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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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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

Infect Immun 2013 Apr;81(4):1306-15
An Epicutaneous Model of Community-Acquired Staphylococcus aureus Skin Infections.
Prabhakara R, Foreman O, De Pascalis R, Lee GM, Plaut RD, Kim SY, Stibitz S, Elkins KL, Merkel TJ

Infect Immun 2013 Feb;81(2):585-97
IL-6 is essential for primary resistance to Francisella tularensis LVS infection.
Kurtz S, Foreman O, Bosio CM, Anver MR, Elkins KL

PLoS Pathog 2012 Jan;8(1):e1002494
Development of functional and molecular correlates of vaccine-induced protection for a model intracellular pathogen, F. tularensis LVS.
De Pascalis R, Chou AY, Bosio CM, Huang CY, Follmann DA, Elkins KL

Curr Protoc Immunol 2011 Apr;Chapter 14:Unit14.25
Measurement of macrophage-mediated killing of intracellular bacteria, including Francisella and mycobacteria.
Elkins KL, Cowley SC, Conlan JW

Front Microbiol 2011;2:26
Immunity to francisella.
Cowley SC, Elkins KL

Int J Syst Evol Microbiol 2010 Aug;60(Pt 8):1717-8
Objections to the transfer of Francisella novicida to the subspecies rank of Francisella tularensis.
Johansson A, Celli J, Conlan W, Elkins KL, Forsman M, Keim PS, Larsson P, Manoil C, Nano FE, Petersen JM, Sjöstedt A

Vaccine 2010 Jun 23;28(29):4539-47
Utilization of serologic assays to support efficacy of vaccines in nonclinical and clinical trials: meeting at the crossroads.
Madore DV, Meade BD, Rubin F, Deal C, Lynn F, Meeting Contributors

J Immunol 2010 May 15;184(10):5791-801
Lung CD4- CD8- double-negative T cells are prominent producers of IL-17A and IFN-gamma during primary respiratory murine infection with Francisella tularensis live vaccine strain.
Cowley SC, Meierovics AI, Frelinger JA, Iwakura Y, Elkins KL

Microbes Infect 2010 Jan;12(1):28-36
Survival of secondary lethal systemic Francisella LVS challenge depends largely on interferon gamma.
Elkins KL, Colombini SM, Meierovics AI, Chu MC, Chou AY, Cowley SC

J Immunol 2009 Dec 15;183(12):7984-93
Tumor progression locus 2 (Map3k8) is critical for host defense against listeria monocytogenes and IL-1beta production.
Mielke LA, Elkins KL, Wei L, Starr R, Tsichlis PN, O'Shea JJ, Watford WT

Infect Immun 2009 May;77(5):2010-21
T cells from lungs and livers of Francisella-immune mice control the growth of intracellular bacteria.
Collazo CM, Meierovics AI, De Pascalis R, Wu TH, Lyons CR, Elkins KL

Microbiology 2009 May;155(Pt 5):1489-97
Characterization of the pathogenicity island protein PdpA and its role in the virulence of Francisella novicida.
Schmerk CL, Duplantis BN, Wang D, Burke RD, Chou AY, Elkins KL, Ludu JS, Nano FE

Proc Natl Acad Sci U S A 2009 Mar 17;106(11):4343-8
Antigen-specific B-1a antibodies induced by Francisella tularensis LPS provide long-term protection against F. tularensis LVS challenge.
Cole LE, Yang Y, Elkins KL, Fernandez ET, Qureshi N, Shlomchik MJ, Herzenberg LA, Herzenberg LA, Vogel SN

Microbes Infect 2009 Jan;11(1):49-56
NK cells activated in vivo by bacterial DNA control the intracellular growth of Francisella tularensis LVS.
Elkins KL, Colombini SM, Krieg AM, DePascalis R

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

 

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