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Malaria is an infectious disease in humans caused by a group of parasites known as Plasmodium. The disease is spread by mosquitoes and is found in most tropical and subtropical countries including Asia and America. The disease is caused by multiplication of the parasite inside red blood cells after being bitten by a mosquito, which acts as a vector. There are twenty-five different species of Plasmodium, but only four of these cause malaria in humans (Liu et al., 2010).There four human malarias are; Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale. Plasmodium vivax is the most common of the plasmodium which infect humans but it only causes mild symptoms and is rarely life threatening. The clinical outcome of Plasmodium ovale is similar to vivax in that it produces a very mild illness which is not life threatening. Plasmodium malariae causes more severe symptoms but the outcome is usually good. The most dangerous of the human malarias is caused by Plasmodium falciparum which kills hundreds of thousands of people every year globally (Breman, 2001).
Over 2 billion people, which is over 40% of the world's population, live in malarial regions. Malaria is broadly distributed and affects people in both the tropics and sub-tropics. The majority of cases of malaria occur in sub-Saharan Africa but other malaria endemic areas include most of Asia and South America. Malaria accounts for 25% of all the deaths in children living in Africa under the age of five and costs the continent $12 billion annually. (Snow et al., 2004). In many temperate areas such as Europe and the USA, malaria have been successfully eliminated other than cases caused by travel to infected regions.
Although the main global impact of malaria is the number of deaths, it impacts on many other aspects such as loss of income, reduced economic output and medical costs. Malaria was once seen as a consequence of poverty but it is now mainly seen as one of its causes as experts say that the disease slows African economic growth by up to 1.3% per year (Sachs and Malaney, 2002).
A partnership known as the global Roll Back Malaria (RBM) partnership was initiated by the World Health Organisation, UNICEF, the World Bank and the United Nations Development Program (UNDP) in 1998. This program had to the aim that by 2010, this combination of research groups, governments, development agencies and the media could reduce the global number of cases of malaria by half. They focus on the following areas of control and prevention;
Vector control and insecticide-treated bed nets
Early diagnosis of the infection followed by prompt treatment
Prevention and response to epidemics.
Increased focus on malaria treatment for pregnant woman
There are many charities that also help to achieve these goals. These include Malaria No More, Against Malaria and Spread the Net. A charity founded by Bill Gates, The Bill and Melinda Gates Foundation, is also funding many different projects and research towards potential vaccines.
Origins and Evolution
The origin of the Plasmodium parasite is currently unknown. Some groups of researchers believe it originated in Africa and has coevolved along with its hosts and non-human primates. A paper written in 2005 by Poinar, described the discovery of malaria parasites in mosquitoes that had been preserved in amber that were about 30 million years old, from the Palaeogene period. Research carried out by Hayakawa et al., 2008 and Joy et al., 2003, suggests that malaria has been a human pathogen for as long as humans have existed. A paper recently published in nature by Liu et al., 2010, suggests that humans may have originally transmitted P. Falciparum from gorillas. About 10,000 years ago, which was about the time that agriculture originated in Africa, malaria began to impact on the survival of the human species. A consequence of this impact on survival was the natural selection for genes which conferred Sickle Cell Anaemia and other blood disorders which gave a selective advantage against Malaria (Canali, 2008). Sickle Cell Anaemia, for example, causes red blood cells to be sickle shaped and these abnormally shaped cells cannot house the Plasmodium parasite, so infection cannot occur.
Human behaviour has been the major factor in the spread or eradication of the disease throughout history. Shifting population centres, varied standards of living and changes in methods of farming changing farming methods have contributed the rise and fall of malaria over time. Due to the majority of cases of malaria occurring in areas of poverty, where people cannot afford health care nor have access to hospitals, exact statistics do not exist. A consequence of this is that the majority of malaria cases are undocumented (Bremam, 2001). A recent study carried out in India suggested that the number of cases of malaria there has been hugely underestimated due to poverty and a lack of adequate diagnosis (Dhingra et al.,2010). Poverty has allowed malaria to remain in a large percentage of the worlds countries over history and will continue to allow its survival, while it has been eradicated in many others (Worrall et al., 2005). "Malaria is moulded and altered by local conditions that it becomes a thousand different diseases and epidemiological puzzles" (Hackett, 1938).
