Everything about Ague totally explained
Within the red blood cells the parasites multiply further, again asexually, periodically breaking out of their hosts to invade fresh red blood cells. Several such amplification cycles occur. Thus, classical descriptions of waves of fever arise from simultaneous waves of merozoites escaping and infecting red blood cells.
Some
P. vivax and
P. ovale sporozoites don't immediately develop into exoerythrocytic-phase merozoites, but instead produce hypnozoites that remain dormant for periods ranging from several months (6–12 months is typical) to as long as three years. After a period of dormancy, they reactivate and produce merozoites. Hypnozoites are responsible for long incubation and late relapses in these two species of malaria.
The parasite is relatively protected from attack by the body's
immune system because for most of its human life cycle it resides within the liver and blood cells and is relatively invisible to immune surveillance. However, circulating infected blood cells are destroyed in the
spleen. To avoid this fate, the
P. falciparum parasite displays adhesive
proteins on the surface of the infected blood cells, causing the blood cells to stick to the walls of small blood vessels, thereby sequestering the parasite from passage through the general circulation and the spleen. This "stickiness" is the main factor giving rise to
hemorrhagic complications of malaria.
High endothelial venules (the smallest branches of the circulatory system) can be blocked by the attachment of masses of these infected red blood cells. The blockage of these vessels causes symptoms such as in placental and cerebral malaria. In cerebral malaria the sequestrated red blood cells can breach the
blood brain barrier possibly leading to coma.
Although the red blood cell surface adhesive proteins (called PfEMP1, for
Plasmodium falciparum erythrocyte membrane protein 1) are exposed to the immune system they don't serve as good immune targets because of their extreme diversity; there are at least 60 variations of the protein within a single parasite and perhaps limitless versions within parasite populations. and malaria in pregnant women is an important cause of
stillbirths, infant mortality and low birth weight, particularly in
P. falciparum infection, but also in other species infection, such as
P. vivax.
Evolutionary pressure of malaria on human genes
Malaria is thought to have been the greatest
selective pressure on the
human genome in recent history. This is due to the high levels of
mortality and
morbidity caused by malaria, especially the
P. falciparum species.
Sickle-cell disease
The best-studied influence of the malaria parasite upon the human genome is the blood disease,
sickle-cell disease. In sickle-cell disease, there's a mutation in the
HBB gene, which encodes the beta globin subunit of
haemoglobin. The normal allele encodes a
glutamate at position six of the beta globin protein, while the sickle-cell allele encodes a
valine. This change from a hydrophilic to a hydrophobic amino acid encourages binding between haemoglobin molecules, with polymerization of haemoglobin deforming red blood cells into a "sickle" shape. Such deformed cells are cleared rapidly from the blood, mainly in the spleen, for destruction and recycling.
In the merozoite stage of its life cycle the malaria parasite lives inside red blood cells, and its metabolism changes the internal chemistry of the red blood cell. Infected cells normally survive until the parasite reproduces, but if the red cell contains a mixture of sickle and normal haemoglobin, it's likely to become deformed and be destroyed before the daughter parasites emerge. Thus, individuals
heterozygous for the mutated allele, known as sickle-cell trait, may have a low and usually unimportant level of
anaemia, but also have a greatly reduced chance of serious malaria infection. This is a classic example of
heterozygote advantage.
Individuals
homozygous for the mutation have full sickle-cell disease and in traditional societies rarely live beyond adolescence. However, in populations where malaria is
endemic, the
frequency of sickle-cell genes is around 10%. The existence of four
haplotypes of sickle-type hemoglobin suggests that this mutation has emerged independently at least four times in malaria-endemic areas, further demonstrating its evolutionary advantage in such affected regions. There are also other mutations of the HBB gene that produce haemoglobin molecules capable of conferring similar resistance to malaria infection. These mutations produce haemoglobin types HbE and HbC which are common in
Southeast Asia and
Western Africa, respectively.
