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BCG Vaccine | Current use, safety & development

The BCG vaccine is the only TB vaccine currently available, although there are other TB vaccines under development. Although far from perfect, the BCG vaccine is a relatively inexpensive, safe, and readily available vaccine that is still the only vaccine available for the prevention of human forms of TB.

Who is given the BCG vaccine?

The BCG vaccine is normally given to children as it has been shown to provide very good protection against the disseminated forms of TB in children, including TB meningitis. However the protection provided against pulmonary TB in adults is very variable, and so the BCG vaccine is not generally given to adults.1“Immunization surveillance, assessment and monitoring”, WHOwww.who.int/immunization_monitoring/diseases/tuberculosis/

BCG Vaccine © Pasteur Merieux Connaught, Canada

The BCG vaccine is one of the most widely used of all current vaccines, and overall it reaches more than 80% of all new born children and infants in countries where it is part of the national childhood immunization programme.2“BCG vaccine”, WHO www.who.int/biologicals/areas/vaccines/ The World Health Organisation (WHO) monitors the estimated coverage of the BCG vaccine in every country. In 2011 in countries where the aim was to vaccinate every child, levels ranged from 53% in Equatorial Guinea and 54% in Ethiopia, to more than 99.5% in India and China.3“Reported estimates of BCG coverage”, WHO//apps.who.int/immunization_monitoring/en/globalsummary/timeseries/tscoveragebcg.htm

Not every country that could do so vaccinates all children. Generally countries where there is a high level of TB use the BCG vaccine to vaccinate all children, whilst some countries with a low level of TB, such as the United States and England do not give all children BCG, but only those considered at particular risk. The United States has never vaccinated all children, but in the United Kingdom all children were given the BCG vaccine until 2005.4“The BCG World Atlas”, www.bcgatlas.org/index.php

The BCG vaccine and the TB skin test

People who have had the BCG vaccine will often then have a positive result to a TB skin test which makes it more difficult to establish whether someone has latent TB. This is one of the reasons that the BCG vaccine is not used in some countries.5“When is the BCG (TB) vaccine needed? – Vaccinations – NHS Choices”, NHS choiceswww.cdc.gov/tb/topic/testing/

The skin test will often be given before BCG vaccination. If there is a positive result to the skin test indicating that the person already has some immunity to TB, then the BCG vaccination will not be given. Giving the BCG vaccine to someone who already has some immunity, provides no benefit and could cause unpleasant side effects.6“BCG (tuberculosis) vaccination – When it is needed”, NHS Choices,www.nhs.uk/Conditions/BCG/Pages/When-it-is-needed.aspx

BCG vaccine safety issues

It is estimated that more than a billion people have received the BCG vaccine since it was first used in humans in 1921, and until recently the safety of the vaccine has not been an issue. There is though a concern now that the use of the BCG in children who are immune compromised, such as children with HIV, could result in them having an infection caused by the BCG vaccine itself. This is because the BCG vaccine contains a live but very weakened form of a bacteria called Mycobacterium bovis. This is not the same bacteria though as the bacteria that causes TB in humans, which is called Mycobacterium tuberculosis.7BCG – the current vaccine for tuberculosis, WHOwww.who.int/vaccine_research/diseases/tb/vaccine_development 8“The Difference Between Latent TB Infection and Active TB Disease”, CDC,www.cdc.gov/TB/publications/factsheets/general/LTBIandActiveTB.htm

In 2012 the there was a worldwide recall of the BCG vaccine by the manufacturer Sanofi Pasteur, after it was feared that some of the vaccine might have been contaminated during the manufacturing process.9“Tuberculosis vaccine unavailable for NZ children”, ONE News //tvnz.co.nz/national-news/tuberculosis-vaccine-unavailable-nz-children-4941809

The BCG vaccine – its development and early use

Albert Calmette

BCG is an abbreviation of Bacillus Calmette-Guerin, meaning the bacilli of Calmette and Guerin. Albert Calmette and Camille Guerin were two French scientists who from 1905 had been working on developing a vaccine against TB.

Between 1905 and 1918, Calmette and Guerin carried out research into the mechanisms of tuberculosis infection. They demonstrated that small doses of injected and weakened animal bacilli could be used as a protective vaccine against TB, in cattle and various species of monkey. So they then cultured the bacillus, and found that successive culturing weakened the bacillus.

Calmette and Guerin tried to produce ever more weakened strains of the bacillus by successive sub culturing every three weeks. The research had to stop during the first world war, but was resumed in 1918. By 1921 the tubercle bacillus had been sub cultured 230 times, and it was so weakened that it was believed that it could confer immunity without causing disease in humans.10“Albert Calmette (1863-1933)”, The Pasteur Institute Archives, www.pasteur.fr/infosci/archives/e_cal0.html 11“Camille Guerin (1872-1961)”, The Pasteur Institute Archives, www.pasteur.fr/infosci/archives/e_gue0.html 12Calmette A, “Preventive vaccination against tuberculosis with BCG”, Proc Roy Soc Med, 1931; 24: 85-94www.ncbi.nlm.nih.gov/pmc/articles/PMC2182232/

The first use of the BCG vaccine in humans

The BCG vaccine was first used in humans in 1921 when it was given to a child in Paris by Dr Weil-Hale. The baby’s mother, who had tuberculosis, had died just after the baby was born, and the baby was due to be brought up by its grandmother who also had tuberculosis. The baby was given 6 mg. of BCG orally, and was said to have developed into a perfectly normal boy. During the next three years (up to July 1924) a further 317 infants were also vaccinated.13Calmette A, “Preventive vaccination against tuberculosis with BCG”, Proc Roy Soc Med, 1931; 24: 85-94 www.ncbi.nlm.nih.gov/pmc/articles/PMC2182232/

