Malaria is a potentially fatal infectious disease caused by a number of a unicellular parasite species belonging to the Plasmodium genus. The parasite is transmitted to humans via bites from infected mosquitoes. Malaria mosquitoes belong to the Anopheles genus.
The clinical presentation of malaria is not specific. The disease starts with a high fever 8 to 30 days after infection, sometimes accompanied by headaches, muscle pain, weakness, vomiting, diarrhea, or coughing. Typical cycles of alternating fever, shakes with cold sweats and heavy perspiration may then ensue. This is a malaria attack. The frequency of these cycles depends on the species of parasite responsible, and coincides with parasite replication and the rupture of red blood cells, which also leads to anemia. Malaria caused by P. falciparum may be fatal if untreated. In some cases, the infected red blood cells may obstruct the blood vessels to the brain: this is cerebral malaria, and is often fatal.
In regions where malaria is highly endemic, the population contains a proportion of asymptomatic carriers. After many years of chronic parasitic infection, some individuals tolerate its presence and develop natural immunity. This is known as acquired immunity.
Malaria affects about one hundred of the world's countries, particularly underprivileged countries in the tropical zones of Africa, Asia and South America (see map). Africa is by far the most affected continent, with 90% of African malaria cases reported in its inter-tropical areas. Outbreaks may occur when populations with little previous exposure move into highly endemic regions.
There are imported malaria cases in Europe. In France, 3,560 imported cases were reported in 2011 (source: InVS).
The various Plasmodium species
Five species of the Plasmodium genus parasite are responsible for causing malaria disease in humans:
- Plasmodium falciparum is the most pathogenic species, causing fatal cases. It is present in the tropical regions of Africa (where it is the dominant species), South America and Asia;
- Plasmodium vivax co-exists with Plasmodium falciparum in many parts of the world, and is present in
- some temperate regions;
- Plasmodium ovale, mainly found in West Africa, is not responsible for fatal forms of the disease, but may cause relapses four or five years after primary infection;
- Plasmodium malariae is found across the globe, with widely varying degrees of prevalence. It is not a killer, but may cause relapses for up to 20 years after primary infection.
- Plasmodium knowlesi, a parasite that usually infects macaque monkeys, has caused thousands of cases in Southeast Asia, and is considered an emerging threat.
Malaria is transmitted to humans by the bite of female Anopheles mosquitoes, that got infected by biting an infected subject. Female mosquitoes require a blood meal to produce eggs, parasites present in the blood meal are thus ingested with the blood. The parasites migrate to the salivary gland of the mosquito, which injects them into the host while feeding. Males do not bite.
Transmission of Plasmodium from one person to another is therefore dependent on mosquitoes, with Anopheles gambiae being the main vector in Africa. The only instance of direct human-to-human contamination is the transmission of the disease from an infected pregnant woman to her child by transplacental transmission. This is rare.
The parasite cycle
The Plasmodium cycle is complex, and includes two main stages: an asexual phase in humans, and a sexual phase in mosquitoes.
The female Anopheles injects the parasite into a human host in the form of a sporozoite. The sporozoite enters the bloodstream and migrates to the liver. It invades hepatic cells, where it rapidly divides, resulting in tens of thousands of new parasites within just a few days. These are known as merozoites. The hepatic cells rupture, releasing the parasites into the bloodstream, where they invade red blood cells and multiply. These red blood cells subsequently burst, releasing a new generation of merozoites into the bloodstream, which then infect new red blood cells. This is the erythrocytic cycle.
After several of these cycles, some of the merezoites inside the red blood cells develop into sexual forms of the parasite, known as gametocytes. When a mosquito bites an infected person, it ingests these gametocytes, which subsequently mature into male and female gametes. Fertilization then gives rise to a zygote, which differentiates into an oocyst in the mosquito's gut. Oocysts produce sporozoites, which migrate to the mosquito's salivary glands. A new cycle then begins.
