Overview
Robert Gwadz

Malaria Drugs
Rob Ridley

Malaria Vector Control in Africa: Strategies and Challenges
Yeya Touré

International Collaboration and Malaria as a Re-Emerging Disease
Martin Alilio

General Discussion

Malaria in Africa: An Overview

Bob Gwadz

Introduction

I'll try to start the whole thing off by giving you an introduction to malaria. Most of you probably are not experts in malaria. I'm with the laboratory of parasitic diseases at the National Institute of Allergy and Infectious Diseases at NIH. I'm also the executive officer of the Malaria Vaccine Development unit. I say this with some pride because the NIH and the US government in general has made a major decision in the last few years to put extra funds into malaria, primarily into the area of vaccine development.

I'm not a true vaccinologist but I can give you a little summary of where things are going with malaria vaccines, and then our other speakers are going to talk about other areas of research.

This is a quote from 1967 from Byron Wood at NASA: "It's time to close the book on infectious diseases." The point is that there was a great deal of optimism some time ago that infectious diseases were [going to be] a thing of the past, that we didn't have to worry about infectious diseases. Well, here's a graph from 30 years later, from 1997, and you can see that, of worldwide cause of death, parasitic and infectious diseases remain far and away the most serious cause of death. And within this group malaria certainly sits very high on the list if not right at the top of the list. But in fact some say "Malaria? Do we still have malaria?" The reason that people don't pay much attention is that this is the face of malaria. [Refers to photograph, i.e., malaria is a developing country problem]. This is the face of malaria in Africa, and it's children, it's infants, and there are probably a lot of grandmothers in this group, and there are mothers there. But it is the children in Africa that suffer the most. How many deaths every year? I don't think anybody really knows, but the number that can be bandied about is anywhere from 1.5 to 2 million deaths per year in Africa among children under the age of five, and that number could be considerably higher.

And this is the critter that causes it all -- the mosquito. Malaria is a mosquito-borne disease. You don't have mosquitoes, in essence you don't have malaria. And this is in fact the mosquito that we're most concerned with, and Dr. Toure will talk about this mosquito in detail in a little bit, but this is anopheles gambiae. Anopheles gambiae and other members of the anopheles gambiae complex are the primary vectors of malaria in sub-Saharan Africa. They're great vectors because they like to live close to humans, they like to feed on humans, and they live long enough to develop the malaria parasite and very effectively transmit it.

I'll tell you a little story. I got back from Africa a week ago tomorrow, and I was there with one of my colleagues from University of Maryland, who had gotten there two weeks earlier and had gone up country to a very dry area, during the dry season, so nobody's worried, you can't even find mosquitoes there. And he's a physician and of course physicians are all-knowing and all-wise, and when he got back last week, he had malaria. Son of a gun. Well I was wise enough to take my pills. But then I'm not a physician.

You know the difference between physicians and God, don't you? God doesn't think he's a physician. I'm sorry, I can't help itŠ

The Life Cycle of the Malaria Parasite

Malaria starts out by the bite of an infected mosquito. Mosquitoes are not born with malaria, they get it from somebody else with malaria. The mosquito bite injects the sporozoa. Now remember, malaria is a protozoan. It's not a virus, it's not a bacteria. It's a real animal. It's single-celled, but it's kind of a distant cousin to an amoeba. It's a real creature, and it's a hell of a tough thing to fight. It also has a very complex life cycle. The mosquito injects salivary fluids to facilitate the feeding process, and in the salivary fluid are sporozoites. Those sporozoites are probably cleared from the circulation in about 20 minutes, and they take up residence in the liver and undergo a sexual development in the liver cells. At this stage they are haploid organisms. After about a week's development in the liver they rupture out of the liver cells and enter into the red blood cells. It's the cycle of development in the erythrocytes, in the red blood cells, that are usually associated with the pathology that we think of with malaria. The two most important malaria species are plasmodium falciparum, very pernicious, and plasmodium vivax, less pernicious, more temperate in its range, have a developmental cycle of 48 hours, from the time of invasion to the time of rupture and re-invasion.

