Lhere or somewhere completely different: for most people in Germany, tuberculosis (TB) somehow sounds far away. But the number of new cases is increasing worldwide – and roughly 1.5 million people die from the bacterial infection every year. According to experts, an effective vaccination is urgently needed – several preparations are currently being tested. It remains to be seen whether and to what extent they can help to combat the disease.
Tuberculosis is comparatively rare in this country. The trend has been declining for decades – albeit with a slight increase recently, due to immigration from Eastern Europe, for example. In 2022, the Robert Koch Institute (RKI) registered 4076 cases of the notifiable disease, which corresponds to an incidence of 4.9 new cases per 100,000 inhabitants, after 4.7 in the previous year.
The bacterial infectious disease between Flensburg and Freiburg has become so rare that some doctors no longer recognize any signs of it. “We keep seeing cases in Germany that are only diagnosed very late,” says RKI expert Barbara Hauer. Even with a conspicuous X-ray, doctors would sometimes no longer think of tuberculosis.
The situation was fundamentally different just 100 years ago: In 1923 – and by then tuberculosis was already on the decline – more than 10 percent of all people who died in Baden and Württemberg still succumbed to the disease commonly known as consumption, according to the State Statistical Office. For comparison: According to the RKI, 116 people nationwide died of tuberculosis in 2022.
Tuberculosis trend in the European Economic Area
Decisive for the decline since the 19th century were neither the better treatment options nor the vaccine BCG (Bacille Calmette-Guérin), which was developed in 1921 and which contains weakened bovine tuberculosis bacteria and has only been no longer recommended in Germany since 1998 because of the low risk of infection . The decisive factors were the living conditions: hygiene, better nutrition, less cramped living conditions.
“No other disease reflects the social conditions so much,” says Christoph Lange, Medical Director of the Borstel Research Center. A look at the Baltic States shows this for the recent past: In Estonia, the incidence in 2000 – shortly before EU accession in 2004 – was still 65 new cases per 100,000 inhabitants, in 2021 it was 9. In Latvia it fell from 95 in the same period to 16. In both countries, a drop of well over 80 percent.
In the entire European Economic Area – the EU plus Liechtenstein, Norway and Iceland – the incidence in 2019 was below 10 per 100,000 inhabitants. “If the trend continues, tuberculosis would be largely eliminated in the European Economic Area by 2040,” says Lange. What sounds encouraging quickly gives way to disillusionment when you look beyond this area. “Tuberculosis is the bacterial infectious disease with the most deaths worldwide,” says Ralf Otto-Knapp from the German Central Committee to Combat Tuberculosis (DZK) in Berlin. The doctor points out that around 1.6 million people worldwide will die of tuberculosis in 2021 – more than in previous years.
The World Health Organization (WHO) had set itself the goal of reducing TB incidence by 90 percent by 2035 compared to 2015, and mortality by as much as 95 percent. But recently, the global burden of disease has even increased. According to the WHO, the global incidence in 2021 was 134 cases per 100,000 inhabitants, which corresponds to 10.6 million cases. “There have never been so many new cases in one year,” says Lange. In Africa, the incidence in 2021 was 212, in South and East Asia even 234.
Tuberculosis comes slowly and goes slowly
And the treatment of tuberculosis is extremely lengthy. “The disease comes slowly and it goes slowly,” says Lange. The lengthy therapy is mainly due to the fact that the bacteria only multiply very slowly. The generation time lasts roughly 20 hours. For comparison: With E. coli bacteria it is only 20 minutes. Infection with the pathogen – especially Mycobacterium tuberculosis, the discovery of which was announced by Robert Koch on March 24, 1882 in Berlin – occurs mainly through droplets and usually affects the lungs, but in principle the pathogens can also colonize other organs. The spectrum of possible symptoms varies accordingly, ranging from coughing to tiredness, lack of appetite, night sweats and fever to weight loss.
