Essentially, the parasite has a number of cloaking mechanisms, and keeps most of them in reserve. As it encounters resistance from the human immune system the parasite is capable of tailoring its cloaking to the immune system. The parasite has dozens of genes designed to get past the immune system, and what the researchers found was that as one gene was activated, that also trigger the suppression of the others. In this way, the malaria parasite is able to try one method after another to infect the host, and reduce the risk that the host might quickly develop an immunity against most or all of the parasite’s cloaking methods.

As HHMI researcher Alan Cowman put it in a press release announcing the discovery,

It’s like a leopard being able to change its spots. New forms come up, and the immune system beats them down again. Because of this a lot of people think you need five years of constant exposure to malaria in its different disguises to gain immunity.

Unfortunately too many people, especially children, die long before they can develop immunities to the malaria parasite’s numerous tricks. Even among people who develop immunity, that immunity can be quickly lost if the individual is not consistently exposed to malaria parasites.

This sort of research could one day lead to a treatment for malaria that might, for example, defeat this mechanism and allow for those exposed to malaria to quickly develop immune responses to all of its cloaking mechanisms.

Sources:

How malaria dupes immune system. BBC, December 29, 2005.

Scientists Lift Malaria’s Cloak of Invisibility. Press Release, Howard Hughes Medical Institute, December 28, 2005.

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This is a traditional method that was commonly used before the introduction of DDT in the 1950s and is once again being looked at as part of the solution to malaria.

The idea is to stock ponds, rivers and wells with fish like guppies that feed on the mosquito larvae. Dr. VP Sharma of the COuncil for Medical Research said that while the technique could not be used everywhere, in places where it was appropriate to use it had virtually eliminated a subspecies of malaria-carrying mosquito in some districts where mosquito-eating fish were introduced.

According to the BBC, Sharma credited the fish introduction program for India’s falling malaria rate which declined by about 200,000 cases per year after the program’s introduction. Sharma did add that, “It will take another five years before the real impact would be known” from the numerous fish introduction programs that the World Bank is underwriting.

Source:

Fish eat away at malaria in India. Richard Black, BBC, January 5, 2004.

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Specifically, Attaran argues that by favoring expensive traditional malaria therapies over newer, more effective — but more expensive –treatments such as artemisinin combination therapies, the WHO is guilty of the equivalent of “medical malpractice.”

Attaran notes that WHO itself concedes that the drugs it using in Africa are growing increasingly ineffective,

WHO now writes of “global malaria control . . . being threatened on an unprecedented scale” by continued use of outdated drugs such as chloroquine, which is ineffective in most parts of Africa, and sulfadoxine-pyrimethamine, which is becoming so. For example, in East Africa, surveillance and clinical trial data show that up to 64% of patients given chloroquine and 45% given sulfadoxine-pyrimethamine will fail treatment, and those figures are climbing.

When treatment failure becomes so frequent, malaria deaths rise greatly, especially in children. In West Africa (Senegal), results of a 12-year community-based study showed that the onset of chloroquine resistance at least doubled childhood malaria death risk, and in some sites, increased it up to 11-fold in the youngest children. In East and southern Africa, the proportion of children dying from malaria doubled as chloroquine and later sulfadoxine-pyrimethamine resistance took hold from the 1980s to the 1990s, even as deaths from other causes declined. Elsewhere in Africa, chloroquine resistance increased the proportion of admissions to hospital and deaths from malaria by two-fold to four-fold.

Moreover, Attaran argues,

The superiority of ACT is now so established that of the five treatments WHO recommends for drug resistant P falciparum malaria, four are ACTs (the other is a “short-term solution” for countries that cannot use ACT immediately).3 ACT is now the preferred policy for WHO and the Roll Back Malaria campaign as a whole:

“Recently WHO has formulated policy that elevates combination drug therapy to preferred first therapy for all malaria infections in areas where P falciparum is the predominant infecting species of malaria. Combination therapy (CT) with formulations containing an artemisinin compound (ACT) is the policy standard . . .”22

However, WHO violates its own policy standard regularly. Most African countries reluctantly cling to chloroquine, sulfadoxine-pyrimethamine, or the insignificantly better combination of chloroquine and sulfadoxine-pyrimethamine, because ACT is ten times more expensive and, therefore, unaffordable to them.2,23 When those same countries seek financial aid from the Global Fund for AIDS, Tuberculosis, and Malaria (GFATM) to purchase ACT, they are forcefully pressured out of it by governments such as the USA, whose aid officials say that ACT is too expensive and “not ready for prime time”.24 WHO acquiesces to this pressure to cut costs, and despite a policy that names ACT as the gold standard of treatment, WHO signs its approval when GFATM funds cheap but ineffective chloroquine or sulfadoxine-pyrimethamine to treat P falciparum malaria.

