BCG vaccine

The formulation of international requirements for the manufacture and control of BCG vaccine was first considered by the WHO Expert Committee on Biological Standardization in its thirteenth report. In its fourteenth report, the Committee requested WHO to make arrangements as soon as possible for the formulation of such requirements. These requirements were approved by the WHO Expert Committee on Biological Standardization at its eighteenth meeting and appeared as Annex 1 to its report.

Mycobacterium tuberculosis (Mtb), the ethiological agent of tuberculosis (TB), is a leading cause of human disease and death, particularly in developing countries. In the global context, TB in intimately linked to poverty, and control of TB is ultimately a question of justice and human rights. In some areas with a high burden of TB, existing strategies for TB control are currently overwhelmed by the rising numbers of cases of TB occurring in parallel with or the HIV/AIDS pandemic. Emerging mycobacterial drug resistance is further complicating the situation. After decades of steady decline, the incidence of TB is also increasing in industralized countries, mainly as the result of outbreaks in particularly vulnerable groups.

The bacille Calmette-Guérin (BCG) vaccine has existed for 80 years and is one of the most widely used of all current vaccines, reading >80%of neonates and infants in countries where it is part of the national childhood immunization programme. BCG vaccine has a documented protective effect against meningitis and disseminated TB in children. It does not prevent primary infection and, more importantly, does not prevent reactivation of latent pulmonary infection, the principal source of bacillary spread in the community. The impact of BCG vaccination on transmission of Mtb is therefore limited.

The biological interaction between Mtb and the human host is complex and only partially understood. Recent advances in areas such as mycobacterial immunology and genomics have stimulated research on numerous new experimental vaccines, but it is unlikely that any of these urgently need vaccines will be available for routine use within the next few years. In the meantime, optimal utilization of BCG is encouraged.

Background

Public health aspects

Human TB has existed for thousands of years. No country is TB-free, and the disease is endemic in most poor countries of the world. It is estimated that about one-third of the current global population is infected asymptomatically with Mtb, of whom 5-10% will develop clinical disease during their lifetime. According to WHO estimates for 2001, there are 16-20 million cases of TB worldwide, with more than 8 million new cases and over 1.8 million deaths each year. Most new cases and deaths occur in developing countries where infection is often acquired in childhood. The annual risk of TB infection in children in high-burden countries is estimated to be 0.5-2%. Childhood deaths from TB are usually caused by meningitis or disseminated disease.

Co-infection with Mtb and HIV has been shown to be a lethal combination. In areas of sub-Saharan Africa where HIV is most prevalent, the annual incidence of TB has risen to more than 300 cases per 100 000 inhabitants. In some of these places, nearly 50% of the HIV-infected population is co-infected with TB and more than two-thirds of TB patients are infected with HIV. For HIV-infected persons, the liftime risk of developing TB disease is as high as 30-50%. In some parts of south-east Asia, an estimated 20-25% of TB cases will be directly attributable to HIV within the next few years. In most industrialized countries, decades of declining TB incidence halted towards the end of the 20th century when increasing annual numbers of TB cases were recorded. In several regions of the former Soviet Union, the recent rise in TB incidence has been dramatic. In industrialized settings, new cases of TB usually occur in the elderly. In recent years, however, TB has also been found increasingly in immigrants from endemic countries, in HIV-positive individuals and in socially deprived groups including drug-dependent individuals and prisoners.

The pathogen

The genus Mycobacterium is characterized by slender, non-motile rods with complex, lipid-rich cell walls resisting de-staining by acid alcohol (hence "acid fast"). Mycobacteria are strictly aerobic and grow on fairly simple solid or fluid media. The many members of this genus are conventionally differentiated by rate and optimal temperature of growth, production of pigments and biochemical tests. Some mycobacterial species as Mtb, M. africanum, M. ulcerans and M. bovis share growth characteristics and biochemical reactions and are classified together within the M. tuberculosis complex. The BCG vaccine is derived from M. bovis. More than 55 species of environmental mycobacteria are known, half of which may cause disease in humans. The prevalence of environmental mycobacteria is higher in hot than in cold climates. The M. avium-intracellulare complex is the most ubiquitous of the environmental mycobacteria.

M. tuberculosis has a long generation time (8-24 hours), and growth on solid media such as the Lowenstein-Jensen medium is detectable only after 2-6 weeks. With fluid media and automated detection systems, growth may be detected within 1-2 weeks. Under field conditions, the diagnosis of TB is usually based on microscopy, demonstrating acid-fast bacilli in sputa or other clinical specimens using the Ziehl-Neelsen staining technique or a fluorescent acid-fast dye such as autamine. Isolation of the organism is required for a definitive species diagnosis and determination of antibiotic sensitivity. Modern molecular techniques based on nucleic acid amplification and genetic probes may provide rapid species information directly on clinical material and are now routinely used in modern laboratory settings as supplements to more conventional diagnostic methods. In recent years, DNA probes have become available that allow detailed epidemiological studies using DNA fingerprint techniques.