Thalassaemias
Another well documented set of mutations found in the human genome associated with malaria are those involved in causing blood disorders known as
thalassaemias. Studies in
Sardinia and
Papua New Guinea have found that the
gene frequency of
β-thalassaemias is related to the level of malarial endemicity in a given population. A study on more than 500 children in
Liberia found that those with β-thalassaemia had a 50% decreased chance of getting clinical malaria. Similar studies have found links between gene frequency and malaria endemicity in the α+ form of α-thalassaemia. Presumably these genes have also been
selected in the course of human evolution.
Duffy antigens
The
Duffy antigens are
antigens expressed on red blood cells and other cells in the body acting as a
chemokine receptor. The expression of Duffy antigens on blood cells is encoded by Fy genes (Fya, Fyb, Fyc etc.).
Plasmodium vivax malaria uses the Duffy antigen to enter blood cells. However, it's possible to express no Duffy antigen on red blood cells (Fy-/Fy-). This
genotype confers complete resistance to
P. vivax infection. The genotype is very rare in European, Asian and American populations, but is found in almost all of the indigenous population of West and Central Africa. This is thought to be due to very high exposure to
P. vivax in
Africa in the last few thousand years.
G6PD
Glucose-6-phosphate dehydrogenase (G6PD) is an
enzyme which normally protects from the effects of
oxidative stress in red blood cells. However, a genetic deficiency in this enzyme results in increased protection against severe malaria.
HLA and interleukin-4
HLA-B53 is associated with low risk of severe malaria. This
MHC class I molecule presents
liver stage and
sporozoite antigens to
T-Cells. Interleukin-4, encoded by IL4, is produced by activated T cells and promotes proliferation and differentiation of antibody-producing B cells. A study of the Fulani of Burkina Faso, who have both fewer malaria attacks and higher levels of antimalarial antibodies than do neighboring ethnic groups, found that the IL4-524 T allele was associated with elevated antibody levels against malaria antigens, which raises the possibility that this might
be a factor in increased resistance to malaria.
Diagnosis
Severe malaria is commonly misdiagnosed in
Africa, leading to a failure to treat other life-threatening illnesses. In malaria-endemic areas,
parasitemia doesn't ensure a diagnosis of severe malaria because parasitemia can be incidental to other concurrent disease. Recent investigations suggest that malarial
retinopathy is better (collective sensitivity of 95% and specificity of 90%) than any other clinical or laboratory feature in distinguishing malarial from non-malarial
coma.
Symptomatic diagnosis
Areas that can't afford even simple laboratory diagnostic tests often use only a history of subjective fever as the indication to treat for malaria. Using Giemsa-stained blood smears from children in Malawi, one study showed that unnecessary treatment for malaria was significantly decreased when clinical predictors (rectal temperature, nailbed pallor, and splenomegaly) were used as treatment indications, rather than the current national policy of using only a history of subjective fevers (sensitivity increased from 21% to 41%).
Microscopic examination of blood films
The most economic, preferred, and reliable diagnosis of malaria is microscopic examination of
blood films because each of the four major parasite species has distinguishing characteristics. Two sorts of blood film are traditionally used. Thin films are similar to usual blood films and allow species identification because the parasite's appearance is best preserved in this preparation. Thick films allow the microscopist to screen a larger volume of blood and are about eleven times more sensitive than the thin film, so picking up low levels of infection is easier on the thick film, but the appearance of the parasite is much more distorted and therefore distinguishing between the different species can be much more difficult. With the pros and cons of both thick and thin smears taken into consideration, it's imperative to utilize both smears while attempting to make a definitive diagnosis.
