Minke Holwerda, BSc Biomedical Sciences
This October, the Director-General Dr Tedros Adhanom Ghebreyesus of the World Health Organization (WHO) called it a ‘historic moment’, when the WHO officially recommended the use of the first vaccine against malaria in children living in sub-Saharan Africa .
Malaria is a disease caused by Plasmodium parasites that are transmitted to humans by Anopheles mosquitoes and is one of the leading causes of death in low-income countries [2, 3]. In 2019, there were approximately 229 million malaria cases in 87 endemic countries, leading to over 400.000 deaths . A disproportionately high percentage of these cases and deaths of 94% was in the WHO African region . The most vulnerable group comprises children under five, accounting for 67% of all malaria deaths worldwide in 2019, and over 200.000 children dying in Africa each year [2, 4]. Due to the devastating burden of malaria, the WHO has set the ambitious goal to reduce the case incidence and mortality rates by at least 90% by 2030 . Now, besides trusted measures such as insecticide-treated bed nets and artemisinin therapy, there is a new addition to the toolbox: the RTS,S/AS01 (RTS,S) vaccine .
The RTS,S vaccine (or MosquirixTM) is a vaccine over 30 years in the making, as it was already created in 1987 . Developing vaccines for parasites is more complicated than for bacteria or viruses since parasites have highly complex life cycles . The RTS,S vaccine targets the ‘pre-erythrocytic stage’ of the Plasmodium lifecycle .
But what does this mean exactly? The pre-erythrocytic stage comprises the injection of so-called Plasmodium sporozoites in the skin by the infected Anopheles mosquito and subsequent sporozoite invasion of the liver . Then, in the cells of the liver, hepatocytes, the sporozoites multiply into the tens of thousands and – to add to our confusion – are renamed into ‘merozoites’. After multiplication, the merozoites progress to the erythrocytic stage, in which the merozoites burst into the blood-stream and start infecting red blood cells. This is what causes clinical disease and enables transmission to the next Anopheles mosquito .
Developing a vaccine that targets the pre-erythrocytic state would therefore prevent both disease and further transmission . This is exactly what the RTS,S vaccine aims to do: it contains the circumsporozoite protein (CSP) present on the sporozoite and therefore induces an immune response against the sporozoite. This mainly prevents invasion of hepatocytes and eliminates already infected hepatocytes [6, 8, 9].
In a large phase III study between 2009-2011 that enrolled over 15.000 infants and children, the RTS,S vaccine showed a significant reduction of up to 36% in severe malaria, with the best results in children receiving three doses of the vaccine and a booster dose 20 months after the first vaccination [1, 7, 10, 11]. After this trial, research proceeded in the roll-out of a large pilot study in 2019 in Ghana, Kenya and Malawi to determine the feasibility of implementing this vaccine in a real-life setting. Up till now, the WHO reports a reduction of 30% in deadly severe malaria. In addition, the RTS,S vaccine is safe, likely to be highly cost-effective, and feasible to deliver – even in the midst of the COVID-19 pandemic [1, 12].
However, due to its modest efficacy, the RTS,S vaccine is not some panacea that will instantly eradicate malaria. For example, in the participants of the 2009-2011 phase III study, vaccine efficacy had declined to 4% when they were followed-up after seven years . Furthermore, the vaccine was less effective in Plasmodium parasites that were genetically different from the Plasmodium strain the vaccine was based on, and therefore efficacy might differ from place to place . So, this vaccine is no reason to throw all other protective measures out the window. In other words: the battle goes on.
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