Malaria – a growing threat

Key text

Mosquitoes spread the disease

Malaria is caused by parasites (Plasmodium sp.) that live in red blood cells and cells of the liver. The parasites are transmitted from person to person by the female Anopheles mosquito (Box 1: Life cycle of malarial parasite).

What has been done to control malaria?

During the 1950s the World Health Organization carried out a program to eradicate malaria from some parts of the world. Insecticides, mainly DDT, were used to control mosquito populations. At first this program was successful, and malaria was eradicated from southern Europe, the United States and the former Soviet Union. But it soon became clear that, in hotter and more humid climates where mosquitoes are present all year long, they had become resistant to the insecticides being used.

Related site: Malaria: Past and present Describes the history of malaria research and early attempts to control the disease. (Nobelprize.org, Sweden)

Other methods to control malaria were attempted, including drug treatment of whole populations, but the malarial parasites became resistant to the drugs. By 1970, with the number of cases of malaria increasing, it became obvious that the program had failed.

Fighting malaria on two fronts

Today, the battle against malaria is continuing on two fronts: fighting mosquitoes and fighting the disease itself (Box 2: Controlling malaria).

• Fighting mosquitoes. A range of methods are used to deal with mosquitoes. A simple but effective method is for people to sleep under nets that have been soaked in insecticide. This has been tried in Vietnam and parts of Africa and has been found to reduce the incidence of the disease.

• Fighting the disease. Good health care, with early detection and full treatment with drugs, is essential. Unfortunately, most cases of malaria occur in countries that cannot afford such programs.

Drugs can treat malaria

Malaria can be treated successfully with a variety of drugs if it is caught early enough. Until recent years, quinine was the most effective drug given for cases of cerebral malaria. But some forms of the malarial parasite have become resistant to quinine. New and more expensive drugs have to be administered in these cases.

Fortunately, two recent studies have shown that an old Chinese herbal remedy made from the shrub, Artemisia annua, can effectively treat quinine-resistant malaria. The active compound – artemisinin – derived from this plant has been shown to clear the parasite from the blood more quickly and with fewer side effects than quinine-based drugs. This is good news for Africa, where the majority of malaria cases occur. The recent discovery of exactly how artemisinin kills the malarial parasite may lead to a series of new anti-malarial drugs.

Progress towards a malaria vaccine

Related site: Malaria vaccines Describes a number of campaigns aimed at controlling malaria and Australian research on malaria vaccines. (Medical Journal of Australia)

Vaccines work by getting the body's immune system to respond to particular antigens produced by the disease-causing organism – in this case, the malarial parasite. Unfortunately, the malarial parasite is constantly changing, so its antigens are also constantly changing. But progress is being made, with researchers around the world racing to produce effective anti-malaria vaccines (Box 3: Anti-malaria vaccine).

Malaria in Australia

The last major outbreak of malaria in Australia occurred at the end of World War II, when servicemen infected with malaria returned from Papua New Guinea. But it was not until 1981 that Australia was officially declared malaria-free by the World Health Organization. Even so, there are about a thousand reported cases of malaria in Australia each year, and one death a year. However, the vast majority of these people contracted the disease overseas.

Fortunately, the isolation of communities in northern Australia and the small population ensure that there is no human reservoir of the disease. If a person does contract malaria, the health services are quickly informed, the infected person is treated and the community is tested for malaria.

Box 1. Life cycle of malarial parasite

In the host's liver cells the parasite multiplies repeatedly. After about 5 days there are in the order of 40,000 new parasites, called merozoites. At this stage, the liver cell bursts and the merozoites attack red blood cells. In the red blood cells, the parasite divides again, forming about 16 new merozoites which are released to invade new red cells. From time to time, some merozoites form gametocytes. These can be taken up by a mosquito with a blood meal.

1. Malarial parasites mature into sporozoites in the salivary glands of a mosquito and enter a human when the mosquito bites.