From the thick film, an experienced microscopist can detect parasite levels (or
parasitemia) down to as low as 0.0000001% of red blood cells. Microscopic diagnosis can be difficult because the early trophozoites ("ring form") of all four species look identical and it's never possible to diagnose species on the basis of a single ring form; species identification is always based on several trophozoites. Please refer to the articles on each parasite for their microscopic appearances:
P. falciparum, P. vivax, P. ovale, P. malariae.
Field tests
In areas where microscopy isn't available, or where laboratory staff are not experienced at malaria diagnosis, there are
antigen detection tests that require only a drop of blood. Immunochromatographic tests (also called: Malaria Rapid Diagnostic Tests, Antigen-Capture Assay or "Dipsticks") have been developed, distributed and fieldtested. These tests use finger-stick or venous blood, the completed test takes a total of 15-20 minutes, and a laboratory isn't needed. The threshold of detection by these rapid diagnostic tests is in the range of 100 parasites/µl of blood compared to 5 by thick film microscopy. The first rapid diagnostic tests were using P. falciparum
glutamate dehydrogenase as antigen .
PGluDH was soon replaced by P.falciparum
lactate dehydrogenase, a 33 kDa oxidoreductase [EC1.1.1.27]. It is the last enzyme of the glycolytic pathway, essential for ATP generation and one of the most abundant enzymes expressed by P.falciparum. PLDH doesn't persist in the blood but clears about the same time as the parasites following successful treatment. The lack of antigen persistence after treatment makes the pLDH test useful in predicting treatment failure. In this respect, pLDH is similar to pGluDH. The OptiMAL-IT assay can distinguish between P. falciparum and P. vivax because of antigenic differences between their pLDH isoenzymes.
OptiMAL-IT will reliably detect
falciparum down to 0.01%
parasitemia and non-
falciparum down to 0.1%.
Paracheck-Pf will detect parasitemias down to 0.002% but won't distinguish between
falciparum and non-
falciparum malaria. Parasite nucleic acids are detected using
polymerase chain reaction. This technique is more accurate than microscopy. However, it's expensive, and requires a specialized laboratory. Moreover, levels of parasitemia are not necessarily correlative with the progression of disease, particularly when the parasite is able to adhere to blood vessel walls. Therefore more sensitive, low-tech diagnosis tools need to be developed in order to detect low levels of parasitaemia in the field. Areas that can't afford even simple laboratory diagnostic tests often use only a history of subjective fever as the indication to treat for malaria. Using Giemsa-stained blood smears from children in Malawi, one study showed that unnecessary treatment for malaria was significantly decreased when clinical predictors (rectal temperature, nailbed pallor, and splenomegaly) were used as treatment indications, rather than the current national policy of using only a history of subjective fevers (sensitivity increased from 21% to 41%).
Molecular methods
Molecular methods are available in some clinical laboratories and rapid real-time assays (for example,
QT-NASBA based on the polymerase chain reaction) are being developed with the hope of being able to deploy them in endemic areas.
Laboratory tests
OptiMAL-IT will reliably detect
falciparum down to 0.01%
parasitemia and non-
falciparum down to 0.1%.
Paracheck-Pf will detect parasitemias down to 0.002% but won't distinguish between
falciparum and non-
falciparum malaria. Parasite nucleic acids are detected using
polymerase chain reaction. This technique is more accurate than microscopy. However, it's expensive, and requires a specialized laboratory. Moreover, levels of parasitemia are not necessarily correlative with the progression of disease, particularly when the parasite is able to adhere to blood vessel walls. Therefore more sensitive, low-tech diagnosis tools need to be developed in order to detect low levels of parasitaemia in the field.
Treatment
Active malaria infection with
P. falciparum is a
medical emergency requiring
hospitalization. Infection with
P. vivax,
P. ovale or
P. malariae can often be treated on an outpatient basis. Treatment of malaria involves supportive measures as well as specific antimalarial drugs. When properly treated, someone with malaria can expect a complete recovery.
Antimalarial drugs
There are several families of drugs used to treat malaria.
Chloroquine is very cheap and, until recently, was very effective, which made it the antimalarial drug of choice for many years in most parts of the world. However, resistance of
Plasmodium falciparum to chloroquine has spread recently from Asia to Africa, making the drug ineffective against the most dangerous Plasmodium strain in many affected regions of the world. In those areas where chloroquine is still effective it remains the first choice. Unfortunately, chloroquine-resistance is associated with reduced sensitivity to other drugs such as
quinine and
amodiaquine.
