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  4. New Ways to Predict How Well Vaccines Protect Against Tuberculosis, Tularemia and Other Bacteria That Live Inside Cells
  1. Science & Research (Biologics)

New Ways to Predict How Well Vaccines Protect Against Tuberculosis, Tularemia and Other Bacteria That Live Inside Cells

Principal Investigator: Karen Elkins, PhD
Office / Division / Lab: OVRR / DBPAP / LMDCI

General Overview

Most licensed bacterial vaccines are killed bacteria or non-living, isolated parts of bacteria. These vaccines usually stimulate the immune system to produce antibodies that protect the body against bacteria that live outside cells. Antibodies are present in body fluids, such as blood and lymph, and are relatively easy to measure.

In contrast, other kinds of immune responses protect against bacteria that live inside cells. These immune responses, which occur in certain tissues and organs such as lymph nodes and spleens, target bacteria like Mycobacterium tuberculosis, which causes tuberculosis, and Francisella tularensis, which causes tularemia. Tuberculosis damages the lungs, and tularemia ("rabbit fever") can cause fever, swollen lymph nodes, skin ulcers, eye infection, and pneumonia, among other symptoms.

The immune responses to intracellular bacterial infections are more varied and technically much more difficult to measure than antibody responses to extracellular infections. These responses, which are controlled by cells called T lymphocytes, are not well understood.

Although non-living vaccines provide poor protection against intracellular bacteria, vaccination with live, attenuated (weakened) strains of bacteria, such as M. bovis BCG for tuberculosis, is usually more effective. However, live vaccines pose potential safety problems, such as the possibility of living microorganisms causing disease in children and people with poor immune systems. Furthermore, while some vaccines protect against exposure to infection that starts in the skin, they are not effective against inhaled bacteria. The reasons for these differences also remain poorly understood.

Most importantly, researchers have not been able to identify any conveniently measured immune responses (correlates) that can be used to predict whether vaccines will protect against intracellular pathogens. Such correlates would significantly assist in the design and conduct of human clinical trials for new vaccines for intracellular pathogens. They would also facilitate evaluation of the benefits and risks associated with live vaccines and help us to design appropriate manufacturing and clinical testing strategies for these products.

Therefore, our research program is trying to discover immune mechanisms responsible for protecting against intracellular bacteria, particularly protection provided by vaccines. To do so, we are characterizing immune responses induced in mammals by intracellular bacteria, specifically, the time course, the types of immune cells involved, the molecules these cells produce and secrete, and the nature of the bacterial component(s) these immune cells recognize.

We perform these investigations in vaccinated and infected mice, as well as in tissue culture using isolated cells and bacteria. This includes studying immune cells from all sites of infection, including both lymphoid (spleen, lymph node) and non-lymphoid (lung, liver) tissues.

Scientific Overview

Most bacterial vaccines in use today are killed or subunit preparations that provide protection against extracellular bacteria by stimulating production of specific antibodies. Antibodies, present in body fluids such as serum, are relatively easy to measure. In contrast, cell mediated immune responses, which are critical for protection against intracellular bacteria such as Mycobacterium tuberculosis and Francisella tularensis, are much more difficult to assess. To date, protective T cell mediated immune responses have been best stimulated by vaccination with live attenuated bacterial strains, such as M. bovis BCG for tuberculosis. Indeed, so far subunit vaccines have provided poor protection against intracellular bacteria. Live vaccines have safety concerns, however, including the possibility of causing disease themselves in immunocompromised people.

Furthermore, some vaccines can provide protection against systemic exposure to infection, but not against aerosol or mucosal exposure. The reasons for these differences and the mechanisms of protection for intracellular bacteria in general, remain poorly understood. Moreover, no reliable and conveniently measured correlates of vaccine-induced efficacy against intracellular pathogens have been identified to date. This research program therefore seeks to understand the fundamental mechanisms of protective immunity against intracellular bacteria in order to develop useful correlates of protection.

To do so, we are characterizing primary and memory immune responses induced in mammals by intracellular bacteria, in terms of the temporal patterns of immune events, cell types involved, the effector molecules produced, the cell surface receptors necessary for bacterial recognition, and the nature of the bacterial component(s) recognized.

Studies using mouse models and novel in vitro tissue culture systems are directed at 1) identifying early innate immune responses to infection itself and to vaccine candidates; 2) mechanisms of vaccine-stimulated T lymphocyte cell control of intracellular bacterial growth (especially effector mechanisms other than production of interferon gamma); 3) the role of B lymphocytes in addition to their ability to produce antibodies; and 4) the role of chemokines during immune responses to intracellular infections.

