The Long Road to Eradication

Written by Nabeela Bhaloo

Though relatively uncommon in the UK, parasitic diseases are still rampant in areas of the developing world- a staggering 3.2 billion people, which is half of the world’s population, are at risk of malaria. Work is being done to eradicate these diseases around the world, though there is still much work to be done before eradication will be achieved.

Malaria

Malaria is transmitted to people when they are bitten by a female Anopheles mosquito infected by the Plasmodium parasite (of which there are five different varieties). The life cycle of the malaria parasite is complex, as it spreads to the red blood cells and the cells of the liver. Patients typically present with chills, fever, and flu-like illness, and in some cases develop complications such as haemolytic anaemia, acute respiratory distress syndrome, and neurological abnormalities. Left untreated, malaria can be fatal. Because the parasite cannot complete its growth in temperatures below 20°C, malaria is typically spread in tropical and subtropical climates. Transmission is more intense and occurs year-round in regions close to the equator, such as Sub-Saharan Africa, due to warmer temperatures being favourable for the parasite.

Over the past 15 years, the incidence of malaria around the world has decreased by 37%. This can be attributed to prevention methods such as vector control (primarily through the use of pyrethroid-based insecticides and long-lasting insecticidal nets) and chemoprophylaxis for travellers visiting endemic areas.
Currently, the World Health Organization Global Malaria Programme (GMP) has set the target of reducing malaria incidence and mortality rates by 90%, eliminating malaria in a minimum of 35 countries, as well as preventing a resurgence in countries where malaria has already been
eradicated, by the year 2030. It aims to achieve this by setting global policies and guidance on malaria control and elimination and assisting endemic countries to establish national strategic plans, provide universal access to malaria interventions, and malaria surveillance systems.

malaria
Malaria patient at Tasahn research site

Though rates of incidence of malaria are falling globally, the path to eradication is now being challenged by increasing resistance to insecticides and antimalarial drugs. Drug resistance can occur due to patients not finishing the full course of their medication (for financial reasons or due to drug side effects), or patients taking counterfeit drugs, which only contain a small amount of the active drug- the parasite is exposed to subtherapeutic drug concentrations and can thereby develop resistance to it. Mass administration programs also contribute to resistance as they expose larger populations of the parasite to the drug, giving them the opportunity to become resistant.

Considering the fact that Plasmodium Falciparum is resistant to nearly all antimalarials- including sulfadoxine, mefloquine, halofantrine, and quinine, it is evident that new medications will be required to treat malaria. One prospect is compound DDD107498, which was developed at the University of Dundee. It is particularly promising because it targets malaria at multiple stages of its lifecycle (by blocking an elongation factor essential for protein synthesis by the parasite), and was found to cure malarial infections and act as chemoprotection in mouse models. Due to its long half-life, it has the potential to treat malaria with a single-dose, reducing the problem of non-compliance, and at the low cost of approximately $1USD per/dose, it is extremely accessible even to those living in poverty. It has now progressed to the advanced non-clinical development stage, and will hopefully move forward to human clinical trials.

Despite over thirty years of research, there is still no anti-malarial vaccine available. Over twenty vaccines are in various stages of development, however, the most promising candidate is the RTS,S/AS01 vaccine. It affects the sporozoite phase of the malaria lifecycle (sporozoites are the first phase of the malarial lifecycle and are injected into the skin by the female mosquito). It has progressed through Phase III of clinical trials, and was found to reduce clinical cases of malaria by 18% in infants and 28% in young children6. However, the trials noted that the vaccine only offers a short duration of protection, meaning that further development is required before the vaccine can be a suitable method of malaria prevention.

Onchocerciasis

Onchocerciasis is considered a “neglected tropical disease”- meaning that despite the fact that it has been almost completely eradicated from the developed world, it still persists in poor communities, especially in Sub-Saharan Africa. Caused by the parasitic worm Onchocerca Volvulus and transmitted by blackflies of the genus Simulium, it is called “River Blindness” because the infectious blackflies live and breed in close proximity to rivers and streams. It can cause skin disease as well as blindness- meaning that it is incredibly debilitating for those who are infected. An estimated 25 million people are infected worldwide, out of which 800,000 are visually impaired.

Since there is currently no prophylactic medication of vaccination for onchocerciasis, a popular form of disease-control relies on the use of insecticides. Vector control was implemented in West Africa in 1974. Mass drug administration of Ivermectin began in endemic African countries in 1995, which significantly reduced the prevalence of the infection. The African Programme for Onchocerciasis Control (APOC) was also launched in 1995, which focused on establishing community-directed Ivermectin treatment and environmentally safe methods of vector control. It closed in 2015 after the transition to onchocerciasis elimination began, and was replaced in May 2016 by the Expanded Special Project for the Elimination of Neglected Tropical Diseases in Africa (ESPEN)- which will support the eradication of neglected tropical diseases such as onchocerciasis by providing fundraising and technical support to affected regions in designing more effective interventions, and aiming to increase coordination between endemic African countries in order to achieve this. A target has been set by the World Health Organization to eradicate onchocerciasis in 80% of African countries by 2025.

The problem with the use of Ivermectin is that it acts against the larvae causing disease, but does not kill adult worms, meaning that after a few months the adult worms can resume production of larvae, leading to re-infection. Therefore Ivermectin administration is required bi-annually. Since many of the areas affected by onchocerciasis are undergoing conflicts that delay or interrupt disease control programmes, a long-term solution is needed if the target of eradication is to be met. One potential new treatment is Moxidectin, which requires annual administration. A Phase II clinical trial found that Moxidectin had a higher and longer-lasting efficacy compared to Ivermectin, meaning that it may be a valuable tool in the process or elimination of onchocerciasis.

Currently, The Onchocerciasis Vaccine for Africa (TOVA) Initiative is working towards developing a prophylactic vaccine. There are currently three vaccine candidates which have a proven efficacy in three different animal models, and the aim to have at least one vaccine in phase 2 efficacy trials by the year 2020. If a vaccine is developed, it will likely first be used to protect vulnerable children (under the age of 5) living in endemic areas where ivermectin is contra-indicated due to a severe adverse reaction risk. The vaccine will act by decreasing the adult worm burden and fecundity.

It will be interesting to follow the progress of these new developments over the coming years, and see if they are able to successfully lower rates of malaria and onchocerciasis around the world.

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