There are several other substances which are used for treatment and, partially, for prevention (prophylaxis). Many drugs may be used for both purposes; larger doses are used to treat cases of malaria. Their deployment depends mainly on the frequency of resistant parasites in the area where the drug is used. One drug
currently being investigated for possible use as an anti-malarial, especially for treatment of drug-resistant strains, is the
beta blocker propranolol. Propranolol has been shown to block both
Plasmodium's ability to enter red blood cell and establish an infection, as well as parasite replication. A December 2006 study by
Northwestern University researchers suggested that propranolol may reduce the dosages required for existing drugs to be effective against
P. falciparum by 5- to 10-fold, suggesting a role in combination therapies.
Currently available anti-malarial drugs include:
The development of drugs was facilitated when
Plasmodium falciparum was successfully
cultured. This allowed in vitro testing of new drug candidates.
Extracts of the plant
Artemisia annua, containing the compound
artemisinin or semi-synthetic derivatives (a substance unrelated to quinine), offer over 90% efficacy rates, but their supply isn't meeting demand. One study in Rwanda showed that children with uncomplicated P. falciparum malaria demonstrated fewer clinical and parasitological failures on post-treatment day 28 when amodiaquine was combined with
artesunate, rather than administered alone (OR = 0.34). However, increased resistance to amodiaquine during this study period was also noted.
Since 2001 the
World Health Organization has recommended using
artemisinin-based combination therapy (ACT) as first-line treatment for uncomplicated malaria in areas experiencing resistance to older medications. The most recent
WHO treatment guidelines for malaria
recommend four different ACTs. While numerous countries, including most African nations, have adopted the change in their official malaria treatment policies, cost remains a major barrier to ACT implementation. Because ACTs cost up to twenty times as much as older medications, they remain unaffordable in many malaria-endemic countries. The molecular target of artemisinin is controversial, although recent studies suggest that
SERCA, a calcium pump in the
endoplasmic reticulum may be associated with artemisinin resistance. Malaria parasites can develop resistance to artemisinin and resistance can be produced by mutation of SERCA. However, other studies suggest the mitochondrion is the major target for artemisinin and its analogs.
In February 2002, the journal
Science and other press outlets announced progress on a new treatment for infected individuals. A team of French and South African researchers had identified a new drug they were calling "G25". It cured malaria in test primates by blocking the ability of the parasite to copy itself within the red blood cells of its victims. In 2005 the same team of researchers published their research on achieving an oral form, which they refer to as "TE3" or "te3". As of early 2006, there's no information in the mainstream press as to when this family of drugs will become commercially available.
In 1996, Professor Geoff McFadden stumbled upon the work of British biologist Ian Wilson, who had discovered that the plasmodia responsible for causing malaria retained parts of chloroplasts, an organelle usually found in plants, complete with their own functioning genomes. This led Professor McFadden to the realisation that any number of herbicides may in fact be successful in the fight against malaria, and so he set about trialing large numbers of them, and enjoyed a 75% success rate.
These "
apicoplasts" are thought to have originated through the endosymbiosis of algae and play a crucial role in fatty acid bio-synthesis in plasmodia. To date, 466 proteins have been found to be produced by apicoplasts and these are now being looked at as possible targets for novel anti-malarial drugs.
Although effective anti-malarial drugs are on the market, the disease remains a threat to people living in endemic areas who have no proper and prompt access to effective drugs. Access to pharmacies and health facilities, as well as drug costs, are major obstacles.
Médecins Sans Frontières estimates that the cost of treating a malaria-infected person in an endemic country was between
US$0.25 and $2.40 per dose in 2002.
