• Health The pandemic gives wings to tuberculosis
  • Immunization Final stretch for the Spanish tuberculosis vaccine

In his office at the University of Zaragoza, clearly visible, Carlos Martín has a map showing the route Balmis followed in the early nineteenth century to bring the smallpox vaccine to America and Asia. It is his way of keeping in mind that expedition, the first mass vaccination campaign, which is considered a milestone in the history of Medicine. On the world map, with small blue post-its, the researcher has been marking the particular itinerary that until now has followed the research with MTBVAC, the vaccine against tuberculosis that he devised and in which he began working more than 30 years ago and that is in the final stretch of the investigation, "at the decisive moment".

"It's the moment of truth," summarizes Martín, professor of Microbiology at the University of Zaragoza and head of the Mycobacteria Genetics research group at the Center for Biomedical Research in Network (CIBER) of Respiratory Diseases of the Carlos III Health Institute, who has dedicated his career to finding an effective weapon against the infectious disease that kills the most in the world.

Martín's vaccine, whose industrial development is carried out by the Spanish biopharmaceutical company Biofabri, of the Zendal group, has just started phase III trials, the decisive stage to confirm its efficacy against tuberculosis. The product has demonstrated in previous trials its safety and its ability to generate an adequate immune response, but it must now prove its real efficacy, its protective capacity in scenarios where the disease is endemic. Therefore, it has begun to be administered in a double-blind randomized trial to newborns in South Africa, Madagascar and Senegal. One of the keys to the research, which will have 7,120 participants from the three countries, is to demonstrate whether MTBVAC offers better results than BCG (acronym for bacillus Calmette-Guérin), a vaccine with more than 100 years of history and the only one authorized so far that, although it offers protection against severe forms of the disease, It does not work well against respiratory tuberculosis, so it is not useful to stop transmission.

Tuberculosis is an infectious disease that is transmitted by air and is caused by the bacterium Mycobacterium tuberculosis, also known as Koch's bacillus in honor of the researcher who discovered it. In up to 90% of cases, after contagion the infection does not progress, since the immune system manages to control the pathogen. However, in the remaining 10% tuberculosis develops. If no treatment is received, which requires taking several drugs for about six months, half of those affected die.

"In the last year, 1.6 million people have died from tuberculosis. It is a real barbarity that must be stopped, "says Martín, who recalls that if MTBVAC works as previous tests have shown, it can mark a before and after, "it can be key to help eradicate tuberculosis".

The Spanish vaccine is one of the most seasoned candidates in the task of finding an effective weapon against tuberculosis. But a final sprint is needed, a push in the form of funding that allows the latest studies to be streamlined, says Martín.

"We need support to be able to prove that a vaccine that would be produced from start to finish in Spain can put an end to the disease that has killed the most in history," says the researcher.

As he explains, for the start of phase III the project has funds from the European Union, but a new impetus is needed to be able to complete this phase III of efficacy, which aims to monitor children vaccinated with MTBVAC or BCG during the following five or six years to check their evolution. "We want Spanish institutions, companies and philanthropists to participate and take the project as their own. It can be a very important milestone for humanity and it can be Spanish, as was the Balmis expedition two centuries ago, "says the researcher.

"That a vaccine developed in Spain and also produced in Spain manages to contribute significantly to the eradication of the disease can be a reality," adds Martín, who recalls that, to promote this impulse that the vaccine needs, the T.END Foundation has just been constituted. Chaired by Carlos Martín himself, the agency seeks to concentrate efforts and channel donor funding. "Like in the movies, we want a happy ending, a the end of tuberculosis," sighs Martin.

Achieving this would put a finishing touch to a three-decade project that, as the Aragonese researcher recalls, "began with a tragic event": an outbreak of multidrug-resistant tuberculosis in the old Hospital del Rey in Madrid, which caused the death of a hundred people and was produced by the care in the same space of patients with HIV and patients who had been infected with tuberculosis.

