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Mosquitoes versus humankind

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The fight against vector-borne diseases is in dire need of new insecticides. But it’s unlikely that real alternatives will make it to the market in time, writes Julia Gross.

20.12.2016-malaria-590.jpg [Related Image]
A female Anopheles gambiae mosquito trying to feed on a human. © Anthony James

A couple of years ago local authorities in Boa Vista, located in northern Brazil, found a patient with Dengue fever, a severe and painful viral disease transmitted by mosquitoes. This particular patient had been infected with DENV-4. What made this discovery significant is that there are four types of Dengue viruses but DENV-4 had not been present in Brazil for almost 30 years. Successive Dengue infections with different virus types might lead to serious, life-threatening complications. So health officials in the city of Boa Vista immediately launched intensive mosquito control measures. They searched for breeding grounds, applied larvicides and ordered repeat fogging against adult mosquitoes using an insecticide called Deltamethrin. According to the current guidelines of Brazil’s Dengue Control program, which adheres closely to WHO guidelines, it was a prime example of how to handle a case like this.

But investigations in the weeks and months after this brought sobering results: the number of mosquito eggs found after the intervention was nearly as high as before. In Boa Vista, there were about as many Dengue cases as in previous years. And after three months, the Deltamethrin resistance rate of the local mosquitoes had doubled. After half a year, it tripled. Seven months after the intervention in Boa Vista, DENV-4 was detected in nine of 27 Brazilian states. Two years later, it was present in 23 of the 27 states.

© Eliza Powell
Testing insecticide resistance in the lab: you put the insecticide inside plus some mosquitoes, leave it and then look later to see how many of them are still alive. Ifakara Health Institute in Tanzania. © Eliza Powell

The Boa Vista case is special only in how accurate the resistance data was tracked. In every other aspect, the same is happening around the globe. Mosquitoes can acquire resistance through random gene mutations – and they did, against almost every poison humans have ever used against them. With a short reproduction period of about two weeks and females that lay several hundred eggs, a population adapts rapidly. In South America and Asia it is an exception if tiger mosquitoes – which may transmit not only Dengue but also Zika, yellow fever and Chikungunya – are still susceptible to all classes of insecticides. According to WHO data, malaria mosquitoes are resistant to at least one class of insecticides in 60 of 96 countries. Ethiopia, Sudan and Afghanistan have mosquitoes which are able to deal with all four available classes. The WHO even thinks this might have caused the recent pick-up in malaria transmission in some countries. Until recently, after accounting for population growth, transmission is estimated to have decreased by 37 per cent between 2000 and 2015.

Malaria
Cause: Plasmodium parasites infecting and destroying red blood cells.
Vector: Anopheles mosquitoes
Symptoms: Fever, vomiting, headaches.
Global population at risk: 3.2 billion
Key facts: According to WHO data there were 212 million new cases and 429,000 deaths in 2015, the majority (88 per cent) in Africa. Malaria incidence fell by 37 per cent since 2000, malaria mortality rates among populations at risk decreased by 60 per cent, thanks to the usage of long-lasting insecticidal nets and better access to antimalarial drugs.

Dengue
Cause: Dengue Virus (4 different types)
Vector: Aedes aegypti, Aedes albopictus
Symptoms: severe headaches, muscle and joint pain (Dengue is also called ‘breakbone fever’), fever, in severe cases: internal bleeding
Global population at risk: 3.9 billion
Key facts: There are no proper case statistics, but a recent estimate puts the number of Dengue infections at 390 million per year. Where good medical care is available, fatality rates are below 1 per cent. The number of cases has been increasing dramatically in recent decades. The disease is also spreading to new areas. There is no specific treatment for Dengue.

Zika
Cause: Zika virus
Vector: Aedes aegypti mosquito. Sexual transmission from human to human possible
Symptoms: mild fever, skin rash, conjunctivitis, muscle and joint pain
Global population at risk: The 2015/2016 outbreak so far has affected 65 countries in the Americas and Southeast Asia
Key facts: Zika was first detected in humans in 1952 in Uganda and Tanzania. Since then, there have been several isolated outbreaks. Since the 2015 outbreak in Brazil scientists have concluded that Zika virus infection during pregnancy is a cause of congenital brain abnormalities, and that Zika virus is a trigger of Guillain-Barré syndrome with mostly reversible paralysis.

