TB's relative values

August 1, 1997

SCIENTISTS are puzzled why the BCG vaccine against pulmonary tuberculosis appears to offer little protection in some tropical countries, while boosting immunity in higher latitudes.

Researchers at the London School of Hygiene and Tropical Medicine are studying to see whether genetic or environmental factors are the reason for BCG's uneven effects.

Paul Fine, professor of communicable disease epidemiology at the London School, says TB is responsible for more adult deaths than any other infectious disease. The incidence of HIV and subsequent weakened immunity has added to the death toll.

The vaccine is given to more than 50 million people every year to combat mycobacterium tuberculosis, which claims three million lives, but its uneven effectiveness is a puzzle. Professor Fine has spent the past 17 years working with ten colleagues at the London School and 80 staff studying cases of leprosy and TB among a population of 180,000 living in northern Malawi.

He suggests that differences in genetic make-up may be partly responsible for the uneven effects, but adds that Asians living in Britain respond well to vaccination, whereas those living in the Indian subcontinent often do not. Other explanations are that the vaccines produced by different manufacturers differ, or that the tuberculosis bacillus itself may differ between populations.

"What people are thinking increasingly is that this variance may have to do with the fact that there are many other mycobacteria in the environment, relatives of the tubercle and leprosy bacilli, and we are exposed to them in soil, dust and water - even from the biofilm inside our water pipes. The warmer and wetter the environment, the more of these things there are. If you live in the tropics you effectively breathe and eat a diet of concentrated mycobacteria," Professor Fine said.

He suggests that exposure to a variety of mycobacteria means that people are likely to encounter bacteria which share antigens common to the tubercle bacillus and to BCG - which is itself derived from the tubercle bacillus of cattle. They therefore may have a level of natural immunity and already as much protection as can be provided by the vaccine.

Professor Fine points out that no part of the world today has as much TB as there was in London in the last century. "Were conditions in London that much worse than anywhere else in the world today? Or is this another reflection of geographic differences in natural protection, and the fact that people in London 100 years ago suffered the poor socioeconomic conditions associated with disease, but lacked the sort of natural mycobacterial exposures which provide some protection in the tropical regions today?" he asked.

The team, with Pounds 2 million funding largely from the Wellcome Trust, hopes to answer this question. It is looking at the individuals who contract TB and leprosy in Malawi, and comparing their genes to those of individuals free of these diseases. The team will also examine whether people with different genetic make-up, or those who have been previously exposed to infections, both in Malawi and England, respond differently to the BCG vaccine.

They are looking at the immune system's ability to be "taught" by the vaccine to recognise certain components of the tubercle and leprosy bacilli.

Their work is made possible because scientists are near to discovering the genetic code of both tubercle and leprosy bacilli. This should help reveal which components cause the disease and which stimulate the immune response.

The researchers have noted clusters of leprosy, caused by a close relative of the tubercle bacillus, in families and in certain valleys. Though this may reflect genetics "there is strong evidence that this may be to do with basic ecology", said Professor Fine. He suggests that factors such as soil type, PH, moisture and vegetation may influence the pattern of environmental mycobacteria in an area and hence determine the natural immunity of a population.

"We are identifying patterns of mycobacteria over our study area, to see which ones are growing where we find leprosy and TB, and which ones grow where the diseases are less prevalent. This may indirectly lead us to what sorts of exposures induce effective immune responses and hence may provide hints towards better vaccines than today's BCG."

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