Close-up on research

In the Battle Against Malaria

By Silke Weber

The molecular biologist Francine Ntoumi established independent malaria research in Africa and is now involved in developing a promising vaccine against this tropical disease.

Francine Ntoumi
Francine Ntoumi (Photo: David Matthiessen)

No more than just six millimetres long: the anopheles mosquito is slight and self-effacing. But when the little creature bites, it transmits one of the deadliest diseases in the world: a person dies of malaria every twelve seconds. The fact that so many people die as a result of a mere mosquito bite is “one of the greatest tragedies of the 21st century” according to Margaret Chan, Director-General of the World Health Organization (WHO).

For Francine Ntoumi, it is not just a tragedy but, rather, a challenge and the motivation to find a solution. The molecular biologist walks down the long, white corridors of the Institute for Tropical Medicine at the University of Tübingen where she is currently working thanks to a Humboldt Foundation Georg Forster Research Award. She wants to find what many have long considered impossible: an effective vaccine against malaria. Ntoumi is 53. She has spent many years of her life in labs, doing research on the most serious infectious diseases like HIV, tuberculosis and malaria. Her friends say that she would even enquire about the progress of her work from her sickbed.

Francine Ntoumi, currently a Georg Forster Research Award Winner in Tübingen, is considered a pioneer of infection research in Africa.
Francine Ntoumi, currently a Georg Forster Research Award Winner in Tübingen, is considered a pioneer of infection research in Africa. (Photo: David Matthiessen)

Ntoumi points to a chart showing the malaria parasite plasmodium falciparum, a human being and a mosquito. The tiny, single-cell parasites find their way into the human bloodstream in the saliva of the anopheles mosquito. The sporozoites then proceed to the liver tissue where they reproduce until there are so many of them that the liver cell bursts and releases the pathogens into the bloodstream. There they attach themselves to the red corpuscles, reproduce and attack other red corpuscles. “This is when the first symptoms kick in: headache, fever, rheumatic pains,” says Francine Ntoumi.

Across the globe, 850 new drugs and vaccines were approved or recommended between 2000 and 2011. 307 of them relate to neuropsychiatric disorders, cancer and cardiovascular diseases. The so-called neglected, poverty-related diseases – such as malaria, tuberculosis and diarrhoeal diseases – fall way behind in the statistics.
Across the globe, 850 new
drugs and vaccines were
approved or recommended
between 2000 and 2011.
307 of them relate to neuro-
psychiatric disorders, cancer
and cardiovascular diseases.
The so-called neglected,
poverty-related diseases –
such as malaria, tuberculo-
sis and diarrhoeal diseases
– fall way behind in the
statistics.

Source: Belen Pedrique et
al.: The drug and vaccine
landscape for neglected
diseases (2000–11). The
Lancet Global Health
2013 (Vol. 1)

The pathogen is a complex being

For years, the molecular biologist searched for a weak link in the parasite’s lifecycle and characterised types of parasite in order to try and prevent proliferation. But it is not easy to discover a vaccine – malaria parasites are pretty complex beings. They spend half of their lives in a cold-blooded insect and the other half in a warm-blooded human being. During their lifecycle they change their appearance seven times. A vaccine that might work during one stage may stop being effective when the pathogen changes again.

In the entire course of human history, no other disease has claimed as many lives as malaria. It has plagued humanity for more than 4,000 years. Even today, roughly one third of the global population is at risk from malaria, particularly in tropical and subtropical areas of Africa. According to the WHO, in 2013 alone, 200 million people suffered from malaria, some 600,000 of them did not survive. By comparison: since the outbreak of the most recent Ebola epidemic in West Africa, the WHO has registered roughly 25,000 infections and over 10,000 deaths.

Researchers have been trying to find a remedy for malaria for years. This has produced curious experiments like the development of a perfume for cows which was supposed to attract the mosquitoes to cattle instead of people. Up to now, the most reliable protection in risk areas has been mosquito nets treated with insecticide and targeted mosquito control. Although millions have been pumped into research, success has been modest so far: there are still no effective long-term vaccines against malaria. Even the protection provided by the so-called RTS,S vaccine, which could hit the market in 2016, did not prove to be particularly long-lasting in the vaccine trials, nor was it effective in all cases. Only 30 to 50 per cent experienced temporary immunity.

“In the entire course of human history, no other disease has claimed as many lives as malaria.”

“We have to start there,” says Ntoumi, “at the beginning.” She is now pointing at the mosquito on the chart which is just sticking its proboscis into human skin and transferring the pathogenic sporozoites into the human bloodstream. The RTS,S vaccine attacks the parasite when it wants to enter the liver to reproduce. “But the ideal vaccine,” claims Francine Ntoumi, “would not allow the pathogens to proceed to the liver and enter the bloodstream in the first place; it would immediately unleash an immune reaction to all the stages of malaria.”

Born in Congo, Ntoumi studied at the distinguished Université Pierre et Marie Curie in Paris, France, gaining a doctorate in sickle cell genetics at the age of 26. As a child in Africa she often suffered from malaria. Far away in Paris, she could have left all that behind her. The so-called swamp fever died out in the areas around the Danube, Rhine and Seine at the end of the 19th century. Nowadays, economic considerations mean pharmaceutical companies tend to focus on cancer, diabetes and cardiac drugs. But Ntoumi was not indifferent to the issue of malaria in her own continent. She had respected her father’s wishes and moved to France to get a better education, like her parents before her. Now, with a doctorate and initial research experience under her belt, she wanted to return to Africa to focus on malaria.

