By David N. Leff

While affordable HIV drugs hold center stage in Africa these days, AIDS is not the Dark Continent¿s number one disease scourge. That distinction goes to malaria.

¿In some parts of the world, like Africa,¿ observed microbiologist Abdu Azad, ¿malaria, TB and HIV/AIDS are the three most important public health problems. Because if you look at the statistics, more African children are dying from malaria than from AIDS.¿ Azad is on the faculty at the University of Maryland, Baltimore, in the department of microbiology and immunology.

Molecular parasitologist Altuf Lal has looked at those statistics, ¿which cite estimates that 500 million people worldwide are infected every year with malaria,¿ he pointed out. ¿There are about 100 million clinical cases annually, and around 2 million deaths a year. Most of the mortality and morbidity occurs in sub-Saharan Africa. The disease predominates in children under 5, and in pregnant women.¿

Lal is chief of the molecular vaccine section in the division of parasitic diseases at the Centers for Disease Control and Prevention, in Atlanta. He is lead author of a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated April 24, 2001. Its title: ¿Anti-mosquito midgut antibodies block development of Plasmodium falciparum and Plasmodium vivax in multiple species of Anopheles mosquitos and reduce vector fecundity and survivorship.¿ The article¿s senior author is Maryland¿s Abdu Azad.

P. falciparum and P. vivax are the two major malarial parasites that inflict the infection on people ¿ Homo sapiens. The former parasite kills its victims; the latter merely makes them extremely sick.

Anopheles mosquitos, of which there are hundreds of distinct species, furnish aerial transport to malarial parasites in particular ¿ but that¿s not all. From their needle-nose proboscis to their salivary gland and digestive midgut, these insects provide their pathogenic passengers with meals on wings and nose-cone delivery systems that bite open the skins of their victims. The mosquito¿s midgut plays main midwife to the birth of these parasitical sporogenic stages.

Deadly Parasite Defeats All Stratagems

From the now-banned DDT pesticide to bed netting, to draining stagnant water ¿ to deprive mosquitos of their larval stage ¿ anti-malarial campaigns against Anopheles have tried and failed over the years. For a time it seemed that sophisticated drugs aimed at the parasites themselves had a chance to curb the pandemic, but drug resistance now is making winners of the Plasmodia.

Experimental vaccines against the parasite¿s weirdly convoluted transmission life cycle ¿ from mosquito bite to victim¿s liver to bloodstream, and back to its frequent-flying airlift ¿ are beginning to proliferate.

¿There¿s excitement and enthusiasm in the malaria vaccine community right now,¿ Lal told BioWorld Today. ¿This particular finding by our group in the PNAS paper provides us with another avenue to design and develop vaccines. Its advantage,¿ he continued, ¿is that one can target several species of human malaria parasites and target different mosquito populations at the same time.¿

¿Our whole concept is new,¿ Azad told BioWorld Today. ¿There are several vaccine approaches,¿ he explained, ¿which are called altruistic approaches. That is, if we make antibodies to the antigen of a parasite, which is not seen by the host during infection, those antigens can block infection inside the mosquito. So what we showed is a way to make antibody against mosquito midgut antigens, which can be directed against several different species of Anopheles.

¿The other novel part in this work,¿ Azad went on, ¿was its effect upon the mosquito¿s survival and egg deposition. Because it can affect the insect¿s egg production, that result reduces the number of mosquitos.¿

Azad and his co-authors immunized mice with mosquito midgut antigens. The serum from these animals blocked development of parasites in the insect¿s midgut. ¿The parasite was taken in together with the antibody,¿ he recounted, ¿so by the time Plasmodium developed, it was not able to pass through the gut to establish its transmission cycle.¿

The midgut antigens to these prospective vaccine antibodies, he explained, ¿are on blood cells. In the insect¿s gut lining, there is only one row of cells, which mostly absorb and digest food. The antigens are on the surfaces of proteins. So, when we added the antibody to that, it blocked the antigen, so that the parasite, which may be using those antigens to get in to the midgut, can¿t.

¿We could maintain mosquitos on a sugar diet for a while,¿ Azad went on. ¿Then for egg deposition they needed a blood meal. We took the gut out of a blood-fed mosquito, made a homogenate, and inoculated it into the mice. Then, we used their spleen cells to generate monoclonal antibodies.

¿The results of these experiments,¿ Azad summed up, ¿clearly confirmed our hypothesis ¿ that if you make antibody against any kind of important protein in the gut cells, which are epithelial cells, you can block it and not allow the parasite to complete its transmission cycle. And what is really exciting about this work is that it works across the board, so you can use it for different Anopheles mosquitos, and different parasites ¿ as we showed for vivax malaria, falciparum malaria and rodent malaria.¿

Next Hurdle: Finding Gene For Midgut Antigen

CDC¿s Lal pointed out that, ¿Azad and others have collaborated with us on this project over the last several years. The next step is to identify and characterize the gene that encodes this protein of interest. Then if everything works, my goal is to incorporate this gene with other genes. We have a candidate vaccine; and we have this Anopheline determinant target, which we will combine with our Plasmodial candidate. Our idea,¿ he went on, ¿is to formulate a multistage and multicompetent vaccine, designed to induce responses that are specific against both the parasite and the mosquito vector. In other words, induce multiple layers of immunity. But such a vaccine is several years down the road.¿

In conclusion, the PNAS paper proposed ¿that a combination of mosquito antigens involved in host-parasite interactions together with parasite antigens could form a highly effective multivalent malaria vaccine. Furthermore,¿ it added, ¿midgut-based transmission-blocking immunity could also find uses against other arthropod-transmitted human diseases (e.g., dengue and filariasis) in which case one midgut antigen-based vaccine may block transmission of many vector-borne diseases.¿

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