Our studies focus on the specific roles of white blood cells, such as lymphocytes, natural killer cells, macrophages, dendritic cells, neutrophils, and their anti-bacterial products (including cytokines, cytotoxic granules, and antibodies) in the immune response to intracellular bacteria. We are specifically studying immune cells from all sites of infection, including both lymphoid (spleen, lymph node) and non-lymphoid (lung, liver) tissues. The in vivo, three-dimensional organization of immune responses to bacteria within infected tissues is also being investigated using immunohistochemistry coupled with confocal microscopy and in vivo imaging.

One goal of these studies is to translate the research findings into practical correlates of vaccine efficacy, as well as the design of appropriate manufacturing and clinical testing strategies for new vaccines. Determining practical correlates would greatly advance the conduct of human clinical trials for new vaccines for intracellular pathogens, and improve evaluation of the benefits and risks associated with these products.

Publications

  1. PLoS Pathog 2024 Jun 11;20(6):e1011915
    Systems genetics uncover new loci containing functional gene candidates in Mycobacterium tuberculosis-infected Diversity Outbred mice.
    Gatti DM, Tyler AL, Mahoney JM, Churchill GA, Yener B, Koyuncu D, Gurcan MN, Niazi MK, Tavolara T, Gower A, Dayao D, McGlone E, Ginese ML, Specht A, Alsharaydeh A, Tessier PA, Kurtz SL, Elkins KL, Kramnik I, Beamer G
  2. Microbiol Spectr 2024 Jun 28 [Epub ahead of print]
    Francisella tularensis Live Vaccine Strain training of murine alveolar and bone marrow-derived macrophages.
    Khan H, Bhargava V, Elkins KL
  3. PLoS Pathog 2024 Mar 7;20(3):e1012069
    Multiple genetic loci influence vaccine-induced protection against Mycobacterium tuberculosis in genetically diverse mice.
    Kurtz SL, Baker RE, Boehm FJ, Lehman CC, Mittereder LR, Khan H, Rossi AP, Gatti DM, Beamer G, Sassetti CM, Elkins KL
  4. Vaccines 2024 Feb 26;12(3):242
    Host genetic background influences BCG-induced antibodies cross-reactive to SARS-CoV-2 spike protein.
  5. PLoS One 2023 Aug 3;18(8):e0289358
    Transcriptional signatures measured in whole blood correlate with protection against tuberculosis in inbred and outbred mice.
    Kurtz SL, Rydén P, Elkins KL
  6. Infect Immun 2023 Jul;91(7):e0016823
    Intravenous BCG vaccination of diversity outbred mice results in moderately enhanced protection against challenge with Mycobacterium tuberculosis compared to intradermal vaccination.
    Kurtz SL, Mittereder LR, Lehman CC, Khan H, Gould VA, Elkins KL
  7. Front Microbiol 2023 Jul 13;14:1224480
    In vivo and in vitro immune responses against Francisella tularensis vaccines are comparable among Fischer 344 rat substrains.
    De Pascalis R, Bhargava V, Espich S, Wu TH, Gelhaus HC, Elkins KL
  8. PLoS One 2023 Mar 27;18(3):e0283161
    IL-12p40 is essential but not sufficient for Francisella tularensis LVS clearance in chronically infected mice.
    Mittereder LR, Swoboda J, De Pascalis R, Elkins KL
  9. NPJ Vaccines 2022 Aug 17;7(1):95
    Working correlates of protection predict SchuS4-derived-vaccine candidates with improved efficacy against an intracellular bacterium, Francisella tularensis.
    De Pascalis R, Frey B, Rice HM, Bhargava V, Wu TH, Peterson RL, Conlan JW, Sjöstedt A, Elkins KL
  10. Lancet Infect Dis 2022 Apr;22(4):e108-20
    Accelerating research and development of new vaccines against tuberculosis: a global roadmap.
    Cobelens F, Suri RK, Helinski M, Makanga M, Weinberg AL, Schaffmeister B, Deege F, Hatherill M, TB Vaccine Roadmap Stakeholder Group
  11. Vaccine 2022 Mar 15;40(12):1681-90
    Building the concept for WHO Evidence Considerations for Vaccine Policy (ECVP): tuberculosis vaccines intended for adults and adolescents as a test case.
    Kochhar S, Barreira D, Beattie P, Cavaleri M, Cravioto A, Frick MW, Ginsberg AM, Hudson I, Kaslow DC, Kurtz S, Lienhardt C, Madhi SA, Morgan C, Momeni Y, Patel D, Rees H, Rogalski-Salter T, Schmidt A, Semete-Makokotlela B, Voss G, White RG, Zignol M, Giersing B
  12. Pathogens 2021 Jun 23;10(7):795