Pathogenicity of Plasmodium
The life cycle of the Plasmodium parasite is complex and varies in terms of incubation time and rates of reproduction between the different species (Sawyer, 1993). Figure 1 shows the life cycle diagrammatically, showing that both the human and mosquitoes are used as hosts. When a mosquito carrying the parasite bites a human, it injects parasites (sporozoites) into the subcutaneous tissue. The sporozoites then travel in the bloodstream directly to the liver. A study carried out by Mota et al., 2001, suggested that the sporozoites move through many hepatocytes before parasite development occurs. Each sporozoite develops into thousands of merozoites inside the hepatocytes and they then invade red blood cells after being released from the liver. The Malaria disease only begins once the parasite has begun to replicate asexually in the red blood cells. This is the way the disease can occur. P. Vivax and P. falciparum develop in red blood cells for two days, and produce roughly twenty merozoites per parasite. Some of the asexual parasites become gametocytes and they are essential for transmitting the infections to others as they are taken up by anopheles mosquitoes and the cycle continues (Breman, 2001).
Figure 1. The life cycle of the Plasmodim parasite.
Plasmodium uses both the mosquito and the human as a host. The mosquitoes act as a vector which continues the life cycle by housing the disease after biting an infected human and then infecting further individuals.
The Plasmodium parasite is mainly protected from the host's immune system due to it residing inside red blood cells and liver cells for most of its human life cycle, so is hidden from immune surveillance. To avoid the red blood cell, in which there are residing, being destroyed by the liver, the P. flaciparum parasite displays adhesive proteins on the surface of the red blood cells, which cause them to adhere to the surface of blood vessels and avoids entering the spleen (Chen et al., 2000). It is this adherence to blood vessels that lead to hemorrhagic complications in malaria as vessels can become blocked with masses of infected blood cells.
Treatment of Malaria
The first treatment of malaria was with quinine, a compound isolated from the bark of the Cinchona tree of South America. Technically quinine does not cure malaria as it does not kill all species of the parasite, but it kills enough of them to cure many people. It also does not kill at all stages of the Plasmodium life cycle but it can control the fevers of malaria and provide relief from suffering. In some areas where new anti-malarial drugs are unavailable, too expensive or ineffective, quinine is still used to treat malaria.
Quinine is an alkaloid that acts as a weak gametocide and blood schizonticidal against P.malaiae HYPERLINK "http://en.wikipedia.org/wiki/Plasmodium_vivax"and HYPERLINK "http://en.wikipedia.org/wiki/Plasmodium_vivax"P. vivax. An alkaloid is a naturally occurring chemoical compound containing mainly nitrogen atoms. It is accumulated in the food vacuoles of species of Plasmodium, in particular in, P.HYPERLINK "http://en.wikipedia.org/wiki/Plasmodium_falciparum" falciparum. It inhibits the hemozoin biocrystallization, and facilitates an accumulation of cytotoxic heme (Dondorp et al., 2005). As a blood schizonticidal agent, Quinine is much less effective than chloroquine but it is still widely used for the treatment of acute cases of P.falciparum. In areas where there are high levels of resistance to other drugs such as chloroquine and mefloquine, quinine is especially useful and it is also used in post-exposure treatment for people returning from a malaria endemic region.
Synthetic anti-malarial drugs
The first synthetic anti-malarial medication was developed in the 1930s. It was called Atrabrine and was used by troops in World War II. Other anti-malarial medications were also developed at this time including doxyxlycline and chloroquine.
Doxycycline is the most prevalent anti-malarial drugs prescribed as it is relatively cheap and effective. It is a tetracycline compound derived from oxytetracycline. Tetracyclines were one of the earliest groups of antibiotics to used and are currently still used to treat many infections. It is a bacteriostatic agent which binds to the 30s ribosomal subunit, which inhibs the process of protein synthesis, by preventing the 30s and 50s units from bonding. Doxycycline is used primarily used in areas where there is resistance to chloroquine but it can also be used in combination with quinine to treat cases of P.falciparum that are resistant. It cannot treat acute malaria as a monotherapy as it is not effective enough.
