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Vaccines Have Serious Side Effects

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Malaria, one of the most widespread diseases, is caused by a Plasmodium parasite and is transmitted to humans by the Anopheles mosquito. It infects several hundred million people each year, results in several million deaths annually, and is a complex disease to treat. The causative agent is a group of parasitical protozoa of the Plasmodium genus transmitted by the female Anopheles mosquito. Its original treatment was quinine that became the prototypical molecule for the first generation of synthetic antimalarial drugs. The target for drug treatment and prophylaxis is the parasite, and each advance in the drug treatment of this disease has resulted in the parasite developing resistance. One of the most effective preventions is controlling the mosquito population that is the vector carrying the parasite to humans. The human immune system does respond to the parasite, but the development of an effective vaccine has been a challenge. Sequencing the plasmodium genome is providing information that may lead to other approaches to prevent and treat this debilitating disease.

History

Malaria's name is derived from "mala aria" or bad air, and has been called ague, intermittent fever, marsh fever, and The Fever}'2 The name is based on the early knowledge that malaria was associated with swamps and badly drained areas. The use of quinine for treating malaria has been known since the 17th century. Although malaria is an ancient disease, its upsurge seems to coincide with the advent of farming about 20,000 years ago. The clearing of land provided areas for ponds containing still water. The Anopheles gambiae mosquito uses still water that sits in ponds and containers to breed. The gathering of humans in farming communities provided the necessary concentration of people to form a reservoir of hosts for the parasite and "food" for the mosquitoes breeding in the ponds.3-6

Proof that the Anopheles mosquito is the carrier of the causative protozoa was obtained by Dr. Ronald Ross who was recognized in 1902 by receipt of the Nobel Prize in Medicine. In a scenario somewhat similar to that where definitive proof that yellow fever was transmitted by the Aedes aegypti mosquito was required, Dr. Ross strongly argued that malaria was transmitted by an insect vector and finally demonstrated that the parasite was carried in the stomach and salivary glands of the Anopheles mosquito. The latter discovery was important because it helped resolve the dispute whether malaria was spread by the bite of the mosquito or drinking water containing mosquito eggs and larvae.7 The impact of malaria on the human species continues to be devastating. The role of diseases such as smallpox, plague, yellow fever, and polio on human history is fascinating, but, fortunately, is mostly historical. Although smallpox has been eliminated, the latter three diseases do reappear, but the cases are isolated. Plague is treated effectively with antibiotics, and there are vaccines for yellow fever and polio.

There are three potential ways to control malaria: elimination of the vector, drug therapy, and vaccination. Elimination of the vector is the simplest and most cost-effective. Drug therapy has the same challenges as those with development of antibiotics, resistance to the drug. The current antimalarial drugs, although reasonably effective, also have significant adverse reactions, and resistance is increasing. So far, no effective vaccine has been developed that is effective in vivo, but that may be changing because of a better understanding how the human immune system interacts with the parasite. The malaria parasite does elicit an immune response as evidenced by the fact that children with an initial exposure are more likely to die than adults who have recurring attacks.

Because malaria has been eliminated from North America, Europe, and parts of Asia, it becomes a potential problem when citizens from a malaria-free area travel into an area where malaria is endemic. It is common for these travelers going into areas where malaria is endemic to receive prescriptions for antimalarial drugs and use them prophylac-tically.8 Many times, citizens of malaria-free countries returning from areas where malaria is endemic plus citizens of the latter countries who are coming to the malaria-free countries will have contracted malaria and will require antimalar-ial drugs for several months following their return. Also, there will be restriction on their ability to be blood donors. Most prescriptions for antimalarial drugs in North America are indicated for prophylaxis of travelers going to and coming from areas of the world where malaria is endemic.

Malaria

Malaria is caused by four species of the one-cell protozoan of the Plasmodium genus. They are:

Plasmodium falciparum: This species is estimated to cause approximately 50% of all malaria. It causes the most severe form of the disease and, because patients feel ill between acute attacks, debilitating form of the disease. One of the reasons it leaves the patient so weak is because it infects up to 65% of the patient's erythrocytes. Plasmodium vivax: This species is the second most common species causing about 40% of all malarial cases. It can be very chronic in recurrence because it can reinfect liver cells.

Plasmodium malariae: Although causing only 10% of all malarial cases, relapses are very common. Plasmodium ovale: This species is least common.

Figure 7.1 outlines the steps of the parasite as it is injected into the victim and where drug therapy might be effective. The mosquito stores the sporozoite form of the protozoan in its salivary glands. Upon biting the patient, the sporozoites are injected into the patient's blood. Ideally, this would be a good site for intervention before the parasite can infect the liver or erythrocyte. In the case of drug therapy, people living in areas endemic with malaria (and the mosquito vector) would need to take the drug constantly. Although this would be plausible for people living temporarily in these areas, it is not practical for the permanent residents. It is true that anti-malarial drugs could be formulated into implanted depot dosage forms, but these are expensive, and many times require trained medical personnel to implant the drug.

Within minutes after being injected into the patient's blood, the sporozoites begin entering hepatocytes where they become primary schizonts and then merozoites. At this point, there are no symptoms. Depending on the Plasmodium species, the merozoites either rupture the infected hepatocytes and enter systemic circulation or infect other liver cells. The latter process is seen with P. vivax, P. malariae, and P. ovale, but not P. falciparum, and produces secondary schizonts.

This secondary infection of the liver can be very damaging and is one of the sites for possible drug intervention. Killing the secondary schizonts would accomplish two things, protect the liver from further damage and eliminate a reservoir of schizonts that can change to merozoites and enter systemic circulation. It needs to be noted that, as the protozoan changes from sporozoite to schizont to merozoites, its immunological character changes. Determination of the Plasmodium genome has shown that each form of the parasite produces a different set of proteins. At the same time, once the merozoites have left the hepatocyte and are in systemic circulation, they are susceptible to attack by the patient's immune system provided that it has "learned" to recognize the parasite. Therefore, another site for vaccine development is the merozoite stage. Depending on the Plasmodium species, a merozoite vaccine may or may not provide much protection to the liver, but it could reduce subsequent infection of the erythrocytes.

Merozoites in systemic circulation now infect the patient's erythrocytes where they reside for 3 to 4 days before reproducing. The reproduction stage in the erythrocyte can either produce more merozoites or another form called ga-metocytes. The latter has different immunological properties from the other forms. Either way, the newly formed merozoites or gametocytes burst out of the infected erythro-cytes. The new merozoites infect additional erythrocytes and continue the cycle of reproducing, bursting out of the erythrocytes, and infecting more erythrocytes. The debris from the destroyed erythrocytes is one of the causes of severe fever and chills. Also, the patient's immune system will respond with repeated exposure to the parasite, and this will contribute to the patient's discomfort.

The conversion of merozoites results in male and female gametocytes. After entering the mosquito, they "mate," producing zygotes in the mosquito's stomach. The latter reside in the mosquito's stomach endothelium oocysts. Eventually, they migrate as sporozoites to the mosquito's salivary gland where the cycle begins again when the mosquito bites a

Figure 7.1 • Stages of the parasite that causes malaria after injection into its victim. See discussion in the text. □ indicates site of antimalarial drug action in humans.

human. Note that, in effect, there are two reservoirs or vectors for the parasite: the mosquito that infects humans and humans that infect mosquitoes. Consistent with the latter, there have been some attempts at developing prophylactic agents that would be in the blood ingested by the mosquito. These drugs would stop further development of the parasite in the mosquito, preventing the insect from being a carrier.

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