Oral bacillus Calmette-Guérin vaccine against tuberculosis: why not?

The bacillus Calmette-Guérin (BCG) vaccine is the only licensed vaccine for human use against tuberculosis (TB). Although controversy exists about its efficacy, the BCG vaccine is able to protect newborns and children against disseminated forms of TB, but fails to protect adults against active forms of TB. In the last few years, interest in the mucosal delivery route for the vaccine has been increasing owing to its increased capacity to induce protective immune responses both in the mucosal and the systemic immune compartments. Here, we show the importance of this route of vaccination in newly developed vaccines, especially for vaccines against TB.

The mc2-CMX vaccine induces an enhanced immune response against Mycobacterium tuberculosis compared to Bacillus Calmette-Guérin but with similar lung inflammatory effects

Although the attenuated Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccine has been used since 1921, tuberculosis (TB) control still proceeds at a slow pace. The main reason is the variable efficacy of BCG protection against TB among adults, which ranges from 0-80%. Subsequently, the mc2-CMX vaccine was developed with promising results. Nonetheless, this recombinant vaccine needs to be compared to the standard BCG vaccine. The objective of this study was to evaluate the immune response induced by mc2-CMX and compare it to the response generated by BCG. BALB/c mice were immunised with both vaccines and challenged withMycobacterium tuberculosis (Mtb). The immune and inflammatory responses were evaluated by ELISA, flow cytometry, and histopathology. Mice vaccinated with mc2-CMX and challenged with Mtb induced an increase in the IgG1 and IgG2 levels against CMX as well as recalled specific CD4+ T-cells that produced T-helper 1 cytokines in the lungs and spleen compared with BCG vaccinated and challenged mice. Both vaccines reduced the lung inflammatory pathology induced by the Mtb infection. The mc2-CMX vaccine induces a humoral and cellular response that is superior to BCG and is efficiently recalled after challenge with Mtb, although both vaccines induced similar inflammatory reductions.

DNA encoding individual mycobacterial antigens protects mice against tuberculosis

Over the last few years, some of our experiments in which mycobacterial antigens were presented to the immune system as if they were viral antigens have had a significant impact on our understanding of protective immunity against tuberculosis. They have also markedly enhanced the prospects for new vaccines. We now know that individual mycobacterial protein antigens can confer protection equal to that from live BCG vaccine in mice. A critical determinant of the outcome of immunization appears to be the degree to which antigen-specific cytotoxic T cells are generated by the immune response. Our most recent studies indicate that DNA vaccination is an effective way to establish long-lasting cytotoxic T cell memory and protection against tuberculosis.

Immune factors and immunoregulation in tuberculosis

Pathogens causing tuberculosis and other chronic infectious diseases of major public health importance commonly have complex mechanisms involved in their persistence in the host despite specific and sometimes strong immune responses. These diseases are also associated with the lack of efficient vaccines, difficult therapeutics and a high mortality rate among susceptible individuals. Here, we will review features of the host immune response that contribute to the occurrence of disease. In addition, we propose that the immune responses observed in tuberculosis cannot be interpreted solely on the basis of a Th1-Th2 counter-regulatory paradigm since there is growing evidence that natural regulatory T cells may play an important role in the regulation of host immune responses against Mycobacterium tuberculosis. Thus, the development of more effective vaccines against this bacterial disease should take into account the role of natural regulatory T cells in the progression to severe disease and persistence of infection. Finally, new treatments based on manipulation of regulatory T cells should be investigated.

HIV/tuberculosis co-infection: a request for a better surveillance

The increasing endemicity of tuberculosis resulting from causes such as immigration, poverty, a declining public health infrastructure and co-infection by HIV/Mycobacterium tuberculosis, is leading to a change in tuberculosis control programmes. One of the main reasons for the resurgence of tuberculosis is HIV infection - the risk of tuberculosis is greater in HIV patients than in the majority of the population as can be seen from numerous research projects. The need for systematic testing for HIV infection in all tuberculosis patients by undertaking confidential HIV tests on admission to a tuberculosis programme is brought out. This measure would increase the number of cases diagnosed and provide data for better surveillance of the co-infection.

