Tag Archives: malaria

The Global Experiment with Malaria Vaccine Starts in African States

Thirty years in the making, RTS,S, the malaria vaccine, also known by its brand name, Mosquirix, targets Plasmodium falciparum, the most common and most lethal of four malaria parasite species. It is an answer to a dire need. After decades of declining numbers of cases and deaths, the fight against malaria has stalled. Parasites resistant to the most widely used treatment, called artemisinin-based combination therapy, are spreading, while malaria mosquitoes are increasingly resistant to insecticides. And yet the rollout in Malawi and in two other African countries, isn’t quite the breakthrough the field has been waiting for. Mosquirix’s efficacy and durability are mediocre: Four doses offer only 30% protection against severe malaria, for no more than 4 years. Some experts question whether that is worth the cost and effort

The biggest concerns, however, are about the vaccine’s safety. In the largest trial, children who received Mosquirix had a risk of meningitis 10 times higher than those who received a control vaccine. Mosquirix may not have triggered the meningitis cases—there are other possible explanations—but the possible risk worried the global health community so much that, rather than rolling out the vaccine across Africa, the World Health Organization (WHO) has decided to set up a pilot in Malawi, Ghana, and Kenya in which the vaccine will be given to hundreds of thousands of children.

The Malaria parasite  is a challenging target for a vaccine. It has a complex life cycle that begins when an infected female mosquito bites a human and spits Plasmodium cells called sporozoites into the bloodstream. They multiply in the liver, emerge as another cell type named merozoites, invade red blood cells, and continue to multiply. The blood cells burst, causing fever, headache, chills, muscle aches, and often anemia. (They also flood the blood with gametocytes—the parasite’s reproductive cells—ready to be picked up by the next mosquito.) Along the way, the parasite frequently changes its surface proteins. That makes it an elusive target for the immune system, and for a vaccine.

Mosquirix, developed in the 1980s by a team in Belgium at SmithKline-RIT, now part of GlaxoSmithKline (GSK), stimulates an immune response against a protein that occurs only on the sporozoites’ surface. To bolster the response, the research team fused the vaccine protein with a hepatitis B surface protein and added an adjuvant….

A relative outside, Danish anthropologist and vaccine researcher Peter Aaby of the Bandim Health Project in Guinea-Bissau, offered another argument against introduction. After reanalyzing the data from the biggest trial, Aaby discovered that although the vaccinated children had malaria less often, they did not die less often. Among girls, overall mortality was almost doubled, Aaby told his colleagues at the meeting. “This vaccine is killing girls,” he recalls saying. Whereas WHO expects the vaccine to save one life per 200 children vaccinated, Aaby believes one in 200 will die as a result of it; he predicts “a nightmare.”

Aaby and Christine Stabell Benn, a global health professor at the University of Southern Denmark, have an explanation. The married couple has studied routine vaccinations in Africa for decades and believes vaccines can “train” the immune system in ways that don’t affect just the target disease. Vaccines that contain a living, weakened pathogen—such as the vaccines against measles and tuberculosis—strengthen the immune system generally, Aaby and Stabell Benn say, making recipients better able to fight off other infections. But vaccines that contain a killed pathogen or only bits of it weaken the immune system, their theory goes—especially in girls, because their immune systems seem to respond more strongly to vaccines in general.

Excerpts from Jop de Vrieze, A Shot of Hope, Science Magazine, Nov. 29, 2019, at 1063

Imperfect Tools Used Imperfectly: 400 000 Malaria Deaths

According to a report, published on December 4th, 2019 by the World Health Organization,  there were 228 million cases of malaria in 2018, which resulted in 400,000 deaths. Most victims were young children in Africa. That is a far cry from targets set in 2015 for the near-elimination of malaria by 2030.  These targets depended on a $6 billion a year being poured into malaria-control efforts. Funding in recent years, however, has been about $3 billion a year. More money would surely help. But substantial gains can be made by doing things more efficiently—something at which malaria programmes have been dismal.

