Pott’s disease, consumption, scrofula, white plague; tuberculosis (Tb), a disease almost as old as civilization itself, has had many names throughout history. Although a lot of progress has been made in the prevention and treatment of Tb, the disease remains a serious healthcare problem today. Renowned microbiologist Robert Koch won the 1905 Nobel Prize in medicine for his discovery of Mycobacterium tuberculosis (in 1882) as the causative agent for Tb. Unfortunately, Mr. Koch was unavailable for an interview, but we got the next best thing! Kris Huygen, head of the department of immunology at the Scientific Institute for Public Health (WIV-ISP), has studied Mycobacterium tuberculosis and potential new vaccines for over 20 years. We called on her expertise for a better insight into the infectious disease.
While Tb might seem like a faraway problem and many people in Western countries have forgotten about the disease, the infectious lung disease still claims many lives. Last year, 9 million new cases of Tb were reported, of which 1.5 million were fatal.
Tuberculosis is, to a large extent, a poverty-related disease.
“Mostly Asian and African countries with poor socio-economic conditions suffer from high Tb incidences," says Huygen. "In more industrialized countries Tb usually strikes in poor communities, such as the homeless or refugees from Tb risk regions. In Belgium, most Tb cases are found in the Brussels-Capital region, since these population groups are most abundant in large cities and metropolitan areas. The countryside traditionally has little Tb issues.”
The two-faced balance
The fact that Tb is more widespread in poor countries is no coincidence. Apparently, this can be linked to the immune system; the M. tuberculosis bacillus can only cause the disease when the immune system is having a tough time. Huygen explains: “Estimates are that one third of the world population is infected with M. tuberculosis. Yet, only 5% becomes sick after contact with the bacterium. In all other cases, the infection becomes latent: infected individuals are carriers of the Tb pathogen, but the infection shows no symptoms. Persons with a latent infection are also non-contagious. However, these individuals can get sick after a reactivation of the bacterium.
The immune system is the most important factor in this reactivation, and only when the immunity is compromised, can a reactivation occur. A HIV infection, which cripples the immune system, sharply increases the risk for Tb. Also the elderly are at a higher risk, since the immune system wanes with old age. This is also the case for impoverished people, often living in small, badly ventilated places, and for the homeless, in whom the problem of alcoholism is also a factor impairing the immune defense.
For this reason, the question whether or not Tb is a successful pathogen remains ambiguous. A pathogen that infects 1/3 of the world’s population seems successful at first, but the immune system can clearly handle the infection. We observe T-cells that recognize and control the bacillus in infected individuals. The immune system is not completely victorious. Tb and immunity balance between two sides. I personally believe that the scales tip in favor of the immune system, because it is only when this system fails, that M. tuberculosis can cause the disease.”
Back in the U.S.S.R.
Luckily, good treatment is available for the cases where Tb wins the battle against the immune system. A combination of 3 antibiotics, taken for 6 months, usually does the trick. Sadly, antibiotic resistance is gradually becoming a problem for Tb treatment.
“M. tuberculosis is a bacterium that multiplies rather slowly, so it is important to continue the treatment long enough. Usually, most patients feel better after two months, and have the tendency to stop taking their antibiotics, which is extremely dangerous. Not only can it result in relapses, but cessation of therapy also increases the risk for antibiotic-resistant bacteria. This is the case for all bacterial infections, including Tb. The World Health Organization promotes the implementation of a system called DOTS, ‘directly observed therapy short-course’, in order to reduce this risk of relapse and resistance."
Sustaining therapy is not the only problem. The quality of the antibiotics used can sometimes be questionable in developing countries. Also when the former Soviet Union and its medical system collapsed, the misuse of antibiotics resulted in a lot of resistance. Poor patients selling their medication is another issue that further complicates the matter.
“Two variants of antibiotic resistant Tb have been defined,” says Huygen. “MDR-Tb does not respond to the 2 most widely used antibiotics in Tb treatment, rifampicin and isoniazid. XDR-Tb simply does not respond to anything. These cases of Tb are dramatic, because the patients cannot be treated, and the medical staff should be thoroughly protected in order to avoid infection at all cost. Of course, this should be put into context. In Western countries, therapy is usually fully completed, and the largest part of Tb infections are neither MDR, nor XDR.”