Age transition of tuberculosis incidence and mortality in Brazil

OBJECTIVE: Before the Aids pandemic, demographic transition and control programs prompted a shift in the age of incidence of tuberculosis from adults to older people in many countries. The objective of the study is to evaluate this transition in Brazil. METHODS: Tuberculosis incidence and mortality data from the Ministry of Health and population data from the Brazilian Bureau of Statistics were used to calculate age-specific incidence and mortality rates and medians. RESULTS: Among reported cases, the proportion of older people increased from 10.5% to 12% and the median age from 38 to 41 years between the period of 1986 and 1996. The smallest decrease in the incidence rate occurred in the 30--49 and 60+ age groups. The median age of death increased from 53 to 55 years between 1980 and 1996. The general decline in mortality rates from 1986 to 1991 became less evident in the 30+ age group during the period of 1991 to 1996. A direct correlation between age and mortality rates was observed. The largest proportion of bacteriologically unconfirmed cases occurred in older individuals. CONCLUSIONS: The incidence of tuberculosis has begun to shift to the older population. This shift results from the decline in the annual risk of infection as well as the demographic transition. An increase in reactivation tuberculosis in older people is expected, since this population will grow from 5% to 14% of the Brazilian population over the next 50 years. A progressive reduction in HIV-related cases in adults will most likely occur. The difficulty in diagnosing tuberculosis in old age leads to increased mortality.

Tuberculosis en la Ciudad de la Habana, 1995-1999

OBJETIVO: La tuberculosis es un importante problema mundial de salud que recibe una atención priorizada del Sistema de Salud Cubano. Lo objetivo del trabajo es describir el comportamiento de los indicadores del Programa de Control de Tuberculosis cubano. MÉTODOS: A partir de una revisión de los documentos de la vigilancia de la tuberculosis en los registros del Centro Provincial de Higiene y Epidemiología se expone la infraestructura sanitaria, las estrategias del Programa de Control en la ciudad, se describen las tasas de incidencia, indicadores de localización, diagnóstico y manejo de casos. RESULTADOS: Se hallaron 8 sintomáticos respiratorios por cada mil consultantes de medicina general; la tasa de incidencia de tunerculosis en todas sus formas descendió de 16,4 (1995) a 12,0x105 habitantes (1999); la tuberculosis pulmonar descendió de 15,1 a 10,45 habitantes mientras la tuberculosis extrapulmonar ascendió de 1,3 a 1,6 x 105 habitantes, en igual período. Del total de los casos nuevos, el 40-50% fueron identificados en los policlínicos, el 67% fueron diagnosticados por baciloscopías, el 15,2% por cultivos, el 13.8% sólo por evidencias clínicas y radiológicas; el 0,9% y el 1,5%, respectivamente, fueron diagnosticados por biopsia o hallazgos de necropsia. Los grupos de 15-64 años incrementaron su incidencia en 1996-1997 y disminuyeron en 1998-1999; los casos >64 años de edad disminuyeron progresivamente de 1995 a 1999; en general, la tasa de incidencia de casos disminuyó. La demora promedio entre primeros síntomas y diagnóstico mejoró de 42 días en 1995 a 28,6 en 1999. CONCLUSIONES: La reversión de la tendencia de la notificación de casos nuevos parece haberse detenido en 1996. La situación de los indicadores de tuberculosis revelan cambios satisfactorios en el período analizado.