Stopping malaria relies on three things: insecticide-treated bed nets to prevent nocturnal mosquito bites; the spraying of homes with insecticides; and the treating of pregnant women and children with rounds of preventive medication. These are all “imperfect tools, often used imperfectly”, says Pedro Alonso, head of the malaria programme at the World Health Organisation. Countries usually deploy the same package of measures everywhere, even though infection rates and their seasonal patterns vary a lot between regions, and particularly between cities and the countryside. Transmission reaches a peak in the rainy season, when mosquitoes are abundant, so preventive mass-treatment of children then can make a huge difference. Regional variations are particularly pronounced in large countries like Nigeria—a place that, by itself, accounts for a quarter of the world’s malaria cases.

The typical approach of a malaria-control programme is to bombard a country with bed nets and then use whatever cash remains for sporadic rounds of preventive medication. But in many big cities, such as Dar es Salaam and Nairobi, cases are few and far between, so deploying nets there is a waste. Overspending on nets at the expense of other things happens partly because nets are easy to count—a feature that aid programmes are particularly fond of. Results which cannot be attributed directly to money a donor spends tend to fall further down that donor’s list of priorities. This kind of reasoning tips the scales, because foreign aid accounts for two-thirds of the money spent on malaria.

Excerpts from Tropical disease: Malaria infections have stopped falling, Economist, Dec. 7, 2019

How Venom from Spiders Kills Malaria Mosquitoes

In the 1980s, the village of Soumousso in Burkina Faso helped launch one of the most powerful weapons against malaria: insecticide-treated bed nets, which had early field trials there and went on to save millions of lives. But as mosquitoes developed resistance to widely used insecticides, the nets lost some of their power. Now, researchers are hoping the village can help make history again by testing a new countermeasure: a genetically modified (GM) fungus that kills malaria-carrying mosquitoes. In tests in a 600-square-meter structure in Soumousso called the MosquitoSphere—built like greenhouse but with mosquito netting instead of glass—the fungus eliminated 99% of the mosquitoes within a month, scientists report in the  magazine Science.

MosquitoSphere, Burkina Faso

The fungus also has clear advantages, however: It spares insects other than mosquitoes, and because it doesn’t survive long in sunlight, it’s unlikely to spread outside the building interiors where it would be applied.  Fungi naturally infect a variety of insects, consuming the host’s tissues in order to reproduce, and they have been used for decades to control a wide variety of crop pests….Researchers have tested dozens of different fungal strains against disease-carrying mosquitoes, but none was effective enough to pass muster. So researchers from the University of Maryland (UMD) in College Park and the Research Institute of Health Sciences & Centre Muraz in Bobo-Dioulasso, Burkina Faso, endowed a strain called M. pingshaense with a gene for a toxin isolated from spider venom that turns on when it contacts hemolymph, the insect version of blood. In the lab, the team showed its creation could kill mosquitoes faster and that just one or two spores could cause a lethal infection. 

Burkina Faso was a promising place for a field test: Unlike many countries in Africa, it has an established system to evaluate and approve the use of GM organisms. It also has one of the highest rates of malaria in the world, and insecticide-resistant mosquitoes are widespread. For those and other reasons, the U.S. National Institutes of Health funded the MosquitoSphere, which is specifically designed to test GM organisms.

Excerpts fromGretchen Vogel  Fungus with a venom gene could be new mosquito killer, Science, May 31, 2019

Eradicate Mosquitoes Forever: Gene Drives

The mosquitoes are being fitted with a piece of dna called a gene drive. Unlike the genes introduced into run-of-the-mill genetically modified organisms, gene drives do not just sit still once inserted into a chromosome. They actively spread themselves, thereby reaching more and more of the population with each generation. If their effect is damaging, they could in principle wipe out whole species.. If gene drives were to condemn to a similar fate the mosquitoes that spread malaria, a second of humankind’s great scourges might be consigned to history.