A number of anti-malarial drugs are used in combination. The treatment regimen varies according to the medication being used. The combination therapy of quinine and doxycycline is very effective against P.falciparum but but causes a number of side effects including hearing problems, nausea and depression. Chloroquine is a synthetic version of quinine and is better tolerated. Plasmodium, however, has become resistant to chloroquine in many countries. Some of the medications that are used to treat malaria are also used to prevent the disease. These drugs can be taken before travelling to malaria endemic regions to prevent infection by the parasite if bitten by an infected mosquito.
Artemisinin and its derivatives are a group of drugs that possess the most rapid action of all current drugs against P.falciparum malaria. Artemisinins are established antimalarial drugs with an extremely good safety profile (White, 2008). Artemisinin-based combination therapies (ACTs) are now recommended by the World Health Organization (WHO) as first-line treatment of uncomplicated falciparum malaria in all areas in which malaria is endemic. The starting compound, artemisinin is isolated from the plant Artemisia annua, a herb described in Chinese traditional medicine although it is usually chemically modified and used in combination with other medications. Use of the drug by itself as a monotherapy is highly discouraged by the WHO as there have been signs that malarial parasites are developing resistance to the drug. Combination therapies that include artemisinin are the preferred treatment for malaria and are both effective and well tolerated in patients. The drug is also increasingly being used to prevent and treat P.vivax infections (Dondorp et al., 20009).
Replacing ineffective, failing treatments (chloroquine and sulfadoxine pyrimethamine) with artemisinin-based combination therapies has reduced the morbidity and mortality associated with malaria. (Barnes et al., 2009) Parenteral artesunate is replacing quinine for the treatment of severe malaria. Recently, there have been signs that the efficacy of ACTs and artesunate monotherapy has decreased in western Cambodia. Artemisinin resistance would be disastrous for global malaria control (Dondorp et al., 2009).
The main method of malaria diagnosis is the microscopic examination of blood. As well as blood other samples have been investigated as a less invasive method including urine and saliva. (Sutherland and Hallett, 2009). In areas where laboratory diagnosis tests are not available, diagnosis is simply made using only a history of subjective fever. A paper written by Redd et al. in 2006, describes that by using clinical predictors including rectal temperature and nail bed palor, instead of using only the history of subjective fever, a correct diagnosis increased from 2% to 41%.
Each of the four Plasmodium parasites have distinguishing characteristics so currently the most economic and reliable method of malaria diagnosis is the microscopic examination of blood films. Traditionally, two different types of blood film are used; thin films and thick films. The parasite is best preserved in the thin films and this allows species identification. The thick films allow a larger volume of blood to be observed and are about eleven times more sensitive than the thin film, allowing low levels of infection to be detected. In the thick films, however, the appearance of the parasite is much more distorted so it is difficult to distinguish between species. In most cases, due to the pros and cons of each film, both films are used to give an accurate diagnosis. (Warhurst, 1996).
In many areas, microscopy is not available or there is a lack of experienced laboratory staff to carry out diagnosis. In these areas commercial antigen detection tests are generally used to diagnose malaria (Pattanasin et al., 2003). These immunochromatographic tests use venous blood or finger-stick and takes 15-20 minutes for a diagnosis, which is just displayed as coloured lines on a dipstick. These antigen tests are qualitative not qualitative, so it can be determined if a Plasmodium parasite is present but not how many are in the sample.
The first rapid diagnostic test for malaria used glutamate dehydrogenase as an antigen (Ling et al., 1986) but this was soon replaced by falciparum lactate deydrognase (PLDH), which is one of the most abundant enzymes expressed by P.falciparum.
Malaria can be diagnosed using rapid real-time assays. PCR, and other molecular methods, are more accurate than other methods of diagnosis, but to the high expense and need for experienced laboratory workers it is currently not suitable for use in developing countries (Mens et al., 2005). There are many diagnosis methods which use PCR to differentiate between species of Plasmodium. Multiplex PCR, nested PCR and real-time PCR can all be used for diagnosis of the disease (Boonma et al., 2007).
Malaria is an acute febrile disease whose course and severity depend upon the strain and species of the parasite which infects as well as the geographical origin of the infection. It also depends upon the age of the infected person, their genetic constitution, nutritional status and state of immunity.
