Correlates of Protection for Vaccination against Tularemia, Tuberculosis and Other Intracellular Bacteria

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

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Overview

Public Health Issue: Most bacterial vaccines in use today are killed or subunit preparations that provide protection against extracellular bacteria by stimulating production of specific antibodies. In contrast, cell mediated immune responses are critical for protection against intracellular bacteria, such as Mycobacterium tuberculosis and Francisella tularensis. Improved cell mediated immune responses result from vaccination with live attenuated bacterial strains, such as M. bovis BCG for tuberculosis. Indeed, to date, subunit vaccines have generally provided poor protection against intracellular bacteria. Live vaccines have safety concerns, however, including the possibility of causing disease themselves in immunocompromised people. Further, some vaccines may 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, and to date no reliable and conveniently measured correlates of vaccine efficacy against intracellular pathogens have been identified.

Regulatory Contribution: This research program seeks to understand the mechanisms of protective immunity against intracellular bacteria. The research findings, in turn, may be translated into the establishment of correlates of vaccine efficacy that will be useful in human clinical trials, to the development of tests to improve the evaluation of vaccine candidates, and to the improved evaluation of the benefits and risks associated with live vaccines.

Research Approach: The importance of cell mediated immunity, including T cell-mediated production of interferon gamma, has been demonstrated for many intracellular pathogens including Mycobacterium tuberculosis and the Live Vaccine Strain (LVS) of F. tularensis. Nonetheless, interferon gamma production does not predict successful vaccination, and other correlates have not been clearly identified. Thus, we are characterizing mammalian primary and memory immune responses induced 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 identifying early innate immune responses to infection itself and to vaccine candidates; mechanisms of vaccine-stimulated T lymphocyte cell control of intracellular bacterial growth (especially effector mechanisms other than production of interferon gamma); the role of B lymphocytes, apart from their ability to produce antibodies, in protection against intracellular infections; and the role of chemokines during immune responses to intracellular infections. The effective immune response to intracellular bacteria will be identified by studies that 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 immunity to intracellular bacteria. Immune cells from all sites of infection, including both lymphoid (spleen, lymph node) and non-lymphoid (lung, liver) tissues, are being studied. The in vivo, three dimensional organization of immune responses to bacteria within infected tissues is also being investigated using immunohistochemistry coupled with confocal microscopy, as well as in vivo imaging. Such information may, in turn, be used to direct efforts to establish protective correlates, and design appropriate manufacturing and clinical testing strategies for new vaccines.

Mission Relevance & Outcomes: These studies will provide information on correlates of immune protection against intracellular bacteria, that may be useful for assessing vaccine efficacy. In addition, the information gleaned will facilitate the development of new tests to assess vaccine safety and consistency of manufacture of live attenuated bacterial vaccines.

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Publications

Infect Immun 2008 Sep;76(9):4311-21
Diverse myeloid and lymphoid cell subpopulations produce gamma interferon during early innate immune responses to Francisella tularensis live vaccine strain.
De Pascalis R, Taylor BC, Elkins KL

J Bacteriol 2008 Jul;190(13):4584-95
The Francisella Pathogenicity Island Protein PdpD is required for full virulence and associates with homologues of the type VI secretion system.
Ludu JS, de Bruin OM, Duplantis BN, Schmerk CL, Chou AY, Elkins KL, Nano FE

J Infect Dis 2008 Jul 15;198(2):284-92
The Membrane Form of Tumor Necrosis Factor Is Sufficient to Mediate Partial Innate Immunity to Francisella tularensis Live Vaccine Strain.
Cowley SC, Goldberg MF, Ho JA, Elkins KL

J Immunol 2008 May 15;180(10):6885-91
Macrophage proinflammatory response to Francisella tularensis live vaccine strain requires coordination of multiple signaling pathways.
Cole LE, Santiago A, Barry E, Kang TJ, Shirey KA, Roberts ZJ, Elkins KL, Cross AS, Vogel SN

J Immunol 2007 Dec 1;179(11):7709-19
Differential Requirements by CD4+ and CD8+ T Cells for Soluble and Membrane TNF in Control of Francisella tularensis Live Vaccine Strain Intramacrophage Growth.
Cowley SC, Sedgwick JD, Elkins KL

Infect Immun 2007 Aug;75(8):4127-37
Toll-like receptor 2-mediated signaling requirements for Francisella tularensis live vaccine strain infection of murine macrophages.
Cole LE, Shirey KA, Barry E, Santiago A, Rallabhandi P, Elkins KL, Puche AC, Michalek SM, Vogel SN

Ann N Y Acad Sci 2007 Jun;1105:284-324
Innate and adaptive immunity to Francisella.
Elkins KL, Cowley SC, Bosio CM

J Immunol 2006 Jun 1;176(11):6888-99
Immunologic consequences of Francisella tularensis live vaccine strain infection: role of the innate immune response in infection and immunity.
Cole LE, Elkins KL, Michalek SM, Qureshi N, Eaton LJ, Rallabhandi P, Cuesta N, Vogel SN

Microbes Infect 2006 Mar;8(3):779-90
Myeloid differentiation factor-88 (MyD88) is essential for control of primary in vivo Francisella tularensis LVS infection, but not for control of intramacrophage bacterial replication.
Collazo CM, Sher A, Meierovics AI, Elkins KL

J Exp Med 2005 Jul 18;202(2):309-19
CD4-CD8- T cells control intracellular bacterial infections both in vitro and in vivo.
Cowley SC, Hamilton E, Frelinger JA, Su J, Forman J, Elkins KL

J Bacteriol 2004 Oct;186(19):6430-6
A Francisella tularensis pathogenicity island required for intramacrophage growth.
Nano FE, Zhang N, Cowley SC, Klose KE, Cheung KK, Roberts MJ, Ludu JS, Letendre GW, Meierovics AI, Stephens G, Elkins KL

J Immunol 2004 Jan 15;172(2):1163-1168
Mice Deficient in LRG-47 Display Increased Susceptibility to Mycobacterial Infection Associated with the Induction of Lymphopenia.
Feng CG, Collazo-Custodio CM, Eckhaus M, Hieny S, Belkaid Y, Elkins K, Jankovic D, Taylor GA, Sher A