Frequently Asked Questions about BCG

Professor P D O Davies, Director,
Tuberculosis Research Unit,
Cardiothoracic Centre,
Liverpool. UK

Does it work?

Trials of the vaccine have been undertaken since it was first developed in the 1920s. The results have been variable. About a third of the total trials have shown no protective effect. The remainders have shown protection of up to 80%* at best lasting a maximum of 15 years. No trials on second or subsequent vaccinations have shown any protective effect.
(*Protective efficacy is a measure of the proportion of people who would have got the disease had they not had the vaccination. 80% protection means that 4 out of 5 individuals are protected. Efficacy for most vaccines exceeds 95%. BCG is therefore a relatively weak protective vaccine.)

In summary

50% randomised control trials show it to be effective.70% Case-Control studies show it to be effective.

Why is the effectiveness is variable?

The reasons for variability are not fully understood. There have been a number of theories put forward, none of which seem to provide a total explanation.

1.Methodological. All studies varied slightly in the way they were designed
2.Different vaccines. The development of BCG has meant that strains vary according to the time at which each has been developed. Different vaccine strains were used in the trials and are in use across the world today.
3.Tuberculin status of subjects. Within trials some individuals in both control or vaccinated group may have been tuberculin positive and therefore had “natural “ protection. This may not have been accounted for in some of the trials.
4.Different strains of M.tuberculosis. New molecular techniques have demonstrated that there are a large number of different strains of the bacterium. It is possible that different areas of the world have different strains, which may vary in virulence.
5.Genetic differences in population. There is variation in individual susceptibility to tuberculosis. This could have caused disparity in results.
6.Intensity of infecting dose. Infection and susceptibility to disease may be affected by the quantity of bacteria inhaled.
7.Nutritional differences. It is known that different nutritional states can vary susceptibility to disease. The poorly fed individual is more susceptible.
8.Protection of controls by environmental mycobacteria. These free living mycobacteria which resemble M.tuberculosis sometimes cause disease. They may be responsible for infecting individuals therefore providing partial immunity to M.tuberculosis.

How is BCG used in the UK?

Studies carried out by the British Medical Research Council in the 1950s showed that BCG, when given to teenage school children gave about 75% protection for 15 years.(1). From 1953 until July 2005 it was national policy to vaccinate all children aged 12-13. Thus in theory the entire population received protection from early teenage years through to about the age of 30. The reason for choosing that age range was because in the 1950s cases rates were highest in young adults. The limited length of time for which BCG appeared to be protective would therefore be maximal at the age when most people suffered from the disease. Secondly the form of tuberculosis which pre-teenage children suffer from (primary) is not usually infectious, whereas the form suffered by adults is infectious.

However as rates of tuberculosis in teenagers and young adults have declined reasons for discontinuing the policy of teenage vaccination have emerged. (2,3)
First it is no longer cost effective. The rates of disease in the group receiving protection are now so low that about 10,000 vaccinations are needed to prevent a single case (see below). This is to prevent diease which is usually relatively easy to treat in the age group 14-30.
Secondly the harm done in adverse effects from the vaccine, usually abscesses at the sight of injection, outweigh the preventive effect.

BCG is still given at birth to babies born into high risk groups. These includes those who have a family history of tuberculosis, ethnic minorities at increased risk of TB and those born in areas with a high prevalence.
BCG is also given to those who may be at risk of increased exposure to tuberculosis such as health care workers (2).
Is the policy of BCG vaccination the same throughout the world?
No, mainly because of variation in trial results. Most countries give BCG at birth to provide protection in the early years when infection can often lead to devastating widespread disease such as miliary tuberculosis or tuberculous meningitis. This is particularly important in high prevalence countries where the chance of being infected in very early life is high. Some countries such as the USA have chosen not to use it because most trials there have not shown any protective effect.

Why is there not international agreement on how to use BCG?

Again because of variation in trial results across the world.
In 1994 a “metanalysis” of all the trials was published. (2)This looked at a total of 1264 articles, 70 in depth, 14 prospective trials and 12 case-control studies. The authors found that seven trials show a protective effect from death of 71%, five trials showed protection from meningitis of 64%, three, protection from disseminated disease of 78% and three, protection from laboratory-confirmed disease of 83%.

The authors concluded that geographical site of study explained 66% of variability.
They also found that on average BCG reduces risk of infection leading to disease by 50%.
This is probably an erroneous conclusion, as the efficacy of BCG cannot be averaged. Trials show it to be 80% protective in one place and 20% in another. Average efficacy should not be taken.

Is the efficacy of BCG waning?

