Malaria

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229 million cases worldwide in 2019

94% of African malaria cases reported in inter-tropical areas in Africa

In France, approximately 5,500 imported cases each year

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Cause

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.

Symptoms

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.

Epidemiology

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). The African region is by far the most affected, with 94% of malaria cases reported in this region. Outbreaks may occur when populations with little previous exposure move into highly endemic regions.

There are imported malaria cases in Europe. In France, approximately 5500 imported cases are reported each year (source: Malaria fact sheet by WHO, et WHO 2019 Malaria report).

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, (divided into two subspecies, Plasmodium ovale curtisi and wallikeri), 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 long-tail macaque monkeys but can also infect men. It is only present in certain regions of Southeast Asia (Malaysia, Singapore, Thailand, Myanmar, Vietnam, Philippines and Cambodia).

Transmission

Malaria is transmitted to humans by the bite of female Anopheles mosquitoes, that got infected by biting an infected subject: female mosquitoes, by taking the blood meal necessary to produce eggs, injects the parasite to her host. Males do not bite. Transmission of Plasmodium from one person to another is therefore dependent on mosquitoes, with Anopheles gambiae being the main vector on the African continent.  Direct human-to-human contamination is possible, from an infected pregnant woman to her child (transplacental transmission) or by blood transfusion.

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 and P. ovale 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).
Prevention involves vector control and preventive treatments.

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.

For more information, see the Institut Pasteur medical center.

See also the WHO 2019 Malaria report.

Vaccine Research

Today, the only vaccine available against malaria is "RTS,S". This vaccine has had favorable results in phase III, and a pilot has been underway since 2018 in various African countries to establish its efficacy under normal use conditions.

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.

 

“The Geopolitics of the Mosquito” - Go further with our experts!

 

 

At the Institut Pasteur

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 eliminating malaria.


April 2021



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