Despite significant advances in reducing mortality in recent decades through improved diagnosis and drug treatment regimens, in an estimated In addition to enormous human suffering, TB causes substantial economic burden and is one of the major drivers of global inequity. Whilst neonatal BCG vaccination is partially efficacious at protecting infants and young children, particularly from the most severe consequences of TB disease, it is poorly protective against pulmonary disease in adolescents and adults, and therefore at reducing Mtb transmission. Vaccines also offer the best chance to contain the accelerating spread of multi-drug resistant tuberculosis.
Clinical trials are evaluating both modifications to the existing BCG immunization methods and also novel TB vaccines, designed to replace or boost BCG.
Candidate vaccines in clinical development include live mycobacterial vaccines designed to replace BCG, subunit vaccines designed to boost BCG and therapeutic vaccines designed as an adjunct to chemotherapy.
There is a great need for validated animal models, identification of immunological biomarkers of protection and field sites with the capacity for large-scale efficacy testing in order to develop and license a novel TB vaccine or regimen.
BCG, clinical trials, mycobacteria, prophylactic, subunit, therapeutic, tuberculosis, vaccine Tuberculosis TB has been one of the major causes of morbidity and mortality worldwide for centuries and control of the spread of Mycobacterium tuberculosis infection remains a public health priority.
Following documentation of the pathogenesis of TB by anatomists and Tuberculosis the trials for the development identification of the tubercle bacillus by Robert Koch in the 19th Century, various control strategies have been attempted, principally the prompt detection, diagnosis and treatment of TB cases and prophylactic vaccination [ 1 ].
Robert Koch produced tuberculin, or purified protein derivative PPDwhich was initially introduced as an ineffective treatment for TB disease, before its diagnostic properties were realized, leading to the identification of latent infection with M. Early treatment regimens for TB, including bed rest and fresh air in sanitoria, and pulmonary collapse therapies, were poorly effective.
The TB vaccine M. BCG has been part of the Expanded Program on Immunization since and is given soon after birth in countries with a high burden of TB disease and to infants of high-risk groups or children with negative TSTs in countries with a low burden of TB disease [ 2 ].
It remains the only licensed TB vaccine and the oldest vaccine currently in use but has variable efficacy, hence case detection and treatment are necessary concurrent TB control strategies.
The first chemotherapeutic agents were introduced in the s and s in the form of para-aminosalicylic acid, streptomycin and the oral antibiotics, isoniazid and rifamycin, which remain the principal agents used for treating TB today [ 1 ].
This was despite the routine use of BCG as part of the Expanded Program on Immunization schedule throughout the developing world for 20 years, and the World Bank identifying combination drug treatment for TB to be among the most cost effective of all available health interventions.
However, TB cases and mortality continued to rise, which is largely attributed to the HIV epidemic and the emergence of multidrug-resistant MDR and extensively drug-resistant strains of M.
Additional factors disrupting existing control measures are internal migration to high-density urban areas, immigration from high-burden countries and economic crises [ 5 ].
It is clear that the existing strategies of mass immunization with BCG, effective case detection and combination chemotherapy are insufficient to control the TB epidemic. The Stop TB Strategy, introduced inis broader in approach, with the express targets of halting and reversing TB incidence by and halving TB prevalence and deaths by compared with [ 6 ].
The current global situation is that there were 9. Eastern Europe and the Eastern Mediterranean have reversed the incidence and halved the prevalence rate but not mortality rate [ 7 ]. Southeast Asia regions are on track to achieve the Stop TB Partnership targets of halving prevalence and death rates bycompared with a baseline of However, the TB incidence, prevalence and death rate continues to rise in African countries even with a low prevalence of HIV, and it is unlikely that the targets of halving prevalence and mortality worldwide will be realized by [ 7 ].
In addition to addressing the issues of TB—HIV coinfection and MDR-TB; the needs of poor and vulnerable populations, strengthening health infrastructures, engaging care providers and empowering patients and communities, the Stop TB strategy also advocates for, and promotes research into, the development of new diagnostics, drugs and vaccines.
Novel interventions and an emphasis on prevention are vital components of the Stop TB strategy if the targets are to be successful in all regions. Indeed, a mathematical model evaluating the potential benefit of novel interventions indicated that novel vaccines, drug regimens and diagnostics would each offer significant benefits in reducing TB incidence and TB mortality, but a combination of the three would augment the benefits [ 8 ].
Attributes of an ideal TB vaccine include safety and efficacy in at-risk infants, children and adults including HIV infection ; effectiveness against all forms of TB including pulmonary and MDR-TB, logistically practical timing of vaccination and noninterference with other childhood immunizationsand a formulation that can be feasibly manufactured on a mass scale and stored and administered under low-technology conditions.
Ongoing TB vaccine clinical trials are evaluating hypotheses for the variable efficacy of BCG; alterations to the methodology of BCG administration and novel candidate vaccines designed either to replace or enhance BCG.
The existing TB vaccine: Complications of BCG vaccination are extremely rare. Significant local reactions severe ulceration or regional lymphadenitis occur in less than one per individuals and fatal disseminated BCG disease in less than two per million vaccinees [ 2 ].
The majority of serious complications occur in immunocompromised individuals, due to disseminated infection. This is a major disadvantage of the vaccine. The WHO has kept lyophilized seed lots of each strain since in order to prevent further alterations from the original BCG [ 2 ].
Different BCG strains induce different immune responses in humans as well as animal models and the same strains perform differently in different locations, but there is no evidence that these phenotypic differences relate to differences in protective immunity between strains [ 1718 ].
Skin test delayed-type hypersensitivity responses to PPD prior to vaccination were higher in adolescents and young adults in Malawi than the UK but increased to a greater extent in the UK following BCG Glaxo vaccination, such that postvaccination responses were similar in both populations [ 22 ].
Chronic helminth infection Chronic helminth infections are common in areas where BCG is less effective and are associated with a shift towards Th2-type immune responses, which are usually associated with impaired antigen-specific and Th1-type responses [ 24 ].Keywords: Tuberculosis, Clinical trials, Middle development, Phase IIC, STEP, Drug development, Regimen development Background New regimens are urgently needed for the .
development in tuberculosis, it is desirable that a broader range of drugs and combinations be more consistently studied across a greater range of phase 2 endpoints than is currently available.
36 Journal for Clinical Studies Therapeutics Challenges in Conducting Tuberculosis Clinical Trials in Developing Countries: Lessons Learned Tuberculosis (TB) is a global epidemic of considerable. Several new or repurposed antimicrobial drugs are in advanced trial stages for MDR tuberculosis, and two new antimicrobial drug candidates are in early-stage trials.
Several trials to reduce the duration of therapy in MDR and drug-susceptible tuberculosis are ongoing. We review the latest WHO guidelines and global recommendations for treatment and management of drug-sensitive and drug-resistant tuberculosis, and provide an update on new drug development, results of several phase 2 and phase 3 tuberculosis treatment trials, and other emerging adjunct therapeutic options for MDR and XDR tuberculosis.
Development of Tuberculosis Diagnostic Kit The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.