2. Sporozoites invade liver cells and reproduce asexually many times, forming large numbers of merozoites.

3. The infected liver cells burst, releasing merozoites.

4. Merozoites invade red blood cells and continue to reproduce asexually. Each red blood cell produces an average of 16 to 20 merozoites. Occasionally 32 merozoites are seen. This is because the red blood cell was originally infected with two parasites.

5. Infected red blood cells rupture and release the parasites and the toxins that cause fever and chills.

6. Some of the parasites are able to form gametocytes.

7. A female Anopheles mosquito picks up gametocytes when she bites an infected person. The gametocytes become gametes. Sexual reproduction of the parasite occurs in the mosquito’s gut.

Related sites

• Malaria (Department of Medical Entomology, University of Sydney, Australia)

• Walter and Eliza Hall Institute, Australia
  • Biology of Plasmodium parasites and Anopheles mosquitos
  • WEHI-TV – the infection pathway of the malaria parasite (Requires Quicktime)

• From mosquito to microscope: Research on malaria at the Advanced Light Source (Lawrence Berkeley National Laboratory, USA)

Box 2. Controlling malaria

A little thought will show why better treatment of malaria is more important than mosquito control. A single malaria infection, if untreated, can last in a human for more than a year. Adult mosquitoes only live a very short time (on average 3-4 days), so it's unlikely that malaria can persist in the mosquito population for more than about 3 weeks. If you kill the mosquitoes but don't treat the people, you have to eradicate ALL the mosquitoes for more than a year. Total eradication is basically impossible at an acceptable environmental cost. On the other hand, you could eradicate malaria by treating all the people for about a month.

We have had outbreaks of malaria in Australia in the past, and we still have plenty of mosquitoes that can transmit malaria. An increased population density and a trend towards more outdoor living are factors that ought to make malaria more prevalent, and yet we have been officially malaria-free since 1981. The reason we no longer have malaria in northern Australia is an example of the effectiveness of prompt treatment. It takes about 10 days after you get sick from malaria before the gametocytes mature enough to infect mosquitoes. So if a person is treated in the first 10 days after getting sick, there is no chance of that person giving malaria to mosquitoes. In Australia, it is now highly unlikely that someone will be sick with malaria for 10 days and not be treated. Hence no malaria.

A particularly good example of the effectiveness of early detection and treatment of malaria has been the eradication program in China. Malaria in China has fallen from around 8,000,000 cases per year to about 50,000 in the last 15 years, almost entirely as a result of putting in place a case detection and treatment program. This involves checking everyone for malaria if they have a fever. If someone has malaria they get medicine for it; and if there are several cases in a village, then everyone gets medicine, regardless of whether they are sick or not.

Widespread spraying programs have rarely been used as a control program for malaria. They are costly and ineffective. By far the most common form of spraying has been to spray houses with a contact insecticide. This kills mosquitoes when they rest on the walls. Selective spraying like this has a relatively minor impact on the environment.

Related sites

• Malaria: What you should know (ABC Online's Special Lab Feature)

• Malaria (ABC radio's The Health Report, 28 February 2000)

• Control of malaria vectors in Africa and Asia (University of Minnesota, USA)

Box 3. Anti-malaria vaccine

The malaria parasite of the Plasmodium genus is a molecular chameleon that can change its guise to deceive even the wondrously adaptable weaponry of its host's immune system.

Australian scientists are working on vaccine

Dr Anders' research group is working on a vaccine against Plasmodium falciparum, deadliest of the four human malaria parasites. Ideally, he says, the vaccine will also protect against Plasmodium vivax.

Genetic diversity of the parasite presents difficulties

Relentless selection pressure from the human immune system has seen some of the parasite's genes become extremely polymorphic. This means that new strains are constantly emerging as meiosis reassorts the various alleles of these genes. In a single village in Papua New Guinea, for instance, individuals may have antibodies to many different parasite strains. This genetic diversity presents a formidable obstacle to a vaccine, says Dr Anders.

