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[Immunization against tuberculosis: new vaccination strategies or is there an alternative to BCG?].

Consistently high tuberculosis rates in many developing nations, the surprising increase in tuberculosis cases in numerous industrialized countries, together with the emergence of multi-drug-resistant strains of Mycobacterium tuberculosis have sharpened public interest in this ancient scourge. Improved tuberculosis control could best be achieved by an efficacious vaccine. The available attenuated vaccine strain, Mycobacterium bovis BCG, has only limited efficiency. This vaccine is capable of protecting against disseminated miliary tuberculosis in the newborn, but it is unable to prevent stable infection and to cause sterile pathogen eradication. Hence, adult tuberculosis, representing the majority of all tuberculosis cases, is not preventable by BCG vaccination. Due to the extraordinarily high rate of asymptomatic M. tuberculosis infection (1/3 of the total world population) any novel vaccination strategy has to fulfil two major tasks: first, prevention of stable infection, second, eradication of already established infection. T lymphocytes represent the major target for any vaccine strategy, because they serve as central mediators of acquired immunity. They segregate into distinct populations, characterized by different activation conditions and biological functions. These T cell populations do not act independently from, but rather interact with, each other mostly through cytokines. Although CD4 T lymphocytes of T helper 1 type are essential for protection, CD8 T cells expressing cytolytic functions are required, in addition. Perhaps other T cell populations, such as gamma/delta T cells and double negative alpha/beta T cells, also participate. An effective vaccine has to stimulate the precise combination of T cells and cytokines required for the different tasks. It remains to be clarified in how far this can be achieved by a single vaccine.

Adult↗

Improved humoral immunity against tuberculosis ESAT-6 antigen by chimeric DNA prime and protein boost strategy.

Ag85A and ESAT-6 proteins of Mycobacterium tuberculosis (M.TB) are important protective antigens. The 32-kDa Ag85A is a strong immunogen in both small and large animals. However, the 6-kDa ESAT-6 has relatively low inherent immunogenicity, especially in large animals. To improve the immunogenicity of ESAT-6 in animals, we made chimeric DNA vaccines, HG856K and HG856A, by inserting the esat-6 gene into the Kpn I or Acc I endonuclease restriction site of the ag85a gene, respectively. BALB/c mice were injected intramuscularly three times with the 10-microg singular DNA vaccine (HG85 encoding for Ag85A or HG6 encoding for ESAT-6) or chimeric DNA vaccine (HG856K or HG856A) followed by electroporation (EP). Ten days after the last DNA vaccination, mice received a booster immunization intraperitoneally with 50-microg pure recombinant protein Ag85A or ESAT-6 without adjuvant. Additional groups of mice immunized with chimeric DNA vaccines were boosted with two mixed proteins (Ag85A/ESAT-6) at the same time. The results showed that the immunogenicity of M.TB ESAT-6 antigen was not improved by priming with the HG6 DNA vaccine. However, the humoral immunity against the ESAT-6 antigen was significantly increased in the mice primed with chimeric DNA vaccines, HG856K or HG856A, followed by boosting with ESAT-6 or ESAT-6/Ag85A mixed proteins.

Acyltransferases↗

Failure of the Mycobacterium bovis BCG vaccine: some species of environmental mycobacteria block multiplication of BCG and induction of protective immunity to tuberculosis.

The efficacy of Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine against pulmonary tuberculosis (TB) varies enormously in different populations. The prevailing hypothesis attributes this variation to interactions between the vaccine and mycobacteria common in the environment, but the precise mechanism has so far not been clarified. Our study demonstrates that prior exposure to live environmental mycobacteria can result in a broad immune response that is recalled rapidly after BCG vaccination and controls the multiplication of the vaccine. In these sensitized mice, BCG elicits only a transient immune response with a low frequency of mycobacterium-specific cells and no protective immunity against TB. In contrast, the efficacy of TB subunit vaccines was unaffected by prior exposure to environmental mycobacteria. Six different isolates from soil and sputum samples from Karonga district in Northern Malawi (a region in which BCG vaccination has no effect against pulmonary TB) were investigated in the mouse model, and two strains of the Mycobacterium avium complex were found to block BCG activity completely.

Acyltransferases↗

Present knowledge of immunization against tuberculosis.

