Professor Gilla Kaplan: TB research needs to address key assumptions about TB that could be mistaken

Changing the perspective of research to end TB: a global venture

“Suboptimal tools to detect, treat or prevent TB necessitate development of new tools,” said Professor Gilla Kaplan, speaking at the Stop TB Symposium, that was held on October 30, 2013, a day before the 44th Union World Conference on Lung Health. Prof Kaplan is a highly respected basic scientist who has recently joined the TB team at the Bill and Melinda Gates Foundation. But she believes the field is hampered by gaps in knowledge and some inaccurate — or at least unproven — assumptions about TB pathogenesis and natural history, and that eliminating TB will require greater investments in basic science research.

Problems with our existing tools

Prof Kaplan first discussed the problems with the tools that we do have. First, the existing diagnostics are detecting only some of the people with active TB, or drug resistant TB. Treatment with existing drugs is lengthy and complex and does not necessarily lead to sterilization of infection in either drug susceptible or drug resistant TB patients. This means that even those who are diagnosed and treated do not necessarily find themselves completely and totally cured of tuberculosis – many of them are likely to reactivate. Furthermore, having the disease does not confer protection against subsequent disease so that even those who are cured from their disease are likely to become infected again if they are in high incidence areas and are exposed to the bacilli again. Finally, the BCG vaccine does not prevent transmission, and consequently we have no strategy to protect against infection or be relevant to disease in MTB-infected persons.

“The TB elimination strategy has relied on the idea that we will have vaccines to protect against TB, but this has been lagging behind due to the complexity of the problem,” said Prof Kaplan. “And what we have learnt recently in the last few years has actually shown us that our assumptions, our beliefs – or the basis upon which we have conducted both our research, and our interventions – might be suboptimal.”

Beliefs that underlie our current approach to TB disease and MTB infection

Prof Kaplan described four examples of assumptions about TB pathogenesis that appear to be mistaken.

The first is the idea that MTB is a uniform organism. Under a microscope TB, bacilli all look the same, and “the assumption amongst scientists for many years has been that MTB, is MTB is MTB,” said Prof Kaplan.

However, recent animal model studies suggest this is not the case. For instance, if mice are infected by different, clinical isolates of MTB, they die at different rates. Similarly, some strains have been shown to lead to progressive cavitary disease in rabbits that ultimately die of tuberculosis, while rabbits infected with other strains can control the infection and actually establish latency, very reminiscent of the diversity seen in humans with different manifestations of disease.

Prof Kaplan believes this may be relevant to humans as well. For instance, recent studies have found that different clinical isolates are associated with different disease manifestation seen in human populations — with some strains more likely to be associated with pulmonary disease and other, TB meningitis.[1]’[2]

The next assumption, that infection and disease are a binary state regards the understanding of the natural history of the disease.

“The dogma which has guided us in research and in treatment has been that among those infected with Mtb, about ninety to ninety-five percent that are infected will show signs of the infection, [as evidenced by conversion of their tuberculin skin test (TST) response] and yet will not develop disease. They will be latently infected but will not have any signs of pulmonary disease or extra-pulmonary disease when examined clinically,” said Prof Kaplan. “The other five to ten percent of those who are infected, on the other hand, will actually develop signs and symptoms associated with active disease. We need to understand and compare these as we move forward in developing new interventions and control of the disease.”

Recent results have suggested that there is a whole spectrum between exposure and disease however.

–       Those that are exposed who never become infected;

–       Those that are exposed, become infected and do not develop disease;

–       Those that are at the cusp of progressing from infection to disease, and are the ones that are going to become infectious within a few months; and

–       Those who have active, clinical disease.

If we could identify the individuals who are infected and are just about to progress to becoming infectious — making sure they are promptly treated would reduce the extent of disease and reduce the chances that others in the community would be exposed to infectious MTB.

“But we don’t know how to identify these people who have no clinical signs [of TB],” said Prof Kaplan. There are probably changes in the immune responses prior to the TB activating but further research is needed to better understand the immunologic state of individuals along the spectrum of TB infection.

The third assumption concerns how a vaccine could protect against primary MTB infection and block progression from infection to active disease — by inducing gamma-interferon expression. Vaccine candidates have been chosen for their ability to induce CD4 cells to express gamma-interferon, which is believed to trigger immune responses of controlling and potentially even killing the bacilli.

However, the results of the most recent large vaccine study — of the TB vaccine candidate MVA85A in 2,797 infants in the Western Cape province of South Africa — seem to call that into question. The vaccine showed modest improvements in the immune response, but failed to protect against MTB infection.

Professor Kaplan recalled results from a smaller vaccine study that she and colleagues initiated over ten years ago. In the study, they vaccinated neonates with BCG and then examined the immune response of these neonates, asking: ‘Is T-cell activation associated with control of infection, when those neonates are exposed?’ Could they measure T-cells, and predict which child will not develop TB?

“We were actually flummoxed by the fact that this assumption was incorrect,” she said. “The babies that developed disease versus the babies that did not develop disease – had similar levels of activated CD4 cells, expressing not only gamma-interferon but also inducing other hormones of the immune response that are considered protective. Now that means that our entire assumption for what protects against TB, was wrong.”

