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
The pandemic (worldwide epidemic) of tuberculosis (TB) is an international public health tragedy: More than 8 million new cases of TB are detected each year and 2 million people die annually from this disease. The extreme susceptibility of HIV-infected individuals to TB and the increasing emergence of multiple drug-resistant strains of TB have significantly magnified the global impact of this disease in recent years.
Much research worldwide has focused on improving TB vaccination strategies to curb this pandemic. Although the current TB vaccine (BCG) does reduce the incidence of childhood TB, it is largely ineffective in preventing the most common form of this disease--adult pulmonary TB. Using a mouse model of pulmonary TB, our laboratory is developing and characterizing novel, more potent ways to immunize people against TB. In collaboration with investigators at the Albert Einstein College of Medicine, we characterized more than 30 highly active live, attenuated TB vaccines. Such vaccines contain live organisms (which work better than inactive organisms) that have been weakened so they cannot cause disease. In separate studies, we tested new ways to increase the effectiveness of the current BCG vaccine, including simultaneously administering TB proteins with the BCG preparation.
In addition to testing novel TB vaccines, we have been trying to identify biological molecules that might play important roles in vaccine activity. We recently defined several vaccine-induced molecules that appear to be essential in preventing TB in the mouse model. Our identification of specific molecules that are important for vaccine activity, perhaps providing important correlates of protection that can be used in preclinical and clinical studies should accelerate vaccine development and simplify regulatory review.
To facilitate TB vaccine use in humans, we have also been developing tests to analyze the safety and effectiveness of new TB vaccines. With support from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, we created a practical in vitro ("test tube") assay to assess TB vaccine potency. Furthermore, in collaboration with the Aeras Global TB Vaccine foundation, our laboratory developed an in vivo test to analyze the safety of TB vaccines designed for use in individuals who have previously been infected with TB. The use of both of these assays by vaccine manufacturers should reduce regulatory concerns about the safety and potency of new vaccines during FDA regulatory reviews of these products.
Finally, earlier studies had suggested that vaccinations against one organism could be compromised if a person were simultaneously infected with a different organism. For example, in regions of Africa where TB and malaria are common, individuals can be infected with both malaria parasites and TB bacilli. Therefore, we are using a mouse model to determine if a concurrent malarial infection will reduce the safety and activity of TB vaccines. To date, data from the mouse model studies suggests that malaria does not decrease the capacity of TB vaccines to control TB infections. This suggests that concurrent malaria infections will not complicate the evaluation of TB vaccines in developing countries. This finding should be important for sponsors of new TB vaccines who plan to test their vaccines in areas with high malaria infection rates.
Our studies in recent years have focused on 5 specific projects related to TB research.
1. Characterization of novel, live attenuated vaccines against TB. In collaboration with investigators at the Albert Einstein College of Medicine, we have been characterizing novel attenuated mutant TB strains with improved immunogenicity and reduced virulence. In particular, we found that gene deletions that create pro-apoptotic phenotypes and amplify induction of IL-12 are more effective vaccines in pre-clinical studies.
2. Assessment of prime boost strategies against TB. For several infectious organisms, a heterologous prime-boost immunization strategy has been shown to amplify vaccine-induced protective immunity. We are investigating the effectiveness of viral-vectored vaccines (adenovirus and MVA) expressing TB antigens as boosting agents. In particular, we found that priming with a TB protein/adjuvant formulation followed boosting with a TB MVA vector yields high levels of persistent anti-tuberculosis protective immunity.
3. The identification of in vivo correlates of protective immunity for TB vaccines. To evaluate immune responses that may correlate with anti-tuberculosis protective immunity, we assessed early post-challenge responses in the lungs of vaccinated mice using PCR arrays. In these studies, an early cytokine response profile which correlated with protection against TB was elucidated. Furthermore, we have been investigating whether the induction of multi-functional T cells (MFT) expressing multiple cytokines by TB vaccines correlated with levels of vaccine-induced protection. Our preliminary data suggest that the extent of MFT induction also correlates with the level of protective immunity evoked by vaccination.
4. Creating a practical in vitro potency assay for evaluating TB vaccines. To facilitate vaccine development, we generated in vitro mycobacterial intra-macrophage growth inhibition assays designed for BSL-2 labs, which measure the capacity of vaccine-induced immune splenocytes to control the growth of BCG (or TB). Using these assays, we were able to detect the protective immune responses evoked by 4 types of TB vaccines. Importantly, the levels of vaccine-induced protection seen in these in vitro assays correlated with the in vivo protection detected in the mouse model.
5. Characterization of the impact of concomitant diseases on the safety and effectiveness of TB and malaria vaccines. Despite considerable progress in the development of new vaccines for TB and malaria, the safety and effectiveness of these vaccines in regions where concomitant diseases are prevalent remain unknown and is a potential barrier to licensure. It is uncertain, for example, whether the immunogenicity and efficacy of new TB vaccines will be impacted by concurrent malarial infections or whether the administration of specific TB vaccines will alter the course of malarial infections. In initial studies, we showed that concomitant malarial infections do not impact the safety and effectiveness of TB vaccines in the mouse model. Interestingly, however, injection of specific TB vaccines can reduce malarial parasitemia.
