The Nobel Prize in Physiology or Medicine 2015 – W.C. Campbell and S. Ōmura "for their discoveries concerning a novel therapy against infections caused by roundworm parasites"
Introduction
Parasitic diseases are a major global health issue mostly affecting the world’s poorest populations (Nobel prize.org). For many years’ treatment options were limited, making the control of these diseases difficult. Satoshi Ōmura and William Campbell’s discovery of the group of drugs called Avermectins has revolutionised the treatment of parasitic diseases. In order to discover these drugs, Ōmura discovered a group of bacteria (Streptomyces) then Campbell identified that this group of bacteria had antiparasitic properties. This allowed the useful bacterium called Steptomyces avermitilis to be purified into Avermectins. Ivermectin, a key drug in the Avermectin group, treats two parasitic diseases Onchocerasis and Lymphatic Filariasis (LF) . Both of these diseases have devastating symptoms that can lead to further issues including social problems due to the stigmatism surrounding disabilities. The significance of Ōmura and Campbell’s work was recognised when they were awarded the Nobel Prize.
Parasitic infections
Parasitic infections are very common and affect over a third of the world’s population (Nobel prize.org) and are caused by a variety of organisms such as Nematodes (roundworms). Nematodes are a kind of parasite that cause Onchocerciasis and LF. These parasitic infections are particularly prevalent in Saharan Africa, south Asia and central south America (See Figures 1 and 2).
Onchocerciasis, also known as river blindness, is an infection caused by Onchocera Volvulus (Chen, 2016). The disease is extremely prevalent with around 37 million people in the world being affected (CDC.org). Onchocerciasis is transmitted by simulium blackflies, they infect the host and then develop in adults in nodules in the subcutaneous tissue of the skin, where they can live for over 15 years. After the worms have mated they can release around 1000 microfilariae (larvae) a day that move around the body and can live for 1-2 years. When these microfilariae die the body has an inflammatory response which leads to itching, lesions, depigmentation of the skin and rashes. Onchocerciasis can cause blindness if the microfilariae migrate to the corneas and cause an inflammatory response.
Lymphatic Filariasis is an infection caused by parasitic worms from the Filariodidea family. Currently LF affects over 100 million people (Nobel prize.org) and is the leading cause of permanent disabilities globally (CDC.org). Once the worms have been transmitted by mosquitos, they move from the skin to the lymphatic system where they mature into adults. The infection can lead to debilitating chronic conditions such as lymphedema, scrotal hydrocele and the thickening and hardening of skin.
Discovery, Mechanism and Development
The discovery of Ivermectin began with the work of microbiologist Ōmura, when he discovered a group of bacteria called Streptomyces, that were known to have antibacterial properties. He made this discovery by isolating natural products from soils near a golf course in Japan. Having collected the samples, he isolated new strains of the bacteria and cultured them in a laboratory at the Kitasate Institute. Ōmura isolated around 1000 cultures and then selected the 50 most promising for further analysis. Ōmura’s samples were sent to Merck, where Campbell was able to explore them further. Campbell discovered an anthelmintic component in the Streptomyces avermitilis bacteria which was effective against parasites in domestic and farm animals. With help from colleagues at Merck Campbell was able to name these compounds the Avermectin group. With further research Avermectin was chemically modified further to produce Ivermectin, hydrogenated Avermectin forming 22,23-dihydroavermectin B1. In 1975 it was named Ivermectin and by 1981 the drug was being used medically on animals.
Ivermectin is an anthelmintic drug, this means that its mode of action is based upon selective toxicity for the parasite. Ivermectin works by binding with glutamate-gated chloride channels in nerve and muscle cells. This causes the cells to be increasingly permeable to chloride ions, which causes the hyperpolarisation of the cell. This allows the paralysis of the parasite as only invertebrates have glutamate-gated chloride channels. Paralysis of the parasite means that the host is able to remove the parasite from the body.
When it underwent initial testing, Ivermectin was shown to be effective against many nematodes and arthropods. It was in 1977 that Campbell suggested that human trials would be useful (Gilman, 2016). Initial human trials were disappointing as the drug was not effective against adult parasites. This disappointment meant that the drug was further tested on horses and cows against the Onchocera species. Successful results from this led to testing on humans in 1978, one of the first trials validated the effectiveness of Ivermectin in treating humans effected by the Onchocera species (Gilman, 2016).
Global Impact
Ivermectin has had a large global impact, one of the main reasons for this is that the Merck CEO at the time decided to donate the amount of Ivermectin that was needed to treat Onchocerciasis for free. This decision was unprecedented and became a model for cooperation between pharmaceutical companies and countries unable to afford important drugs. Ivermectin was commercially named Mectizan and it was donated to those who needed it the most. In 1988 Merck expanded its commitment donating more Mectizan in order to treat LF in combination with the drug albendazole (donated by GSK). Since 1987 Merck has donated more than 2.8 billion treatments (Merck.com).
Before the creation of control programs, over 100 million people in Africa lived in areas at high risk of the diseases (Merck.com). The creation of Ivermectin has allowed over a billion people to be treated for key parasitic diseases (Molyneux et al, 2015). Recently WHO confirmed that Columbia, Ecuador, Mexico and Guatemala are all now free of Onchocerciasis. In 2017, Togo became the first country to have removed this health risk. Ivermectin has been so successful that areas of the world that were once plagued by these diseases are now on the brink of eradicating them entirely.
Ivermectin’s impact is set to continue because around 200 million people annually are expected to take the drug over the next decade (Crump et al, 2011), as part of control programs. In 2017 Merck further expanded their donation program in order to reach a further 100 million people annually through to 2025. The impact of this incredible drug has been recognised by many key teams including the UNESCO world science report who stated that the drug donation programs are one of the “most triumphant public health campaigns ever waged in the developing world” (UNESCO, 2005). The success was most notably recognised in 2015 when Campbell and Ōmura were awarded the Nobel Prize. The Nobel assembly said that “Campbell [and] Ōmura …have transformed the treatment of parasitic diseases. The global impact of their discoveries and the resulting benefit to mankind are immeasurable.” (Nobelprize.org).
Conclusion
It has been over 30 years since the creation of these drug control programs and many countries in Africa are now on their way to eliminating these diseases. Furthermore WHO have verified that 4 out of 6 countries in South America are now clear of Onchocerciasis. Onchocerciasis caused blindness in over 270,000 people, so the true impact of this medication on reducing stigmatism and revolutionising the quality of life for many people is truly immense. The Mectizan donation program is the world’s longest running drug donation program and has been very important in the creation of other programs, including community run programs in Africa. The fact that Ōmura and Campbell’s work has had such a vast and widespread impact is incredibly important and Nobel’s recognition acknowledges this.