Gene drives can in principle be used against any creatures which reproduce sexually with short generations and aren’t too rooted to a single spot. The insects that spread leishmaniasis, Chagas disease, dengue fever, chikungunya, trypanosomiasis and Zika could all be potential targets. So could creatures which harm only humankind’s dominion, not people themselves. Biologists at the University of California, San Diego, have developed a gene-drive system for Drosophila suzukii, an Asian fruitfly which, as an invasive species, damages berry and fruit crops in America and Europe. Island Conservation, an international environmental ngo, thinks gene drives could offer a humane and effective way of reversing the damage done by invasive species such as rats and stoats to native ecosystems in New Zealand and Hawaii.

Such critics fear that the laudable aim of vastly reducing deaths from malaria—which the World Health Organisation puts at 445,000 a year, most of them children—will open the door to the use of gene drives for far less clear-cut benefits in ways that will entrench some interests, such as those of industrial farmers, at the expense of others. They also point to possible military applications: gene drives could in principle make creatures that used not to spread disease more dangerous… The ability to remove species by fiat—in effect, to get them to remove themselves—is, like the prospect of making new species from scratch, a power that goes beyond the past ambit of humankind.

Gene drives based on crispr-Cas9 could easily be engineered to target specific bits of the chromosome and insert themselves seamlessly into the gap, thus ensuring that every gamete gets a copy . By 2016, gene drives had been created in yeast, fruitflies and two species of mosquito. In work published in the journal Nature Biotechnology in September, Andrea Crisanti, Mr Burt and colleagues at Imperial showed that one of their gene drives could drive a small, caged population of the mosquito Anopheles gambiae to extinction—the first time a gene drive had shown itself capable of doing this. The next step is to try this in a larger caged population.

There are also worries about how gene drives might be used to create a weapon. …The need to find ways to guard against such attacks is one of the reasons that the Pentagon’s Defence Advanced Research Projects Agency (darpa) gives for its work on gene drives. Renee Wegrzyn, programme manager for darpa’s “Safe Genes” project, says the work is to prevent “technological surprise”, whether in the form of an unintended consequence or nefarious use. One of the academic teams she funds has made progress in developing anti-crispr enzyme systems that one day might be able to inhibit a drive’s operation.

Oversight needs not just to bring together a range of government agencies; it requires co-operation between governments, too. The Cartagena Protocol on Biosafety, which entered into force under the un Convention on Biological Diversity (cbd) in 2003, provides controls on the transfer of genetically modified organisms. But how it applies to gene drives is unclear—and besides, America has never ratified the convention. An attempt to ban gene-drive research through the cbd, which was backed by the etc Group and other ngos, failed at the convention’s biennial meeting in Cancún in 2016…Like the reintroduction of vanished species advocated by the rewilding movement, gene-drive technology will provide new arenas for the fight between those who wish to defend nature and those who wish to tame it.

Excertps from Gene Drives: Extinction on Demand, Economist, Nov. 10, 2018, at 24

The Malaria Experiment at Comoros Islands

What if it were possible to get rid of malaria? Not just bring it under control, but wipe it from the face of the Earth, saving 660,000 lives a year, stopping hitherto endless suffering, and abolishing a barrier to economic development reckoned by the World Bank to cost Africa $12 billion a year in lost production and opportunity? It is an alluring prize, and one that Li Guoqiao, of Guangzhou University of Chinese Medicine, thinks within reach.

Dr Li is one of the researchers who turned a Chinese herbal treatment for the disease into artemisinin, one of the most effective antimalarial drugs yet invented. Now he is supervising experiments in the Comoros, using a combination drug therapy based on artemisinin, to see if malaria can be eradicated from that island country. If it works, he hopes to move on to somewhere on the African mainland, and attempt to repeat the process there….

Dr Li’s approach is to attack not the mosquito, but the disease-causing parasite itself. This parasite’s life cycle alternates between its insect host (the mosquito) and its vertebrate one (human beings). Crucially, as far as is known, humans are its only vertebrate host. Deny it them and it will, perforce, wither away—an approach that worked for the smallpox virus, which had a similarly picky appetite. In the case of smallpox, a vaccine was used to make humans hostile territory for the pathogen. Since there is no vaccine against malaria, Dr Li is instead using drugs.