Late relapses seen in malaria infections caused by P. vivax are a result of the ability of these species to remain in a dormant form, known as hypnozoites, in human hepatic cells.
Prevention and treatment
A number of antimalarial molecules may be used for therapeutic or prophylactic purposes (preventive therapy during travel to endemic regions). The best known are chloroquine and quinine. In many areas, parasites have developed chloroquine resistance and resistance to multiple antimalarials. The treatment recommended nowdays for patients living in endemic areas is to use artemisinin-based combination therapies.
Preventive treatment is strongly recommended for travelers
It is dangerous to visit high malaria transmission zones without regularly taking preventive treatment, particularly for children and pregnant women, for whom there is a much higher risk of severe malarial illness. The preventive treatment should be prescribed by a doctor, who will take into consideration the area visited (risk, resistant strains or otherwise), length of stay and also the person's individual circumstances: age, previous pathologies, antimalarial intolerance, possible drug interactions, pregnancy, etc. However, antimalarial drugs do not guarantee absolute protection against infection and it is also important to take protective measures against mosquito bites (mosquito nets, insect repellents, etc.).
No single preventive measure guarantees total protection and, even if a suitable treatment has been taken in the correct way, a malaria attack – sometimes late-onset – remains possible. Early symptoms often cause little alarm, but malaria may be fatal if treatment is delayed. A doctor should therefore be consulted urgently if fever (even low-grade), headaches, muscle aches or fatigue occur during the stay or in the months following return. A blood test is required to confirm the diagnosis. A fever occurring following return from a tropical area should automatically be considered as malaria until proven otherwise.
An intricate process
One of the major problems hampering development of a vaccine against Plasmodium is the fact that the parasite has several successive development phases in its lifecycle, including phases of intense asexual multiplication in humans (the hepatic phase, which takes place in the liver, and then the erythrocytic phase, in the red blood cells) followed by a sexual reproduction phase and multiplication in insects. Each phase ends with the release of a parasite in a different form, carrying different antigens and eliciting different immune responses. This considerably complicates vaccine research.
At the Institut Pasteur
A number of teams at the Institut Pasteur are dedicated to malaria research. In addition to vaccine research, several teams are carrying out more fundamental research both on humans and on the Plasmodium parasite and its vector, the Anopheles mosquito. This research is vital if we are to succeed in finding new ways of fighting malaria.
The Institut Pasteur is also taking part in a major European program, known as EVIMalaR, which involves 17 research institutes and universities from 7 European countries, as well as partners from 3 African countries (Mali, Sudan and Uganda). It seeks to integrate malaria research that is directed towards a better understanding of the basic knowledge of the parasite, its vector and of the biology of the interactions between the parasite and both its mammalian host and vectors.
This project started in 1st October 2009 and is currently funded until 30 September 2014.The research interest shall be focused on studies in the biology and pathology of the malaria parasite including immunobiology, pathophysiology, parasite molecular and cell biology, vector-parasite interactions and modelling and systems biology.
Development of novel antimalarials is a long and expensive process. Focus so far has been mainly on Plasmodium blood stages. The Malaria Proteases Inhibition (MaPI) project, coordinated by Jean-Christophe Barale aims at replenishing the drug pipeline with antimalarials active on new targets, expressed at different stages of both Plasmodium falciparum and Plasmodium vivax, the two main parasites responsible for malaria. The project builds on the recent validation by the Institut Pasteur team of hits targeting proteins, called SUB1 and SUB2, that orchestrate a cascade of events culminating in the egress of the parasite and invasion into new host cells. Importantly, available evidence indicates that these proteins play essential roles in blood stage as well as in liver stages. This R&D proposal will capitalise on these recent drug discovery efforts to execute, in collaboration with Sanofi, the translational research activities needed for the critical hit to develop a new generation of anti-malarial lead compound qualified to enter into pre-clinical phases.