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 [1].
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 [2]. A disproportionately high percentage of these cases and deaths of 94% was in the WHO African region [2]. 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 [5]. 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 [6].
The RTS,S vaccine (or MosquirixTM) is a vaccine over 30 years in the making, as it was already created in 1987 [6]. Developing vaccines for parasites is more complicated than for bacteria or viruses since parasites have highly complex life cycles [7]. The RTS,S vaccine targets the ‘pre-erythrocytic stage’ of the Plasmodium lifecycle [8].
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 [8]. 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 [8].
Developing a vaccine that targets the pre-erythrocytic state would therefore prevent both disease and further transmission [8]. 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 [13]. 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 [14]. So, this vaccine is no reason to throw all other protective measures out the window. In other words: the battle goes on.
References
1. Organization, W.H. WHO recommends groundbreaking malaria vaccine for children at risk. in, Vol. 2021 (2021).
2. Organization, W.H. World Malaria Report 2020. in, Vol. (World Health Organization (WHO), Geneva 2020).
3. Organization, W.H. The top 10 causes of death. in, Vol. 2021 (2020).
4. Ashley, E.A. & Poespoprodjo, J.R. Treatment and prevention of malaria in children. Lancet Child Adolesc Health 4, 775-789 (2020).
5. Organization, W.H. Global technical strategy for malaria 2016-2030, 2021 update. in, Vol. (2021).
6. Laurens, M.B. RTS,S/AS01 vaccine (Mosquirix™): an overview. Hum Vaccin Immunother 16, 480-489 (2020).
7. Van Den Berg, M., et al. RTS,S malaria vaccine pilot studies: addressing the human realities in large-scale clinical trials. Trials 20, 316 (2019).
8. Marques-Da-Silva, C., et al. Pre-Erythrocytic Vaccines against Malaria. Vaccines (Basel) 8(2020).
9. Meibalan, E. & Marti, M. Biology of Malaria Transmission. Cold Spring Harb Perspect Med 7(2017).
10. Rts, S.C.T.P. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet 386, 31-45 (2015).
11. Arora, N., et al. Towards Eradication of Malaria: Is the WHO’s RTS,S/AS01 Vaccination Effective Enough? Risk Manag Healthc Policy 14, 1033-1039 (2021).
12. Ndeketa, L., et al. Cost-effectiveness and public health impact of RTS,S/AS01 (E) malaria vaccine in Malawi, using a Markov static model. Wellcome Open Res 5, 260 (2020).
13. Olotu, A., et al. Seven-Year Efficacy of RTS,S/AS01 Malaria Vaccine among Young African Children. N Engl J Med 374, 2519-2529 (2016).
14. Neafsey, D.E., et al. Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine. N Engl J Med 373, 2025-2037 (2015).