J Infect Dis 2013 Jan 1;207(1):164-74
Radiation-induced cellular and molecular alterations in asexual intraerythrocytic Plasmodium falciparum.
Oakley MS, Gerald N, Anantharaman V, Gao Y, Majam V, Mahajan B, Pham PT, Lotspeich-Cole L, Myers TG, McCutchan TF, Morris SL, Aravind L, Kumar S
J Microbiol Methods 2012 Sep;90(3):245-9
Characterization of an intracellular ATP assay for evaluating the viability of live attenuated mycobacterial vaccine preparations.
Kolibab K, Derrick SC, Jacobs WR, Morris SL
PLoS One 2012;7(3):e32959
Formulation of a mmaA4 gene deletion mutant of Mycobacterium bovis BCG in cationic liposomes significantly enhances protection against tuberculosis.
Derrick SC, Dao D, Yang A, Kolibab K, Jacobs WR, Morris SL
PLoS One 2011;6(12):e28164
Malaria infections do not compromise vaccine-induced immunity against tuberculosis in mice.
Parra M, Derrick SC, Yang A, Tian J, Kolibab K, Oakley M, Perera LP, Jacobs WR, Kumar S, Morris SL
J Clin Microbiol 2011 Jun;49(6):2380-1
Sensitivity to Isoniazid of Mycobacterium bovis BCG Strains and BCG Disseminated Disease Isolates.
Kolibab K, Derrick SC, Morris SL
Vaccine 2011 Apr 5;29(16):2902-9
Vaccine-induced anti-tuberculosis protective immunity in mice correlates with the magnitude and quality of multifunctional CD4 T cells.
Derrick SC, Yabe IM, Yang A, Morris SL
Microbiology 2011 Mar;157(Pt 3):793-804
Induction of cell death after localization to the host cell mitochondria by the Mycobacterium tuberculosis PE_PGRS33 protein.
Cadieux N, Parra M, Cohen H, Maric D, Morris SL, Brennan MJ
PLoS One 2011 Jan 10;6(1):e15857
Lysine auxotrophy combined with deletion of the SecA2 gene results in a safe and highly immunogenic candidate live attenuated vaccine for tuberculosis.
Hinchey J, Jeon BY, Alley H, Chen B, Goldberg M, Derrick S, Morris S, Jacobs WR Jr, Porcelli SA, Lee S
Clin Vaccine Immunol 2010 May;17(5):793-801
Highly persistent and effective prime/boost regimens against tuberculosis that use a multivalent modified vaccine virus Ankara-based tuberculosis vaccine with interleukin-15 as a molecular adjuvant.
Kolibab K, Yang A, Derrick SC, Waldmann TA, Perera LP, Morris SL
Vaccine 2009 Dec 11;28(2):317-22
A practical in vitro growth inhibition assay for the evaluation of TB vaccines.
Kolibab K, Parra M, Yang AL, Perera LP, Derrick SC, Morris SL
PLoS One 2009 Aug 27;4(8):e6793
Pathogenic roles of CD14, galectin-3, and OX40 during experimental cerebral malaria in mice.
Oakley MS, Majam V, Mahajan B, Gerald N, Anantharaman V, Ward JM, Faucette LJ, McCutchan TF, Zheng H, Terabe M, Berzofsky JA, Aravind L, Kumar S
Clin Vaccine Immunol 2009 Jul;16(7):1025-32
The Development of a Murine Mycobacterial Growth Inhibition Assay for Evaluating Vaccines Against Mycobacterium tuberculosis.
Parra M, Yang AL, Lim J, Kolibab K, Derrick S, Cadieux N, Perera LP, Jacobs WR, Brennan M, Morris SL
Vaccine 2009 Jul 16;27(33):4412-23
Novel recombinant BCG expressing perfringolysin O and the over-expression of key immunodominant antigens; pre-clinical characterization, safety and protection against challenge with Mycobacterium tuberculosis.
Sun R, Skeiky YA, Izzo A, Dheenadhayalan V, Imam Z, Penn E, Stagliano K, Haddock S, Mueller S, Fulkerson J, Scanga C, Grover A, Derrick SC, Morris S, Hone DM, Horwitz MA, Kaufmann SH, Sadoff JC
Vaccine 2009 Mar 26;27(15):2121-7
A multi-valent vaccinia virus-based tuberculosis vaccine molecularly adjuvanted with interleukin-15 induces robust immune responses in mice.
Perera PY, Derrick SC, Kolibab K, Momoi F, Yamamoto M, Morris SL, Waldmann TA, Perera LP
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):2279-88
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
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
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
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