HEALTH


researchers treat cattle and goats with a formulation containing a mix of fatty acids associated with human sweat, which makes them smell like people - a scent mosquitos find irresistible. The cows can be treated with a deworming medication like anthelmintics, which causes any mosquitoes feeding on them to die. ‘Diverting mosquitoes away


from humans to cattle by itself prevents large portions of mosquitoes in areas with livestock from transmitting malaria between people,’ says Mafra-Neto. ‘There are well known models that indicate if one manages to reduce the mosquito bites in an area by 30%, malaria can be contained. Our results indicate that, in a side by side comparison, we can divert more than 50% of the mosquitoes from humans to goats.’ Unlike conventional controls, the


three ISCA treatments are reported to require only tiny amounts of insecticide to control very large populations. For example, Mafra- Neto says that to sufficiently control pests in soya bean crops, you would need a tanker truck load of traditional insecticide, while just one barrel of his product will do the same job. The team is currently seeking approval from the US Environmental Protection Agency, and expects to be able to bring products to market by the end of 2018.


Mafra-Neto isn’t the only scientist using semiochemicals to trap mosquitoes. Takken’s group in Wageningen


has shown that children with malaria release special semiochemicals that make them more attractive to female mosquitoes, and that infected mosquitoes themselves are significantly more attracted to human odours than uninfected mosquitoes.2


They have developed


a synthetic blend, MB5, which mimics human odour and contains semiochemicals that all humans produce on their skin. In a recent field study, they demonstrated that using this blend for mass trapping of malaria mosquitoes led to significantly fewer mosquito bites and less malaria.3 Laurence Zwiebel, professor


of biological sciences and pharmacology at Vanderbilt University, Nashville, Tennessee, US, is working with Takken’s group


developing MB5. His lab is also developing a new generation of excito-repellents that aim to overload the mosquitoes’ sense of smell. These excito-repellents target a recently discovered aspect of insects’ olfactory systems. In mammals, odorant receptors (ORs) line the surface of nerve cells in the nose, causing the neurons to fire when a particular odour molecule attaches to the receptor. In insects, however, the ORs lining the antennae are also coupled to a new class of receptor, known as the nonconventional coreceptor (Orco). Through screening over 100,000 molecules, Zwiebel’s lab discovered a class of molecule that activates Orco directly, known as VUAA1.4 When hyperactivated across all of its sensory neurons, Orco overloads the mosquito’s sense of smell, creating a highly aversive signal that stops them finding blood. Tests show it to be thousands of times more powerful than DEET. The end product could be a wearable insect-repellant device that protects people when they are outside. ‘There is a lot of interest in the use of odours to lure insects into traps, disadvantageous breeding sites and towards the consumption of insecticides, which has often taken the form of attractive toxic sugar baits,’ Zwiebel says. ‘ISCA’s approach is another welcome page in that book. Taken together with other innovative strategies, it may ultimately bring us closer towards effective insect control strategies that target disease vectors, agricultural pests and nuisance insects without turning to the large-scale over deployment of insecticides, which harm the environment, as well as beneficial insects and animals.’ WHO estimates there were 212m cases of malaria in 2015 and 429,000 deaths. Of these, 92% of deaths were in Africa, and 70% of deaths were in children under five. Other approaches to combating mosquitoes continue to be actively pursued. British biotech company Oxitec, for example, is developing a strain of mosquito that produces sterile offspring. The male mosquitoes have a gene inserted into their DNA that causes any offspring to die before they can reproduce.


Emerging drugs


Vectrax contains a mix of sugars and proteins that mimic 20 common semiochemical signals used by plants to attract mosquitoes to nectar-producing flowers. These are blended with insecticides to trick the mosquitoes into eating poison.


212m


Resistance to current antimalarials, such as sulfadoxine/pyrimethamine (SP), chloroquine and artemisinin- based combination therapies, means that pharmaceutical companies are always on the lookout for new drugs. GSK’s tafenoquine targets a latent dormant stage of the Plasmodium vivax parasite, which is able to ‘sleep’ within the liver and evade the immune system before resurfacing weeks or months after the first mosquito bite. In June 2017, GSK reported the results of two Phase 3 studies which showed that tafenoquine, when given alongside chloroquine, reduced the risk of relapse in patients with P. vivax malaria significantly more than placebo. GSK is also developing the world’s


cases of malaria in 2015 and 429,000 deaths, according to WHO estimates


first malaria vaccine called RTS,S or Mosquirix. Final results from the 2014 Phase 3 trial showed that the vaccine helped protect children and infants from malaria for at least three years after first vaccination. In 2018, WHO will embark on a pilot implementation of RTS,S involving 750,000 children in Ghana, Kenya and Malawi. Another candidate in the pipeline, KAF156, is being developed by the Medicines for Malaria Venture (MMV) and Novartis. The two companies announced in August 2017 that KAF156 would be the first compound from the imidazolopiperazines, a novel class of antimalarials, to enter Phase 2b combination studies. Clinical trials have started in adults in Mali, and are expected to expand to include adolescents and children in nine countries across Africa and Asia in 2017-2018.


References 1 T. Dekker et al, PLOS Neglected Tropical Diseases, 2016, 10, 10.


2 J. G Logan et al, PLoS ONE, 2013, 8(5), e63602.


3 T. Homan et al, Lancet, 2016, 388, 1193.


4 P. L. Jones et al, PNAS, 2011, 108(21), 8821.


A Phase 2a proof-of-concept trial of KAF156 showed that the drug candidate can target multiple stages of the parasite’s lifecycle; clear both P. falciparum and P. vivax parasites from the host; cure infections; and block transmission of the parasite. Because it has a different mode of action, it could also treat drug-resistant strains of the malaria parasite. MMV chief scientific officer,


Timothy Wells says: ‘The fact that the candidate has a different resistance mechanism to other antimalarials makes this compound really exciting.’


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