. . .

These are very obvious errors of scientific and medical judgment; and although WHO might be expected to spearhead a corrective intervention, the evidence suggests that it instead exacerbated the errors. In Kenya, Ethiopia, and Uganda, WHO’s country representatives reviewed the funding proposals in which inappropriate drugs were sought–and signed their approval. Those signatures follow a declaration that WHO “has participated throughout the . . . process” of developing the proposal to GFATM, and that it “reviewed the final proposal and [is] happy to support it”.31-33

These decisions are indefensible. For WHO and GFATM to provide chloroquine and sulfadoxine-pyrimethamine treatments in the countries we cite as examples at least wastes precious international aid money, and at most, kills patients who have malaria. If one takes the measured increase in childhood malaria mortality that follows P falciparum drug resistance (two-fold to 11-fold) and extrapolates it to populations in which GFATM is funding chloroquine or sulfadoxine-pyrimethamine despite resistance (more than 100 million people in the four countries we name), then at least tens of thousands of children die every year as a direct result. Those patients who survive will often become much sicker and require retreatment, at some further expense of time and money. We do not exaggerate to state that, based on the outcomes, there is no ethical or legal difference that separates them from conduct otherwise condemned as medical malpractice (compare the case in which a doctor or pharmacist who, like these institutions, knowingly furnished treatments that failed perhaps 80% of the time, while withholding the alternatives as “too expensive”).

WHO responded with a letter to Lancet saying that it does encourage use of ACT, but that its high cost has hampered efforts to distribute it in Africa,

Although progress is encouraging, there are still major challenges to the adoption of ACTs, especially sustainable financing. Although with growing demand a price decrease can be expected in the coming years, the cost of growing the raw ingredient, Artemisia annua, means that ACTs will remain relatively expensive. Governments need to trust that sustainable funding from the Global Fund and other sources will be available before they can make the commitment–of up to US$2 per head per year–of switching to ACTs. WHO and its partners are developing a new mechanism to facilitate access to quality medicines and other products for malaria control. WHO will continue to work with the public and private sectors, and major institutions such as the Global Fund, to make ACTs more widely available through lowered costs, increased access, and technical cooperation.

The bigger problem is that so little money is devoted worldwide to fighting malaria.

Sources:

WHO, the Global Fund, and medical malpractice in malaria treatment. Amir Attaran, et al, The Lancet 2004; 363: 237-40.

Response to accusations of medical malpractice by WHO and the Global Fund. Fatoumata Nafo-Traoré, The Lancet 2004; 363.

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The International Artemisinin Study Group looked at 16 clinical trials involving 6,000 patients who were administered artemisinin along with other anti-malarial drugs. Artemisinin is an extract from sweet wormwood has been used for centuries in Asia to treat malaria.

Their review found that adding artemisinin to existing compounds doubled the rate of parasite clearance (the level of parasites removed from the blood) with no additional side effects. Additionally, patients taking artemisinin combination therapies were less likely to suffer a relapse of the disease after ending treatment.

In an article in Lancet describing the results of the survey, the International Artemisinin Study Group wrote,

If used widely, this inexpensive, fixed-dose artemisinin-based combination antimalarial could make important contributions to ‘rolling back malaria’.

Sources:

Drug cocktail ‘may beat malaria’. The BBC, January 2, 2004.

Drug combinations for malaria: time to ACT?. The Lancet, January 3, 2004.

Combination therapy, the best way to tackle malaria: Lancet. January 2, 2004.

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In announcing the donation, Gates said it was time for the world to get serious about dealing with malaria,

Malaria is robbing Africa of its people and potential. Beyond the extraordinary human toll, malaria is one of the greatest barriers to Africa’s economic growth, draining national health budgets and deepening poverty.

About 90 percent of malaria cases occur in Africa, where the disease kills more than 900,000 people annually — mostly children.

$100 million of Gates’ grant will be devoted to vaccine research, $40 million to develop drugs to combat drug-resistant strains of malaria, and $28 million to research ways to use existing drugs to lower infections in infants.