Some workers believe that it is(5). This is because the BCG vaccine is continually being reproduced as part of the manufacturing process and in common with other live organisms, which undergo this process, may be becoming less virulent and therefore less able to provide immunity to those who are vaccinated.
In contrast sequential studies form the UK show that the 75% efficacy has been maintained (6,7)
Does giving BCG prevent the use of the tuberculin test in determining the presence of infection with M. tuberculosis?
This is another area of controversy . BCG converts the tuberculin test from negative to positive. Workers are split as to whether it is possible to tell the difference between a positive test due to BCG alone and a positive test due to infection with M.tuberculosis whether the individual has had previous BCG or not.
In the UK we believe it is possible to do this on the basis of the degree of positivity.(6) The USA do not use BCG partly for the reason that they do not believe it is possible to make the distinction.

The importance of this is the decision to give preventive therapy for Latent Tuberculosis Infection (LTBI). The USA has relied on prevention by determining whether infection (without disease) is present on the basis of regular tuberculin testing for those at risk of infection such as health workers. BCG is not given as it is believed to interfere with the interpretation of the tuberculin test. Other countries, such as the UK, do give BCG but in cases where infection has occurred in addition to BCG and where the risk of disease is appreciable, such as in co-householders of Sputum Smear positive patients, preventive therapy can be given if the tuberculin test is strongly positive.(7)
Does BCG protect against drug resistant tuberculosis?
The probable answer to this is yes though evidence for this is necessarily sketchy. It is probably more effective in preventing disease than providing preventive therapy to those infected; a procedure for which there is no evidence of any efficacy at all. For health care workers who may be exposed to drug resistant tuberculosis, even a low protective efficacy of BCG would make vaccination worthwhile.

In a recent study of a mathematical model, BCG was preferred by small margin over post-infection chemoprophylaxis. Threshold for protective efficacy was 26%.
BCG should be considered for health care workers with risk of MDRTB exposure.(9)
Should BCG still be used in low prevalence countries?
As rates of tuberculosis have declined the argument for continuing routine BCG to the whole population becomes weaker. (10)For example if rates of disease are 2/100,00 and even if it is assumed that BCG gives 80% protection for 15 years then vaccinating 100,000 people would prevent (0.8x2)x15=24 cases over 15 years.
Conditions necessary to stop giving BCG include a good control programme, good reporting especially of TB meningitis and the prevalence of HIV.
“Arguments against use of BCG vaccine in a mass programme are not about efficacy but cost effectiveness.” (11)

Can BCG be harmful?

Abscesses at the site of BCG injection are frequently reported. It is often assumed that this is due to bad technique, as the injection should be given intra-cutaneaously and an accidental intramuscular injection may result. Proximal lymph node swelling and abscess formation may rarely occur. If the injection is given at the correct site, over insertion of Deltoid in the upper arm, the swelling will develop in the axillary lymph nodes.
Very rarely indeed, disseminated BCG disease may result in the immunocompromised infant. This is usually fatal. For this reason BCG should not be given to symptomatic HIV positive individuals.

Summary

Where tuberculosis is prevalent and the risk of infection is high such as in certain risk groups and developing countries, continuation of BCG is worthwhile. Where tuberculosis is uncommon a full programme BCG becomes no longer cost effective and resources are better directed at other methods of controlling the disease.

References

1.Hart PD. Efficacy and applicability of mass BCG vaccination in tuberculosis control BMJ 19677;1:587-592.
2. http://www.nice.org.uk/page.aspx?o=296657.
3.http://www.dh.gov.uk/PublicationsAndStatistics/PressReleases/

PressReleasesNotices/fs/en?CONTENT_ID=4115146&chk=r12J/w.
4.Colditz GA et al.Efficacy of BCG Vaccine in the prevention of TuberculosisJAMA 1994;271:698-702.Newborns and infants.Paediatrics 1995;96:29-35.
5.Behr MA, Small PM Has BCG attenuated impotence?Nature 1997;389:133-134. Casts doubt on continued efficacy
6.Sutherland I, Springett VH Effectiveness of BCG vaccination in England and Wales in 1983.Tubercle 1987;68:81-92.
7.Capewell S. et al.The current value of tuberculin testing and BCG vaccination in school children Br. J. Dis. Chest 1986;80:254-264.
8.Joint Tuberculosis Committee of the British Thoracic SocietyControl and prevention of tuberculosis in the United Kingdom:Code of practice 2000 Thorax Thorax 2000;55:887-901.
9.Stevens JP Daniel TMBCG immunization of health care workers exposed to MDRTB: a decision analysisTubercle & Lung Dis. 1996;77:293-4.
10.Tala EO et al. Pros and Cons of BCG Vaccination in Countries with Low Incidence of Tuberculosis.Infection Control and Hospital Epidemiology 1994;15:497-499.
11.Watson JM BCG - mass or selective vaccination?J. Hosp. Infect. 1995;30:508-513.
Further reading.
Hans L Rieder BCG vaccination, in Clinical Tuberculosis 3rd Editn. Edit PDODavies, Arnold, London 2003 pp337-354.
Also references 2 and 3 above for information from the National Institute of Health and Clinical Excellenceand the Department of Health.
All pages copyright ©Priory Lodge Education Ltd 1994-2006.

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