"Malaria is no longer a neglected disease,” says award-winning Brazilian parasitologist

Luiz Hildebrando Pereira da Silva, recipient of the Conrado Wessel Award for Science, explains how his studies may contribute to the near-complete elimination of the disease in the Amazon in the coming years.

By Karina Toledo

Agência FAPESP – World-renowned for his study of tropical diseases, parasitologist Luiz Hildebrando Pereira da Silva is the recipient of the Conrado Wessel Foundation Prize (FCW), one of Brazil’s most established science awards.

Together with José Rodrigues Coura (from the Parasitic Diseases Laboratory at the Oswaldo Cruz Institute in Rio de Janeiro), who won the award in the category of Medicine, and Niède Guidon (of the American Human Museum Foundation in Piauí), who received the prize in the category of Culture, Hildebrando was awarded in the category of Science and was selected from among 400 Brazilians distinguished in their respective fields. The nominations were made by academic and research institutions from across Brazil at the invitation of the FCW.

The prize recipients were selected on the basis of their body of work and the social nature of the work itself. The awards ceremony for the 12th edition of the FCW Prize for Science, Culture and Medicine was held on Monday, June 6, 2014, at the Sala São Paulo, in downtown São Paulo.

A 1953 recipient of a medical degree from the University of São Paulo (USP), Hildebrando was the director of the Cell Differentiation and Experimental Parasitology units at the Pasteur Institute in Paris. After several frustrating attempts to come back to Brazil during the military dictatorship, he returned in 1998 after 32 years in exile and took up residence in Porto Velho (state of Rondônia), where he helped set up a research group that has achieved promising results in the treatment of malaria.

As the head of the Tropical Pathology Research Institute in Rondônia (Ipepatro), an agency that is currently associated with the Oswaldo Cruz Foundation (Fiocruz) of Rondônia, he coordinates studies aimed at discovering new drugs to fight leishmaniasis, malaria and other parasitoses. He also coordinates studies to develop monoclonal antibodies for use in the diagnosis and treatment of diseases such as influenza, rabies, hantavirus and yellow fever, and in serum therapy to treat snakebites.

In an interview with Agência FAPESP, Hildebrando describes the principal breakthroughs he has achieved in the fight against tropical diseases, particularly malaria, since his return to Brazil.

To what do you attribute your nomination for the FCW Prize? Luiz Hildebrando Pereira da Silva – I believe it may be due to the nature of the work we’ve been doing in Rondônia since I came back to Brazil in 1998, particularly with regard to fighting malaria. When I returned, I decided to settle in Amazônia because I think there’s a problem that the region needs to solve, which is promoting the population’s socioeconomic development and, at the same time, promoting the region’s environmental preservation. Since then, we’ve been able to bring together an excellent team of specialists that has allowed us to make great headway in the fight against malaria.

Agência FAPESP – How has your return to Brazil and the formation of this research group been?
Luiz Hildebrando Pereira da Silva – When I was still directing the Pasteur Experimental Parasitology Unit, I had begun several collaborative initiatives with USP in Rondônia through Professor Erney Camargo. We traveled all over the Amazon region to find the place where we would be most interested in working, and we chose Rondônia because it has the highest incidence of malaria as well as excellent physical facilities, such as the Cemetron Hospital of Porto Velho. So, we established a collaboration between the Pasteur Institute, USP and the State Department of Health. A few years earlier, in inland Rondônia, Dr. Mauro Tada had established the Center for Research in Tropical Medicine (CEPEM). CEPEM’s initial objective was to test a Colombian vaccine for malaria. The center was then transferred to Porto Velho and became associated with the State Health Department. Around this nucleus, an initial research group was gathered, and it became a little stronger when I retired from Pasteur in 1997 and settled in Porto Velho. I retired from USP in 1998 and was able to obtain a grant from the National Council for Scientific and Technological Development (CNPq) to come to work in Rondônia. Tada and I took up in a wing of the Cemetron Hospital, where we set up the CEPEM laboratories for the purpose of studying malaria. We worked with resources from CNPq and the Ministry of Health. In 2001, with funding from the Ministry of Health, we set up the Tropical Pathology Research Institute (Ipepatro), a private, non-profit institution; an NGO associated with the Ministry of Science, Technology and Innovation. In 2010, Ipepatro became associated with Fiocruz Rondônia.