To deny the parasites their human hosts long enough to exterminate them in a given area, the researchers administer three doses of Artequick, spaced a month apart. To add extra power, the first dose is accompanied by a third drug, primaquine. Dr Li and his colleagues call this approach Fast Elimination of Malaria through Source Eradication, or FEMSE.

And it works—almost. The Comoros has three islands: Moheli, Anjouan and Grande Comore. Before the experiment started, more than 90% of the inhabitants of some villages on these islands had malaria. Song Jianping, Dr Li’s lieutenant in the Comoros, blitzed Moheli with Artequick in 2007. The number of cases there fell by 95%, though reinfection from other islands caused a small subsequent rebound. In 2012 he did the same thing on Anjouan. There, the number of cases fell by 97%. In October 2013 the campaign moved to Grande Comore, the most populous island. When the process is complete there, nearly all of the 700,000 Comorans will have taken part in FEMSE.

Ninety-five percent, or even 97%, is not eradication. But it is an enormous improvement and creates a position from which eradication can be contemplated. To do that, though, means keeping an effective surveillance programme permanently in being so that those who become infected can be treated quickly, to stop them spreading the parasite…

A more immediate concern is the safety of the drugs. Artemisinin and piperaquine are pretty safe, but primaquine ruptures red blood cells in people with a deficiency of an enzyme called G6PD. That can kill. And a lot of Africans—in particular, 15% of Comorans—are G6PD-deficient….

There is also the question of informed consent to the drugs. Smallpox vaccination permanently protected the person being vaccinated. There was thus an individual as well as a collective benefit to offset any possible side-effects. Prophylactic drug treatment protects only for as long as the drugs stay in the body—which is a few weeks (and explains the need for three rounds of treatment). Dr Song’s results suggest the benefit is real. But it is a collective benefit. That changes the moral calculus. On the one hand, there is the risk of healthy people being harmed by side-effects. On the other, there is the risk of their free-riding, by taking the collective benefits while not taking the drugs themselves.

To avoid such free-riding, a lot of official encouragement to participate has happened—encouragement some people regard as tipping over into pressure and propaganda. In a public meeting in Niumadzaha, a village in the south of Grande Comore, for example, the chief doctor of the local health centre shouted through a megaphone: “This drug is safe and effective. You are not being used as guinea pigs. The WHO would not allow this administration to happen if you were being used as guinea pigs.”

Certainly, there is a lot riding on the project. Dr Mhadji says FEMSE will save the Comoros $11m a year in direct and indirect costs (for comparison, its annual health-care budget is $7.6m), as well as preserving many lives that would otherwise have been lost and saving survivors from the brain damage malaria can cause. The eradication of malaria will also, he hopes, make the Comoros more attractive as a destination for tourists.

Others hope to profit, too. Artepharm has high expectations of Artequick and is using the drug’s success in the Comoros in its marketing campaigns in South America, South-East Asia and Africa. Moreover, the arm of the Chinese government that administers that country’s foreign aid, and is thus helping pay for the project, is the Ministry of Commerce—for Chinese largesse is more explicitly tied to the promotion of the country’s business than is aid from most Western countries.

Not that the West is a disinterested party, for Western firms, too, manufacture artemisinin-based malaria therapies. On that point Dr Mhadji has strong views. He dismisses criticism of the experiment as fuelled by competition between Western and Chinese pharmaceutical companies.

As Nick White, a malaria researcher at Oxford University’s School of Tropical Medicine who has been working for years on eradicating malaria, says, “This research is radical. It is controversial. It is led by a very famous Chinese physician and investigator. There are lots of very serious questions here and a lot of unknowns.” Or, as Oscar Wilde more succinctly put it, “The truth is rarely pure and never simple.”

Malaria eradication: Cure all?, Economist, Jan 25, 2014, at 66