malaria vaccines in malaria-infected mice is also being evaluated because of the possible intereference with vaccine activity by concurrent infections.

Mission Relevance & Outcomes: These studies will provide important scientific information and tools to evaluate the safety and effectiveness of new TB and malaria vaccine candidates to accelerate global TB vaccine development.

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Publications

Clin Vaccine Immunol 2009 Jan;16(1):122-6
Early pulmonary cytokine and chemokine responses in mice immunized with three different vaccines against Mycobacterium tuberculosis determined by PCR array.
Lim J, Derrick SC, Kolibab K, Yang AL, Porcelli S, Jacobs WR, Morris SL

Infect Immun 2008 Nov;76(11):5173-80
Mycobacterium bovis BCG immunization induces protective immunity against nine different Mycobacterium tuberculosis strains in mice.
Jeon BY, Derrick SC, Lim J, Kolibab K, Dheenadhayalan V, Yang AL, Kreiswirth B, Morris SL

Vaccine 2008 Nov 11;26(48):6092-8
The safety of post-exposure vaccination of mice infected with Mycobacterium tuberculosis.
Derrick SC, Dheenadhayalan V, Yang A, Kolibab K, Morris SL

Infect Immun 2008 May;76(5):2249-55
Vaccine-elicited 10-kilodalton culture filtrate protein-specific CD8+ T cells are sufficient to mediate protection against Mycobacterium tuberculosis infection.
Wu Y, Woodworth JS, Shin DS, Morris S, Behar SM

J Clin Invest 2007 Aug 1;117(8):2279-2288
Enhanced priming of adaptive immunity by a proapoptotic mutant of Mycobacterium tuberculosis.
Hinchey J, Lee S, Jeon BY, Basaraba RJ, Venkataswamy MM, Chen B, Chan J, Braunstein M, Orme IM, Derrick SC, Morris SL, Jacobs WR, Porcelli SA

Nat Med 2007 Jul;13(7):843-50
Multifunctional T(H)1 cells define a correlate of vaccine-mediated protection against Leishmania major.
Darrah PA, Patel DT, De Luca PM, Lindsay RW, Davey DF, Flynn BJ, Hoff ST, Andersen P, Reed SG, Morris SL, Roederer M, Seder RA

Immunology 2007 Feb;120(2):192-206
Characterization of the protective T-cell response generated in CD4-deficient mice by a live attenuated Mycobacterium tuberculosis vaccine.
Derrick SC, Evering TH, Sambandamurthy VK, Jalapathy KV, Hsu T, Chen B, Chen M, Russell RG, Junqueira-Kipnis AP, Orme IM, Porcelli SA, Jacobs WR Jr, Morris SL

Cell Microbiol 2007 Jun;9(6):1547-55
The ESAT6 protein of Mycobacterium tuberculosis induces apoptosis of macrophages by activating caspase expression.
Derrick SC, Morris SL

Infect Immun 2006 Nov;74(11):6491-5
Protection elicited by two glutamine auxotrophs of Mycobacterium tuberculosis and in vivo growth phenotypes of the four unique glutamine synthetase mutants in a murine model.
Lee S, Jeon BY, Bardarov S, Chen M, Morris SL, Jacobs WR Jr

Vaccine 2006 Sep 11;24(37-39):6309-20
Mycobacterium tuberculosis DeltaRD1 DeltapanCD: a safe and limited replicating mutant strain that protects immunocompetent and immunocompromised mice against experimental tuberculosis.
Sambandamurthy VK, Derrick SC, Hsu T, Chen B, Larsen MH, Jalapathy KV, Chen M, Kim J, Porcelli SA, Chan J, Morris SL, Jacobs WR Jr

Antimicrob Agents Chemother 2006 Jun;50(6):1982-8
Novel Conjugate of Moxifloxacin and Carboxymethylated Glucan with Enhanced Activity against Mycobacterium tuberculosis.
Schwartz YS, Dushkin MI, Vavilin VA, Melnikova EV, Khoschenko OM, Kozlov VA, Agafonov AP, Alekseev AY, Rassadkin Y, Shestapalov AM, Azaev MS, Saraev DV, Filimonov PN, Kurunov Y, Svistelnik AV, Krasnov VA, Pathak A, Derrick SC, Reynolds RC, Morris S, Blinov VM

Vaccine 2006 Apr 24;24(17):3522-9
Protection against an aerogenic Mycobacterium tuberculosis infection in BCG-immunized and DNA-vaccinated mice is associated with early type I cytokine responses.
Goter-Robinson C, Derrick SC, Yang AL, Jeon BY, Morris SL

J Microbiol Methods 2005 Dec;63(3):318-30
Microarray and allele specific PCR detection of point mutations in Mycobacterium tuberculosis genes associated with drug resistance.
Tang X, Morris SL, Langone JJ, Bockstahler LE

Infect Immun 2005 Nov;73(11):7727-35
Vaccination with a Sindbis Virus-Based DNA Vaccine Expressing Antigen 85B Induces Protective Immunity against Mycobacterium tuberculosis.
Derrick SC, Yang AL, Morris SL

Infect Immun 2005 Feb;73(2):1196-203
Long-term protection against tuberculosis following vaccination with a severely attenuated double lysine and pantothenate auxotroph of Mycobacterium tuberculosis.
Sambandamurthy VK, Derrick SC, Jalapathy KV, Chen B, Russell RG, Morris SL, Jacobs WR Jr

Vaccine 2004 Dec 21;23(6):780-8
A polyvalent DNA vaccine expressing an ESAT6-Ag85B fusion protein protects mice against a primary infection with Mycobacterium tuberculosis and boosts BCG-induced protective immunity.
Derrick SC, Yang AL, Morris SL

Expert Opin Biol Ther 2004 Sep;4(9):1493-504
Tuberculosis vaccine development: research, regulatory and clinical strategies.
Brennan MJ, Morris SL, Sizemore CF

J Clin Microbiol 2004 Jul;42(7):3225-31
Antigenic evidence of prevalence and diversity of Mycobacterium tuberculosis arabinomannan.
Glatman-Freedman A, Casadevall A, Dai Z, Jacobs WR Jr, Li A, Morris SL, Navoa JA, Piperdi S, Robbins JB, Schneerson R, Schwebach JR, Shapiro M