Malaria Research Foundation
| Introduction |
Why isn’t there a vaccine for malaria? There are vaccines for smallpox (since 1796!) diphtheria, hepatitis, influenza, encephalitis, measles, mumps, polio, rubella, typhoid and yellow fever, so why not for malaria? Why do malaria vaccines work well in the lab but always prove ineffective in field trials? This problem has baffled scientists for decades and has been the major roadblock to malaria eradication. Ground-breaking thinking and research has now removed this barrier. The scientific and practical implications of this work are profound. How did all this come about? In late 2005, Dr. Lys Guilbride, an immunologist, molecular biologist and old friend, phoned to say she had figured out why malaria vaccines fail in the field. The idea was very simple but radically opposed to established thinking. Novel ideas are hard to fund and applying for conventional research funding from a government or a foundation normally takes many months, particularly for a new voice in a field. Lys needed to prove her hypothesis quickly. One million babies die of malaria each year; that's a person every 30 seconds! Who could say anything but 'start your research and we'll find the funds, somewhere'! It took Lys and an assistant until the end of 2008 to prove the basic idea was right. Their work used the latest molecular and cellular immunobiology and computational analysis facilities at the German Cancer Research Center (DKFZ) in Heidelberg. It took until now, to confirm their experiments, write up and get the current paper published. Four years of intense effort! One part of their research identifies, from the blood of people previously infected with malaria, the cells thwarting the vaccines and also replicates the vaccine-blocking function in the laboratory. This did not happen in blood from people who never had malaria parasites in their skin, just as predicted by the model. This (ex vivo) characterization of the basic immunological mechanism will be published by Dr. Guilbride in the coming months. As a stringent (in vivo) test of the model, they carefully re-analyzed the results of 1,916 previously published vaccine trial experiments. Meta-analysis results (conducted on all experiments showing full protection) confirmed their model in live animals and people in every case. They now knew why vaccines failed! Live malaria parasites in the skin inhibit vaccine function. This means we can now work around that block to make a vaccine that works in the field. The Malaria Research Foundation was able to fund this vital research thanks to the generous support of some dear friends. Without them, scientists today would still be scratching their heads about why their malaria vaccines keep failing in the field. Our heartfelt thanks go to each of our donors. The benefits of this research go far beyond malaria. Malaria and cancer are caused by very closely related kinds of immune malfunction. Lys and her team are also applying their research on malaria to obtain insights in the fight against cancer and autoimmune diseases. Sincerely, The Malaria Research Foundation Press Release - 19 May 2010 Enigma of malaria vaccine failures solved Newswise - Why one after another new malaria vaccine tests well in the laboratory but fails in field trials has frustrated legions of malaria researchers, and has been the main stumbling block to malaria eradication. Now, a research team from Germany has unraveled that puzzle and shown that the problem is all about the skin and how it controls the immune system. The implications are profound. Publishing in the current issue of PLoS ONE, an open-access, peer-reviewed journal, the researchers show that a suppressive immune response to live malaria parasites in the skin is the unavoidable result of a malaria-infected mosquito bite. People who have already had live parasites in the skin will have a ready-made suppressive response to any vaccine antigen. "In these people, vaccination induces further tolerance, not immunity," explains D. Lys Guilbride, PhD, the study’s lead author. How did Dr. Guilbride and her co-investigators, Pawel Gawlinksi, PhD and Patrick D.L. Guilbride, MRCVS, reach this conclusion? "While doing research on malaria, I was reading literature about cancer immunology and regulatory T cells which shut down the immune response,” she recalls. “I saw that these mechanisms applied well to malaria vaccine problems, but couldn’t see exactly how the parasite made it happen." When attending a cellular biology seminar on parasites in the skin, it suddenly dawned on her where - and exactly how - the malaria parasite must be switching off or subverting the immune system by making regulatory T cells. It was in the skin and the skin-draining lymph nodes. "To prove my hypothesis of parasite-triggered, skin-initiated blocking of immune responses to malaria, we needed to isolate the regulatory T cells involved," she explains. "Then we needed to test the model with bigger experiments in animals and people to confirm that these cells acted via the skin to block vaccines, the way the model predicted." After