Malaria: a continuing challenge

April 25th was World Malaria Day (www.worldmalariaday.org) and this prompted me to look at developments in combatting this pernicious and widespread disease. The World Health Organisation estimates there were 243 million cases of malaria in 2008. However, a huge increase in support for malaria control interventions in recent years has resulted in a reduction in the death rate; where once over a million people died of the disease annually, the figure is now closer to 790,000.

Nonetheless, malaria continues to be a global problem of huge significance. In Asia, resistance to the only drugs that can beat severe malaria (artemisinin-based combination therapy drugs) poses a real threat to the realisation of malaria elimination globally. All over sub-Saharan Africa, already struggling economies are being battered by the economic burden of the disease, which is estimated to cost Africa $12 billion a year.

This maintains pressure on the life sciences industry to keep up research into new ways of preventing and treating malaria. My own extremely modest efforts in this area occurred around 20 years ago and involved research into the use of bacterial pathogens to kill the mosquito vector of the malaria parasite and the use of peptide display technology to develop a vaccine capable of blocking transmission of the parasite. Neither approach met with any real success in combatting a parasite with such a complex life cycle.

So, what successes have been achieved in the last couple of decades? Artemisinin, a trioxolane derivative produced by the plant Artemisia annua (wormwood), was identified as a result of a research programme initiated by the Chinese army in the 1960’s. This natural product is very effective at removing the majority of parasites at the start of treatment but is less effective at dealing with the remaining parasites. In 2004 WHO recommended as the preferred treatment for malaria the use of artemisinin in combination with a partner drug that eradicates the last parasites. However, as noted above, resistance to these combination drugs is now a real problem.

GlaxoSmithKline has a malaria vaccine candidate in development. Research started in 1987 and In January 2001, GSK and the PATH Malaria Vaccine Initiative (MVI, www.malariavaccine.org) – with grant monies from the Bill & Melinda Gates Foundation to MVI – entered into a public-private partnership to develop the vaccine for use in infants and young children in sub-Saharan Africa. Encouraging data from Phase II clinical trials led to launch of a large-scale Phase III multi-centre efficacy trial in May 2009. The Phase III trial is underway in seven African countries (Gabon, Mozambique, Tanzania, Ghana, Kenya, Malawi, and Burkina Faso). This trial, which will enrol up to 16,000 infants and children, is expected to become the largest malaria vaccine trial to date. If all goes well the vaccine could be approved for use in 2013.

Alongside new funding for drugs and vaccines against the malaria parasite, donors and companies are increasing investment in “vector control”, as people in the field call the battle against malarial mosquitoes. This is because only when transmission levels and parasite loads in human populations have been reduced through co-ordinated mosquito control campaigns will drugs and vaccines have a chance of driving the disease towards elimination.

Ironically, the pesticide DDT was very effective at killing mosquitoes and was used to successfully control malaria in many parts of the world before its widespread and serious environmental side effects became apparent.

Recent campaigns are much better focused, through the provision of long-lasting insecticide treated nets (LLINs) and indoor residual spraying (IRS) – coating with insecticide the walls and ceilings of houses or huts, where mosquitoes settle before and between blood meals. However, resistance to pyrethroids (the most widely used mosquito killers) has become a serious constraint on vector control in Africa.

The rapid evolution of resistance to existing insecticides highlights the urgent need for replacements. No new mosquito killer has reached the public health market since the 1980s. This need is being addressed by is the Innovative Vector Control Consortium (IVCC, www.ivcc.com), based at the Liverpool School of Tropical Medicine, which was set up in 2005 with a $50.7m grant from the Gates Foundation followed by a further $50m last year.

Last year, BASF agreed to collaborate with IVCC and the London School of Hygiene and Tropical Medicine to develop malaria prevention products based on chlorfenapyr, a broad-spectrum insecticide developed by BASF, including bed nets and wall sprays. Chlorfenapyr is used mainly for killing insects on vegetable and fruit crops. The company hopes the chemical’s good safety record and low toxicity to mammals will lead to quick approval in the public health market, possibly as soon as next year.

Another priority is to find a way to prolong the active life of insecticides on bed nets and wall coverings. Vestergaard Frandsen, based in Switzerland and the largest manufacturer of treated bed nets, is leading the way with a wall covering called ZeroVector Durable Lining. This is a simple woven cloth – impregnated with insecticide – that can be nailed to the walls of huts and houses. The insecticide remains active for at least three years. Most IRS applications to hard walls lose effectiveness in six to nine months.

Looking further ahead, IVCC hopes that collaboration with academic researchers and the chemical industry will produce three new active ingredients for mosquito control by 2020.

But killing mosquitoes is not necessarily the only way to control them. IVCC is also investigating the use of pheromones to lure mosquitoes into traps, and evaluating the potential to develop better mosquito repellents that would stop the insects entering homes. The goal is a super-repellent that works much better than Deet, the standard ingredient in consumer products.

Another long-term prospect is the “sterile insect” approach being pioneered by Oxitec (www.oxitec.com), a biotechnology company based near Oxford. The idea is to release vast numbers of male mosquitoes, sterilised by genetic engineering, that would mate with all available females and swamp the fertile wild males in the vicinity. This approach is showing promise with the Aedes mosquitoes that spread dengue, but Oxitec scientists have found it hard to engineer sterility into the Anopheles species that spreads malaria.

Controlling malaria must be one of the few global challenges where natural product chemistry, vaccines, agrochemicals, consumer products and the Chinese army have all played a significant role. The fight against malaria remains to be won but it is noticeable that many of the innovations in this field are being developed by public-private initiatives such as PVI, IVCC and the Medicines for Malaria Venture (www.mmv.org). In this respect malaria may be providing an operational role model for the rest of the pharmaceutical industry.