Director and Scientific Member at the Max Planck Institute for Infection Biology, Berlin
Breaking the Wall of Unequally Distributed Diseases. How Immunology Can Contribute to One Healthy World
In April 2009 a new pathogen emerged: the swine flu virus, officially termed pandemic influenza H1N1 2009. As of November 2009, 500,000 cases have been counted worldwide and about 6,000 deaths. Yet, the pandemic was received with great vigilance, and necessary measures were initiated immediately. Seven months later, we already have a vaccine. Almost 6,000 deaths have been caused by swine flu thus far, slightly more than 0.1% of the 5 million deaths caused by the major plagues HIV/AIDS, malaria, and tuberculosis (TB) every year.
A threat, but is it the iceberg, or is it the tip of the iceberg? Let’s talk about pandemics of the past, present, and future. The three major pandemics, HIV/AIDS, TB, and malaria, mostly afflict people in the developing world who are stricken by poverty. Hence, they are diseases of inequality. They afflict the poor far more than the rich. Let us focus on the example of TB today. Nine million people developed TB disease last year; every 5 seconds one person falls ill. About 2 million people died; every 20 second someone dies. This is happening year after year, decade after decade, and century after century. Hence, TB is more than a pandemic. It is both spatially and temporally non-restricted. TB anywhere is TB everywhere. This is, however, also a major drawback of TB. We have lived with this situation for centuries. We have gotten used to it. We have become complacent.
One more figure, one third of our global population is infected with the TB bacillus. This is actually interesting. Two billion people are infected, but only 10 million new cases develop. In TB, only 10% of those who are infected indeed develop disease. All others remain healthy, but latently infected. Their immune system controls the pathogen and prevents disease outbreak, but it fails to eradicate the pathogen. Thus, in one of the most devastating diseases of past and present, the immune system is actually highly efficacious in the vast majority of infected individuals and protects them. This is an important lesson. We can learn how the immune response controls infection in these healthy individuals. There is hope – we can learn how to rationally design a vaccine to prevent TB and how to rationally design biomarkers to diagnose TB.
Why is TB such an enormous threat? Don’t we have drugs? Don’t we have a vaccine? Let’s look back to the past for a moment. One hundred and twenty-five years ago, exactly in Berlin, about 50% of all deaths were caused by TB, which was referred to then as the “white plague”. Actually, 125 years ago was also the most active time of TB research ever. Here in Berlin in 1882, Robert Koch not only described the etiology of TB but also performed the first diagnostic test. Thirty years later, between 1906 and 1920, the French scientists Albert Calmette and Camille Guérin, developed the live attenuated vaccine bacille Calmette-Guérin, in short, BCG. In the 1940s, the US scientist, Selman Waksman described the first drug, streptomycin. Until the 1960s and 1970s, numerous TB drugs were developed.
This was promising, but afterwards things unfortunately became quiet, very quiet. Thus, in 1989 when the Wall came down, the industrialized world considered TB history. We forgot the developing world. We forgot HIV/AIDS, which has become the driving force of the re-emergence of TB.
Today, we still use the diagnostic test developed by Robert Koch in the 19th century, we still use the vaccine developed in the early 20th century, and we still use the antibiotics developed between the 1940s and 1970s. Clearly this is insufficient. The diagnostic sputum test fails to correctly diagnose TB in about half of all patients. BCG protects toddlers but not their parents, and is ineffective against the most prevalent form of disease: pulmonary TB in adults. Rising incidences of multidrug- resistant (MDR) and extensively drug-resistant (XDR) TB render therapy a serious problem. In fact, XDR-TB cannot be treated with currently available drugs, and this is often a death sentence, even in developed countries. Today, 50 million people are infected with multiresistant TB. Many of them live in Easter European countries, including Members of the EU.
The embarrassing conclusion to this story is that our inability to control TB today is the result of our complacency over the last 40 years. Change is urgently needed but we must be mindful that even if we increase our research efforts today, new medicines for TB patients will only become available in a decade or so.
Industry incentives alone are insufficient for developing new TB medicines. New partnerships are urgently needed between public and private domains. As a Max Planck Institute, we are dedicated to our philosophy of excellence in science. Nothing can compromise the quality of our research. But, we also attend to the needs of society. Nothing can compromise the issues we target. We analyse the problem, not the model. We have exploited basic immunology for the design of rational vaccines and biomarkers, because we are convinced that science can make a difference.
Our body has a specialized organ that fights invading pathogens: the immune system. Macrophages monitor our body and engulf and kill invading pathogens. The TB bacillus hides in these macrophages. Therefore, the pathogen evades the immune response. Lymphocytes also scan our body. They recognize pathogens in a highly specific way. B lymphocytes recognize pathogens directly, and then produce antibodies that fight pathogens. T lymphocytes do not see pathogens directly; they recognize the infected cell. In our case, this is a macrophage harbouring the TB bacillus. T lymphocytes, therefore, are the prime target of novel vaccination strategies against TB.