Counterfeit drugs
Sophisticated
counterfeits have been found in Thailand, Vietnam,
Cambodia and China, and are an important cause of avoidable death in these countries. There is no reliable way for doctors or lay people to detect counterfeit drugs without help from a laboratory. Companies are attempting to combat the persistence of counterfeit drugs by using new technology to provide security from source to distribution.
Prevention and disease control
Methods used to prevent the spread of disease, or to protect individuals in areas where malaria is endemic, include prophylactic drugs, mosquito eradication, and the prevention of mosquito bites. There is currently no
vaccine that will prevent malaria, but this is an active field of research.
Many researchers argue that prevention of malaria may be more cost-effective than treatment of the disease in the long run, but the capital costs required are out of reach of many of the world's poorest people. Economic adviser
Jeffrey Sachs estimates that malaria can be controlled for US$3 billion in aid per year. It has been argued that, in order to meet the
Millennium Development Goals, money should be redirected from
HIV/
AIDS treatment to malaria prevention, which for the same amount of money would provide greater benefit to African economies.
Brazil, Eritrea, India, and Vietnam have, unlike many other developing nations, successfully reduced the malaria burden. Common success factors included conducive country conditions, a targeted technical approach using a package of effective tools, data-driven decision-making, active leadership at all levels of government, involvement of communities, decentralized implementation and control of finances, skilled technical and managerial capacity at national and sub-national levels, hands-on technical and programmatic support from partner agencies, and sufficient and flexible financing.
Vector control
Before DDT, malaria was successfully eradicated or controlled also in several tropical areas by removing or poisoning the breeding grounds of the mosquitoes or the aquatic habitats of the larva stages, for example by filling or applying oil to places with standing water. These methods have seen little application in Africa for more than half a century.
Efforts to
eradicate malaria by eliminating mosquitoes have been successful in some areas. Malaria was once common in the
United States and southern
Europe, but the draining of wetland breeding grounds and better sanitation, in conjunction with the monitoring and treatment of infected humans, eliminated it from affluent regions. In 2002, there were 1,059 cases of malaria reported in the US, including eight deaths. In five of those cases, the disease was contracted in the United States. Malaria was eliminated from the northern parts of the USA in the early twentieth century, and the use of the
pesticide DDT eliminated it from the South by 1951. In the 1950s and 1960s, there was a major public health effort to eradicate malaria worldwide by selectively targeting mosquitoes in areas where malaria was rampant. However, these efforts have so far failed to eradicate malaria in many parts of the developing world - the problem is most prevalent in Africa.
Sterile insect technique is emerging as a potential mosquito control method. Progress towards transgenic, or
genetically modified, insects suggest that wild mosquito populations could be made malaria-resistant. Researchers at
Imperial College London created the world's first transgenic malaria mosquito, with the first plasmodium-resistant species announced by a team at
Case Western Reserve University in
Ohio in 2002. Successful replacement of existent populations with genetically modified populations, relies upon a drive mechanism, such as
transposable elements to allow for non-Mendelian inheritance of the gene of interest.
On
December 21,
2007, a study published in
PLoS Pathogens found that the hemolytic C-type
lectin CEL-III from
Cucumaria echinata, a
sea cucumber found in the
Bay of Bengal, impaired the development of the malaria parasite when produced by transgenic mosquitoes. This could potentially be used one day to control malaria by using genetically modified mosquitoes refractory to the parasites, although the authors of the study recognize that there are numerous scientific and ethical problems to be overcome before such a control strategy could be implemented.
Prophylactic drugs
Several drugs, most of which are also used for treatment of malaria, can be taken preventively. Generally, these drugs are taken daily or weekly, at a lower dose than would be used for treatment of a person who had actually contracted the disease. Use of prophylactic drugs is seldom practical for full-time residents of malaria-endemic areas, and their use is usually restricted to short-term visitors and travelers to malarial regions. This is due to the cost of purchasing the drugs, negative
side effects from long-term use, and because some effective anti-malarial drugs are difficult to obtain outside of wealthy nations.