Targeting specific antigens is not the answer

Any vaccine that targets a narrow spectrum of antigens is unlikely to be protective, because at different times and in different populations the immune system may be targeting quite different antigens. Moreover, immunising against specific antigens may only impose pressure on the parasite to change its identity. Dr Anders says monkeys immunised against a malaria antigen of low variability in nature became immune, but the parasite broke through by deleting the gene for that antigen.

Parasite can change its spots

Most protozoan parasites have a remarkable ability to 'change their spots', by switching between forms of a highly variable protein antigen. In malaria, this antigen is expressed on the surface of infected red blood cells. The immune system limits the initial parasitaemia by directing its antibody attack at this antigen. But the parasite then switches off the gene for that antigen and begins expressing another variant.

Why does the parasite betray its presence?

The parasite itself is safely hidden inside a red blood cell, where it feeds and multiplies. So why does it express its antigen on the surface of the cell where it is visible to the immune system? Dr Anders says it cannot avoid doing so. During the latter half of its 48-hour asexual phase, the different forms of the variant antigen serve to anchor the parasitised red cells to the lining of blood vessels in a range of different tissues. This means the parasite can avoid passing through the spleen, which swarms with hostile phagocytes and antibody-secreting B-cells. After rupturing, the infected cells release a new flush of parasites into the bloodstream, triggering the recurrent waves of fever typical of malaria.

Will scientists be able to produce an effective vaccine?

So what is the prospect for an effective vaccine, when the very idea of a vaccine is to elicit a protective immune response against specific, constant antigens?

'Several things make us very optimistic,' says Dr Anders. 'First, immunity does develop naturally – most human deaths from malaria are in children under the age of four. After that, symptoms become less severe and people develop significant immunity and suffer less severe, briefer episodes of parasitaemia than non-exposed individuals.

'Those who have acquired immunity may be making antibodies against secreted toxins that cause the classic symptoms of malaria, rather than against structural antigens, which opens another promising avenue for vaccine development.'

By comparing antibodies from villagers in Papua New Guinea, monkeys and mice, the Australian researchers have identified shared features in several antigens from the blood stages of each parasite species.

Vaccine could reduce the incidence of malaria

'Our evidence suggests that the protective immune response is against the asexual blood stage, which is the major cause of illness and death in humans. A vaccine against this phase alone could have a dramatic impact on death rates,' Dr Anders said.

But the researchers are exploring multi-component vaccines, combining several antigens from the blood-stage with antigens from other stages of the malaria parasite's life cycle. These blood-stage antigens could be combined with a vaccine such as that being developed by Glaxo Smith Kline, to improve the effectiveness of the vaccine.

Related sites

• Malaria vaccine warrants more support (Australasian Science, September 2008)

• Australian Broadcasting Corporation (transcripts)
  • The hunt for a malaria vaccine (The Science Show, 27 July 2002)
  • Sequencing the malaria genome (The Science Show, 2 March 2002)
  • Malaria vaccine (Quantum, 27 May 1999)

• Cooperative Research Centre for Vaccine Technology

Activities

• Science upd8 (UK)
  You will need to register to access activities but they are free.
  • Mosquitoes versus malaria – students evaluate the benefits and uncertainties with the use of genetically-modified mosquitoes.

• Global Education (AusAID, Australia)
  • Managing mozzies – a series of activities relating to the spread of vector-borne diseases (eg, malaria) in the Pacific. A case study and teachers notes are also available.

• National Center for Case Study Teaching in Science (University of Buffalo, USA)
  • To spray or not to spray: A debate over malaria and DDT – students read a case study then discuss a series of questions. Case teaching notes are available.

Activity 1. Malaria in Australia

• Explain why occasional cases of malaria are reported in Australia.

Teachers notes

Most of the cases reported in Australia have been contracted overseas, in regions where malaria is prevalent.

Activity 2. Aspects of the life cycle of the malarial parasite

• Explain this phenomenon in terms of the life cycle of the malarial parasite.