Sources:

Gates boosts war on malaria. The BBC, September 21, 2003.

Bill Gates Donates $168 Million to Fight Malaria. Wambui Chege, Reuters, September 23, 2003.

Bill Gates donates $168 M for malaria research. Associated Press, September 22, 2003.

Africa’s Malaria Death Toll Still “Outrageously High”. Afshin Molavi, National Geographic News, June 12, 2003.

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The prevailing hypothesis had been that artemisinins interfered molecules that the malaria parasite uses to consume haemoglobin. But the British researchers at St. George’s Hospital in London discovered that artemisinins in fact appear to disable part of the parasite that transfers calcium out of cells in order to stabilize calcium levels. With this disabled, calcium levels in the cells of the parasite grow until the cell dies.

Unlike other treatments for malaria, there is no known malarial resistance to artemisinins, raising the possibility that other drugs and vaccines could be developed that also target this calcium transfer mechanism.

Researcher Sanjreev Krishna told the BBC and Reuters,

It’ll take some time to apply our findings, or even to test new artemisinin derivatives which are being developed now. But you can be sure that’s what we’re going to be doing.

. . .

So far there is no evidence at all of any clinical resistance to artemisinins. It’s one of our best hopes for the future and frankly I don’t think we have many other options at the moment.

Sources:

Find could boost malaria fight. The BBC, August 20, 2003.

Scientists find how anti-malaria shrub works. Reuters, August 20, 2003.

Artemisinins target the SERCA of Plasmodium falciparum. U. Eckstein-Ludwig, Nature 424, 957 – 961, 21 August 2003.

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The vaccine in question — RTS,S — has already gone through initial safety testing with human volunteers and appears safe enough. In addition, testing in adults found that the vaccine was effective in preventing malaria in about 71 percent of adults who received it.

An open question, however, is just how good it is at preventing malaria in young children. To that end, the vaccine will be administered to 2,500 children in Mozambique. Final results for the vaccine will be available in about 18 to 24 months.

If the vaccine proves effective there, research will then move on to see if it could be safely and effectively administered to infants, who face the highest death rate from malaria.

Sources:

Clinical Trial of Advanced Malaria Vaccine Candidate to Begin in Mozambique. Press Release, Malaria Vaccine Initiative, July 8, 2003.

Two thousand kids to get experimental malaria jab. Tom Clark, Nature, July 9, 2003.

Malaria Vaccine Trial To Start In Mozambique. United Nations Wire, July 8, 2003.

Malaria vaccine trial begins. The BBC, July 8, 2003.

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Based on surveys of donor countries and external estimates of their spending, Narasimhan and Attaran estimate that RBM receives roughly US$98 million annually. It would need about US$1.5-$2 billion annually to reach its goal of halving malaria deaths.

The odd thing is that this estimate is filled with a bizarre level of uncertainty. Switzerland, for example, told the researchers that not only did they not know how much their country was giving for malaria control, but they did not even know how to go about finding out since malaria control spending was subsumed into larger health spending budgets. Narasimhan and Attaran write that this will pose enormous problems for funding of malaria control efforts,

In short, the Swiss answer, which seems likely to apply to some other donors too, is that the extent of malaria control funding is not just unknown, but actually unknowable. Leaving aside the reasons why this is true (e.g. it is found in integrated health programmes and not easily disaggregated), this poses a huge strategic threat to RBM’s goals: What is the likelihood of increasing malaria control funding, when the donors lack the accounting procedures and ability to know how much they are spending? Without reliable financial surveillance, there is good reason to suspect that aid to malaria control will stagnate, as it has done for decades, without triggering public pressure to demand improvement.

The other interesting thing is that the $98 million spending estimate is significantly smaller than other estimates that put annual malaria control spending at US$130 to $160 million. Part of the reason for the difference is that some organizations, including the World Bank, appear to be exaggerating their malaria control spending (emphasis added),

Although the Bank publicly claims that “at present, World Bank direct financing for malaria control activities is over $200 million in more than 25 countries”, we find on the Bank’s own project list only 10 countries having “active” malaria control projects [22]. In India, where in 1997 the Bank pledged its largest malaria control effort ($164.8 million), the project neared its close in 2003 after disbursing little over a quarter of this amount. In Africa, where 90% of malaria deaths occur, the Bank has only 4 active projects: in the Comoros, Eritrea, Madagascar, and Senegal. Yet not one of these countries suffers particularly intense or sustained malaria transmission – three are hardly malarious at all by African standards – meaning that the Bank’s efforts will contribute little to halving the burden of malaria.