The increase in the number of red blood cells infected with the parasite in different organs such as the brain, heart, kidneys and placenta is characteristic of infected by Plamodium falciparum. The interaction between the host molecules expressed on the red blood cells and the parasite-derived proteins on the surface causes the sequestration. In some cases of malaria, some of the receptors for parasite adhesion have been implicated, including chondroitin sulfate A and hyaluronic acid in infections in the placenta and intercellular adhesion molecule 1 (ICAM-1) in cerebral malaria.
Sometimes there are no diagnostic clinical features of malaria, but some patients will experience the classical periodic febril paroxysms which will occur every 48 or 72 hours, with afebrile asymptomatic intervals and a tendency to relapse over periods of months to years. The incubation period is the length of time between infection and the first clinical sign, which is usually fever, of the primary attack. Plasmodium falciparum has the shortest incubation time, which is roughly 7 days. The most known symptom of malaria is the febrile paroxysm or "ague attack." For 2 to 3 days before the first paroxysm, the patient may experience symptoms such as malaise, fatigue, chest pains and vomiting. Fever may be detected 2-3 hours before the paroxysms. The attack can be divided into 3 stages; cold, hot and sweating. The cold stage starts with a sudden and inappropriate feeling of cold and apprehension. Although the patient's core temperature is high and is quickly rising, there is an intense peripheral vasoconstriction. This phase can last for 15-60 minutes and then the patient feels waves of warmth and the hot phase begins. They will quickly become incredibly hot and experience severe headaches, palpitations and nausea while the body temperature continues to rise as high as 40-41ËšC. The hot stage lasts for 2-6 hours. In the sweating stage the patient sweats profusely and the fever declines over the next 2-4 hours and the body temperature is reduced back to normal. The total duration of a typical malarial attack lasts for 8-12 hours. Figure 2 shows the changes in core body temperature, over four days, in patients infected with one of the four types of malaria. The interval between attacks is determined by the length of the asexual erythrocyte cycle which is 48 hours in P.falciparum, P.ovale and P.Vivax, producing paroxysms on alternate days, a tertian attack. In P.malariae the interval is 72 hours, causing febril paroxysms on days 1 and 4, a quartan attack. Relapses of P.vivax and P.ovale can occur when hypnozoite forms of the parasite are reactivated in the liver.
Figure 2. Changes in core body temperate in patients with infection with P.falciparum, P.vivax. P.malariae and P. ovale over four days.
(Breman J (2001).
It has been estimated that due to the high rate of population increase in malarial regions the number of cases of malaria globally will double in the next decade (Redd, 2006). The burden of malaria is not evenly distributed throughout the world. The global pattern of malaria transmission is due to it being a tropical disease that is centred in the tropics that can also reach sub-tropical regions in five different continents. Temperate regions have also been reached by malaria, they are characterised by strong seasonality and cold winters. The base case reproduction rate of malaria is much lower in temperate regions than in the tropics so targeting of vectors and case management in temperate regions allows malaria to be more easily controlled. Below 18ËšC, Anopheles mosquitoes are much less likely to transmit the disease and at temperatures below 16ËšC, the Plasmodium parasite ceases development completely (Colluzzi, 1999). The seasonal temperature variation is the main factor in explaining the geographical distribution of the disease but other factors such as rainfall and humidity also have an effect on the distribution (Gilles and Warrell, 1993). Malaria also affects the movement of people. The risk of malaria has a great affect on the movement of human populations and the making of new settlements. This has an effect on the development and economic growth of some regions (Sawyer, 1993).
Figure 3. The global distribution of malaria. Map showing the changes in global distribution of malaria between 1946 and 1994. It shows that the disease is slowly being confined to tropical regions.
(Sachs and Malaney, 2002).
Generally, malaria prospers most where humans prosper the least. When studying the global distribution of per-capita gross domestic product (GDP,) there is a striking correlation between malaria and poverty (Gallup and Sachs, 2001). Comparisons between the income of malarial countries and non-malarial countries show that the average GDP in 1995 was US$1,526 in malarial countries compared to US$8,268 in countries without malaria, which is more than a five-fold difference (Gallup and Sachs, 2001). There is also lower economic growth rate in countries with malaria. Between 1965 and 1990, countries where a large proportion of their population lived in malarial regions had an average growth in GDP per year of 0.4%, compared to an increase of 2.3% per year in non malarial countries (Gallup and Sachs, 2001). The correlation between poverty and malaria could be due to malaria causes poverty but could also be due to poverty causing malaria. The causality probably runs in both directions.