Teachers notes

Malarial parasites initially travel to the host's liver. In the host's liver cells the parasite multiplies repeatedly. After about 5 days there are in the order of 40,000 new parasites, called merozoites. At this stage, the liver cell bursts and the merozoites attack red blood cells. In the red blood cells, the parasite divides again, forming about 16 new merozoites which are released to invade new red cells.

The merozoites burst out of the blood cells at regular intervals. The release of the parasites and associated toxins causes a fever. The length of the growth cycle is specific for the species of Plasmodium. There are four types of malarial parasite which infect humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malarial. The first three have a 48-hour blood cycle (causing fever every 2 days); Plasmodium malarial has a 72-hour blood cycle (causing fever every 3 days).

The first attack of fever usually occurs about 2 weeks after a person has been infected. During this time the parasites are multiplying in the liver, and then in the blood, and no fever is experienced by the infected person.

Often people infected with Plasmodium vivax or Plasmodium ovale experience no symptoms for a number of years after their initial illness. During this time the parasite remains dormant in the liver, but can become active again, causing a relapse.

Further reading

Nature
19 November 2009, pages 298-300
Malaria: Evolution in vector control (by Yannis Michalakis and François Renaud)
Answers a series of questions on malaria and its control by targeting mosquitos.

27 May 2009
Malaria vaccine enters phase III clinical trials (by Anjali Nayar)
Provides an update to the development of a malaria vaccine.

New Scientist
29 May 2009, pages 38-41
Brain-scrambling bugs could tackle mosquito plagues (by Rachel Nowak)
Looks at a method of preventing mosquito-borne diseases using bacteria.

3 May 2008, page 16
Enzyme could be malaria's weakest link
Describes research on the parasite that causes malaria.

Scientific American
January 2008, pages 21-22
A better mosquito net (by Eva Kaplan)
Discusses the need for more innovative designs of mosquito nets to fight malaria.

December 2005, pages 56-63
Tackling malaria (by Claire Panosian Dunavan)
Scientists are using nets, insecticides, combinations of drugs and studying survivors of childhood illness to prevent malaria or lessen its severity.

Useful sites

Describes the lifecycle of the malaria parasite in an interactive animation. A range of other information on malaria biology, control and health issues is also available on the website.
http://malaria.wellcome.ac.uk/node40036.html

Malaria (Department of Medical Entomology, University of Sydney, Australia)

Gives information about malaria and its presence in Australia. Also provides links to FAQs about insect-borne diseases.
http://medent.usyd.edu.au/fact/malaria.htm

Malaria – An on-line resource (Division of Laboratory Medicine, Royal Perth Hospital, Western Australia)

Information for medical practitioners and laboratory scientists, written in an accessible style. Topics covered are diagnosis, history, prophylaxis, treatment and test and teach. Test and teach includes photomicrographs of blood films for malaria identification.
http://www.rph.wa.gov.au/malaria.html

Malaria special (Nature.com, UK)

Provides information on many aspects of malaria including parasite genome sequencing, treatment options, vaccines and a plasmodium lifecycle movie.
http://www.nature.com/news/specials/malaria/index.html

Risk of malaria transmission (The Exploratorium, USA)

Provides a map showing an increase in conditions suitable for malaria transmission in Europe and the eastern United States.
http://www.exploratorium.edu/climate/global-effects/data3.html

World Health Organization

• Malaria
  http://www.who.int/health_topics/malaria/en/

• Malaria fact sheet number 94
  http://www.who.int/mediacentre/factsheets/fs094/en/

Drug tactic cuts childhood malaria by 86 per cent (Science and Development Network, UK)

Suggests that the incidence of malaria in children can be reduced by giving artemisinin treatment during the transmission season.
http://www.scidev.net/en/news/drug-tactic-cuts-childhood-malaria-by-86-per-cent.html

Australian Broadcasting Corporation

• Malaria drugs may get new lease of life (News in Science, 25 September 2009)
  Reports on Australian research that shows how the malaria parasite resists an anti-malarial drug.
  http://www.abc.net.au/science/articles/2009/09/25/2693886.htm
• Malaria vaccine (Innovations, 25 September 2006)
  Reports on Australian research to produce a cheap and effective malaria vaccine.
  http://www.abc.net.au/ra/innovations/stories/s1745882.htm