Immunogenicity of WHO-17D and Brazilian 17DD yellow fever vaccines: a randomized trial

OBJECTIVE: To compare the immunogenicity of three yellow fever vaccines from WHO-17D and Brazilian 17DD substrains (different seed-lots). METHODS: An equivalence trial was carried out involving 1,087 adults in Rio de Janeiro. Vaccines produced by Bio-Manguinhos, Fiocruz (Rio de Janeiro, Brazil) were administered following standardized procedures adapted to allow blocked randomized allocation of participants to coded vaccine types (double-blind). Neutralizing yellow fever antibody titters were compared in pre- and post-immunization serum samples. Equivalence was defined as a difference of no more than five percentage points in seroconversion rates, and ratio between Geometric Mean Titters (GMT) higher than 0.67. RESULTS: Seroconversion rates were 98% or higher among subjects previously seronegative, and 90% or more of the total cohort of vaccinees, including those previously seropositive. Differences in seroconversion ranged from -0.05% to -3.02%. The intensity of the immune response was also very similar across vaccines: 14.5 to 18.6 IU/mL. GMT ratios ranged from 0.78 to 0.93. Taking the placebo group into account, the vaccines explained 93% of seroconversion. Viremia was detected in 2.7% of vaccinated subjects from Day 3 to Day 7. CONCLUSIONS: The equivalent immunogenicity of yellow fever vaccines from the 17D and 17DD substrains was demonstrated for the first time in placebo-controlled double-blind randomized trial. The study completed the clinical validation process of a new vaccine seed-lot, provided evidence for use of alternative attenuated virus substrains in vaccine production for a major manufacturer, and for the utilization of the 17DD vaccine in other countries.

Reactogenicity of yellow fever vaccines in a randomized, placebo-controlled trial

OBJECTIVE: To compare the reactogenicity of three yellow fever (YF) vaccines from WHO-17D and Brazilian 17DD substrains (different seed-lots) and placebo. METHODS: The study involved 1,087 adults eligible for YF vaccine in Rio de Janeiro, Brazil. Vaccines produced by Bio-Manguinhos, Fiocruz (Rio de Janeiro, Brazil) were administered ("day 0") following standardized procedures adapted to allow blinding and blocked randomization of participants to coded vaccine types. Adverse events after immunization were ascertained in an interview and in diary forms filled in by each participant. Liver enzymes were measured on days 0, 4-20 and 30 of the study. Viremia levels were measured on days 4 to 20 of follow-up. The immune response was verified through serologic tests. RESULTS: Participants were mostly young males. The seroconversion rate was above 98% among those seronegative before immunization. Compared to placebo, the excess risk of any local adverse events ranged from 0.9% to 2.5%, whereas for any systemic adverse events it ranged from 3.5% to 7.4% across vaccine groups. The excess risk of events leading to search for medical care or to interruption of work activities ranged from 2% to 4.5%. Viremia was detected in 3%-6% of vaccinees up to 10 days after vaccination. Variations in liver enzyme levels after vaccination were similar in placebo and vaccine recipients. CONCLUSIONS: The frequency of adverse events post-immunization against YF, accounting for the background occurrence of nonspecific signs and symptoms, was shown for the first time to be similar for vaccines from 17D and 17DD substrains. The data also provided evidence against viscerotropism of vaccine virus.

Distribuição espacial da co-infecção M. tuberculosis/HIV no Estado de São Paulo, 1991-2001

OBJETIVO: Avaliar o padrão espacial de incidência de tuberculose na epidemia de Aids, a fim de verificar a influência do espaço físico na causalidade. MÉTODOS: Foram incluídos os casos de Aids notificados ao Ministério da Saúde, entre 1991 e 2001, provenientes do Estado de São Paulo. Os casos foram estratificados em municípios de residência, em regiões de saúde, em categorias de transmissão de Aids, em sexos e em anos do diagnóstico. Um modelo geoestatístico gaussiano foi usado para construir um mapa temático de risco, utilizando a incidência de tuberculose em casos de Aids como variável de resposta. RESULTADOS: A análise exploratória mostrou dois padrões de incidência de Aids: um, para a capital do Estado, e outro, com risco crescente, para os outros municípios. As regiões mais populosas estão sob maiores riscos de transmissão de tuberculose, mostrando um padrão concordante com o padrão de ocupação do território, do leste para o oeste. As regiões de saúde com os maiores coeficientes de incidência de Aids (por 10 mil habitantes) foram Santos (53,5), São José do Rio Preto (43,1), Ribeirão Preto (42,4) e São Paulo (40,3). As regiões de saúde com maiores incidências de tuberculose em casos de Aids foram Santos (44,9%), Franco da Rocha (39,9%), Osasco (39,6%) e São Paulo (38,9%). CONCLUSÕES: Os resultados permitem concluir que as coordenadas geográficas estão associadas ao risco da tuberculose, mas não de Aids.