Poverty itself does contribute to the spread of malaria. Personal expenditures on prevention methods such as insecticides and bed nets, increased urbanisation and increased funding for government control can all reduce malaria transmission. Economic growth alone however is not enough. There are still wealthy countries with high averages temperatures such as the United Emirates and Oman who still have a high number of cases of malaria and people from wealthy households still die from the disease. When the number of malaria case in African villages is stratified by household income, there are usually only small differences between income classes. (Filmer, 2000.)
Malaria causes high rates of mortality and much of the mortality in endemic areas is concentrated amongst children under the age of five. Apart from the direct demographic consequences of this high rate of mortality there are also many indirect consequences. Evidence, historically has shown that high child mortality rates has lead to high fertility rates, leading to high population growth rates, as well as other factors such as decreased household income (Handa, 2000). The affect of malaria on children includes reduced education due to missing school and more serious effects such as impaired cognitive development and reduced learning ability. There is debate about whether malaria is associated with mental functioning but a number of channels have been identified through which malaria can affect cognitive ability in different way (Holding and Snow, 2000). For example it has been found that children with malaria have a poorer nutritional status than children without the disease (Rowland et al. 1977), which can lead to impaired brain development.
Malaria also has an affect at the foetal stage of life. Due to reduced immunity, pregnant woman are more likely to be infected by malaria and anaemia in pregnant woman due to malaria causes babies to be born with a low birth weight. Studies have shown that this has an impact on cognitive, neurosensory and behavioural development in infants (McCormick et al., 1992). When compared with normal birth weight children, low birth weight causes children to be 2-4 times more likely to experience failure at school, (Taylor, 1994) leading to decreased levels of education in future generations.
One method to try and control malaria is to target the mosquito; the vector which carries and spreads the disease. Human malaria is spread by the Anopheles mosquito which has a two part life cycle. The first part is an aquatic or pupal stage which is followed by a terrestrial adult stage. It is during the adult stage when it can take up the malaria parasite and infect humans. During its pupal stage, the mosquito lives on the surface of water where it is vulnerable. By targeting Anopheles mosquitoes at this stage, where they reproduce, some methods of elimination helped with the reduction of deaths caused by malaria. The draining of rice paddies in the Sichuan Province of China, during the months when they are not used, helped in decreasing the number of cases of malaria. (Qunhua et al., 2004).
Another method of control is the use of chemicals against Anopheles mosquitoes. The first chemical used against mosquitoes was a poison known as "paris green." Paris green (cupric acetoarsenite), is a known poison and it was first used in 1867 in Colorado to control the potato beetle. In the early 1900's it was sprayed from aeroplanes into swamps to try and eradicate mosquitoes in Louisiana. As paris green is not soluble in water, it was mixed with kerosene to be sprayed. Paris green did contribute significantly to the elimination of malaria from the United States as well as Egypt, Brazil and Italy. As the kerosene caused pollution in the form of oily residues washing up on lake shores and after the Second World War, paris green was replaced by another compound known as dichloro-diphynyl-trichloroethane (DDT.) DDT was invented by a German pharmacist, Othmar Zieller, in 1874, but it was Paul Hermann Muller who experimental exposed mosquitoes to DDT in 1939. He showed how effective the chemical was against insects and consequently won a Nobel Prize for his findings.
At first DDT was extremely effective in killing many disease carrying insects and due to it not being readily absorbed into the skin, it appeared to be harmless to humans. As well as killing insects on impact, DDT remains in soil or on plants, and kills weeks or months after it has been applied. In the 1950s problems began to accumulate with the insecticide. DDT does not readily degrade into harmless substances in the environment and some of the products it does break down into are toxic. DDT therefore entered natural food chains and accumulated in the tissues of animals and humans. Another problem with DDT was that it did not kill specifically. DDT is a non-selective poison, therefore as well as killing mosquitoes and other pests it also kills beneficial insects such as bees, butterflies and other pollinators. The final problem that arose with DDT was that its effectiveness against mosquitoes began to decline as more resistant mosquitoes survived where the more susceptible ones were killed. This produced a species of mosquito that are resistant to DDT. Other promising strategies exist and ongoing research is being conducted into malaria prevention. A particularly interesting area of research currently underway is the genetic modification of mosquitoes to make them incapable of carrying the Plasmodium parasite (Riehle et al., 2003). Male mosquitoes with genetically engineered genes would be raised in laboratories and released into the environment to compete with wild-type males. If a female Anopheles mosquito, which only mates once in her life, were to mate with a genetically engineered male, the genetic change would be passed onto their offspring and the number of mosquitoes in future generations capable of housing Plasmodium would be reduced.
