A step closer to malaria elimination? The RTS,S/AS01 vaccine recommendation

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In an extraordinary development in vaccine research and implementation, the World Health Organisation (WHO) announced on Wednesday 6 October 2021 that it is now recommending the rollout of the first and highly-anticipated malaria vaccine to children throughout sub-Saharan Africa and regions of moderate malaria transmission beyond the continent.

The vaccine in question, RTS,S/AS01 (brand name Mosquirix), was first developed in the 1980s by biotechnology firm GlaxoSmithKline and is classed as a pre-erythrocytic vaccine. This means that it is aimed at preventing the onset and development of clinical malaria through inhibiting transmitted malaria parasites invading liver cells (hepatocytes) where they begin to replicate, which in turn halts the parasites maturing into the well-known and lethal blood-stages. 

Following a large-scale pilot vaccination programme quantifying safety thresholds, feasibility, and cost-effectiveness amongst children under five in Ghana, Kenya, and Malawi, 2 million doses have been delivered to more than 800,000 children since 2019. The results from this trial demonstrated that RTS,S/AS01 rollout is feasible when delivered alongside routine childhood vaccination programmes, and showed limited interference with existing malaria control interventions, including indoor residual spraying and sleeping under insecticide treated bed nets. Most importantly, the experiment proved that delivery is cost-effective in regions of regular (holoendemic) malaria transmission. 

Malaria—which killed 409,000 people in 2019 and is transmitted via the infected bite of female Anopheles (genus) mosquito vectors—has continually blighted the world’s most marginalised populations. The approval and subsequent recommendation of RTS,S/AS01 vaccination by WHO Director-General Dr Tedros Adhanom Ghebreyesus was highly welcomed and comes just five months after committee members convening at the 74th World Health Assembly requested immediate technical support should an innovative tool against malaria become available. 

“Malaria has continually blighted the world’s most marginalised populations.”

At the 68th World Health Assembly in May 2015, ambitious targets were set to reduce malaria incidence (new cases) and mortality rates globally by up to 90% by 2030. Various factors have hindered the progress attained in malaria control and elimination since the year 2000, including the complex parasite life cycle and reliance of insect vector species for transmission, meaning that disease eradication is sadly not yet attainable. However, since the 2015 declaration there have been numerous cries to diversify the treatment options to those suffering from malaria, since anti-malarial drug resistances, insecticide resistant mosquito vectors, and lack of adherence to vector control interventions continue to threaten the successes achieved by malaria elimination campaigns to date—hence the excitement when RTS,S/AS01 was approved for use.

The results from the phase III clinical trials indicate that among children aged 5–17 months who completed the 4-dose RTS,S/AS01 schedule, 39% of malaria cases were averted and a further 31.5% of severe malaria, malaria hospitalisation, and all-cause hospitalisations were reduced. Not only do these efficacy values fall significantly short of the WHO’s requested 75% malaria vaccine efficacy by 2030, but they also appear particularly inadequate when compared to routine vaccinations like diphtheria vaccines which has an effectiveness of 97% against infection. Worse still, we are increasingly accustomed to high vaccine effectiveness reporting—such as COVID-19 vaccine effectiveness against hospitalisation ranging between 75–95%—which distracts from the clinical and social importance of the RTS,S/AS01 malaria vaccine. Despite apparent ineffectiveness based on effectiveness values alone, estimates indicate that 4.3 million malaria cases could be averted annually if RTS,S/AS01 vaccinations were prioritised through sub-national administrative units and to children in countries with high malaria parasite prevalence.

“4.3 million malaria cases could be averted annually if RTS,S/AS01 vaccinations were prioritised through sub-national administrative units and to children in countries with high malaria parasite prevalence.”

With 141 malaria vaccine candidates, but presently only two viable vaccine options (RTS,S/AS01 and the unlicenced, experimental R21-Matrix M boasting 77% efficacy in clinical trials), the immediate requirement for novel therapies is obvious. On Tuesday 19 October 2021 Dr Tedros shared a damning reminder of the barriers that may hinder the delivery of RTS,S/AS01 in countries with low and middle incomes, as they have for the COVID-19 vaccine: “The harsh reality of vaccine inequity: the rate of booster doses in high-income countries is approaching the low-income countries primary dose rate. This injustice costs lives and livelihoods and only prolongs the pandemic.” It is therefore imperative that when delivery of RTS,S/AS01 across malaria endemic regions is initiated, delivery be equitable with surveillance networks established to monitor the progression of vaccination campaigns.

It is important to recognise that, despite the perceptions that RTS,S vaccinations will drive us towards malaria elimination, the WHO are recommending using RTS,S as an additional tool in the fight against malaria. Unlike the positive externalities that indoor residual spraying (IRS) or insecticide treated bed nets (ITNs) exert on limiting community-wide malaria transmission by reducing the density of malaria carrying mosquitos, RTS,S/AS01 can only provide protection against disease in those who are vaccinated. It is therefore key to reinforce that ITNs, IRS, and other preventative measures must also be upheld in malaria endemic regions, alongside RTS,S/AS01 vaccine campaigns.

The most effective delivery platform incorporating RTS,S/AS01 has yet to be evaluated. That said, a recent study following 6000 children aged 5–17 months in Burkina Faso and Mali reported reductions in malaria hospitalisation and deaths by as high as 70% in children which received RTS,S/AS01 with conventional seasonal malaria chemoprophylaxis (SMC, Antimalarial Drug Administration). Moreover, a single RTS,S/AS01 vaccination dose delivered prior to the rainy season (when mosquito vectors are most actively breeding, egg laying, and infectious biting) was found to be as effective at reducing clinical malaria in children under five as four annual SMC regimens.

It is hoped that soon, malaria would be controlled effectively by a single-dose multistage vaccine, effective antimalarial drugs, or innovative technologies such as gene drive or self-limiting mosquito populations. In the meantime, treatment options against malaria remain suboptimal. This being said, the introduction of RTS,S/AS01—used in combination with antimalarial chemoprevention in high transmission regions—is an exciting glimpse into the future elimination possibilities of this long standing disease.