Agência FAPESP – What principal breakthroughs did the group achieve during those years?
Hildebrando – The first was to show that there are different types of malaria. There is one that affects riverine populations and another that affects residents of agricultural settlements. The relationship between the mosquitos that transmit the disease to the local population of each of these sites is different, and this impacts the transmission patterns. In addition, we have shown that the malaria vectors in Brazil are different from the ones in Africa, where the disease has been present since the dawn of man. In Africa, the principal vectors are the Anopheles gambiae and the Anopheles funestus. Because they evolved alongside man, the African mosquitos acquired strictly domestic habits and behave in a similar way to the mosquitos that transmit dengue fever. In Amazônia, however, man’s arrival is a more recent occurrence. Here, the principal vector is the Anopheles darlingi, which over millions of years survived by feeding off birds, rodents and other animals. When man arrived and changed nature, the mosquito began to have a new and abundant source of nutrition, which favored the increase of the anopheline population, especially in proximity to large accumulations of water. This process makes the transmission pattern in Amazônia completely different from that in Africa, and different measures for vector control are therefore required. In Amazônia, the activity of the A. darlingi is at once extra-, intra-y and peri-domiciliary [around the house]. However, we have confirmed that the transmission of malaria is essentially intradomiciliar. We have therefore shown that measures such as fumigation with insecticides have had little effect in controlling the vector.

Agência FAPESP – What is the best way to control the disease in the Brazilian case?
Hildebrando – Our third significant contribution to fighting malaria was to show the significance of relapses in cases of malaria caused by the parasite Plasmodium vivax, as well as the significance of asymptomatic cases in maintaining disease transmission. While the Plasmodium falciparum parasite has only one reproductive cycle in the liver before moving into the red blood cells [the phase in which the symptoms manifest themselves and the mosquito can become contaminated by biting an infected human], P. vivax produces parasitic forms that remain in their hepatic form for longer periods. Once the clinical phase of the disease has passed, the parasite can come back and travel from the liver to the bloodstream, causing the patient to have a relapse, or in other words, become contaminated again. Based on this knowledge, we are testing a control strategy known as Selective Intermittent Preventive Treatment (SIPT), which has considerably reduced the levels of malaria in the pilot localities.

Agência FAPESP – How does this strategy work, and where is it being tested?
Hildebrando – The test is being conducted in the municipality of Candeias do Jamari, which is the only place in Rondônia that had an annual parasite index (AIP) over 200 in 2010 and 2011, with a high incidence of P. vivax, basically due to relapses. We are working in this area with funding from the State Department of Health and managed to reduce the AIP to 82 in 2013. The strategy consists of treatment with chloroquine during the clinical phase, followed by continued administration of a single lower dose of the same medication over the course of 12 weeks to prevent a relapse. The dose used to prevent relapse is the same as that indicated for malaria prevention in pregnant women, for example. Furthermore, our CEPEM team, coordinated by Drs. Mauro Tada and Chelio Batista, is running a clinical test with a new drug called tafenoquine, which is produced by the GSK laboratory [GlaxoSmithKline] and is capable of eliminating the hepatic form of P. vivax with a single dose. Another clinical test of the drug is being carried out at the Tropical Medical Foundation in Manaus. If the results of both tests are positive, we will be able to significantly improve the prevention of relapses because the SIPT method used until now requires preventive treatment for several weeks.

Agência FAPESP – What is the current standard treatment, and how might these new strategies contribute to reducing the number of cases?
Hildebrando – Today, a patient infected by P. vivax is treated with chloroquine for the first three days, followed by a 14-day course of primaquine. However, most patients do not complete the full treatment because primaquine is a very toxic drug that has numerous side effects. Patients generally stop taking the medicine when the symptoms of malaria disappear with the chloroquine, and that is when the relapses appear. If tafenoquine is approved from the standpoint of side effects, because it’s already been proven to be effective against the parasite itself, it will be possible to prevent relapses with treatment with just a single dose. The campaign against malaria, which until now had managed to simply control the number of cases, may evolve into, if not eradication, then at least elimination of the disease in nearly all of the Amazon region.

Agência FAPESP – And the cases caused by P. falciparum?
Hildebrando – These have been considerably reduced thanks to the advent of the drug artemisinin. There are areas in which there are next to no cases of falciparum malaria. It is getting to be difficult to conduct research studies on this parasite.

Agência FAPESP – Based on this promising outlook, is malaria still considered to be a neglected disease?
Hildebrando – Not any more. There have even been some attempts at a dengue vaccine. I think today only leishmaniasis, hantavirus and arbovirus, about which little is known, are what we really consider to be neglected diseases. Our group has studied some promising drugs against leishmaniasis.