    Modern development and production of a new live attenuated bacterial vaccine, SCHU S4 delta clpB, to prevent tularemia.
    Conlan JW, Sjöstedt A, Gelhaus HC, Fleming P, McRae K, Cobb RR, De Pascalis R, Elkins KL
  13. Front Cell Infect Microbiol 2021 Jun 21;11:672527
    Enhancement of CD4(+) T cell function as a strategy for improving antibiotic therapy efficacy in tuberculosis: does it work?
    Costa DL, Amaral EP, Namasivayam S, Mittereder LR, Andrade BB, Sher A
  14. PLoS One 2021 Mar 24;16(3):e0249142
    Deficiency in CCR2 increases susceptibility of mice to infection with an intracellular pathogen, Francisella tularensis LVS, but does not impair development of protective immunity.
    Kurtz SL, De Pascalis R, Meierovics AI, Elkins KL
  15. PLoS One 2020 Aug 3;15(8):e0237034
    Production of IFN-gamma by splenic dendritic cells during innate immune responses against Francisella tularensis LVS depends on MyD88, but not TLR2, TLR4, or TLR9.
    De Pascalis R, Rossi AP, Mittereder L, Takeda K, Akue A, Kurtz SL, Elkins KL
  16. Sci Rep 2020 Jul 21;10(1):12023
    Immune lymphocytes halt replication of Francisella tularensis LVS within the cytoplasm of infected macrophages.
    Bradford MK, Elkins KL
  17. mSphere 2020 Apr;5(2):e00097-20
    The diversity outbred mouse population is an improved animal model of vaccination against tuberculosis that reflects heterogeneity of protection.
    Kurtz SL, Rossi AP, Beamer GL, Gatti DM, Kramnik I, Elkins KL
  18. Tuberculosis 2020 Mar;121:101914
    The Many Hosts of Mycobacteria 8 (MHM8): a conference report.
    Larsen MH, Lacourciere K, Parker TM, Kraigsley A, Achkar JM, Adams LB, Dupnik KM, Hall-Stoodley L, Hartman T, Kanipe C, Kurtz SL, Miller MA, Salvador LCM, Spencer JS, Robinson RT
  19. J Immunol Methods 2020 Feb;477:112693
    rM-CSF efficiently replaces L929 in generating mouse and rat bone marrow-derived macrophages for in vitro functional studies of immunity to intracellular bacteria.
    Rice HM, Rossi AP, Bradford MK, Elkins KL, De Pascalis R
  20. Tuberculosis 2020 Jan;120:101895
    Whole genome profiling refines a panel of correlates to predict vaccine efficacy against Mycobacterium tuberculosis.
    Kurtz SL, Gardina PJ, Myers TG, Ryden P, Elkins KL
  21. Pathog Dis 2018 Oct 1;76(7):fty067
    Sequence comparison of Francisella tularensis LVS, LVS-G, and LVS-R.
    Kurtz SL, Voskanian-Kordi A, Simonyan V, Elkins KL
  22. PLoS One 2018 May 25;13(5):e0198140
    A panel of correlates predicts vaccine-induced protection of rats against respiratory challenge with virulent Francisella tularensis.
    De Pascalis R, Hahn A, Brook HM, Ryden P, Donart N, Mittereder L, Frey B, Wu TH, Elkins KL
  23. Microbes Infect 2017 Feb;19(2):91-100
    Murine survival of infection with Francisella novicida, and protection against secondary challenge, is critically dependent on B lymphocytes.
    Chou AY, Kennett NJ, Melillo AA, Elkins KL
  24. Microbes Infect 2016 Dec;18(12):758-67
    GM-CSF has disparate roles during intranasal and intradermal F. tularensis infection.
    Kurtz SL, Bosio CM, De Pascalis R, Elkins KL
  25. F1000Res 2016 Dec 20;5:2884
    Meta-analysis of crowdsourced data compendia suggests pan-disease transcriptional signatures of autoimmunity.
    Lau WW, Sparks R, OMiCC Jamboree Working Group, Tsang JS
  26. Expert Rev Vaccines 2016 Sep;15(9):1183-96
    Progress, challenges, and opportunities in Francisella vaccine development.
    Elkins KL, Kurtz SL, De Pascalis R
  27. Infect Immun 2016 Apr;84(4):1054-61
    Activities of murine peripheral blood lymphocytes provide immune correlates that predict Francisella vaccine efficacy.
    De Pascalis R, Mittereder L, Kennett NJ, Elkins KL
  28. Clin Vaccine Immunol 2015 Oct;22(10):1096-108
    Correlates of vaccine-induced protection against TB immune revealed in comparative analyses of lymphocyte populations.
    Kurtz SL, Elkins KL
  29. PLoS One 2015 May 14;10(5):e0126570
    Francisella tularensis vaccines elicit concurrent protective T- and B-cell immune responses in BALB/cByJ mice.
    De Pascalis R, Mittereder L, Chou AY, Kennett NJ, Elkins KL

 

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