The effectiveness and safety of the BCG vaccine

In 1927 and 1928 there were a number of publications from Calmette reporting on the BCG vaccination of children between 1924 and 1927, as well as between 1921 and 1927. Calmette said that between 1921 and 1927 969 children had been vaccinated, of whom 303 had mothers with TB, and the remainder had close contact with the disease. Of these children only 3.9% died of either tuberculosis or of other unspecified causes, and the comparable rate for unvaccinated children was 32.6%.14Calmette A, “La Vaccination Preventive contra la Tuberculosis”, Masson et Cie, Paris, 1927

There was significant criticism in the medical press of Calmette’s figures. This included criticism of the enormous rate of mortality from TB that was said by Calmette to normally apply to the children of those with TB, as well as children exposed to massive infection.15Greenwood M, “Professor Calmette’s statistical study of B.C.G. vaccination”, BMJ, 1928, 793-795www.ncbi.nlm.nih.gov/pmc/articles/ This was to be just the start of what was to be a long running debate about the effectiveness of the BCG vaccine. Despite this, at the Conference of the League of Nations in Paris in 1928, the vaccine was recognized as safe and its use was encouraged.

Calmette’s main fear at this time was about the safety of the vaccine, and whether the weakened BCG bacilli, having lived for a certain time in an organism, could once again become virulent.16Calmette A, “Preventive vaccination against tuberculosis with BCG”, Proc Roy Soc Med, 1931; 24: 85-94www.ncbi.nlm.nih.gov/pmc/articles/PMC2182232/

The Lubeck catastrophe

In 1930 the Lubeck catastrophe occurred that also cast doubts on the safety of BCG. In the German city of Lubeck 252 infants were given BCG that came originally from the Pasteur Institute in Paris, but it was prepared for administration in the TB laboratory in Lubeck.

Seventy two of the children developed TB and died within a year as a result of the disease. A subsequent investigation carried out by German TB experts, revealed that the vaccine had become contaminated with the distinct virulent human strain during its preparation at a local laboratory. Two people who had worked in the local laboratory were sent to prison in 1932 for “bodily injury due to negligence.”17“Appeal Taken from the Decision in the Lubeck Case”, JAMA, 1932; 98(15):1316-1317 http://jama.ama-assn.org/content/98/15/1316.extract

Although the BCG vaccine itself was eventually exonerated as the cause of the Lubeck disaster, its use declined for several years afterwards. Particularly in England a number of people felt that:

“Calmette’s views as to the freedom from danger of this method of treatment have not been universally accepted. Fears have been expressed that a virulent strain of bacilli, when injected into the human body, might regain its virulence.”

Dr G. B. Dixon, Chief Tuberculosis Officer, City of Birmingham18Dixon, G “Pulmonary tuberculosis in childhood”, BMJ, 1931, 694-697www.ncbi.nlm.nih.gov/pmc/articles/PMC2314871/

These fears though were to prove unfounded, and eventually, with a resurgence of TB during the second world war, the BCG vaccine was again used on a massive scale and public confidence in its safety was restored.

The BCG vaccine – different strains

The BCG vaccine was disseminated throughout the world in the late 1920s, and then each country maintained its own supply. At these other laboratories BCG was propagated in the same conditions as at the Pasteur Institute, and with the same aims. These aims were to prevent BCG from reverting to the virulent form, whilst preserving its potency, and hence its effectiveness. Over the course of the next few decades each of these laboratories developed its own sub strains, or “daughter strain” of BCG. These became called by the laboratory, country or person’s name with which they were associated, for example the Moscow and Gothenburg strains.19Behr, M “BCG – different strains, different vaccines?”, The Lancet Infectious Diseases, 2002, 86www.thelancet.com/journals/laninf/article

The effectiveness of the BCG vaccine

There have been a number of controversies concerning the prevention of TB, and one of these has been concerning the efficacy or effectiveness of the BCG vaccine. In various clinical trials the estimates of effectiveness have ranged from 80% protection to no benefit, and the reasons for these differences are still not clearly understood.20Kernodle, D “Decrease in the Effectiveness of Bacille Calmette-Guerin Vaccine against Pulmonary Tuberculosis”, Clin Infect Dis, 2010, 177 cid.oxfordjournals.org/content/51/2/177.full

Replacing the BCG vaccine

The organisation AERAS was set up in 2003 to develop new, safe, effective and affordable vaccines to replace the BCG vaccine. A new vaccine will need to protect against all strains of TB including the different types of drug resistant TB. The vaccine will also need to be suitable for use in preventing TB in children, adolescents and adults, as well being safe for use in people who are infected with both HIV and TB.21“AERAS – Global Efforts”, AERAS www.aeras.org/about-tb/global-efforts.php

AERAS is supporting the clinical testing of six possible new TB vaccines any one of which could be a suitable vaccine to replace the BCG vaccine. In October 2012 it was announced that in connection with Glaxo, AERAS will in 2013 begin a phase IIB study in Kenya, India and South Africa. It is planned that this vaccine if successful would be used alongside the existing BCG vaccine.22“Aera, GSK will test TB vaccine in India and Africa”, Vaccine News Daily, October 12 2012vaccinenewsdaily.com

Another potential TB vaccine also designed to be used in conjunction with BCG is MVA85A. In February 2013 the results were announced of a phase 2B trial of MVA85A.23“Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebos-controlled phase 2B trials”, The Lancet, February 4 2013 www.thelancet.com/This disappointingly showed that MVA85A did not provide any significant effectiveness against either tuberculosis or M. tuberculosis infection, although some people considered that:

“the findings … are not a terminal prognosis for MVA85A, or for any of the other tuberculosis vaccines in development.”24“A major event for new tuberculosis vaccines”, The Lancet, February 4 2013 www.thelancet.com/


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