Who invented tuberculosis vaccine

By the tubercle bacillus had been sub cultured times, and it was so weakened that it was believed that it could confer immunity without causing disease in humans. The baby was given 6 mg. During the next three years up to July a further infants were also vaccinated. In and there were a number of publications from Calmette reporting on the BCG vaccination of children between and , as well as between and Calmette said that between and children had been vaccinated, of whom had mothers with TB, and the remainder had close contact with the disease.

Of these children only 3. 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.

Despite this, at the Conference of the League of Nations in Paris in , the vaccine was recognized as safe and its use was encouraged. The history of the BCG vaccine nearly came to an end in when the Lubeck disaster occurred. We will also discuss a few of the vaccines that have already been developed and are being tested in clinical trials. Additionally, we will briefly discuss the various regulatory approval processes that are required to test a vaccine before it can finally be approved for release on the market.

Despite its widespread use, BCG delivers only minimal protection and has failed to eradicate or reduce the disease burden of TB. The mechanisms by which BCG works to provide its marginal protection are incompletely understood. Even though BCG provides an imperfect defense against M. In this section of the chapter we will discuss the history of BCG and some possible reasons why it has failed to stem the tide of deaths due to M.

Developed from a virulent strain of Mycobacterium bovis, the BCG vaccine was attenuated by serially passing the strains on potato slices supplemented with glycerol over a period of 13 years until a non-virulent strain was obtained [ 8 - 10 ].

Trials of the newly developed vaccine were performed in cows, monkeys, and African apes and proved to be efficacious [ 11 ] [ 12 ]. The strain was first used as a vaccine in humans in with few adverse side effects observed in the patients who received it [ 8 , 9 ].

The non-virulence of this strain was then established before it was sent out to several laboratories throughout the world and used as a vaccine. The vaccine was then propagated in the various countries in different ways with varying passage numbers, resulting in the emergence of different variants of the BCG vaccine [ 8 , 10 ]. Most countries around the world require that the BCG vaccine be given during childhood.

Most of Europe and Australia did at some point in their history require BCG to be given to children, but have since changed their policies. A huge reason for the widespread use of BCG is that it is considered to be one of the safest vaccines on the market [ 15 ].

Side effects of BCG are very rare with the most common complication being swelling around the injection site [ 15 ]. BCG is thought to convey protection against dissemination of the mycobacteria to other organs during childhood, an event that is highly fatal if left untreated.

BCG does not, however, provide protection against adult pulmonary disease, which is the main route by which M. There are several possible reasons behind the huge variability in the reported efficacy of BCG; we will discuss some of these reasons in this section. It is important to keep in mind that some of the issues surrounding BCG efficacy variability are also issues which apply to the new M. There are at least 11 different types of BCG vaccines currently available throughout the world [ 8 ].

A major reason for the different types of BCG and the genetic variability between the strains is mainly a product of the time period when the vaccine was developed. Those laboratories cultured, grew, and stored BCG, each in their own way.

It must be remembered that this occurred in the early part of the 20 th century, before the advent of current molecular techniques and storage methods that can maintain parent strain homogeneity. Instead, as BCG was grown and cultured in these various laboratories, it accumulated a series of independent mutations that continued to build upon themselves [ 8 ].

It was not until the s, with the introduction of culture seed stocks that soon became the norm, that the standardization of these lines became possible. By that time, however, the various strains of BCG had diverged and modern analysis has demonstrated that there is significant variability in the genetic make-up of these strains [ 8 , 10 ].

The genetic variation in BCG strains can lead to variation in how well they protect against infection due to difference in the cell surface proteins that would elicit an immunogenic response [ 10 ]. However, all of these BCG strains have remained non-virulent and a commonality among all of the strains is the loss of the ESX-1 excretion system. It is still not completely understood how the loss of the ESX-1 system blocks virulence since its re-addition to at least two separate BCG strains does not restore virulence back to wild type levels [ 10 , 18 ].

Due to this variation in BCG strains, it is essential that accurate record keeping be in place when conducting efficacy studies for the vaccine [ 8 ]. The genetic diversity of a population can affect the outcome of any clinical research study and this is an important factor to consider when examining vaccine efficacy. The spectrum of immune system responses to a vaccine can vary from no response to complete activation and protection. Individuals with mutations in these susceptibility genes are also more prone to infection by non-virulent, environmental mycobacteria as well [ 19 ] [ 19 ].

Therefore, it is essential when designing a vaccine study in humans to have a large population that is statistically powerful enough that some variability in immune response will not skew the data. Additionally, no matter where a study is being conducted, the genetic diversity of the population must be considered.

An ethnically homogenous population is more desired for a research study since that population will be more likely to share SNPs, and therefore more likely to respond to a vaccine in a similar manner. It also follows that it may also be useful to test multiple ethnic groups; indeed, some studies have suggested that the reason some vaccine trails show high protection with BCG is because they were conducted within certain population groups [ 15 ]. Another issue that is of huge importance when conducting vaccine efficacy tests is whether or not an individual has been pre-exposed to the pathogen.

The immune response of an individual who has already been exposed may be quite different than someone without prior exposure. Especially in areas where TB is endemic, it is likely that a child will have already been exposed to M. A child could be exposed to both M. Some studies have also suggested that pre-exposure to NTM may provide some protection that cannot be improved upon by BCG delivery [ 9 , 15 , 20 ].

This may indeed be the case with BCG as it has been found that vaccine programs with the highest degree of efficacy are those with more rigorous screening to only include children who had not been previously exposed to the antigen [ 17 ]. Because of the complications that result from pre-exposure to the pathogen, it is essential to have accurate diagnostic methods available when deciding which individuals to include in a study.