This is a selective review, which, after recalling some immunological aspects, analyses the present knowledge on the protective efficacy of BCG vaccination, the vaccination reactions and complications that may be observed, and current methods of vaccine production and control. As regards the application of BCG vaccination, particular attention is given to dosage and vaccination techniques, direct and simultaneous vaccination, and revaccination. Finally, the evaluation of BCG vaccination programmes is briefly discussed.

Adolescent↗

The influence of remaining live BCG organisms in vaccinated mice on the maintenance of immunity to tuberculosis.

The only available vaccine against Mycobacterium tuberculosis, the bacille Calmette-Guérin (BCG) vaccine, is at present being used as a reference for the efficacy of novel vaccines. Herein, we demonstrate that viable BCG can be detected at late time points after vaccination in C57BL/6J mice. If BCG is cleared by antibiotic treatment, the number of mycobacteria-reactive effector cells in the spleen gradually reverts to low levels and consequently immunity in this organ wanes, while resistance in the lung remains stable. The implications for comparing BCG vaccination with experimental vaccines including non-replicating vaccines are discussed.

Animals↗

EXPERIMENTAL studies of vaccination, allergy, and immunity in tuberculosis. II. Effect of varying the dose of BCG.

Results are given for one of a series of projects designed to investigate the relation between observable post-vaccination responses and acquired resistance to tuberculosis. Controlled variations in the dose of BCG vaccine have previously been shown to cause systematic variations in the degree of skin sensitivity to tuberculin and the size of vaccinal lesions in human beings: the purpose of the present project was to see if similar variations would be produced in guinea-pigs and then, by infecting the animals with virulent tubercle bacilli, to see how survival time correlates with tuberculin allergy and vaccinal lesions.Four doses of freshly prepared BCG vaccine, ranging from 1/100 to 10 times the dose ordinarily used for intradermal vaccination of humans, and one dose of heat-killed BCG 100 times that strength, were used to vaccinate five groups of guinea-pigs, each containing 120 animals. A sixth group of 120 animals was not vaccinated. All animals were tuberculin-tested just before and five weeks after vaccination, challenged with a strong dose of H-37 Rv, and then allowed to die, so that survival time could be used as a measure of resistance.As the dose of living BCG was increased, groups of guinea-pigs showed a progressive increase in the average degree of post-vaccination tuberculin allergy, size of vaccinal lesion, and length of survival after virulent infection. The heat-killed BCG resulted in weak allergy and a short survival time, yet the vaccinal lesions averaged about as large as would be expected from a corresponding dose of living BCG. These results (excluding studies of survival time) correspond closely to those found in human studies.The implications of the results with respect to practical BCG vaccination programmes, while no more than speculative at present, point toward possible advantages in inducing high degrees of tuberculin allergy and toward the dubious significance of the vaccinal lesion as an index of a vaccine's immunizing potency.

Animals↗

[Skin manifestations of immune restoration syndrome in treated tuberculosis].

INTRODUCTION: Immune restoration syndrome was first described in 1998 and involved mycobacterium avium complex. We report the case of a patient with acquired immunodeficiency syndrome who had disseminated cutaneous lesions due to Mycobacterium tuberculosis, following initiation of highly active antiretroviral therapy. CASE REPORT: A 42 year-old HIV-infected man, was admitted for fever, cough, nocturnal sweat and impaired of general condition. He had a viral load of 127,200 copies/ml and 199/ml CD4 T-cells. He was treated with triple tuberculosis combination therapy according to tuberculous contagium, positivity of the tuberculin intradermoreaction (15 mm) and right upper lung nodule on thoracic scan. M. tuberculosis was not found. Fever improved at day 3. Highly active antiretroviral therapy with zidovudine, lamivudine, indinavir, was started at day 11 and 33 days after, fever and dermohypodermal nodules with necrotising evolution appeared. Skin biopsy specimen showed tuberculoid granuloma. The levels of viral load and CD4 T-cells were less than 200 copies/ml and 497/ml respectively. Fever and cutaneous lesions spontaneously resolved without changing therapy. DISCUSSION: Immune restoration syndrome appears after initiation of antiretroviral therapy, in patients with advanced HIV infection and without prophylactic treatment versus MAC. This case report probably involves mycobacterium tuberculosis. Bacterial lysis and immune restoration take part in cutaneous pathogenesis. Subclinical mycobacterial infection should be monitored during initiation of antiretroviral therapy in patients with advanced HIV infection.

Adult↗