In malaria after a while you develop a very synchronous infection, the chills and fever of malaria that occur every other day. And that's because of the parasite going back into the red cells. A lot of other things are happening in the circulation as well, but for reasons that are not always clear some of these parasites, instead of developing asexually in the red blood cell, go ahead and develop as sexual parasites -- the gametocytes, the micro and macro gametocytes. All the time that this is happening, remember, these people that are infected are sleeping in the village, they're being fed on by mosquitoes. The mosquitoes are feeding every night on them. They're taking in a blood meal, and in that blood meal are malaria parasites. And if there are gametocytes in those malaria parasites, those gametocytes will then undergo gametocytic genesis in the gut of the mosquito. You have eggs and sperm-like microgametes form, you have fertilization, and for the first time you have a diploid organism which then develops in the gut of the mosquito, again myosis takes place, the sporozoites get to the salivary glands, and about ten days after that mosquito has fed it's ready to infect again.

Effects of Malaria

Well how are people dying? This is a CDC diagram from a few years back. It doesn't add up to two million but as I say we don't really know what the number is. The majority of deaths can be attributed to severe disease. Massive numbers of parasites, and a phenomenon that sometimes occurs with sequestration of parasites in parts of the body, with children it's frequently in the cerebral capillaries in the brain, causing cerebral malaria, so there's death due to that. And with pregnant women there's a great deal of sequestration in the placenta. Well what does that lead to? Blockage of the capillaries of the placenta, reduces the flow of nutrients and oxygen to the developing fetus, you can have spontaneous abortion, but more importantly I think is the fact that you have a lot of low birth-weight babies. Now in the United States you know that everybody says low birth-weight babies cause a lot of problems. Well low birth-weight babies in Africa are probably the rule rather than the exception, because of a breakdown in the immune system of the mother, who shouldn't have to worry about malaria because she's survived her fifth birthday and now she's semi-immune, but apparently during the first pregnancy there's a breakdown in the immune system and you have this tremendous proliferation of malaria parasites, you have severe damage done to the developing fetus.

Another group, not insignificant, doesn't have high parasitemias, they have low chronic parasitemias, but remember every time this parasite goes through its cycle it explodes a red blood cell. You explode enough red blood cells over time and you start having anemia. None of these things augur well for the development of this child because now it's wide open to a whole series of other infections, so that while a child may not die of measles in the United States, they may very well die of measles in Africa, and all sorts of other diseases. So not only do you have children that are dying [of malaria] but you have children that are suffering from a wide variety of other maladies that are indirectly associated with malaria.

This is the worldwide range of malaria, and as you can see it is strongest in sub-Saharan Africa, but you have malaria all throughout South America, you have it in some parts of Mexico, you have it in Central America, through India, the Indian sub-continent -- this is an old graphic so you don't see anything in China but in fact there is a lot of malaria in China and southeast Asia. Malaria has been around for a long time. Baruch Blumberg, the Nobel laureate in virology has stated that half of all human deaths from the beginning of time can be attributed to malaria. As someone who works in malaria, I'll accept that. We always say that our disease is the big disease to worry about, and we don't have a hard time defending the position because in fact there is a terrible problem.

Aims of Research

Since I wasn't originally supposed to give one of the talks, I've had to pull together all different slides. I'm just going to use these as representing different areas of work on malaria. One of the main areas of research, obviously, is in entomology. If you don't have mosquitoes you don't have malaria. And where malaria control has been successful in the last 50 years, it has been through control of the mosquito vector. Now, Rob Ridley might take some offense at that statement, but in fact vector control programs, properly applied and properly operated, can be very effective in controlling malaria. It's not easy, and these programs in the main have been insecticide-based, and obviously we can debate the goodness or badness of using insecticides, but in public health they certainly have a place.

Remember, it's only the female mosquito that transmits the malaria parasite, and the female doesn't do it because she wants to be mean and nasty. She takes blood, she takes another blood meal because she wants to be a mother, she requires the blood to produce a batch of eggs and she's only doing what she has to do. That's why she's on this earth, to make another generation.

I just show this picture, this is one of the new laboratories in Mali, and I'm going to be talking a little more about Mali specifically. This really is one of the main aims of what I suppose is the US government program on fostering malaria research competence in Africa, and Dr. Touré will be talking about that in a few minutes. Malaria research in Africa has traditionally been an expatriate function. "Safari science" of the worst kind. People rushing in, collecting their specimens, carrying them back to their laboratories, and occasionally, if at all, acknowledging that there might be an African involved in their research. The NIH certainly under Dr. Varmus and hopefully under his successor, and certainly under my institute director Tony Fauci, have made it absolutely clear that the days of expatriate science in Africa should be finished. It is our goal, and certainly the goal of the laboratory of parasitic diseases, and certainly the goal of the Fogarty Center, to do everything we can to increase the competence of the African scientists to conduct the research themselves. And [in this picture] is a young medical student working in an entomological lab doing molecular biology of mosquito vectors.