A vaccine to save us all
Huygen leads the research into a new Tb vaccine at the WIV. According to Huygen, vaccination is of utmost importance in the control of Tb.
“Tuberculosis control is based on 3 factors: earlier and easier diagnostics, an improved treatment (preferably one that doesn’t take 6 months to complete), and lastly, a better vaccine. The fact that patients spread Tb into their environment before diagnosis and treatment, is a crucial problem. A vaccine would elegantly solve this issue. The less people catching the disease, the slower it can spread. Intervening at the start of the chain can truly have a lot of impact. The current Tb vaccine, BCG, is based on an attenuated Mycobacterium bovis strain, but it only protects children and the protection varies widely. Adults experiencing a reactivation remain vulnerable.”
A disease that kills 1.5 million people every year, can hardly be said to be ‘under control’. If we want to eradicate Tb in the long run, a better vaccine is essential.
Tb is a tricky pathogen to vaccinate against, and some unknowns still need to be uncovered to develop an efficient vaccine. Despite these issues, the relatively new method of DNA vaccination offers great potential.
“We know that the cellular immune response is important in Tb infections, but the exact mechanism of protection is complex and not yet fully understood. For some pathogens, we have a clear ‘correlate of protection’: a certain amount of antibody against a toxin, for example, conferring immunity. Once these correlates are uncovered, a vaccine can be developed to fulfill this specific function. There are presumptions for what these correlates could be in Tb, but no concrete facts.
Whether or not a vaccine can be developed for a certain disease depends on the infection and what kind of immune response is necessary to counter it. For diseases such as tetanus or diphtheria, good vaccines are available because antibodies against their toxins are sufficient to clear these infections. In those cases, it’s fairly easy to formulate a vaccine; the required antigen is formulated in an adjuvant and can be administered. This is not yet the case for HIV, malaria or Tb, for which there are no vaccines available so far. The immune response to these pathogens is more complex than antibody production.
Presently, we are investigating the potential of DNA vaccines in preventing Tb. These vaccines contain plasmids encoding a specific Tb antigen. The rationale is that, after DNA uptake, our own cells produce the antigen and present it to the immune system. Our studies show that the cellular immune response, more specifically the activation of CD8+ T-cells, is important in the clearance of Tb. By letting our own cells process and present the antigen, a strong CD4+ and CD8+ response can be elicited. DNA is also much easier to produce and purify than proteins, which is a nice advantage to have. Research into antibody vaccines is still very useful, since antibodies may interact with Tb in an early stage, when the bacterium enters the lungs. A combination DNA/antibody vaccine might be an effective way to counter tuberculosis.”
Together with a British group, Kris Huygen’s group was the first to report on DNA vaccines for tuberculosis, back in 1996. Today, still no DNA vaccines have been approved for human use, but they already had some successes in the veterinary world, particularly for viral diseases.
When asked whether she believes tuberculosis is under control, Huygen replies resolutely : “In Belgium and most of the Western world, tuberculosis is more or less under control, but a disease that kills 1.5 million people every year, can hardly be said to be ‘under control’. If we want to eradicate Tb in the long run, a better vaccine is essential. Vaccines can easily be applied in socio-economically weaker countries, where the bulk of deadly cases are present. That’s when a real shift will be possible.”
For more in-depth information on tuberculosis and DNA vaccines, visit:
Brennan, Michael J., and Jelle Thole. "Tuberculosis vaccines: a strategic blueprint for the next decade." Tuberculosis 92 (2012): S6-S13.
Bruffaerts, Nicolas, Kris Huygen, and Marta Romano. "DNA vaccines against tuberculosis." Expert opinion on biological therapy 14.12 (2014): 1801-1813.
Bruffaerts, Nicolas, et al. "Increased B and T Cell Responses in M. bovis Bacille Calmette-Guérin Vaccinated Pigs Co-Immunized with Plasmid DNA Encoding a Prototype Tuberculosis Antigen." PloS one 10.7 (2015): e0132288.
Evans, Thomas G., et al. "Preventive vaccines for tuberculosis." Vaccine 31 (2013): B223-B226.
Image courtesy of Leonard Bently (middle) and Government & Heritage Library, State Libray of NC (bottom), https://creativecommons.org/licenses/by/2.0/legalcode