Worst of all, the Bank has practically reneged on the dramatic pledge it made to two dozen African heads of state at Abuja in April 2000 to provide “up to $500 million more…for the fight against malaria in Africa” [23]. Nearly three years after that pledge, Eritrea is the only country to receive a new loan expressly including malaria control (the loan package is $40 million, split among 4 diseases). Assuming that the each disease in the Eritrea loan package receives an equal share, then the Bank’s new lending for malaria control since Abuja amounts to only $10 million; and three years after Abuja, up to $490 million of the $500 million that the Bank promised remains uncommitted and unspent. Furthermore, at this writing (December 2002), the Bank’s own malaria project list shows not one new African malaria control project in the planning pipeline. There seems to be no activity underway at the Bank to keep the promise that was made.

The authors recommend that the World Bank appoint a malaria “czar” to oversee malaria control projects in much the same way it appointed an AIDS “czar” to oversee AIDS control projects.

They also criticize views in Western donor nations that malaria spending is wasted because developing nations do not have the health care infrastructure to meaningfully absorb the aid. Instead, they argue that this is a sort of chicken-or-egg problem — additional spending on malaria would drive the creation of additional health care infrastructure. I suspect donor nations are a bit more skeptical than are Narasimhan and Attaran. As the authors themselves concede, the United States, for example, spent billions on malaria control in the 1960s with very little to show for it.

Source:

Roll Back Malaria? The scarcity of international aid for malaria control. Vasant Narasimhan and Amir Attaran, Malaria Journal, April 15, 2003.

Malaria project in funding crisis. BioMed Central, Press Release, April 25, 2003.

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The malaria parasite uses large amounts of glucose. The St. George’s researchers were the first to prove that the parasite uses a special transport protein to absorb the glucose. The importance of this finding is that if a way can be found to block that transport protein, the malaria parasite can be effectively starved.

St. George’s researcher Sanjeev Krishna said of the discovery,

This discovery proves for the first time that it is worth going after transport proteins of the malaria parasite and that parasites cannot live without this transporter working properly.

. . .

We are very excited about this research, as this new information gives us the potential to design new drugs against malaria.

The research of Dr. Krishna and his colleagues was published in the Proceedings of the National Academy of Sciences.

Sources:

Scientists starve malaria parasite. The BBC, June 4, 2003.

Parasite’s sweet tooth may provide malaria cure. Ananova, June 3, 2003.

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According to The State of the World’s Vaccines and Immunization, as many as 37 million children under the age of one are not immunized against the six major vaccine-preventable diseases of childhood: tuberculosis, tetanus, whooping cough, diphtheria, polio and measles.

Moreover, the inability of underdeveloped countries to pay for vaccines combined with ongoing property rights disputes over ownership of drugs and vaccines in such countries acts as disincentive for further research into vaccines for diseases that plague the developing world.

According to the report,

Today, vaccine manufacturers have little commercial incentive to develop vaccines against diseases such as HIV/AIDS, TB and malaria, which kill millions of people in developing countries, but relatively few in the developed world. For example, of the approximately US$600 million a year invested in HIV vaccine research, the majority comes from the US National Institutes of Health (a public sector institution). To put that amount in perspective, in 1999, research spending on drugs to treat HIV/AIDS was about US$3 billion in Europe and the United States alone. Other diseases fare just as badly. In the 1996 report Investing in Health Research and Development, WHO highlighted some of the distortions in global health research funding. At the time of the study, acute respiratory infections, diarrheal disease and TB — which together account for almost 8 million deaths a year, mainly among the poor — attracted an estimated US$99-133 million. . . By contrast, more was spent on research into asthma — an estimated US $127-158 million — which accounts for 218,000 deaths a year worldwide.

Of course the report ignores the possibility that the relatively heavy funding in asthma is what is responsible for such a low worldwide death toll, but even so the amount estimated to be spent on research into diseases that kill 8 million people is staggeringly low.

Source:

Vaccine policy leaves millions at risk. The BBC, November 20, 2002.

State of the World’s Vaccines and Immunization Report (PDF). UNICEF, 2002.

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