Yellow fever
Cause: Yellow fever virus
Vector: Aedes and Haemagogus mosquitoes
Symptoms: fever, muscle pain with prominent backache, in severe cases: jaundice, dark urine, vomiting, bleeding
Global population at risk: Yellow fever is present in 47 countries in Africa and Central-/South America. A modelling study estimated the burden of yellow fever during 2013 was up tp 170 000 severe cases and 29 000–60 000 deaths.
Key facts: Many people experience light cases and do not even show symptoms. But severe Yellow fever has a mortality of 50 per cent. A very efficient vaccine against the disease is available with lifelong protection.

Chikungunya
Cause: Chikungunya virus
Vector: Aedes aegypti and Aedes albopictus
Symptoms: fever, severe joint pain
Global population at risk: Chikungunya has been identified in over 60 countries in Asia, Africa, Europe and the Americas.
Key facts: There is no global reporting system for Chikungunya cases. In the Americas, there were about 730,000 cases in 2015. There have also been small outbreaks with local transmission in Italy and France in recent years. There is no specific medication and no vaccine against Chikungunya. In some cases, joint pain may persist for several months or even years.

The blood meal

The WHO explains that vectors, many of which are bloodsucking insects, are living organisms that can transmit infectious diseases between humans or from animals to humans. The vectors ingest disease-producing microorganisms during a blood meal from an infected host (human or animal) and later inject it into a new host during their subsequent blood meal.

When it comes to fighting vector-borne diseases, most of the funding goes into the search for vaccines and new medicines. But this is only part of the solution: the brand new vaccines against malaria and Dengue are far less effective than expected. The malaria parasite Plasmodium has become resistant to at least one class of drugs in many regions of the world. For Dengue, yellow fever or Zika, specific medications don’t even exist. To fight the spread of these diseases, the most important measure is preventing mosquitoes from biting people. Insecticides still play an essential role in this, but they become increasingly useless, and the pipeline for substitutes looks bleak.

One reason we ended up in this situation is the fact that today’s insecticides have been used for decades. All substances used in mosquito control originated from fighting insects in agriculture. But this kind of technology transfer from farms to public health doesn’t work so well anymore because the requirements today are actually quite different.

The Baden Aniline and Soda Factory (BASF) is the world’s largest chemical producer. Egon Weinmüller, Head of BASF’s Public Health division, explains, ‘In agriculture, pests usually ingest the toxin, whereas mosquitoes must be killed by contact only. On the field, chemicals need to work fast and then break down and don’t leave a trace. But in mosquito control you want products that stay active for at least six months.’

So, any new insecticides against mosquitoes would have to be developed specifically for this use. But the commercial opportunity is deemed too small by transnational agrochemical companies. According to manufacturers, the development of an insecticide costs around €250 million ($266 million), while global market volume for mosquito control paid by public health authorities and NGOs is estimated to be less than €1 billion ($1.06 billion) per year. Farmers spend around €45 billion ($48 billion) annually on agricultural pesticides.

That’s why scientists from the Liverpool School of Tropical Medicine founded the International Vector Control Consortium (IVCC) 11 years ago. Funded by foundations and development aid organizations, they work together with six large agrochemical companies to find new active ingredients.

There has been some progress, but so far none of the substances offer real innovation – they all come from the companies’ vast compound libraries. Most target very similar parts of the mosquitoes’ organism, and since they have been used for other purposes for decades, mosquitoes might well have been exposed enough to develop resistance against them, too.

Take Actellic, a substance designed for indoor residual spraying (IRS) in malaria prevention, touted a great achievement by the IVCC. It was developed in 1967 to protect stored grains. It hasn’t been widely used for IRS though, that is because it’s currently four times more expensive than the widely used insecticide class of pyrethroids. Separately, Bayer has developed an insecticidal mosquito net with particularly long-lasting effect, but it’s unlikely to have an immediate success, as its production costs are three times the amount of current bednets with pyrethroids. The WHO approval of BASF’s pesticide, chlorfenapyr, against malaria mosquitoes is expected in 2017, but it’s not a new active ingredient either. After all, three compounds from Bayer’s substance library, which don’t belong to the well-known classes of insecticides, are expected to enter field tests in 2017. But that also means they are still years away from approval.