identifying the cells involved, the research team compared their model with the results of hundreds of previously published experiments investigating vaccine protectivity. This procedure was more stringent than comparing it to only one experiment of their own. Out of 1,916 malarial immunization studies carried out between 1965 and April 2010, a careful meta-analysis of all 177 experiments that showed complete protection proved their hypothesis perfectly – that live malaria parasites in the skin shut down immune responses and block vaccine function. "Since malaria is transmitted by mosquito bite, this means that malaria vaccines are inevitably thwarted by an immunosuppressive response set off by the pre-existing effects of an early malaria infection in the skin," she notes. Most laboratory-based experimental infections, however, bypass the skin entirely. In this case, responses to malaria antigens do not get shut off, and so behave protectively in the lab tests. As a result, these antigens get selected as vaccine candidates, but fail in field trials, because there - unlike in the lab - most people already have the parasites in the skin. "This also explains why vaccines that are partly effective in those who are malaria-naïve - such as infants - do not work in those who have already been infected with malaria. These pre-infected people already have set up a skin-initiated suppressive immune response to vaccines," concludes Dr. Guilbride. According to Dr. Guilbride, the critical immune effects of the skin stage have been overlooked until now because that stage of infection is very rapid, does not involve parasite amplification, and does not create clinical symptoms. The findings force a reassessment of the precepts for malaria vaccine development. "Since we now know why vaccines keep failing, we can now redirect our efforts in a totally new direction to make a vaccine that will work well in the field,” she explains. “This knowledge, this new understanding of what was preventing vaccines from working, resolves the logjam and lets us address the problem specifically." Malaria remains a killer of children and adults worldwide. According to the April, 2010 report from the World Health Organization for World Malaria Day, 2010, the most endemic area of the world for malaria continues to be sub-Saharan Africa. The disease has an especially high mortality rate for children. Malaria statistics are stunning. World wide, one million babies die of malaria annually. Nearly three billion people are at-risk for getting malaria. In Africa, 20 percent of childhood deaths are from malaria. What are the immediate benefits of this research? Changes in vaccination protocols and trials - such as vaccination before infection and avoiding induction of skin-stage immunosuppression - will save countless lives because it will optimize current vaccine function in the short term. Too, the realization that discarded vaccines may find new usefulness when used to vaccinate uninfected individuals (particularly newborns) since even if in the past vaccines failed in adults in endemic areas they should work better in infants who are protected against mosquito bites from birth. Third, it will reveal an important new use for chloroquine: to block the immunosuppression triggered by the parasites in the skin. This allows vaccines to work better. Since chloroquine is well tolerated and can be transmitted to babies via the mother’s milk, it is easy to give, well tolerated, and provides further strong protection against skin-initiated immunosuppression, allowing protective immunity to develop, especially when given along with vaccines. Additionally, chloroquine is inexpensive, so it is realistically accessible to those who need it long-term. Importantly, these findings will redirect the rational focus of malaria vaccine research to prioritize specific and more productive avenues away from unproductive paths. Where to go from here? According to Simon Pinniger, director of the Malaria Research Foundation which sponsored the research, “Explaining this conundrum should make the hundreds of millions being spent each year by the U.S. government, the Gates Foundations and many others, much more effective. It will bring the eradication of malaria a big step closer.” Contact: D. Lys Guilbride Or: Simon Pinniger Scientific Paper - Released 19 May 2010 'Why Functional Pre-erythrocytic and Bloodstage Malaria Vaccines Fail: A Meta-Analysis of Fully Protective Immunization and Novel Immunological Model" published in PLoS One
Simon Pinniger, Lys Guilbride, Carolyne Roehm Briefing on the Malaria Project
What is Malaria? In humans, the parasites are first deposited into the skin by an infected mosquito bite, and quickly invade the blood vessels and travel to the liver. The parasites grow and multiply first in the liver cells and then in the red cells of the blood. In the blood, successive broods of parasites grow inside the red cells and destroy them, releasing daughter parasites that continue the cycle by invading other red cells. The blood stage parasites are those that cause the symptoms of malaria.
