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Vaccines and AMR Case Study: Multi-Drug Resistant Tuberculosis

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TB kills more people than any other infectious disease. In 2017, there were 10 million new cases and 1.6 million deaths throughout the world. Things that make that worse are co-infection with HIV, the emergence of drug-resistant strains, which are much harder to treat, and the burden of latent infection. It’s estimated that a quarter of the world’s population are latently infected with TB. BCG, or Bacillus Calmette-Guérin, is a live attenuated strain of Mycobacterium bovis. It’s the only licenced vaccine against TB, and it’s been around for almost a hundred years. Mycobacterium bovis is the strain of bacteria that usually infects cattle and is the reason why we pasteurise our milk.
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There have been many, many studies looking at how good BCG is at protecting against TB disease throughout the world. And what we know from those studies are that when given at birth, as BCG is throughout most of the world, BCG is very good at protecting against severe disease, disseminated disease, that is spread outside of the lungs. What it is very inconsistent at doing is protecting against lung disease. There are some studies, such as the study in the UK, the British MRC study, showing that BCG is very effective, 80% effective, estimated durability of 20 years. However, there are many studies– for example, some in India, some in Africa– showing the BCG has no effect whatsoever.
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So it’s that variability in efficacy against lung disease that’s the real problem. And what we need is a vaccine that is more universally protective. Multidrug resistant TB are strains of Mycobacterium tuberculosis that are resistant to our two first-line drugs, rifampicin and isoniazid. There were over half a million new cases of TB in 2017 that were resistant to rifampicin, and 82% of those were also resistant to isoniazid. Those two drugs that were developed in the 1950s are the most important drugs in our treatment repertoire for TB. And if you have resistance to them, treatment goes up from a six-month course of treatment to up to two years of treatment.
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That’s a huge amount of time for someone to need to take antibiotics. Furthermore, we also have what is now called extensively drug-resistant strains of TB, which, if you like, is MDR+. It’s multidrug resistance and resistance to at least one of the second-line antimicrobial therapies. And the WHO, when it was first identified, defined XDR TB as virtually untreatable. We can treat XDR TB, but treatment success rates are much lower and treatment duration needs to be at least two years. If we had a vaccine that could be used together with antibiotics, that may reduce the treatment course, and it might improve the cure rates.
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So the idea here would be to give a vaccine to boost the immune system to work in conjunction, or as an adjunct, to those antibiotic agents. So there are scientific reasons why it’s really difficult to make a TB vaccine, and there are political or funding issues. Firstly, the scientific issues. TB is a very clever pathogen. It’s extremely adept at evading the host immune response. That’s why up to a quarter of the world’s population are latently infected. TB can literally hide inside cells. And that means it can be very difficult to get at. We don’t have an immune correlate of protection, which means that we’re sort of developing vaccines blind.
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We know better about what kind of immune response is important for protection, but we don’t know which, if any, of those aspects actually correlate with protection. And we also have a number of animal models that we use to develop TB vaccines, but we don’t know which of any of them is the best predictor of efficacy in humans. So what that means is we have to make a best guess based on the immune response we see and the animal model data. But ultimately, the only way to develop a TB vaccine is to test it in large, expensive, efficacy trials to see if the vaccine actually works to prevent disease. Those trials take a long time and cost a lot of money.
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So those are the scientific reasons why developing a TB vaccine is difficult, but there are also political reasons. TB, unlike HIV and unlike malaria, has suffered from decades of neglect and funding. In the year 2000, there were no new TB vaccines in clinical trials compared with about 50 for HIV and about the same number for malaria at that time. This is despite the fact that TB is one of the oldest pathogens and has been around since the pharaohs. And indeed, the fact that TB now kills more people than any other pathogen is in part because of that lack of funding over the last 50 or 60 years.
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Over the last 20 years, we have had a very significant increase in funding and there’s now been a real critical momentum gained to the development of a new TB vaccine. We now have over a dozen TB vaccines that have been tested in clinical trials. But it’s really important that we keep that momentum going. We now have two vaccine efficacy trials where there’s been a signal of efficacy, which is hugely important. But it’s really important that we keep this momentum going, keep the funding going, and keep the investment going so that we ultimately will have a new TB vaccine. Because the best way to control any infectious disease epidemic is with effective vaccination.
The interview above, with Professor Helen McShane from the Jenner Institute at the University of Oxford, discusses the need for a new TB vaccine, its importance in preventing the spread of MDR TB and the difficulties of developing a new vaccine against TB.
Tuberculosis (TB), a disease caused by the bacteria Mycobacterium tuberculosis, is one of the top 10 causes of death worldwide and a leading killer for HIV positive patients.
Anti-TB medicines have been used for decades and strains that are resistant to one or more of the medicines have been documented in every country surveyed. Drug resistance emerges when anti-TB medicines are used inappropriately, through incorrect prescription by health care providers, poor quality drugs, and patients stopping treatment prematurely.
Increasing numbers of infections due to multi-drug resistant (MDR) and extensively drug resistant (XDR) TB is a current international public health crisis and poses a health security risk.
Watch this video made by Aeras to understand the problem of antimicrobial resistance in TB and the potential impact of a vaccine.

This is an additional video, hosted on YouTube.

In the resources section below you will find a publication detailing the effects of drug resistant TB and what is currently being done to develop new vaccines to fight the disease.
This article is from the free online

The Role of Vaccines in Preventing Infectious Diseases and Antimicrobial Resistance

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