Malaria Vaccine Approaches
Intensive research is being carried out into creating a vaccination against malaria as there are currently no vaccines that can be effectively used in clinical practice. To develop a vaccine to prevent malaria is a very complex process. Many different aspects need to be considered before deciding which specific strategy a vaccine should follow. Due to the development of multiple drug resistant parasites, P.falciparum has shown to be capable of evolutionary change. The PlasmodiumHYPERLINK "http://en.wikipedia.org/wiki/Plasmodium" species has a much greater rate of replication than is actually required for transmission in the life cycle. This allows drug treatments that can reduce the reproductive rate, but not stopping it completely, to produce a high selection pressure, and this causes the development of resistance. When considering a potential vaccine candidate, it is important to consider the process of evolutionary change. The efficacy of any new vaccine could be greatly reduced by the development of resistance and could be rendered a useless treatment within a short period of time. Parasites are much more complex organisms than viruses or bacteria, having more complicated life cycles and structures. This presents problems in vaccine development but also increases the number of potential targets for a vaccine. The initial vaccine develpemnt problems are usually caused the parasites particularly complex life cycle. Despite the large number of vaccines currently available, there are none that specifically target parasitic infections.
Scientists working to produce a vaccine against malaria have to look at the different vaccine candidate and formulations which are designed to activate an immune response in the host which would destroy the Plasmodium parasite. Due to a lack of understanding of the immune response involved in protection against parasitic diseases, the production of a vaccine is a challenge. The Plasmodium parasite is very complex and this has lead to researchers pursuing a variety of different vaccine development approaches. It is possible that a successful vaccine against malaria will have to combine more than one approach to produce a high degree of efficacy.
Types of malaria vaccines
When research first began into the production of a vaccine against malaria, efforts were focused on the parasite's pre-erythrocytic stage. This is when the parasite is in the form of a sporozoite where it enters the blood and travels to the liver. Currently researchers are looking at trying to develop vaccines aimed at three different stages of the life cycle. Figure .shows the three groups and describes the stages which they target.
Figure 4. Vaccine developed focusing on 3 stages; Pre-erythrocytic stage, blood-stage and transmission blocking stage. (www.rollbackmalaria.org)
Pre-erythrocytic vaccine candidates
This group of vaccines aims to protect patients against the earliest stages of the malarial infection. These vaccines would induce an immune response before the parasitic cells invaded the liver to replicate. The research on these vaccines includes the use of recombinant or genetically engineered antigens from the surface of the infected liver cell or from the actual parasite. Live attenuated vaccines which are produced using a weakened version of the parasite are yielding promising results (Van Buskirk et al., 2009). Studies also look into the use of DNA vaccines which contain the genetic information required for producing the vaccine antigen in the patient given the vaccine (Lu et al., 2008).
The most destructive stage of the parasite's life cycle is when they rapidly replicate within the red blood cells. Blood-stage vaccine candidates target Plasmodium at this stage but do not aim to block all infection. By reducing the number of parasites in the circulating blood they aim to reduce the severity of the disease. Studies have shown that people who have been exposed to malaria numerous times throughout their lifetime, and survived, develop a natural immunity to the disease (Gubta et al., 1999). The aim of blood stage candidate vaccines is to allow the body to develop this natural immunity without the risk of suffering from the infection.
By immunising patients with blood-stage merozoite antigens it has been shown that they are protective in some animal models and one blood-stage vaccine tested in humans using different antigens. (Genton et al., 2002)(Collins et al., 2004).
Currently, the leading blood-stage vaccine candidates are all merozoite proteins, either located within the apical organelles or on the merozioite surface, shown on figure 5. Research has been carried into the development of a blood-stage vaccine for many years but little progress has been made.