When certain forms of blood stage parasites are picked up by a female Anopheles mosquito during a blood meal, they start another, different cycle of growth and multiplication in the mosquito. After 10-18 days, the parasites are found as "sporozoites" in the mosquito's salivary glands. When the mosquito takes a blood meal on another human, the sporozoites are injected with the mosquito's saliva into the skin and start another human infection cycle when they parasitize the liver cells. Humans infected with malaria parasites can develop a wide range of symptoms ranging from no apparent illness, to the classic symptoms of fever, chills, sweating, headaches, muscle pains, to severe complications of cerebral malaria, anemia, kidney failure that can result in death. The severity of the symptoms depends on several factors, such as the species (type) of infecting parasite and the human's acquired immunity, genetic background, nutritional state and general health status.
Malaria is endemic in 106 countries in sub-Saharan Africa, Asia, the Middle East, Central & South America, and Oceania. It occurs mostly in poor, tropical and subtropical areas of the world. The area most affected is sub-Saharan Africa, where an estimated 90% of the deaths occur. This is due to a very efficient mosquito vector (Anopheles gambiae), which assures high transmission, and the predominant parasite species (Plasmodium falciparum) that causes the most severe form of malaria.
How does malaria affect people's health?
What is the social and economic toll of malaria? Malaria imposes substantial costs on both individuals and their families. These include constant purchase of drugs; expenses for travel to, and treatment at, dispensaries and clinics; lost days of work with resulting loss of income; expenses for burials in case of deaths and expenses for preventive measures. Malaria illness and death cost Africa approximately $12 billion a year in lost productivity. Malaria imposes substantial costs to governments. These include maintenance of health facilities; purchase of drugs and supplies; public health interventions against malaria, such as insecticide spraying or distribution of insecticide-treated bed nets; and lost opportunities for joint economic ventures and tourism. Such costs can add substantially to the economic burden of malaria on endemic countries and impede their economic growth. Back To TopHow is malaria being ‘controlled’ today? Not well. Governments and multilateral institutions have fought a losing battle for many years to control malaria. These efforts are a ‘non-stick’ Band-Aid at best -- but not a solution. Malaria control does not aim to eliminate malaria totally. Complete elimination of the malaria parasite (and thus the disease) would constitute eradication. While eradication is more desirable, it is not currently a realistic goal for most of the countries where malaria is endemic.
The people most exposed to malaria are often poor and lack education. They often do not know how to prevent or treat malaria. Even when they do know, they often do not have the money to purchase the necessary drugs, bed nets or sprays.
Why isn’t there a good malaria vaccine? Then why isn’t there a good vaccine for malaria or tuberculosis or HIV that together kill 6 million people a year? This question has baffled the world’s best scientists for many years. A vaccine is a substance that causes the immune system to develop responses that protect against a specific disease. A good vaccine would be safe; easy to manufacture; easy to administer; and, when administered in infancy, confer life-long immunity against all forms of the disease. This ideal is rarely achieved and even some of the best vaccines, such as tetanus, must be given repeatedly throughout life to maintain immunity. In practice, most vaccines do not actually prevent infection, but instead enhance the immune system to limit the pathogen's ability to cause disease. The vaccine stimulates antibody and T cell responses that can respond quickly to the infection and prevent the invader from causing serious disease. A good malaria vaccine would prevent all infection by priming the immune system to destroy all parasites, whether free in the blood, while in the liver, or even while in red blood cells. Many in the scientific community believe this degree of protection would be extremely difficult to achieve and might not be technically feasible with current vaccinology art and science. At least 90 teams around the world are working on some aspect of a vaccine, commonly targeting one of three phases: pre-erythrocytic vaccines, blood stage vaccines, or transmission blocking vaccines. All three types have been tested in people, and some have shown promise. The optimal malaria vaccine likely will combine antigens from all three stages of the malaria parasite’s life cycle. Getting there will involve complex studies in the laboratory and in the field to prove that the antigens and the immune responses do not interact in an undesirable manner. Many single-antigen malaria vaccine candidates are being readied for clinical trials, and combination studies are being planned. The vaccine apparently closest to public release, developed by Glaxo-SmithKline in collaboration with the US Army is called RTS,S. In a recent trial in Mozambique it reduced the incidence of malaria in children by only 29% relative to the control group and