Quinine was used starting in the
seventeenth century as a prophylactic against malaria. The development of more effective alternatives such as
quinacrine,
chloroquine, and
primaquine in the twentieth century reduced the reliance on quinine. Today, quinine is still used to treat chloroquine resistant
Plasmodium falciparum, as well as severe and cerebral stages of malaria, but isn't generally used for prophylaxis. Of interesting historical note is the observation by
Samuel Hahnemann in the late
18th Century that over-dosing of quinine leads to a symptomatic state very similar to that of malaria itself. This lead Hahnemann to develop the medical
Law of Similars, and the subsequent medical system of
Homeopathy.
Modern drugs used preventively include
mefloquine (
Lariam),
doxycycline (available generically), and the combination of
atovaquone and
proguanil hydrochloride (
Malarone). The choice of which drug to use depends on which drugs the parasites in the area are
resistant to, as well as side-effects and other considerations. The prophylactic effect doesn't begin immediately upon starting taking the drugs, so people temporarily visiting malaria-endemic areas usually begin taking the drugs one to two weeks before arriving and must continue taking them for 4 weeks after leaving (with the exception of atovaquone proguanil that only needs be started 2 days prior and continued for 7 days afterwards).
Indoor residual spraying
Indoor residual spraying (IRS) is the practice of spraying insecticides on the interior walls of homes in malaria effected areas. After feeding, many mosquito species rest on a nearby surface while digesting the bloodmeal, so if the walls of dwellings have been coated with insecticides, the resting mosquitos will be killed before they can bite another victim, transferring the malaria parasite.
The first and historically the most poplar insecticide used for IRS is
DDT. While it was initially used to exclusively to combat malaria, its use quickly spread to
agriculture. In time, pest-control, rather than disease-control, came to dominate DDT use, and this large-scale agricultural use led to the
evolution of resistant mosquitoes in many regions. During the 1960s, awareness of the negative consequences of its indiscriminate use increased ultimately leading to bans on agricultural applications of DDT in many countries in the 1970s.
Though DDT has never been banned for use in malaria control and there are several other insecticides suitable for IRS, some advocates have claimed that bans are responsible for tens of millions of deaths in tropical countries where DDT had once been effective in controlling malaria. Furthermore, most of the problems associated with DDT use stem specifically from its industrial-scale application in agriculture, rather than its use in
public health.
The
World Health Organization (WHO) currently advises the use of 12 different insecticides in IRS operations. These include DDT and a series of alternative insecticides (such as the pyrethroids
permethrin and
deltamethrin) to both combat malaria in areas where mosquitoes are DDT-resistant, and to slow the evolution of resistance. This public health use of small amounts of DDT is permitted under the
Stockholm Convention on
Persistent Organic Pollutants (POPs), which prohibits the agricultural use of DDT. However, because of its legacy, many developed countries discourage DDT use even in small quantities.
Mosquito nets and bedclothes
Mosquito nets help keep mosquitoes away from people, and thus greatly reduce the infection and transmission of malaria. The nets are not a perfect barrier, so they're often treated with an insecticide designed to kill the mosquito before it has time to search for a way past the net. Insecticide-treated nets (ITN) are estimated to be twice as effective as untreated nets, and offer greater than 70% protection compared with no net. Since the
Anopheles mosquitoes feed at night, the preferred method is to hang a large "bed net" above the center of a bed such that it drapes down and covers the bed completely.
The distribution of mosquito nets impregnated with insecticide (often
permethrin or deltamethrin) has been shown to be an extremely effective method of malaria prevention, and it's also one of the most cost-effective methods of prevention. These nets can often be obtained for around
US$2.50 - $3.50 (2-3
euro) from the
United Nations, the World Health Organization, and others.