After that episode, Martín began to study why and in what way those bacteria had managed to become resistant to the available drugs, which led him to identify the genetic keys to their virulence. It was just the first step.

Martin's team continued to work from the Mt 103 strain of M. tuberculosis bacteria that had been obtained from a clinical sample. After much effort, they managed to eliminate two genes that are fundamental for the virulence and resistance of the pathogen – phoP and fadD26. These two deletions are key to ensuring the safety of the vaccine and, at the same time, allow the stimulation of the immune system that every vaccine aims to achieve.

According to Martín, MTBVAC is the first and only attenuated vaccine based on M. tuberculosis that has reached phase III research in humans. Instead of starting from the microorganism that causes the disease in humans, as is the case with MTBVAC, other candidates are developing from Mycobacterium bovis, the pathogen that causes bovine tuberculosis and the germ on which the current BCG is also based.

Due to its development from a sample obtained from a patient's infection, "MTBVAC contains more than 400 antigens that are not present in BCG," says Martín. For its design, he adds, a strain of lineage 4 has been chosen, the most frequent in Europe, Africa and America, whose protection capacity extends to other strains and lineages, according to laboratory results. Therefore, researchers are optimistic about their capabilities. Administration is performed intradermally, in a single dose.

According to data from the World Health Organization, in 2021 there were more than 10 million new cases of tuberculosis and approximately 1.6 million people died from the disease. According to their data, two-thirds of the total cases occurred in just eight countries: India (28%), Indonesia (9.2%), China (7.4%), the Philippines (7%), Pakistan (5.8%), Nigeria (4.4%), Bangladesh (3.6%) and the Democratic Republic of Congo (2.9%). Therefore, the institutions involved in the development of MTBVAC are committed to making the product accessible at affordable prices in low- and middle-income countries if effective. In its development, the vaccine has had the collaboration of international organizations, such as the Tuberculosis Vaccine Initiative (TBVI) or the International AIDS Vaccine Initiative (IAVI).

However, it is not only these countries that need new weapons to fight the disease. "In Western countries too, we face risks, such as those arising from the strains of multidrug-resistant tuberculosis that are emerging," says the scientist.

Ending the TB epidemic by 2030 is one of the health-related targets set in the 2030 Agenda, but the prospects are not good. Because of the pandemic, the progress made in recent years against this infectious disease has been reversed, taking a significant step backwards. Covid robbed tuberculosis of the first place in the ranking of infectious diseases that kill the most during 2020, the hardest year of the pandemic, but the bacterial disease has once again topped the podium with force. In addition, "due to the impact of the coronavirus, infections have increased and diagnoses and treatment have been reduced, which has produced a significant increase in deaths," says Martín. He adds: "Since 2020, instead of being reduced,deaths have increased by 100,000 cases per year."

The challenge of finding an effective vaccine to curb TB transmission is old and promising candidates have fallen by the wayside, such as the MVA85A vaccine, developed by researchers at the University of Oxford (United Kingdom). In its original plan, this product was designed to complement the BCG and there were high hopes for the prototype. However, in 2013, results from a phase 2b trial with nearly 3,000 South African babies showed that it was not effective in preventing the disease. After a follow-up of more than 37 months, the scientists found that there were hardly any differences in the evolution of the children vaccinated with the candidate and the babies included in the control group, whose ages ranged between four and six months at the beginning of the research. These investigations that did not come to fruition, however, "have helped us a lot to learn from mistakes and design clinical trials," says Martín.

In addition to MTBVAC, there are currently 13 other vaccine candidates under investigation, six of them in phase III, such as the VPM1002 vaccine, developed by the Max Planck Institute in Germany and based on the strain of M. bovis used by BCG that has been genetically modified to achieve a more complete and broad immune response than that currently provided by the centenary product.

"We want to speed up the whole process because the sooner we can know if the vaccine works, the sooner we can start saving lives," says Martín. "Spain can play a key role in the fight against a disease that is once again the champion in terms of deaths. As with the Balmis expedition, we can mark another milestone in the history of vaccines," he concludes.

  • Infectious diseases

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