the vaccine was effective for about 18 months. Protecting a third of the population under clinical trial conditions for a matter of months is not the panacea that it so desperately needed. In ‘real life’ conditions, most poor, rural families would be unable to travel to and pay a facility to administer the vaccine for an entire family or a regular basis. These people live on a dollar a day. While many vaccines have been shown to be safe to administer, and appear to be effective in the laboratory, field trials have been disappointing: the vaccines are not protective, are poorly protective, or are reasonably protective for a very short time, two to three months, or in case of RTS,S, protect only some of the people for some time. The critical question is why do these promising formulations not work well? Dr. Guilbride has now shown why. What’s different about the research we are funding? Dr. Guilbride’s research was not to develop a malaria vaccine – it was to demonstrate why vaccine formulations work in the laboratory but don’t provide adequate protection in the field and how vaccines could be made to work. Four years ago, Dr. Lys Guilbride was at the Centre for Molecular Biology at the University of Heidelberg (ZMBH) and the German Cancer Research Center in Germany (DKFZ) working on a T cell based malaria vaccine research project. Whilst attending a seminar describing where malaria parasites go after a mosquito bite, she realized exactly how the parasite was acting to switch off malaria vaccines. Her hypothesis was both radical and simple. The German Cancer Research Center recognized the scientific merit of it and offered her scarce research space and equipment – but they did not have an authorized budget for her salary. The Malaria Research Foundation immediately offered to fund her salary and expenses. A human’s immune system is set to ignore activation by self-antigens. In other words, healthy humans don’t react against their own tissue, only against foreign or pathogenic invaders, or cells infected by these. Dr. Guilbride hypothesized that by pretending to be self, the malaria parasite is ignored by the body’s immune system, and that it did this by subverting the immune regulatory mechanism, which normally allows us not to react (that is, to be immunotolerant) to self-antigens. Starting July 2006, Dr. Guilbride conducted initial experiments to ‘investigate the CD4+, CD8+ and Treg (regulatory T cell) response of the human body to the malaria parasite and to assess the existence and role of early onset regulatory T-cells in the development of tolerance to malaria. These (ex vivo) data address ‘proof of principle’ and validated her hypothesis. She then verified these data by testing the predictions of the model against all available published experimental results from live vaccine trials. This stringent procedure confirmed the hypothesis, supported by initial laboratory data, in 100% of cases (177 experiments, to be exact). Once the scientific community learns why malaria vaccines don’t work, it will be able to focus its efforts on working around this problem. This research could make the huge effort by the US government, The Bill & Melinda Gates Foundation and the many other fine NGO's seeking an end to malaria, much more effective. Existing malaria vaccines, which have been shown to be safe but non-effective could be re-used in a ‘tweaked’ immune setting, allowing the vaccination formulation to really protect. This would drastically reduce time (and cost) taken to reach an effective vaccine, and could potentially ’activate’ many currently discarded formulations. A second potential spin-off would be a screening method to determine which vaccine would be the most effective on a particular individual, given his particular Treg response profile. This could greatly improve the cost-efficacy of government vaccination programs, once in place. This diagnostic concept would also be applicable to other immunotolerance/evasion conditions, such as cancer metastis. Dr. Guilbride’s research also has application on the Treg-based immune mechanisms involved in the body’s unwanted tolerance to cancers, and in autoimmune diseases like MS, since the same basic immune regulatory mechanism is subverted (and does not respond, as in malaria or cancer), or is dysregulated (and attacks what it should not, i.e. self, as in MS), to cause these diseases. A similar number of people die of lung cancer and tuberculosis each year as die of malaria. Malaria is a powerful model for studying cancer. Many of the immunological malfunctions supporting malaria and cancer are shared between the two diseases. Practically, also, malaria antigens (molecules that stimulate an immune response) are identifiably foreign to our bodies, and so are very useful as defined tools to trigger and study the antigen-specific immune responses of CD4+, CD8+ and Tregs. In cancer, the cancer-antigens are very difficult to distinguish from our normal repertoire of self antigens, making it difficult, expensive and slow to define and elicit cancer-specific immune responses for study. We can use the malaria system to study the same immune responses. A further spin-off of the research is the expansion of antigen-specific Tregs in vitro, which has potential for therapies aimed at autoimmune disorders like MS, or arthritis or hay fever and clinical complications like graft rejections. 