We have generated a vaccine that induces a qualitatively and quantitatively better T lymphocyte response against TB. Our vaccine induces profoundly better protection against TB than the current BCG vaccine. Actually, our vaccine construct is a genetically modified BCG. Recall that the BCG available today is a live attenuated vaccine, which protects children, but not their parents. BCG is recognized suboptimally by the immune system, because it hides within host cells. By genetic modification, we made the new recombinant BCG vaccine more visible for T cells.
This is where we stand today: The vaccine is efficacious; the vaccine is safe. Required safety level approval has been achieved as a prerequisite for use in humans. Large-scale production, according to good manufacturing practice has also been accomplished. The vaccine is licensed to Vakzine Project Management, which sponsors a phase I clinical trial with human volunteers that started summer 2008. The vaccine trial looks extremely promising.
Our vaccine is aimed at replacing BCG. Other vaccine candidates in the field are aimed at boosting BCG. In other words, they are given on top of BCG. These are subunit vaccines, which comprise one or two antigens. Importantly, the most profound effects are expected from combinations of the best prime vaccine, perhaps our recombinant vaccine followed by a boost with the best subunit vaccine. Creation of the best combination vaccine, however, is a long-lasting endeavour.
It can take decades before a combination vaccine has completed its passage through the pipeline of clinical trials. Can we accelerate this process? We believe we can. For this, we need biomarkers. What does this mean? A biomarker reflects a biological process, for example, the cause of infection and disease in TB. Hence, it can predict vaccine efficacy. That is, it can show us early in a clinic trial whether a vaccine is efficacious, and thus whether it protects against TB disease.
We have embarked on a biomarker project that is supported by the Bill & Melinda Gates Foundation. In our Grand Challenge project, we have combined forces with seven partners in Africa; two in South Africa, one in Malawi, one in Uganda, two in Ethiopia, and one in The Gambia. In addition, seven partners from the US and from the European Union have joined forces. Our underlying rational is that an understanding of the host response, which sustains health in contrast to disease, will lead to the rational design of biomarkers for vaccine trials. Recall that more than 90% of those who are infected will never develop TB disease and only about 10% will develop active TB disease.
What do we actually do? Let me briefly explain. First, the human genome comprises about 30,000 genes. Of these, a handful of genes are differentially activated in healthy infected individuals and patients with active TB disease. They can, and are being used as biomarkers of disease and healthiness. Second, our blood is full of small molecules, which stem from metabolic processes, from either the pathogen or host. This is the metabolome. We can use these small metabolites for biomarker discovery. Third, we have identified a group of antigens of the TB bacillus that are specifically recognized by the immune system in patients with active TB disease but not in healthy individuals. We do not believe that a single biomarker can do the job. Rather, a tailor-made biosignature will be used, comprised of a number of the best biomarkers in the different areas.
This is our central study. At the different African sites, individuals are diagnosed with active TB. Household contacts of these patients, who live together in close contact, are followed over 2 years. During this time, several thousand household contacts will have become infected. After 2 years, about 5% will have developed disease, and 95% will remain healthy. During the 2-year study, blood is drawn at different time points. We interrogate the blood samples for markers, which could protect the 95% from TB disease. Based on this, we can design a custom-made biosignature.
Our research activities bring a product, namely, a new TB vaccine candidate from academic research into clinical trial with our partner Vakzine Projekt Management, which is support by the German Ministry of Science and Technology. Our biomarker studies are supported by the largest foundation in this field: the Bill & Melinda Gates Foundation. Attracting private companies in this endeavour will be an essential next step to secure further development of our products. Basic research is particularly needed for diseases of low interest to the private sector. These are the diseases which unequally burden people in poor and rich countries. TB is one of them.
It is true, funding for TB is better than ever before. Today, half a billion US dollars is funnelled into different aspects of TB research and development globally. Yet, we need to increase our research funding to about 2 billion US dollars annually. “Quite a lot”, you may say. I would call it a bargain. Why? The cost of treating all TB cases on this globe, that is, the cost of drugs alone, already amounts to about 2 billion US dollars. The total cost adds up to about 20 million dollars, if you include all additional costs, such as care, lost time at work, etc. Therefore, research over the next 10 years will cost about 20 billion dollars, and this sum represents the loss of financial resources caused by TB every single year.
Treatment and prevention measures for TB are based on research done 50 to 125 years ago. We need to build the basis for medicines today that will be produced in the next decades. Just as Berlin’s falling walls paved the way for an equal Germany 20 years ago, the walls of inequality must fall so that diseases of poverty receive equal attention and empathy in the next 20 years.
Let me end by acknowledging the photographer Jim Nachtwey, who stated, “I have been a witness, and these pictures are my testimony.” He has given a face to the disease I am talking about, TB. Thank you.