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.

Considering the WHO Global Tuberculosis Report 2021 in light of COVID-19

In October of this year, the World Health Organisation (WHO) reported that deaths from tuberculosis (TB) have risen for the first time in a decade, a major blow to their End TB Strategy. Simultaneously, global spending on TB declined by 8.7%, falling far below targets. The report attributed the rise in deaths to the impact of COVID-19 on global healthcare capacity and access. This comes as no surprise—you would be hard-pressed to find a single area of healthcare that has not been negatively affected by the pandemic. However, I find that there is something particularly hard to swallow about the increase in TB deaths attributable to COVID-19.

In comparing the response to these two diseases, I do not intend to downplay the devastation that COVID-19 has wreaked upon our world. As of 1 November 2021, the WHO reports that approximately 5 million people have died of the virus since the start of the pandemic, and the effects of COVID-19 go far beyond the death toll, from economic devastation, to mass burnout of healthcare workers, to major disruption to education. The constant headlines, though tiresome, are certainly well-deserved. My question concerns why TB does not receive comparable media coverage—or more importantly, funding.

TB, one of the oldest infectious diseases to affect humanity, has been termed the “forgotten pandemic”. Prior to the COVID-19 pandemic, it was consistently the top single-agent cause of infectious disease death in the world, and it continues to kill approximately 1.5 million people per year. Along with this death toll come the other, less quantifiable effects many of us are much more familiar with now—missed school, financial ruin, and bereaved families. It is difficult to conceptualise the impact of this toll over the span of decades. And yet, because the brunt of the disease burden is borne by countries with lower incomes, TB rarely makes global headlines. TB is a disease of poverty, endemic in areas where many people do not have access to well-ventilated housing or where malnutrition is common. In endemic regions, TB perpetuates inequalities both within and between countries by acting as a constant financial drain on individuals and healthcare systems, stagnating economic development. Cases in most high-income countries are rare and tend to affect marginalised people such as those who are homeless. The dominant attitude towards TB is complacency. The world has decided that this death toll is not newsworthy.

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“In endemic regions, TB perpetuates inequalities both within and between countries by acting as a constant financial drain on individuals and healthcare systems, stagnating economic development.”

Consider the global vaccine response to COVID-19. Mobilisation to develop a vaccine for COVID-19 was swift, a remarkable and unprecedented success. Thanks to financial investment, researchers were able to develop multiple highly effective vaccines in mere months. The most recent data suggests that the Pfizer and Moderna vaccines are 88% and 93% effective at preventing hospitalisation respectively, both very impressive figures. For TB, by contrast, we have one vaccine, the 100-year-old Bacillus Calmette–Guérin (BCG) vaccine. This vaccine works well for preventing disseminated TB in children, but for pulmonary TB, the main contributor to TB deaths, it varies in efficacy from 0 to 80%. For unknown reasons, vaccine efficacy depends on latitude, decreasing closer to the equator—a cruel and peculiar parallel to the geographic gradient of global disease burden. 

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We need a better vaccine for TB. In the long-term, this will save the most lives, and even moderate improvements in vaccine efficacy would be cost-effective. Through the hard work of those committed to the cause, there are currently 14 vaccine candidates in the pipeline. However, the funding needed to accelerate vaccine development and improve our understanding of TB is simply not there, despite the fact that investing in TB has high financial as well as population health returns. The unfortunate reality is that research for deadly diseases often does not receive sufficient support until those with the most financial and social capital are affected, as we have seen in the past with the HIV pandemic. 

“The unfortunate reality is that research for deadly diseases often does not receive sufficient support until those with the most financial and social capital are affected.”

Most of us in non-endemic regions are lucky enough to not have to think about TB in our daily lives. However, COVID-19 has illustrated that in an increasingly globalised world, infectious disease is everyone’s problem. Although we are far from ending the COVID-19 pandemic, the rapid development of vaccines has shown us what we can accomplish when urgency demands investment. How much longer will the world wait for an effective TB vaccine? We are capable of better. Those affected by TB deserve better.

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The WHO Global Tuberculosis Report 2021 can be found here: https://www.who.int/publications/i/item/9789240037021