The Perfect Mosquito

These are the chromosomes of Anopheles gambiae, and gee they look a lot like Drosophila, well they're polytine chromosomes, but if you look up right there, that little spot, that's a bacterial gene. It's a gene that codes for phosphotransferase, which will knock out an antibiotic. This is a model system, but in fact that's chromosomes from Anopheles gambiae. One of the main important lines of research going in various parts of the world is to develop the perfect mosquito. The perfect mosquito is the mosquito that still bites you at night, because we're not going to eradicate mosquitoes, but it's one that can no longer transmit the malaria parasite. Hopefully we can do this someday by genetic engineering. It's not going to be easy. Even if we had the perfect mosquito, we don't know how to get that mosquito into nature, how to replace populations, how to modify the capacity of a whole population not to transmit the malaria parasite. But there it is. It's a gene, and this gene is stable, it's been in the mosquito since 1987, and the mosquito lives happily ever after, at least in the laboratory. I don't know how it's going to do in the field, but we're not going to release it, we're not going to do anything with this mosquito.

Drugs

Dr. Ridley is going to talk about what really is the first line of defense against malaria, and that is anti-malarial drugs. Not an easy problem now, because of this situation. For years chloroquine was the drug of choice, but then, almost simultaneously in east Asia and in South America, genes for resistance to chloroquine appeared and spread rapidly throughout these areas, then introduced into east Africa in the late 1970s. Chloroquine is essentially useless in most of east Africa now. But why is chloroquine important? It's a safe drug. I don't know how meaningful these numbers are but I've been told it costs 9 cents to cure a child with chloroquine, probably 25 cents to use fancidar, a different class of drugs, as much as 2 and a half dollars to use mefloquine, and something like halofantherine can be as much as 5 dollars. Well in a country that spends between 2 and 5 dollars per person per year on public health, the thought of having to spend 5 or 6 dollars three or four times a year per child is just not really within the realm of possibility.

I show you this picture with no small amount of pride. Again, this is a picture in Mali, there's a PCR machine, and that's Dr. Abdoulaye Djimde. Dr. Djimde has a degree in pharmacology from the University of Mali, from the National School of Medicine and Pharmacy, he is now finishing up a PhD at the University of Maryland School of Medicine, and two weeks ago the Voice of America interviewed him. Dr. Djimde was the first author in a paper published by the New England Journal of Medicine, the final elucidation of the use of the gene for chloroquine in a rapid diagnostic test. So that you can in theory get a person who has malaria, take a drop of their blood, dry it, process it very quickly and find out whether or not the parasite they are carrying is susceptible or resistant to chloroquine. It's been a long difficult stuggle, and it was done by an African, and he is going back home in June and will start a program there in medical biology of drugs and drug resistance.

Vaccines

I might as an aside ask you the question why is the military interested in malaria, and without letting you answer I'll tell you that in Vietnam, more time was spent in hospital due to malaria than to enemy bullets. In the Second World War the Pacific was terrible with regard to malaria. So was North Africa. Galipoli. More Aussies probably died of malaria than died of Turkish bullets. Malaria has really had a major role in affecting the outcome of wars and battles and things like that. It's not something to be ignored by military planners.

The most important type of vaccine would be one that operates against the blood stages, because these are the stages associated with the pathology of malaria. If you could have an effective vaccine that would somehow reduce the ravages of the blood stage infection, you would have quite a weapon. There, the workers are not really expecting sterile immunity. They are hoping to get a vaccine that eliminates mortality, that is, the death of a person infected with malaria, and reduces moribidity -- people getting sick from malaria. There though it may be that a little bit of malaria is not necessarily a bad thing because it continually boosts the immune response.

The third type of vaccine would be a transmission-blocking vaccine. This is the entomologist's vaccine. It works in the guts of the mosquito vector. Let's say that I immunize you with an anti-gamete immunogen. You are producing anti-gamete antibodies. But gametes don't appear in the circulation because the gametocytes are within red blood cells and they're protected. But in the gut of the mosquito, which contains the gametocytes and the antibodies, the parasites get out of the red blood cell and wham, they're hit by the antibodies, and they don't develop the sexual stages. So the mosquito doesn't become infected. So you may have malaria, but you're not going to give it to anybody in your village. It's transmission blocking. It's altruistic. It's probably going to be used in concert with other immunogens because let's say we've developed a very nice vaccine against the asexual stages, the blood stages, but there's possibility that the parasite will develop a way to circumvent that. But if you mixed it with a transmission blocking component, what's going to happen is that every time something breaks out, which might be a one in ten million kind o f thing -- but given the reproductive capacity of these things one in ten million or one in a billion is in fact not a big number -- you would also have a transmission-blocking component. So even though the parasite might occasionally find a way to avoid the immune response, it's not going to infect mosquitoes, it's not going to go through a sexual cycle, it will not be perpetuated.