Household members and health care workers as supervisors of tuberculosis treatment

OBJECTIVE: To compare tuberculosis cure rates among patients supervised by household members or health care workers. METHODS: Prospective cohort study of 171 patients treated by the program in Vitoria, Southeastern Brazil, from 2004 to 2007. Each patient was followed-up for six months until the end of the treatment. Of the patients studied, a household member supervised 59 patients and healthcare workers supervised 112 patients. Patients' sociodemographic and clinic data were analyzed. Differences between groups were assessed using chi-square test or Student's t-test. Significance level was set at 5%. RESULTS: Most patients had smear positive, culture confirmed pulmonary tuberculosis. Two patients were HIV-positive. There were more illiterate patients in the healthcare-supervised group, in comparison to those supervised by their families (p=0.01). All patients supervised by a household member were cured compared to 90% of the patients supervised by health care workers (p = 0.024). CONCLUSIONS: Successful tuberculosis treatment was more frequent when supervised by household members.

Tuberculosis and latent tuberculosis in prison inmates

OBJECTIVE: To estimate the prevalences of tuberculosis and latent tuberculosis in inmates. METHODS: Observational study was carried out with inmates of a prison and a jail in the State of São Paulo, Southeastern Brazil, between March and December of 2008. Questionnaires were used to collect sociodemographic and epidemiological data. Tuberculin skin testing was administered (PPD-RT23-2TU/0.1 mL), and the following laboratory tests were also performed: sputum smear examination, sputum culture, identification of strains isolated and drug susceptibility testing. The variables were compared using Pearson's chi-square (Χ2) association test, Fisher's exact test and the proportion test. RESULTS: Of the 2,435 inmates interviewed, 2,237 (91.9%) agreed to submit to tuberculin skin testing and of these, 73.0% had positive reactions. The prevalence of tuberculosis was 830.6 per 100,000 inmates. The coefficients of prevalence were 1,029.5/100,000 for inmates of the prison and 525.7/100,000 for inmates of the jail. The sociodemographic characteristics of the inmates in the two groups studied were similar; most of the inmates were young and single with little schooling. The epidemiological characteristics differed between the prison units, with the number of cases of previous tuberculosis and of previous contact with the disease greater in the prison and coughing, expectoration and smoking more common in the jail. Among the 20 Mycobacterium tuberculosis strains identified, 95.0% were sensitive to anti-tuberculosis drugs, and 5.0% were resistant to streptomycin. CONCLUSIONS: The prevalences of tuberculosis and latent tuberculosis were higher in the incarcerated population than in the general population, and they were also higher in the prison than in the jail.

