Clin Exp Vaccine Res. 2014 Jul; 3(2): 155–167.
Published online 2014 Jun 20. doi: [10.7774/cevr.2014.3.2.155]

Jae-Min Yuk and Eun-Kyeong Jo

Tuberculosis (TB) remains a worldwide health problem, causing around 2 million deaths per year. Despite the bacillus Calmette Guérin vaccine being available for more than 80 years, it has limited effectiveness in preventing TB, with inconsistent results in trials. This highlights the urgent need to develop an improved TB vaccine, based on a better understanding of host-pathogen interactions and immune responses during mycobacterial infection. Recent studies have revealed a potential role for autophagy, an intracellular homeostatic process, in vaccine development against TB, through enhanced immune activation. This review attempts to understand the host innate immune responses induced by a variety of protein antigens from Mycobacterium tuberculosis, and to identify future vaccine candidates against TB. We focus on recent advances in vaccine development strategies, through identification of new TB antigens using a variety of innovative tools. A new understanding of the host-pathogen relationship, and the usefulness of mycobacterial antigens as novel vaccine candidates, will contribute to the design of the next generation of vaccines, and to improving the host protective immune responses while limiting immunopathology during M. tuberculosis infection.

Keywords: Tuberculosis, BCG vaccine, Host-pathogen interactions, Innate immunity, Aadaptive immunity

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Microbiol. 2014;9(3):327-41. doi: 10.2217/fmb.13.164.

Bruns H1, Stenger S.

Abstract
Mycobacterium tuberculosis is a facultative intracellular pathogen. It infects macrophages where it avoids elimination by interfering with host defense mechanisms. Until recently, it was assumed that the acidification of phagosomes is the major strategy of macrophages to eliminate M. tuberculosis. However, there is emerging evidence demonstrating that human macrophages are equipped with additional antimicrobial effector functions. Specifically, autophagy, efferocytosis and antimicrobial peptides have been identified as mechanisms to restrict mycobacterial proliferation. Here we review recent findings on effector functions of human macrophages and mechanisms of the pathogen to interfere with them.

World Health Organization, 2006

The purpose of the International Standards for Tuberculosis Care (ISTC) is to describe a widely accepted level of care that all practitioners, public and private, should seek to achieve in managing patients who have, or are suspected of having, tuberculosis. The Standards are intended to facilitate the effective engagement of all care providers in delivering high-quality care for patients of all ages, including those with sputum smear-positive, sputum smear-negative, and extra pulmonary tuberculosis, tuberculosis caused by drug-resistant Mycobacterium tuberculosis complex (M. tuberculosis) organisms, and tuberculosis combined with human immunodefi ciency virus (HIV) infection.

American Journal of Respiratory Critical Care Medicine 2005; 172:1169–227

During 1993–2003, incidence of tuberculosis (TB) in the United States decreased 44% and is now occurring at a historic low level (14,874 cases in 2003)… In this statement, the American Thoracic Society (ATS), Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America (IDSA) propose recommendations to improve the control and prevention of TB in the United States and to progress toward its elimination.

MMWR 2003; 52 (RR-11)

The overall goals for treatment of tuberculosis are (1) to cure the individual patient, and (2) to minimize the transmission of Mycobacterium tuberculosis to other persons. Thus, successful treatment of tuberculosis has benefits both for the individual patient and the community in which the patient resides… Prescribing physician responsibility for treatment completion is a fundamental principle in tuberculosis control.

The Open Infectious Diseases Journal, 2008, 2, 59-76

The pathology of tuberculosis in humans starts with an initial Ghon focus in the lungs followed by transmission of bacilli though the blood and lymph to other regions in the lungs and to other organs. While these bacilli usually lie latent without causing further disease, some 10% start foci of adult type disease usually starting in the sub-apical regions of the lungs. Bacilli multiply, killing tissue by caseation and then forming colonies within the caseum. Cavities form connecting to the air in whose walls vigorous bacillary multiplication occurs. The history of the development of antituberculosis chemotherapy is described, starting with the use of multi-drug regimens to prevent the emergence of drug resistance and continuing with the shortening of the treatment period to 6 months by the incorporation in the regimens of rifampicin and pyrazinamide, which are the two drug responsible for bactericidal activity during treatment. Prospects for further shortening of treatment rest with the introduction of higher dosage with rifamycins and with new anti-tuberculosis drugs. These new drugs include the 8methoxyfluoroquinolones moxifloxacin and gatifloxacin which inhibit topoisomerases and protein formation, the diarylquinoline TM-207 which inhibits the mycobacterial ATP synthase and thus energy formation, the nitroimidazopyran PA-824 and the closely related OPC-676832 which are pro-drugs with uncertain modes of action and the pyrrole SQ-109, a cell wall inhibitor. Anti-tuberculosis drugs have widely variable pharmacokinetic characteristics but as they work efficiently together, it is unnecessary to match these when giving drug combinations. The effects of drug-drug interactions are usually small though the interactions with anti-retroviral drugs can pose problems. Dose sizes have usually been chosen to minimize side effects while retaining activity and thus tend to have low therapeutic margins, the exception being the margin of about 20 for isoniazid. The role of high plasma binding, important in limiting the efficacy of rifamycins, is uncertain for the newer drugs. Post antibiotic effects are vital to the prevention of drug resistance and need exploration for new drugs. The main aims of current drug development are (1) to shorten treatment, and (2) to make it more convenient, by for instance using widely intermittent regimens. The current techniques for measuring efficacy during drug development start with in vitro models, including the Hu/Coates models, which should contain bacterial populations resembling the bacterial persisters in lesions that are responsible for the long duration of treatment. The next stage is the mouse model of the chemotherapy of established tuberculosis, which has proved remarkably useful in assessing the value of the different drugs. The main problem in clinical assessment arises from the use of relapse after treatment as the main end-point, and the consequent need for very large numbers of patients required to provide measurable relapse rates in final phase III licensing studies. For this reason, surrogate studies are necessary in phase II which require much smaller numbers of patients. The first such investigations are phase IIA studies of early bactericidal activity which establish whether the drug given alone has bactericidal activity on cavitary bacilli and which can estimate the minimal effective dose of the drug, useful for decisions of dose size. The next step should be phase IIB studies which measure the rate of elimination of viable bacilli in sputum during the initial 8-weeks of treatment with various combinations of the new drug with established drugs. Measurement can be as (1) the proportion of patients with positive sputum at the end of the 8-weeks period, the easiest method but the least sensitive, or (2) as the speed with which sputum cultures become negative in a survival analysis, or (3) as the mean regression in modeling of serial sputum collections colony counts (SSCC). The relation between these surrogate estimates and the amoun of treatment shortening that can be obtained has still to be worked out.

Tuberculosis 2007

From basic science to patient care

Juan Carlos Palomino, Sylvia Leão, Viviana Ritacco, et al.
2007
687 pp