1 - Expand the Research. 2 - Translate Dr. Guilbride's research into a functional vaccine and/or functional therapies. 3 - Use this malaria research as a model to study cancer. 4 - Explore the expansion of antigen-specific Tregs in vitro. Dr. Lys Guilbride is British, was born in Uganda and grew up in East Africa and South America. Her parents worked for the United Nations. Her paternal grandparents died in Kenya and maternal grandparents were from Australia and Jamaica. She has had malaria in her blood for generations. She has a B.Sc. (Hons.) degree in Genetics and a Ph.D. in Molecular Genetics, both from the University of Glasgow. Dr. Guilbride is an independent scientific investigator with an unusual research background in DNA replication and structure, molecular parasitology and cell biology and human T cell immunology, with a previous interest in the role of Tregs in blood stage malaria. From 1993 through 1998 she worked as a post-doctoral researcher in the Department of Biological Chemistry at The Johns Hopkins University School of Medicine. Shortly after starting at Johns Hopkins she was visited by a childhood friend from Mozambique, who suffered a severe malaria attack upon his arrival. After recovering from that bout of malaria, he introduced Lys to Simon and they have all stayed friends ever since. After Johns Hopkins, Dr. Guilbride was invited to work in Brasil (Escola Paulista de Medicina) and the Czech Republic (Faculty of Biological Sciences) as a visiting scientist. In 2002 she moved to the Zentrum für Molekular Biologie-Universitaet Heidelberg (ZMBH) in Germany as a post-doctoral project leader on RNA processes in trypanosomes and then worked as a research associate on developing a T cell based vaccine against blood stage malaria antigen MSP1. It was at this point, January 2005, she had her ‘epiphany’ and realized the research she (and everyone else) was doing was on the wrong track. Dr Guilbride discussed her ideas with experts in T cell immunology, at the German Cancer Research Center (DKFZ) also located in Heidelberg. They thought her radical hypothesis on why malaria vaccines aren’t working had scientific merit but didn’t have funds budgeted for additional research. They did however offer to provide laboratory space, equipment and to peer review her work. This was a highly unusual offer. In December ’05, she telephoned Simon in a very dispirited state to say that she had had an ‘epiphany’ but her contract with ZMBH was ending at the end of the month, that it could take months for her to re-establish herself at another research institution and many more to apply for and receive a research grant to prove her hypothesis – all the time 5,000 a day, 80% kids, may be dying needlessly. Knowing Lys and her commitment to finding a solution to malaria, Simon suggested she focus her efforts on her how to prove her hypothesis and to leave the funding issue to us. Dr. Guilbride then moved to the DKFZ facilities and with the sponsorship of the Malaria Research Foundation, worked full time for three years to ‘investigate the CD4+, CD8+ and Treg response of the human body to the malaria parasite and to assess the existence and role of early onset regulatory T-cells in the development of tolerance to malaria’. Biological research is incredibly complex and frustrating and often, unfortunately, highly political. Billions of dollars are spent on scientific research each year and there is still no cure for the common cold! Without any guarantee of success but with great faith in Dr. Guilbride’s professionalism and dedication, we believed that sponsoring her research was well worth the risk. Fortunately, professionally conducted research always yields valuable information, although not always what was anticipated. In this case, we achieved what we set out to do: Dr. Guilbride solved the enigma of why malaria vaccines fail in the field. What is the Malaria Research Foundation?
Why not approach organizations like the Gates Foundation? We could have applied to a philanthropic organization like The Bill & Melinda Gates Foundation to fund the research but not knowing if the initial phase would take less than a year we elected to start the research immediately. Every hour spent preparing a grant proposal, every hour spent evaluating the proposal and every hour spent implementing the provisions of a research grant, another 120 people (mostly kids) would die. Funding specific scientists doing a specific line of research that showed great promise has been very exciting and we highly recommend it. The next phase of the research will require resources and facilities bigger than the Malaria Research Foundation could fund and in order not to lose precious time, we will apply for more conventional funding. “Vaccines have transformed the entire world by eradicating smallpox, and have largely rid the developing world of polio and measles.” “And no one anywhere gets routinely and effectively immunized against the big global killers – HIV, tuberculosis and malaria, which together take 6 million lives each year – because, even with all the technological prowess of modern medicine, good vaccines for these diseases do not exist.” “MALARIA VACCINE IS NEAR” “EFFORT TO FIGHT MALARIA APPEARS TO HAVE FAILED” “In its ability to adapt and survive, the malaria parasite is a genius. “The world needs ideas so novel “Novel ideas should not have to fight so hard for oxygen” |