Tuberculosis in indigenous children in the Brazilian Amazon

OBJECTIVE: Assess the epidemiological aspects of tuberculosis in Brazilian indigenous children and actions to control it. METHODS: An epidemiological study was performed with 356 children from 0 to 14 years of age in Rondônia State, Amazon, Brazil, during the period 1997-2006. Cases of TB reported to the Notifiable Diseases Surveillance System were divided into indigenous and non-indigenous categories and analyzed according to sex, age group, place of residence, clinical form, diagnostic tests and treatment outcome. A descriptive analysis of cases and hypothesis test (χ²) was carried out to verify if there were differences in the proportions of illness between the groups investigated. RESULTS: A total of 356 TB cases were identified (125 indigenous, 231 non-indigenous) of which 51.4% of the cases were in males. In the indigenous group, 60.8% of the cases presented in children aged 0-4 years old. The incidence mean was much higher among indigenous; in 2001, 1,047.9 cases/100,000 inhabitants were reported in children aged < 5 years. Pulmonary TB was reported in more than 80% of the cases, and in both groups over 70% of the cases were cured. Cultures and histopathological exams were performed on only 10% of the patients. There were 3 cases of TB/HIV co-infection in the non-indigenous group and none in the indigenous group. The case detection rate was classified as insufficient or fair in more than 80% of the indigenous population notifications, revealing that most of the diagnoses were performed based on chest x-ray. CONCLUSIONS: The approach used in this study proved useful in demonstrating inequalities in health between indigenous and non-indigenous populations and was superior to the conventional analyses performed by the surveillance services, drawing attention to the need to improve childhood TB diagnosis among the indigenous population.

Incremental yield of bronchial washing for diagnosing smear-negative pulmonary tuberculosis

OBJECTIVE To assess the increased diagnostic yield for pulmonary tuberculosis using bronchial washing cultures compared with sputum cultures. METHODS Study conducted with 61 adults in Lima, Peru, from January 2006 to December 2007. The yield of sputum cultures was compared with the yield of acid-fast bacilli smears and cultures of bronchial washing for diagnosing pulmonary tuberculosis in suspected cases of clinical tuberculosis with negative acid fast bacilli sputum smears. RESULTS Twenty seven (95%CI 32;58) of the cases were eventually diagnosed with smear-negative pulmonary tuberculosis. Bronchial washing samples detected 23 (95%CI 72;99) of the smear-negative pulmonary tuberculosis cases compared with 15 (95%CI 37;74) for sputum cultures (p = 0.02). The incremental diagnostic yield of acid fast bacilli smear and culture of bronchial washing specimens over sputum culture was 44% (95%CI 25;65). CONCLUSIONS In function of the epidemiological context and the resources available, bronchoscopy should be deployed as part of a comprehensive work up that optimizes smear-negative pulmonary tuberculosis diagnosis and minimizes risk and costs.

Tuberculosis Control Program and patient satisfaction, Rio de Janeiro, Brazil

OBJECTIVE To evaluate factors associated with users’ satisfaction in the Tuberculosis Control Program. METHODS A cross-sectional study of 295 patients aged ≥ 18 years, with two or more outpatient visits in the Tuberculosis Control Program, in five cities in the metropolitan region of Rio de Janeiro, RJ, Southeastern Brazil, in 2010. Considering an estimated population of 4,345 patients, the sampling plan included 15 health care units participating in the program, divided into two strata: units in Rio de Janeiro City, selected with probability proportional to the monthly average number of outpatient visits, and units in the other four cities. In the units, four temporal clusters of five patients each were selected with equal probability, totaling 300 patients. A questionnaire investigating the users’ clinical and sociodemographic variables and aspects of care and service in the program relevant to user satisfaction was applied to the patients. Descriptive statistics about users and their satisfaction with the program were obtained, and the effects of factors associated with satisfaction were estimated. RESULTS Patients were predominantly males (57.7%), with a mean age of 40.9 and with low level of schooling. The mean treatment time was 4.1 months, mostly self-administered (70.4%). Additionally, 25.8% had previously been treated for tuberculosis. There was a high level of satisfaction, especially regarding medication provision, and respect to patients by the health professionals. Patients who were younger (≤ 30), those on self-administered treatment, and with graduate level, showed less satisfaction. Suggestions to improve the services include having more doctors (70.0%), and offering exams in the same place of attendance (55.1%). CONCLUSIONS Patient satisfaction with the Tuberculosis Control Program was generally high, although lower among younger patients, those with university education and those on self-administered treatment. The study indicates the need for changes to structural and organizational aspects of care, and provides practical support for its improvement.