“This is really serious because we have used those assumptions to select for candidate vaccines for the last twenty years. And maybe we have selected the wrong candidate vaccines and thrown out the good candidate vaccines because they didn’t induce the response we assumed would be protective,” she said. [A silver lining in this is that there may still be hope for some of the vaccines that were passed over.]

The final assumption has been that the level of drugs in the blood – or in the plasma – equals the level of drug that the infecting Mtb organisms are exposed to. Once again, however, recent studies suggest that this may not be the case. MTB organisms are generally in the lung or walled up in granulomas (scar-like nodules actually composed of cells of the immune system) in the lung that are where the bacteria can actually persist.

“But most of our drugs – pyrazinamide, isoniazid and rifampicin – are actually not reaching the concentrations that we thought they should reach, to kill the bacteria within the lung or within the lesions. That means is we have to think in a much more sophisticated way in how we treat tuberculosis, how we combine the drugs and what dose we use,” she said.

This could be why it takes so long to cure the infection.

But something similar is true of the new drug, moxifloxacin, which reaches high concentrations in the lung, and is being studied as a way to shorten the course of TB treatment. It gets into the lung and into the cellular component of the granuloma, but study now show it doesn’t seem to get into the centre of the granuloma – where most of the organisms are.^[3]

“So obviously we are going to have to understand much better what happens in tuberculosis lesions; how are we going to reach the organisms and kill them; and what drugs are going to be able to do that, in different parts of the infected lung,” she said.

Current threats and opportunities

Prof Kaplan isn’t certain that TB control will simply improve —there are a number of factors today which could make the epidemic much more difficult to manage than the epidemic that was seen in Europe at the end of the 2nd World War or in Alaska or Canada where TB interventions were so successful in the past. Overcrowding, poverty, more mobile populations and an enormous amount of migration could increase the spread of TB. In addition there is HIV, an epidemic of non-communicable diseases such as diabetes that increase the risk of TB, and spreading drug resistance — which interferes with the treatment of tuberculosis, and requires new drugs and a much longer treatment regimens.

But there is also good news:

“First of all recent advances have better positioned us to tackle the TB epidemic,” said Prof Kaplan, noting the following.

In terms of infrastructure, the standard of living in many low- and middle-income countries is improving.

There is also a consensus on healthcare as a human right that is emerging or established in many countries. There is concern in particular about tuberculosis reflected in awareness and in policies — with WHO’s normative guidance being adopted more broadly. There is also a push to include healthcare rights as a condition to attract trade and investments.

“Countries that have severe disease problems are not going to be so popular,” she said, adding that investors may stay away “if they’re concerned that the labour force may not be very functional because of infectious diseases.”

There is a greater capability in resources to support research – not only in the 1st world, but throughout the world. New research tools, and increased multi-disciplinary collaborations have made research much more feasible.

“From a technology point of view: We have a systems biology approach which enables us to examine the entire response of an individual, the entire response of the blood, the entire response of the lung/s [through] infection and disease. We have management of large datasets possible today; and we’ve actually been able to miniaturize diagnostics to make them much more feasible, and easy to translate into practice. Consequently, rapid and targeted analysis of large quantities of samples and data are possible. Modelling to design more robust experiments and trials has become common; and scalable and cost-effective technologies that are appropriate to resource-poor settings, are now available.

So what next?

“There are two important issues we need to address. One, we need to address the persistent transmission of MTB as a primary problem. New individuals are being infected every minute, as we sit here and discuss this. Two, we also have to address the progression from infection to disease which is our secondary problem because it doesn’t really matter how many people are infected – what really matters is how many people develop disease and continually infect others,” she said.

But Prof Kaplan noted that TB research is sorely underfunded. “Although tuberculosis has claimed a much higher number of lives, and still continues to do so, the amount of money spent on tuberculosis has been much, much smaller than on TB or malaria, she said. “Not to suggest that we spend less on HIV or malaria, but rather that we need to spend more on research and the control of tuberculosis.”

Funding priorities have lagged relative to the morbidity and mortality of tuberculosis

Tuberculosis has led to more deaths in the last 200 years than any other infectious disease…	…but has received significantly less funding in the last 10 years, as compared to HIV and malaria*
1,000,000,000 Tuberculosis deaths	US $  7 Billion Global Funding
30,000,000 HIV/AIDS deaths	US $43 Billion, HIV/AIDS Global Funding

Based on OECD and IHME Development Assistance for Health (DAH) funding dataSource: Global Tuberculosis Report 2012, WHO (2012), Nature Vol. 502, No. 7470 Suppl. S2 (2013), Financing Global Health 2012, IHME

Prof Kaplan said research needs to develop transformative interventions that simultaneously target multiple disease life cycle breakpoints, and that the way to do  this is to create cross-disciplinary teams to contribute to outcome-oriented science research.

“This is not about academic research for research sake. This is about harnessing the intellectual and academic capability of all of those communities that are involved in TB research and then getting them to work together with vaccine development, drug development, diagnostic developments, epidemiology survey and operational research focusing on stopping infection, stopping transmission, stopping the epidemic rather than merely treating those who are infected and have the disease today,” she concluded.