A non-homogeneous population a mixture of non-and pre-exposed individuals can produce misleading results that can hinder accurate interpretation of vaccine efficacy. One of the most common diagnostics for M. It takes two to three days after injection of the purified protein derivative PPD before the results can be read; a delay that can result in loss of study participant compliance or even exposure.

Additionally, the TST, as well as many new serological tests, cannot distinguish between exposure to environmental NTM and infectious M. The complications involved with studying M. Due to the complex nature of the pathogen, M. In this section we will go into more depth as to the specifics of these challenges and how they have delayed the development of a vaccine.

When a researcher decides to investigate the development of a vaccine against M. In the United States, the CDC provides a set of guidelines for the safety measures that need to be in place in order to work with various pathogenic organisms. These biosafety levels range from 1 least likely to cause harm to an individual to 4 most harmful and infectious [ 24 ]. The basis for these biosafety measures are derived from the WHO, which, in turn, base their recommendations upon the availability of effective preventive measures and treatment options [ 25 ].

As the biosafety level of a pathogen increases, it is necessary to increase the safety measures for a person working in these conditions. In the research laboratory setting, M. The various safety measures that must be put in place include laboratory practices, facility construction, security, and safety equipment.

The exact nature of the measures put in place will vary slightly from facility to facility but in general, this includes separate rooms and equipment for work with the pathogen. All work done with the microbe needs to be conducted in a properly outfitted biosafety cabinet and special personal protective equipment e. These biosafety mechanisms can be a limiting factor when attempting to study M. Additionally, these biosafety measures, while necessary, can be relatively uncomfortable, and may therefore limit the time with which a person can work under them.

While these are obviously not insurmountable obstacles, they should be taken into consideration before research of this nature is undertaken. Because it grows so slowly, it is necessary to let a significant amount of time pass after infection in order to resolve differences in vaccine treatments. If an unvaccinated mouse is given a low dose aerosol infection of virulent M. When conducting immunological research, mice are generally sacrificed 30 to days after infection to examine short and long term immunity and determine if a vaccine has had any effect on the reduction in mycobacterial number.

When the animal is sacrificed, the lungs must then be plated on selective agar media in order to enumerate the number of mycobacteria growing in the lungs. The time of plating the lungs until the formation of visible colonies is between weeks. All told, experiments of this nature often require months of work before any data is even collected.

Therefore, when planning out experiments involving infected animals, researchers must consider the significant amount time it will take between the initiation of the experiment and the completion of the study. As mentioned previously, infection with M. In humans, infection with M. At each of these stages, the proteins expressed by the organism are thought to vary significantly and therefore protection in one stage may not protect in all.

After primary infection, in an immunologically healthy individual, an infection will progress to a latent TB infection LTBI. There is significant evidence that sterile clearance of M. In most individuals, this is where the infection will remain unless there is an outside occurrence that reduces the functionality of their immune system [ 1 ].

It is generally believed that when M. The exact immunological events that are required in order for the pathogen to progress from latency into an active state are incompletely understood.

The immune response that humans develop against M. This leads to some interesting questions as to what types of antigens to target for vaccine development. When a person has a LTBI, their immune system is effectively containing the mycobacteria and they do not get sick.

Since , the vaccine has been used as standard of care for the disease, often injected directly into the bladder after surgery to prevent cancer cells from growing or returning there. The vaccine is also being investigated as a potential therapy for colorectal cancers.

Type 1 diabetes Early research has indicated that BCG could hold promise as a potential treatment for autoimmune diseases such as type 1 diabetes.

Additional findings from this year showed, among other results, that BCG was particularly effective in reducing HbA1c levels in participants aged under 21 years. Covid Over 20 clinical trials are currently taking place to investigate whether the BCG jab could be repurposed to protect against Covid , or reduce the risk of severe lung damage from the virus.

While BCG is not currently recommended for use in this context, if trials are successful, the vaccine could provide an alternative means of protection against severe Covid in countries where coronavirus vaccine supplies are limited. In some areas of London, for example, all newborn babies are recommended to have the BCG vaccine. Having a parent or grandparent who was born in a country where there is a high rate of TB Living for three months or more in a country where is a high rate of TB Being in close contact for a prolonged period with someone who has pulmonary TB TB affecting the lungs Babies and children under 16 in any of these risk groups will usually be offered the BCG vaccine.

Apart from the active ingredients the antigens , the vaccine also contains small amounts of the following ingredients: sodium, potassium and magnesium salts glycerol, a common non-toxic stabiliser also used in foods citric acid Other brands of BCG vaccine used in other countries may contain different ingredients.

Side effects. Very common side effect affecting 9 out of 10 people : Hardness at the injection site, followed by a raised blister. Uncommon side effects affecting up to 1 in people at each dose : Headache and a raised temperature fever An ulcer which develops from the blister at the injection site, two to six weeks after injection.

This may be painful and take several weeks or months to heal fully. Swelling of lymph nodes in the armpit larger than 1 cm across An enlarged lymph node that becomes infected lymphadenitis Rare side effects affecting up to 1 in people at each dose : More severe skin reactions. These usually heal within a few weeks. Bone inflammation osteitis or osteomyelitis An abscess at the injection site Anaphylaxis As with any vaccine, medicine or food, there is a very small chance of a severe allergic reaction anaphylaxis.

More information about the vaccine. Page last updated:. Monday, September 9, Other vaccines in this category. Hepatitis B Vaccine. Chickenpox Varicella Vaccine. Hepatitis A Vaccine.