The BCG vaccine
Millions of people fall victim to tuberculosis each year, even though health organizations are trying to increase the rates of immunization against and treatment of the disease, limiting its spread. It is among the main reasons for death from infectious disease, and Number 1 among infectious killers in people living with HIV infection. In 2018 alone, according to the World Health Organization (WHO), roughly 1.5 million people died from tuberculosis.
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The vaccine used against this disease is now almost a hundred years old. Known as the BCG (Bacillus Calmette–Guérin) vaccine due to the specific strain of the tuberculosis-causing germ (Mycobacterium tuberculosis) used to create it, it effectively prevents systemic tuberculosis in infants. However, it is not as effective against the much more common pulmonary or lung form, found in both adults and teenagers.
Medical research has brought forth effective drugs to fight tuberculosis, and this process is continuing. However, multi-drug resistance has emerged, posing a new threat to the world. Such strains of M. tuberculosis are not affected by the two most powerful anti-tuberculous medications that are now being used worldwide.
As scientists try to find a solution to this problem, a new study reports the findings when three different methods were used to immunize macaque monkeys using the BCG vaccine. In the first group, the vaccine was delivered intravenously, in the second, it was injected into the skin, and the third group received it via an aerosol spray that was inhaled.
The intravenous route produced the highest number of T cells responding to the bacterial antigens, compared to the other two groups. T cells are part of the immune system, being lymphocytes that fight against infection either directly, by killing infected cells and infectious agents, or by producing antibodies, or by regulating this process.
The antigen-responsive T cells were found to have infiltrated all parts of the lungs.
When some of these animals were then exposed to M. tuberculosis after 6 months, the scientists observed that 9/10 animals who had received the vaccine intravenously showed a high degree of protection against the vaccine, and 6 had no signs of the presence of the bacteria at all. Thus, there was a 90% protection against a disease-producing strain of the tuberculosis bacteria, even when the criterion for infection was very stringent. This is the first time such a high degree of protection has been achieved with the BCG vaccine against lung tuberculosis.
On the other hand, aerosol and intradermal routes of immunization failed to produce protection, with most animals showing marks of tuberculosis.
The scientists were taken by surprise since the intravenous route was expected to improve the immune response to limit disease severity. However, they did not believe that it would arrest further disease development. The vaccine in the blood causes a T cell population to form in the lungs, which can quickly eliminate the tubercle bacilli.
The mechanisms of protection may be due to; the high T cell responses in the lung tissue, the increased antibodies against the tuberculosis bacteria, or the induction of epigenetic changes in the macrophages (the white cells that engulf the bacteria), enhancing this capability to eliminate them.
The next step is repeating the experiments, trying to achieve the same results. This, if validated, could revolutionize the treatment of tuberculosis, because of the inexpensive nature and widespread availability of the BCG vaccine.
However, the intravenous route first must be proved to be safe, since the vaccine contains live attenuated bacteria. This means that the bacteria are too weak to cause infection in individuals with a normal immune response. However, if injected directly into the bloodstream, the scenario is different, and the risks must be studied first. For instance, if the vaccine production or storage stream allowed contamination by another infectious agent or the M. tuberculosis was not attenuated sufficiently, direct injection into the blood could lead to fatal and disseminated infection. Thus, clinical trials must be preceded by very comprehensive and meticulous safety testing.
A second problem is the logistical difficulty of introducing widespread intravenous vaccination, which requires a high level of cleanliness, safety, and training. This could disqualify it for adoption by low-income countries, where health resources are already stretched beyond breaking point to provide health care at a primary level.
On the other hand, the situation is aggravated by the preponderance of tuberculosis in such regions, making it important that effective immunization is first introduced in such countries. Pharmaceutical companies have displayed little interest in developing and marketing newer drugs for the treatment of tuberculosis, due to the chronic lack of funding by governments. The emergence of non-profit research groups and other entities has changed the face of tuberculosis research, however. For instance, one such group worked alongside a drug company to produce a promising vaccine candidate called M72/AS01E that prevents adults with latent infection (where M. tuberculosis is in the body but produces no signs of disease) from progressing to an active disease, for at least 3 years from the date of vaccination. Another such group has produced a drug, that was approved in 2019 by the US FDA, for use as part of a drug combination for extremely multidrug-resistant tuberculosis. Many more drugs and vaccines are being tested in trials, according to the WHO.
If an intravenous BCG vaccine can help to reduce the number of tuberculosis cases, it could be a crucial step towards achieving the 90% reduction in tuberculosis deaths targeted by the United Nations Sustainable Development Goals by 2030, in addition to the 50 million to 60 million deaths averted by current treatments. Especially in Southeast Asia and in Africa, tuberculosis is prominent even today, and universal vaccination of infants has been advised as one way to help bring this under control. In this situation, any means of improving the vaccine’s effectiveness should receive careful attention.
Darrah, P.A., Zeppa, J.J., Maiello, P. et al. Prevention of tuberculosis in macaques after intravenous BCG immunization. Nature 577, 95–102 (2020) DOI:10.1038/s41586-019-1817-8. https://www.nature.com/articles/s41586-019-1817-8
Editorial. The trick that could inject new life into an old tuberculosis vaccine. Nature 577, 145 (2020). DOI: 10.1038/d41586-020-00003-w. https://www.nature.com/articles/d41586-020-00003-w