However, only a small proportion of those infected become ill – sometimes years later. And because a healthy immune system can keep the pathogen in check, the combination of tuberculosis and an infection with the immune deficiency pathogen HIV, which is common in some places, is particularly bad. In Africa, this affects almost 20 percent of the 2.5 million TB patients. That is why HIV treatment in particular helps in the fight against tuberculosis: after antiretroviral HIV therapies became available in poorer countries, the proportion of HIV-infected patients with tuberculosis worldwide has fallen by more than two thirds, says Lange. “It was the most effective measure to control tuberculosis in the past decade.”
The tuberculosis therapy itself is carried out with special antibiotics. Standard treatment currently requires six months: four preparations over two months, then two remedies over four months. “The treatment takes a long time,” says Otto-Knapp. “Too many patients stop taking the medication when they feel better.” This may be understandable in view of the often serious side effects.
However, the termination not only prevents healing, but also promotes the emergence of resistant pathogens, against which some medicines are powerless. And the elimination of resistant pathogens takes significantly longer at 18 to 24 months, says Lange, and with a lower success rate. But the treatment is currently changing. “We live in a very exciting time when it comes to tuberculosis,” says Lange. Therapy has stagnated for decades. New preparations have only been added since the 1990s.
Around 450,000 people worldwide with multi-resistant pathogens
Experts are worried about the rapid development of resistance. An estimated 450,000 people worldwide carry multidrug-resistant pathogens. “Only 150,000 of them are known, the other 300,000 remain untreated,” explains Lange. According to this, 15 percent of the multi-resistant pathogen strains in Moldova are already resistant to bedaquiline alone – which the expert believes is currently the best active substance – and in South Africa the figure is even 30 percent among people who do not respond to therapy. “And the drug has only been on the market for a few years.”
In some countries such as Russia – estimated incidence: 47 new cases per 100,000 inhabitants – more than half of those infected are infected with multi-resistant pathogens. For comparison: According to RKI expert Hauer, the proportion of multi-resistant cases in Germany is currently just under 6 percent. In view of the global situation, Lange emphasizes: “Without vaccination, we will not be able to get the situation under control.” Although the BCG vaccine, which has been used since the 1920s, is still widely used in risk areas, vaccination protection is limited.
Other vaccines are currently being tested. This includes in particular the preparation VPM1002, which was largely developed by Stefan Kaufmann, the founding director of the Max Planck Institute for Infection Biology in Berlin, who has since retired. VPM1002 contains weakened BCG bacteria that are genetically modified to be better recognized by the immune system. Studies have already shown that the preparation is safe and effective. How well the vaccination actually protects in different scenarios is currently being tested in three clinical phase 3 studies. One of them is testing how well the vaccine protects newborns over the age of three compared to the BCG preparation in five sub-Saharan African countries.
The other two studies are in India, where more than a quarter of all sufferers worldwide live. Prime Minister Narendra Modi has set an ambitious goal of eliminating the disease by 2025. At the same time, the country has the world‘s largest manufacturer of vaccines, the Serum Institute of India.
One of the studies compares VPM1002 to another new drug. It involves 12,000 people who live in households with TB patients and are therefore particularly at risk. Some of the subjects will receive VPM1002, others will receive the Immuvac/MIP vaccine developed by an Indian company, and a third group will remain unvaccinated. Kaufmann expects results at the end of this year or early next year. The second study in India is testing VPM1002 in 2,000 people who have previously been successfully treated for tuberculosis. She tests whether the vaccination can prevent a relapse.
Kaufmann hopes that the vaccination will protect better or be more tolerable than the BCG vaccine – preferably both. The immunologist would rate a vaccination protection of 75 percent as a success. “I’m critical of achieving 100 percent protection,” he says. The Mainz-based pharmaceutical company Biontech is also researching a tuberculosis vaccine. A clinical study that will initially test the safety and optimal dose of the mRNA preparation BTN164 in almost 100 people is scheduled to start in Germany soon. Results are expected by the end of 2025. As helpful as medical advances are in the fight against tuberculosis. Better living conditions worldwide would probably be even more important. “Social issues are extremely important,” says Kaufmann. “But they may be even more difficult to solve than the medical ones.”
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