In Africa, Francine Ntoumi was one of the first researchers to use molecular biological tools to study malaria.
In Africa, Francine Ntoumi was one of the first researchers to use molecular biological tools to study malaria. (Photo: David Matthiessen)

“You’re risking your career”

Everyone said she was mad, she explains in her office in Tübingen. At the beginning of the 1990s, there were neither proper labs nor established researchers in Africa. Her friends, colleagues and even her PhD supervisor thought she was risking her scientific career. “Forget it! You’ll never get anywhere!” they claimed. “You won’t be able to work there.” But the doubters did not know that their misgivings simply fired her engines. And of course, no one guessed that she would establish independent African malaria research in Africa and become one of the world’s most eminent malaria researchers..

Ntoumi was one of the first researchers in Africa to use molecular biological tools to study malaria. She set up a molecular biological laboratory in Congo and taught young researchers at the university in the capital of Brazzaville how to extract DNA. Today, Ntoumi is the project coordinator of the Central Africa Network on Tuberculosis, HIV/AIDS and Malaria, a cross-border research network involving Congo, Cameroon and Gabon. Prior to that, she had already coordinated the Multilateral Initiative on Malaria. For her work on infection control and her efforts to improve research conditions in Africa she has received prizes such as the African Union Award for the continent’s best female researcher in 2012. Ntoumi heads the international publication lists and publishes her articles in the most respected scientific journals like Science and The Lancet. She has even featured in some African magazines alongside the pictures of basketball players and artists. This makes her laugh, as though it were a joke. “Seems that science has become a little bit sexy,” she comments.

“A certain number of mosquito bites lead to immunity.”

When Francine Ntoumi goes out to do something, she usually achieves it. She grew up with five brothers and soon learned to assert herself. Her father, an “educational climber” from a poor background, made no distinctions between boys and girls. He demanded hard work and good marks. She was always supposed to be one of the three best in her class – and this she managed. Her father trained her to be a high-flyer and Francine certainly aimed high. Only once was she fourth in her class, for which she was grounded. The director of the Institute for Tropical Medicine in Tübingen, Peter Kremsner, calls her a “natural leader who can assert herself and stand up to strong men” – although he has to look down on her in conversation. At 1.64 metres, Ntoumi is a fairly short woman who is often underestimated because of her size – rather like the malaria mosquito.

First trials raise hope of success

Ntoumi’s finger is back on the chart with the mosquito and the sporozoites in their saliva. “That is the vaccine,” says the researcher. What is special is that it is a living vaccine. It contains highly infectious plasmodium falciparum sporozoites which are injected directly into the vein. “Tüchmi” is the name of this unusual method of inoculation, Francine Ntoumi explains. The expression was coined by a colleague at the Institute for Tropical Medicine at Tübingen University Hospital with whom she has cooperated closely since 2000. The “TÜ” stands for Tübingen, the “chmi” for Controlled Human Malarial Infection. One might say that Francine Ntoumi and the team of researchers in Tübingen simulate the bite of a malaria mosquito, but under controlled conditions.

The insecticides used to fight malaria are becoming less effective: between 2010 and 2013, many of the countries affected recorded resistance to insecticides amongst malaria mosquitoes.
The insecticides used to fight
malaria are becoming less
effective: between 2010 and
2013, many of the countries
affected recorded resistance
to insecticides amongst
malaria mosquitoes.

Source: based on the WHO
World Malaria Report 2014

A group of Dutch researchers had previously conducted experiments in which humans were shut in an insectarium with mosquitoes so that they became infected. The experiment was also controlled at intervals of four weeks so that the immune system had time to respond. “So we know it works. That a certain number of mosquito bites lead to immunity,” says Ntoumi. “But we can’t shut up the whole of humanity in an insectarium!” So she had sporozoites isolated from the mosquitoes’ salivary glands and discovered how many of them she had to inject to induce immunity. Three inoculations every four weeks are required. At the same time, the patients are given the anti-malarial Chloroquine so that the infection cannot break out. The first clinical trials endorse the approach: the new malaria vaccine really did protect 100 percent of participants from infection. If the follow-up trials are just as promising, the vaccine could be on the market by 2018.

Ntoumi now wants to raise money for the vaccine in the Republic of the Congo in order to carry out further trials and later to market it. She has already gained the support of the oil company Total and is busy convincing the directors of the Congolese airline Compagnie Africaine d’Aviation that a vaccine is better than the mosquito nets they currently distribute for advertising purposes. There are many young people in Congo, according to Francine Ntoumi, whom she could train to become researchers. At the same time, with its wealth of resources and sustained economic growth, there is money in the African country. One just has to bring it all together.

published in Humboldt Kosmos 104/2015

Professorin Dr. Francine Ntoumi is one of the pioneers of infection research in Africa. Born in Congo, she has worked in France, Gabon, the Netherlands, Germany, Tanzania and Congo. In her role as a scientific manager she campaigns for better research conditions in Africa. The molecular biologist has cooperated with the University of Tübingen since 2000, partly as a Georg Forster Research Fellow. In 2014, she was granted the Humboldt Foundation’s Georg Forster Research Award enabling her to continue the collaboration. She now commutes between Tübingen and Brazzaville, Congo, where she is a senior lecturer at Marien Ngouabi University and the President of the Congolese Foundation for Medical Research.