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

mSphere 2020 Apr 15;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
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
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
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
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
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
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
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
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
Expert Rev Vaccines 2016 Sep;15(9):1183-96
Progress, challenges, and opportunities in Francisella vaccine development.
Elkins KL, Kurtz SL, De Pascalis R
Infect Immun 2016 Mar 24;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
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
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