The Combination B vaccine, which showed protection against parasitemia, was conducted over
10 years ago. However, no further testing of this vaccine or any of its components in phase II studies has been conducted since. Currently there are only four blood-stage vaccines which have been tested in phase II trials. Of the two that are published, Combination B showed some degree of efficacy but merozoite surface protein 1 (MSP1)-42 did not. Although RTS,S has shown promising results in many different trials, another pre-erythrocytic vaccine, multi-epitope thrombospondin-related adhesion protein (METRAP) (Bejon et al., 2006) did not give the desired protection.
Figure 5. The structure of the P.falciparum merozoite and major antigens.
There is specific organelles that are involved in erythrocyte invasion at the apial end of the merozoite. The rhoptries and micronemes are thought to release proteins which bind to erythrocyte receptors when invasion occurs. The merozoite also has a plastid remnant known as an apicoplast and dense granules. Vaccine candidate antigens as well as merozoite ligands are present on the surface of the merozoite. Listed in the diagram are the known proteins of the merozoite surface and organelles.
(Bejon et al., 2006).
Transmission- blocking vaccine candidates
Transmission- blocking vaccine candidates aim to introduce antibodies which interrupt the life cycle of the parasite. The parasite would be prevented from maturing in the mosquito after it has bitten a vaccinated person. This vaccine is aimed at reducing the spread of the disease, not to prevent a person from becoming infected. If this vaccine was successful it would hopefully reduce deaths from malaria in endemic communities.
Any vaccine produced would ideally have the ability to be of therapeutic value as well as preventing further transmission and is likely to consist of a combination of antigens from different phases of the parasite's development. The Program for Appropriate Technology in Health (PATH) Malaria Vaccine Initiative has several candidate vaccines in development and clinical trials are underway. There is one candidate vaccine which started phase III evaluation in May 2009, known as RTS,S/AS01, which is aimed at being used for children living in endemic regions and not for travellers (Lell et al., 2009).
Malaria and other diseases
An interesting result which came from a large-scale trial of incecticide-treated bed nets was that the reduction in mortality from the use of bed nets was not just in cases where people died from malaria. The number of reduction in deaths due to the use of bed nets was far greater in total deaths data compared to deaths caused solely by malaria. This suggests that malaria may be closely linked which other diseases in either a casual or direct way. It could also imply that malaria causes patients to be more susceptible to contracting other infections (Snow et al. 1999). Even before birth, the indirect affect of malaria can begin. Pregnant women are much more likely to be infected with malaria and malaria during pregnancy can cause miscarriages and deaths in infants. Infection with both acute and chronic malaria can cause an alteration in the immune system and they way in which the body responds to vaccination, causing an increased susceptibility to other infections. Chronic malaria has also been shown to be an important causal factor in developing anaemia (Hedberg et al., 1993), which has also been shown to have an affect on people physically causing lower worker output and productivity (Scholz et al., 1997). Malaria has been shown to be associated with Burkitt's lymphoma, hyper-reactive malarial splenomegaly, nephrotic syndrome and chronic renal damage. Furthermore, malaria is increasingly becoming a factor involved with the transmission of the human immunodeficiency virus (HIV) as much of the blood supplies in sub-Saharan Africa are infected with HIV and young people with malaria often have blood transfusions.
Malaria has been a dangerous disease for humans for as long as the human race has existed. Not long ago, it seemed that malaria would be eliminated. Today, however, malaria is once against a huge problem in much of the world, killing hundreds of thousands of people each year. Malaria is currently found in 107 countries and over 40% of the world's population lives in malaria endemic areas.
Today, numerous strains of malaria are resistant to many of the medications that have worked against it in the past and the mosquito vector that spreads the disease have developed resistance to many pesticides and drugs. There is an urgent need to design new drugs and vaccines that can continuously interrupt the life cycle of Plasmodium. A huge amount of information is now available from the genome-wide studies of the proteome and transcriptome of Plasmodium and it is now a challenge to utilise this information to develop the appropriate therapeutic agents against the disease. The research into a vaccine against malaria is currently at a crucial stage and it is important that momentum is maintained so that equal progression can be achieved in the future.
The future of malaria is uncertain, but the integrated approach that is being taken and research into vaccines, medications, cultural changes, new safe and effective treatments and genetic modification of organisms may finally help to bring the disease under control.