Fifteen year follow up of trial of BCG vaccines in south India for tuberculosis prevention. Tuberculosis Research Centre (ICMR), Chennai.
[No authors listed]
A large scale community-based double blind randomized controlled trial was carried out in Chingleput district of south India to evaluate the protective effect of BCG against bacillary forms of pulmonary tuberculosis. From among 366,625 individuals registered, 281,161 persons were vaccinated with BCG or placebo by random allocation. Two strains of BCG were used, the French and Danish, with a high dose (0.1 mg/0.1 ml) and a low dose (0.01 mg/0.1 ml) in each strain. The entire population was followed up for 15 years by means of resurveys every 30 months, and selective follow up every 10 months and continuous passive case finding. There were 560 cases (189, 191 and 180 from the high dose, low dose and placebo groups respectively) arising over 15 years, among 109,873 persons who were tuberculin negative and had a normal chest X-ray at intake. This represents a small fraction of the total incidence of 2.6 per 1000 person-years most of which came from those who were initially tuberculin positive. The incidence rates in the three "vaccination" groups were similar confirming the complete lack of protective efficacy, seen at the end of 7 1/2 years. BCG offered no overall protection in adults and a low level of overall protection (27%; 95% C.I. -8 to 50%) in children. This lack of protection could not be explained by methodological flaws, or the influence of prior sensitisation by non specific sensitivity, or because most of the cases arose as a result of exogenous re-infection. The findings at 15 years show that in this population with high infection rates and high nonspecific sensitivity, BCG did not offer any protection against adult forms of bacillary pulmonary tuberculosis.
Postgraduate Institute of Medical Sciences, Bombay Hospital.
With the extended programme of immunisation and since 1985 the universal programme of immunisation and the coverage status of BCG vaccination in India has been very good, although it is still unsatisfactory in the eastern states. It is emphasized that BCG vaccination cannot prevent natural tuberculous infection of the lungs and its local complications, although it reduces the haematogenous complications of primary infection. However, this is not true for malnourished children who, inspite of BCG vaccination, develop serious, and often fatal types of tuberculosis such as miliary, meningitic and disseminated tuberculosis. The tuberculin anergy in malnourished children, is mainly responsible for high morbidity and mortality. BCG vaccinated, well-nourished children manifest modified patterns of tuberculous disease, following infection. The most important manifestation is the increased incidence of intrathoracic tuberculosis, specially enlargement of the various groups of mediastinal nodes and their local complications. Localisation of the disease by T cell immunity, due to BCG vaccination is responsible for this and the much lower incidence of haemotological complications such as neurotuberculosis and disseminated disease. In these children, the clinical picture of neurotuberculosis is also modified, with a tendency for more localised involvement of the brain and meninges. Similarly, vaccinated children may present with hepatomegaly, splenomegaly or isolated organ disease. It is important to relearn the new patterns of tuberculosis disease seen in vaccinated, non-malnourished children, and to a lesser extent in children with grade 1 to 2 protein energy malnutrition (PEM). With these limitations of BCG vaccination, other strategies like chemoprophylaxis need multicentric trials in high risk children, in different parts of the country.
Tuberculosis is a major global public health problem with 8 million new cases of pulmonary tuberculosis in the world per year and 2.89 million deaths. In India in 1989, the approximate morbidity of tuberculosis was 2%, i.e., there were 15 million cases of pulmonary tuberculosis. Of these 25% were sputum positive, posing a serious threat of transmitting the infection to children. Of the 4 million infectious patients, over 1 million would be considered as chronic or relapsing cases who have been partially treated. The Indian National Tuberculosis Program (NTP) has now completed 25 years. Every year, 1 million new cases of adult tuberculosis are detected. 70% of these patients do not complete standard regimens and 45% do not complete short course regimens. In 1983 about 80.71 million children under 16 years old in India were infected. In a survey carried out in 1990 in urban and rural areas of Delhi, BCG vaccination coverage was 90% in the urban and 84.7% in the rural areas. Impact of BCG vaccination has demonstrated that classical or generalized tuberculosis meningitis, miliary TB, disseminated tuberculosis, and other serious complications of primary infections go on occurring in malnourished BCG-vaccinated children. The variable efficacy of the present BCG vaccine observed in different prospective human trials has shown the necessity of conducting research of immunoregulatory mechanisms, and developing newer vaccines for global control of tuberculosis. Other topics include immune responses to the present BCG vaccine (cellular immunity, macrophage, T-lymphocytes); BCG vaccination and tuberculin test; BCG vaccination by nebulization (aerosol BCG vaccine) by the respiratory route; a booster dose of BCG vaccine in the preschool period; protein energy malnutrition and delayed hypersensitivity reaction; BCG test in non-vaccinated and vaccinated children; HIV infections or their symptoms as a contraindication to BCG vaccination; and BCG lymphadenitis in children (7% in seropositive HIV children).