This happens to be one of our coworkers in Mali taking a blood smear from a child. Hopefully by this time next year we may be working with the US Army testing vaccine candidates in the field, and it would be in a setting like this.

Remote Sensing

There are a lot of people at this meeting who are interested in remote sensing. Remote sensing is a very important technology that is going to be useful to us. This is a satellite photo, color corrected to make green the color of vegetation, probably taken in April when the rains are just starting. And towards the end of the rainy season the green area of the country has moved pretty much up to the line of the desert. And then it starts to withdraw again as the rains stop and it starts drying up. Well what does this mean? No mosquitoes, no malaria. No water, no mosquitoes.

This is another rice growing area, it's the area of Nyono, and here is a river and you can see cultivated areas around there. You can start identifying various features of vegetation. Hopefully one could start to look at these pictures and say all right, a certain amount of water, a certain kind of vegetation, a certain amount of water is associated with malaria. If you can predict ahead of time, using climatological parameters and remote sensing parameters, in theory one should be able to put together a predictive model that says if all these things are happening, then four months from now we're going to have a major epidemic in this area. Right now, everything is response to crisis. We respond to famine crisis by seeing children dying on CNN, then a program starts, and by the time the food gets there, the children are either dead, or it has started raining and everything is fine, and the problem is finished. What we'd like to be able to do at least with malaria, is to be able to predict areas that are going to have problems four months down the line, five months down the line, and hopefully Ministries of Health can start programs that can get needed things into these areas, the drugs, the physicians and so forth, anticipating the problem and responding before it happens.

Minority Training Program

Now, I'm going to talk about a program that might be of interest to students, or to faculty members who have students, and this is a program that we put together and is managed by the Fogarty International Center of NIH and is run through the University of Maryland School of Medicine. It's called a minority training program. If I look around the room here, I see the same sort of thing that I see when I go to a tropical medicine meeting. Very few black faces in the audience. Let's put aside that observation. Tropical medicine is fun. It's everything that biomedical research is, it's everything that medicine is, but it's in the tropics! Faraway places with strange-sounding names where you can see the people, you can work with the people you're trying to help, and where small incremental actions can have a great effect. Let's have a program that provides opportunities for young students in the US training systems to get to Africa to see what it's like and maybe some of them will make career choices. The program is aimed at graduate students or advanced undergraduates, medical students, post-doctorals, post graduate MDs, and I'd love to have a young professor, primarily a minority, who says look I'm a biochemist but I want to work on malaria and I need to find out what I can do. And we'll bring them out there, to Mali.

This is the guesthouse, it's got eight bedrooms, so we can accommodate eight students at a time. If you're interested in the program, contact me. You get a ticket, you get all your expenses paid and you get $1,200 a month. We'd like people to stay for a minimum of one month, I think three months is ideal, we have a young woman from Alabama who will have been there for nine months when she finishes. You'll be integrated into the research programs both in the laboratory and in the field, you need to speak French, and you will be integrated into the teaching program of the medical school there. And believe me you will see more diseases and conditions that you've read about there in your first week than you would in the US for the rest of your life.

Q&A:

Q: What is the origin of the word malaria?

A: Bad air. "Mal" "Aria". Bad air. Or the French word, paludisme. Palus, marsh. The belief that malaria somehow rose out of the miasma, the smells, the stink and stench of the marsh. Of course I always tell people, swamp means bad things, right? We have to get rid of them, drain the swamps, clean up the mess. But what's the difference between a swamp and a wetland? One man's swamp is another man's wetland. We would say drain the swamps, and you would say flood the wetlands! We can't win.

Q: Can you put a time frame on any of the vaccine approaches?

A: I wouldn't invest in any biotech firm that was trying to do this. There is no vaccine in a bottle right now that is ready for marketing. There are some vaccines in bottles right now that are getting ready for phase one and phase two clinical trials, so anything at that point, as with any other vaccine, is more than a decade away. The perfect mosquito: decades away. It could have long-term ramifications, so if we work on it for the next twenty years and then it does work, great. Now, we have to do it for every mosquito. Every continent has its own mosquitoes.

AAAS > International Directorate > Africa Program