For maximum effectiveness, the nets should be re-impregnated with insecticide every six months. This process poses a significant logistical problem in rural areas. New technologies like Olyset or DawaPlus allow for production of long-lasting insecticidal mosquito nets (LLINs), which release insecticide for approximately 5 years, and cost about US$5.50. ITNs have the advantage of protecting people sleeping under the net and simultaneously killing mosquitoes that contact the net. This has the effect of killing the most dangerous mosquitoes. Some protection is also provided to others, including people sleeping in the same room but not under the net.
Unfortunately, the cost of treating malaria is high relative to income, and the illness results in lost wages. Consequently, the financial burden means that the cost of a mosquito net is often unaffordable to people in developing countries, especially for those most at risk. Only 1 out of 20 people in Africa own a bed net. Although shipped into Africa mainly from Europe as free development help, the nets quickly become expensive trade goods. They are mainly used for fishing, and by combining hundreds of donated mosquito nets, whole river sections can be completely shut off, catching even the smallest fish.
A study among
Afghan refugees in Pakistan found that treating top-sheets and chaddars (head coverings) with permethrin has similar effectiveness to using a treated net, but is much cheaper.
A new approach, announced in
Science on
June 10, 2005, uses spores of the
fungus Beauveria bassiana, sprayed on walls and bed nets, to kill mosquitoes. While some mosquitoes have developed resistance to chemicals, they've not been found to develop a resistance to fungal infections.
Vaccination
Vaccines for malaria are under development, with no completely effective vaccine yet available. The first promising studies demonstrating the potential for a malaria vaccine were performed in 1967 by immunizing mice with live, radiation-
attenuated sporozoites, providing protection to about 60% of the mice upon subsequent injection with normal, viable sporozoites. Since the 1970s, there has been a considerable effort to develop similar vaccination strategies within humans. It was determined that an individual can be protected from a
P. falciparum infection if they receive over 1000 bites from infected, irradiated mosquitoes.
It has been generally accepted that it's impractical to provide at-risk individuals with this vaccination strategy, but that has been recently challenged with work being done by Dr. Stephen Hoffman of
Sanaria, one of the key researchers who originally sequenced the genome of
Plasmodium falciparum. His work most recently has revolved around solving the logistical problem of isolating and preparing the parasites equivalent to a 1000 irradiated mosquitoes for mass storage and inoculation of human beings. The company has recently received several multi-million dollar grants from the
Bill & Melinda Gates Foundation and the U.S. government to begin early clinical studies in 2007 and 2008. The Seattle Biomedical Research Institute (SBRI), funded by the Malaria Vaccine Initiative, assures potential volunteers that "the [2009] clinical trials won't be a life-threatening experience. While many volunteers [inSeattle] will actually contract malaria, the cloned strain used in the experiments can be quickly cured, and doesn't cause a recurring form of the disease." "Some participants will get experimental drugs or vaccines, while others will get placebo."
Instead, much work has been performed to try and understand the
immunological processes that provide protection after immunization with irradiated sporozoites. After the mouse vaccination study in 1967, Moreover, antibodies against CSP prevented the sporozoite from invading hepatocytes. CSP was therefore chosen as the most promising protein on which to develop a vaccine against the malaria sporozoite. It is for these historical reasons that vaccines based on CSP are the most numerous of all malaria vaccines.
Presently, there's a huge variety of vaccine candidates on the table. Pre-erythrocytic vaccines (vaccines that target the parasite before it reaches the blood), in particular vaccines based on CSP, make up the largest group of research for the malaria vaccine. Other vaccine candidates include: those that seek to induce immunity to the blood stages of the infection; those that seek to avoid more severe pathologies of malaria by preventing adherence of the parasite to blood
venules and
placenta; and
transmission-blocking vaccines that would stop the development of the parasite in the mosquito right after the mosquito has taken a bloodmeal from an infected person. It is hoped that the sequencing of the
P. falciparum genome will provide targets for new drugs or vaccines.
The first vaccine developed that has undergone field trials, is the SPf66, developed by
Manuel Elkin Patarroyo in 1987. It presents a combination of antigens from the sporozoite (using CS repeats) and merozoite parasites. During phase I trials a 75% efficacy rate was demonstrated and the vaccine appeared to be well tolerated by subjects and immunogenic. The phase IIb and III trials were less promising, with the efficacy falling to between 38.8% and 60.2%. A trial was carried out in Tanzania in 1993 demonstrating the efficacy to be 31% after a years follow up, however the most recent (though controversial) study in the Gambia didn't show any effect. Despite the relatively long trial periods and the number of studies carried out, it's still not known how the SPf66 vaccine confers immunity; it therefore remains an unlikely solution to malaria.