• Malaria (Catalyst, 20 July 2006)
  Describes Australian research towards a malaria vaccine about to be trialled.
  http://www.abc.net.au/catalyst/stories/s1692348.htm

• Malaria vaccine (New Dimensions, 19 August 2003)
  Two Australian scientists discuss their approaches to developing an anti-malaria vaccine.
  http://www.abc.net.au/dimensions/dimensions_health/Transcripts/s927466.htm

• The hunt for a malaria vaccine (The Science Show, 27 July 2002)
  Includes interviews with locals in Papua New Guinea about living with malaria as well as reports from scientists who are searching for an effective vaccine.
  http://www.abc.net.au/rn/science/ss/features/suitcase/png/default.htm

• Malaria in Malawi, bittersweet success
  This feature looks at the research associated with the Blantyre Malaria Project in a small central-African republic.
  http://www.abc.net.au/science/slab/malaria/default.htm

Glossary

antibody. A protein produced by the body's immune system in response to a foreign substance (antigen). An antibody reacts specifically with the antigen that induced its formation and inactivates the antigen. Our bodies fight off an infection by producing antibodies.

antigen. Any foreign substance, usually a protein, that stimulates the body's immune system to produce antibodies. (The name antigen reflects its role in stimulating an immune response – antibody generating.)

B-cell (B-lymphocyte). A type of white blood cell that originates and develops in the bone marrow. B-cells can be stimulated to produce antibodies.

cerebral malaria. A type of malaria in which the red blood cells obstruct the blood vessels in the brain. Other vital organs can also be damaged. Cerebral malaria often leads to the death of the patient.

gamete. A cell, such as a sperm or an egg, that is specialised for fertilisation. Gametes have a single set of chromosomes.

gametocyte. A cell that can develop into a gamete.

gene. The basic unit of inheritance. A gene is a segment of DNA that specifies the structure of a protein or an RNA molecule.

genetic diversity. The variety of different types of genes in a species or population. Genetic diversity is really a form of biodiversity.

immune system. The cells, tissues and organs that assist the body to resist infection and disease by producing antibodies and/or altered cells that inhibit the multiplication of the infectious agent.

meiosis. A division of the nucleus that involves the separation of pairs of chromosomes into different cells. Meiosis takes place in the reproductive organs of sexually reproducing organisms. Meiosis involves two nuclear divisions, both of which may take place before division of the cell itself is complete. The eventual result is four cells, each with half the number of chromosomes present in the original cell. Crossing over of chromosomes during meiosis creates new combinations of genes in the progeny that were not present in either adult. For more information see How cells divide: Mitosis versus meiosis (Public Broadcasting Service, USA).

merozoite. A cell formed by asexual reproduction in the life cycle of plasmodium. Merozoites disperse and infect additional red blood cells within the host.

parasitaemia. The presence of parasites in the blood.

parasite. An organism that lives on or in an organism of a different species (the host) and gains some advantage at the host's expense.

pathogen. An organism capable of causing a disease.

phagocyte. A type of white blood cell that can engulf and destroy foreign organisms, cells and particles. Phagocytes are an important part of the immune system.

polymorphic. Literally meaning having more than one form. In terms of genes it means that there are several variants (alleles) of a particular gene that occur simultaneously in a population.

protozoan. A single-celled animal.

quinine. A bitter-tasting drug obtained from the bark of the cinchona tree. This plant is related to coffee and gardenia. Quinine has been used in the treatment of malaria.

sporozoite. One stage of the Plasmodium life cycle. Sporozoites are formed in the mosquito and are transferred to the host where they move to the liver cells.

vaccine. A preparation consisting of antigens of a disease-causing organism which, when introduced into the body, stimulates the production of specific antibodies or altered cells. This produces an immunity to the disease-causing organism. The antigen in the preparation can be whole disease-causing organisms (killed or weakened) or parts of these organisms.