IVCC’s focus is on malaria. The outlook for fighting tiger mosquitoes, carriers of Dengue and Zika, is even less optimistic. ‘There is also a lot less data on Aedes mosquitoes,’ says James Austin, Specialist for Vector Control at BASF. ‘In Africa, there is very good research infrastructure, with test facilities that meet international standards. This is not the case in Asia, where a large proportion of Dengue cases occur.’ Some compounds developed with IVCC may also be used against Aedes mosquitoes. However, bednets have only limited benefits as Aedes prefers to bite during the day. Fogging against adult mosquitoes is regarded as ineffective by an increasing number of scientists: too many mosquitoes get away. ‘People think they are protected, but they are not’, says James Austin, ‘and frequent fogging promotes resistance development.’

© Eliza Powell
A field worker from Ifakara Health Institute in Tanzania identifies mosquitoes caught in a monitoring trap. © Eliza Powell

That means new larvicides are needed. But apart from a handful of really old substances and the more expensive option BTI (a toxin from soil bacteria), the pipeline is empty. In addition, all current larvicides to a varying degree harm other water organisms, such as midges, water fleas, but also dragonflies or crabs.

‘Pyrethroids were originally derived from a plant, so was the antimalarial drug Artemi-sinin. It would not be absurd if the solution to this would also come from nature,’ says Marcello Nicoletti, Professor of Pharmaceutical Biology at the University of Rome. Among others, he collaborates with scientists from Southern India. They continuously look for larvicidal effects in indigenous plants. Flame lilies, Rangoon creeper, apple-of-Peru and Neem turn up in their findings. They discovered that dozens of plant extracts killed mosquito larvae. But none has ever been taken to further development, neither by transnational companies, nor by local entrepreneurs. Why? There are controversial opinions about it.

© Camille Kirnidis
Dead mosquitoes. © Camille Kirnidis

Rajander Sharma, former director of the Indian National vector-borne disease control programme, says it’s not enough to just show the efficacy of a plant extract. ‘We also need data about effects on other aquatic organisms and the toxicity to humans. But above all, a larvicide must be effective at least for seven days – and these botanical pesticides never are.’ This suggests that nature is a good model, but ultimately only a synthetically produced natural compound may meet modern quality requirements.

Nicoletti doesn’t agree. He regards the combination of many different components as a great advantage of plant extracts. ‘One leaf can contain 400 active components,’ he says. He thinks mosquitoes might take longer to develop resistance against a ‘phytocomplex’ than to a single, pure chemical compound. ‘The stability and quality issues of natural products can be partially solved by producing nanoparticles from the plant extracts. This slows down its degradation and facilitates dosage and storage,’ says Nicoletti. But this kind of work takes time, much longer than usual two to three years, for which scientific projects typically get funded, he says. So the researchers, often PhD students, move on.

© Camille Kirnidis
Dead mosquitoes. © Camille Kirnidis

Together with a multidisciplinary network of almost 60 Italian and international scientists, Nicoletti has investigated the potential of Neem for insecticides and other purposes for more than 15 years. The team probably owns the most comprehensive data collection on the subject. But this project also seems to have hit a dead end. ‘What we need now is the technological step towards a commercially viable product,’ Nicoletti explains. But there is no funding. After many unsuccessful attempts to find a sponsor or to partner with a company, Nicoletti now wants to give it a last try. He has asked a private foundation for €1 million ($1.06 million). He says that’s enough to make a product ready for the market. If this attempt also fails, he will give up, and all the data will end up in a file on his shelf.

This project has been funded by the European Journalism Centre (EJC) via its Innovation in Development Reporting Grant Programme (journalismgrants.org), run with financial support from the Bill & Melinda Gates Foundation.

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