The CSP was the next vaccine developed that initially appeared promising enough to undergo trials. It is also based on the circumsporoziote protein, but additionally has the recombinant (Asn-Ala-Pro15Asn-Val-Asp-Pro)2-Leu-Arg(R32LR) protein covalently bound to a purified
Pseudomonas aeruginosa toxin (A9). However at an early stage a complete lack of protective immunity was demonstrated in those inoculated. The study group used in Kenya had an 82% incidence of parasitaemia whilst the control group only had an 89% incidence. The vaccine intended to cause an increased T-lymphocyte response in those exposed, this was also not observed.
The efficacy of Patarroyo's vaccine has been disputed with some US scientists concluding in
The Lancet (1997) that "the vaccine wasn't effective and should be dropped" while the Colombian accused them of "arrogance" putting down their assertions to the fact that he came from a developing country.
The RTS,S/AS02A vaccine is the candidate furthest along in vaccine trials. It is being developed by a partnership between the PATH Malaria Vaccine Initiative (a grantee of the
Gates Foundation), the
pharmaceutical company,
GlaxoSmithKline, and the Walter Reed Army Institute of Research In the vaccine, a portion of CSP has been fused to the
immunogenic "S
antigen" of the
hepatitis B virus; this
recombinant protein is injected alongside the potent AS02A
adjuvant. More recent testing of the RTS,S/AS02A vaccine has focused on the safety and efficacy of administering it earlier in infancy: In October 2007, the researchers announced results of a
phase I/IIb trial conducted on 214 Mozambican infants between the ages of 10 and 18 months in which the full three-dose course of the vaccine led to a 62% reduction of infection with no serious side-effects save some pain at the point of injection. Further research will delay this vaccine from commercial release until around 2011.
Other methods
Education in recognising the symptoms of malaria has reduced the number of cases in some areas of the developing world by as much as 20%. Recognising the disease in the early stages can also stop the disease from becoming a killer. Education can also inform people to cover over areas of stangnant, still water eg Water Tanks which are ideal breeding grounds for the parasite and mosquito thus, cutting down the risk of the transmission between people. This is most put in practice in urban areas where there's large centres of population in a confined space and transmission would be most likely in these areas.
The
Malaria Control Project is currently using downtime computing power donated by individual volunteers around the world (see
Volunteer computing and
BOINC) to simulate models of the health effects and transmission dynamics in order to find the best method or combination of methods for malaria control. This modeling is extremely computer intensive due to the simulations of large human populations with a vast range of parameters related to biological and social factors that influence the spread of the disease. It is expected to take a few months using volunteered computing power compared to the 40 years it would have taken with the current resources available to the scientists who developed the program.
An example of the importance of computer modelling in planning malaria eradication programs is shown in the paper by Águas and others. They showed that eradication of malaria is crucially dependent on finding and treating the large number of people in endemic areas with asymptomatic malaria, who act as a reservoir for infection. The malaria parasites don't affect animal species and therefore eradication of the disease from the human population would be expected to be effective.
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Then simply click through this link from your web page. Our crawlers will verify your link, extract the title of your web page and instantly add a link back to it. If you like you can remove the words Totally Explained and embed the link in article text.
As long as your link remains in place, we'll keep our link to you right here. Please play fair - our crawlers are watching. Your site must be closely related to this one's topic. Any kind of spamming, dubious practises or removing the link will result in your link from us being dropped and, potentially, your whole site being banned. |
