Malaria Vaccines

Alaina Critchlow, Jenny Staves and Claire Watt

(Parasites)

Over 150 Plasmodium species have been identified that infect various species of vertebrates. However, only 4 of these species cause malaria infections in humans: Plasmodium vivax, Plasmodium falciparum, Plasmodium malariae, and Plasmodium ovale (1).

Female Anopheles mosquitoes serve as both the definitive host and biological vector of the malarial parasites. Only about 60 of more than 200 known species of Anopheles are considered to be vectors of malaria (2).

Life Cycle Vocabulary:

It is important to understand the life cycle of Plasmodium when discussing malaria vaccine candidates, as a vaccine could act at one of many distinct stages during the lifecycle of the parasite. Before discussing the life cycle of Plasmodium, however, certain key vocabulary terms must be defined. A trophozoite is the feeding stage of a protozoan parasite. Schizogony is the process of asexual reproduction during which the nucleus undergoes division preceding cell division. Schizogony produces daughter cells known as merozoites, which can develop in to gametocytes or enter new host cells and undergo another cycle of schizogony. Gametocytes, which are derived from merozoites, are cells that are capable of developing into gametes (3).

Plasmodium Life Cycle:

The life cycle of Plasmodium can be divided into two distinct phases: the asexual cycle in humans and the sexual cycle in mosquitoes. To begin the asexual cycle in humans, an infected female Anopheles mosquito injects sporozoites into the new human host during a blood meal. Sporozoites injected into the bloodstream leave the blood vascular system within 30 to 40 minutes and enter the liver. This begins the exo-erythrocytic stage of the life cycle during which asexual multiplication occurs. Within hepatocytes the sporozoites undergo many nuclear divisions to become schizonts. This occurs over a period of 6 to 15 days, after which the schizonts burst and release thousands of merozoites into the circulation (1). This marks the end of the exo-erythrocytic cycle.

Upon release, the merozoites invade the red blood cells where they undergo another asexual cycle called erythrocytic schizogony. This is also known as the erythrocytic cycle. During this stage the merozoites develop to form immature or ring stage trophozoites which then progress to mature trophozoites. The mature trophozoites develop into schizonts. The erythrocytic cycle results in the formation of 4 to 36 new parasites in each infected cell within a 44 to 72 hour period (2). At the end of the cycle, the infected red blood cells burst, releasing the merozoites. At this stage, merozoites can either infect new red blood cells to begin the erythrocytic cycle again, or, through the action of some unknown factor, the merozoites can develop into gametocytes. It is of note that blood stage parasites are responsible for the clinical symptoms of malaria (1). For example, lysis of the red blood cells is an important cause of malaria-associated anemia. In addition, if a significant number of infected cells rupture simultaneously, the resulting material in the bloodstream is thought to induce a malarial paroxysm (2).

Next begins the sexual cycle in mosquitoes. When a female Anopheles mosquito takes a blood meal from an infected person, both male (microgametocytes) and female (macrogametocytes) may be ingested. The microgametocytes and macrogametocytes mature to become microgametes and macrogametes, respectively. In the midgut of the mosquito, the microgametes fertilize the macrogametes, forming a zygote. The zygote becomes elongated and motile, and is then called an ookinete. The ookinetes invade the midgut wall of the mosquito where they develop into oocytes. The oocytes grow and develop and finally rupture to release sporozoites. The sporozoites make their way to the salivary glands of the mosquito so that they can be inoculated in to the new human host during the mosquito’s next blood meal, thus perpetuating the Plasmodium life cycle.

Parasite Distribution:

Currently, Plasmodium vivax and Plasmodium falciparum are “the most commonly encountered malarial parasites” (4). P. vivax is found in nearly all areas where malaria is endemic and is the only one of the four species whose range expands into the temperate regions (2). P. falciparum, on the other hand, is found only in the tropic and subtropic regions, though its prevalence in the tropics is high (4). P. malariae is seen less frequently than either P. vivax or P. falciparum, but it is found in the same regions. Lastly, P. ovale is prominent throughout tropical Africa and on the West African coast; however, its distribution is the most limited of the four human malarial parasites (2, 4). P. vivax, P. malariae, and P.ovale are associated with a low risk of death, whereas P. falciparum carries a high risk of fatality.

Symptoms:

The initial symptoms of malaria infection are nonspecific and can include headache, nausea, vomiting, photophobia and muscle aches (2). A malarial paroxysm is marked by onset of a sudden shaking chill which may last from 10 to 15 minutes or perhaps longer (3). Elevated temperature accompanies the paroxysm and may be sustained for typically 10 hours or more. This cycle repeats itself every 36 to 72 hours depending on which species the human host has been infected with. Complications of malaria can arise, leading to more severe pathologies. Such pathologies include tropical splenomegaly syndrome and renal disease. Falciparum infection may lead to decreased blood flow, tissue hypoxia, anemia and cerebral malaria, in which severe headache precedes drowsiness, confusion and coma (2).

REFERENCES

(1) “Parasites and Health: Malaria.” 5 May 2004. Centers for Disease Control and Prevention. 23 May 2007. <http://www.dpd.cdc.gov/dpdx/HTML/Malaria.htm>

(2) John, David T., and William A. Petri, Jr. Markell and Voge’s Medical Parasitology. 9th ed. St. Louis: Saunders Elsevier, 2006.

(3) Smith, D. Scott. “Malaria.” Lecture. Stanford University, Stanford, CA. 18 May 2007.

(4) Carter, Richard and Kamini N. Mendis. Evolutionary and historical aspects of the burden of malaria. Clin Microbiol Rev. 2002 Oct; 15(4): 565 – 591.

 


© 2007 The Board of Trustees of the Leland Stanford Junior University. All rights reserved.