The world’s first malaria vaccine and beyond

Ashley Birkett, PhD, leads PATH’s efforts to develop and introduce safe and effective vaccines and monoclonal antibodies for the fight against malaria. Following the World Health Organization’s  recommendation for wider use of RTS,S/AS01 and the decision by the board of Gavi, the Vaccine Alliance, to help fund its expanded use, Ashley answers questions on the world’s first malaria vaccine and how it is informing PATH’s work on the next generation of vaccines and biologics.

We are seeing the expansion of vaccine use in Ghana, Kenya, and Malawi—the three countries participating in the pilot program, thanks to a recent grant from Open Philanthropy to PATH. This expansion will make the vaccine available to children in pilot areas not previously eligible to receive the vaccine. RTS,S has received WHO prequalification, a process by which WHO further demonstrates confidence that the vaccine is safe, effective, and meets the needs of national immunization programs. In August, UNICEF announced the award of a supply contract to GSK. And in December 2021, Gavi approved an investment of US$155.7 million to support the introduction of malaria vaccines between 2022 and 2025.

Progress in controlling malaria has stalled. Actually, there has been a reversal of progress in some high-burden countries. To get back on track, the global malaria community has a two-pronged approach: use the tools we already have more effectively and develop new tools.

I think a vaccine has potential for high impact. This thinking is driven in part by the fact that we already have effective ways to deliver vaccines to young children in Africa. Even in some of the poorest regions of Africa, where malaria is a huge problem, we see high coverage with vaccines.

We have seen evidence of this in the ongoing pilot implementation of the RTS,S malaria vaccine in Ghana, Kenya, and Malawi. Importantly, the vaccine is expanding the reach of malaria prevention tools by getting to some children who are not using other forms of malaria prevention, such as long-lasting insecticide-treated nets. This means we are going from reaching 60 percent or 70 percent of kids with nets to reaching around 90 percent of children with either a net, the vaccine, or both.

We have to start with the RTS,S vaccine. In 2021, WHO recommended widespread use of the world’s first malaria vaccine, which is also the first vaccine against a parasite in humans and the first new malaria tool recommended by WHO against malaria in about a decade. RTS,S has now been prequalified, and work is beginning to expand access to the vaccine in the three countries that are participating in the pilot program.

It will be important for us to maximize the impact of RTS,S—what we’re calling a first-generation vaccine—but we’re going to need more than one malaria vaccine because the market is expected to be quite large. This market would be better supported by multiple manufacturers, which is one reason we have high hopes for the R21 malaria vaccine candidate, which is currently in Phase 3 clinical trials. Based on current data, R21 seems to have similar characteristics to RTS,S.

There are several reasons. First, if you only have one supplier, and if that supply runs into manufacturing difficulties for whatever reason, you risk the supply of the vaccine.

The second reason relates to economics. If you have multiple suppliers, you drive competition, which is better for the consumer, as it can impact the price of the vaccine. Competition should also drive innovation, as manufacturers seek to preserve or grow their market share by offering vaccines with superior performance.

Lastly, according to a WHO market study, the projected market for malaria vaccines is approximately 80 million doses per year by 2030 and 110 million doses per year by 2036, which is quite large. Multiple manufacturers have a much greater likelihood of meeting this demand.

We are helping to accelerate the introduction of RTS,S into more areas of Ghana, Kenya, and Malawi—the three countries participating in the pilot implementation of the vaccine—through funding from Open Philanthropy. Their recently announced award for $5 million will allow pilot countries to more quickly expand access to the vaccine.

We’re also assessing opportunities for further dose and schedule optimization to support long term availability, affordability, and sustainability, as well as nearer-term dose-sparing strategies to potentially close the gap between demand and supply.

At the same time, we’re supporting research to continue learning how best to use and deploy the RTS,S vaccine, particularly in highly seasonal malaria settings. Evidence that WHO considered when recommending the vaccine shows the benefits of targeting immunization to align with peak transmission seasons. A study conducted in Burkina Faso and Mali found that the impact of seasonal vaccination with RTS,S is comparable to that of seasonal malaria chemoprevention. SMC is the standard treatment for children in areas of highly seasonal malaria transmission, and we know now that combining RTS,S and SMC can reduce malaria episodes and deaths in children by about 70 percent, compared to either intervention alone.

With regard to malaria vaccines, first-generation vaccines that are currently being assessed have similar performance characteristics to RTS,S: modest efficacy, relatively short durability, and potentially requiring 3-4 doses in a primary regimen, with annual boosters in areas of highly seasonal transmission. When we think of next-generation vaccines, WHO has defined two strategic goals: reducing malaria disease and death and reducing malaria transmission among vulnerable populations. Achieving these goals may involve vaccines to either reduce illness and death, reduce transmission, or a combination vaccine that targets reductions in both disease and parasite transmission in a single product.

Those next-generation vaccines are maybe five or even ten years away. Given the current uncertainty on how best to achieve this goal, we support two pathways: one is to improve current vaccines, which would effectively leverage the investments in scaling up the production and reach of RTS,S that we anticipate over the coming years, and the other is to develop new vaccines. We think there needs to be parallel investment into both pathways until we have more assurance on which approach will work.

We’re working on a range of next-generation vaccines with multiple partners and with support from multiple donors. We’re also working on monoclonal antibodies, an innovative tool with the potential to offer high-level protection against infection and onward transmission.

Our work spans all stages of the Plasmodium parasite’s complex life cycle. Our work includes vaccines targeting the same protein as RTS,S to stop the parasite from entering the blood stream by targeting it before it exits the liver. Our work also includes approaches to combatting the parasite when it reaches the blood stream, vaccines to block transmission of the parasite from humans to mosquitoes, and finally, combination vaccines targeting multiple life cycle stages.

I think it has. It’s challenged the status quo in terms of vaccine development and introduction timelines for other diseases. In much of the world, particularly in wealthy countries, we have viewed COVID-19 as a public health emergency. However, if you’re a mother of a child in most of Africa, where nearly 500,000 young children continue to die every year, malaria may be the public health crisis that concerns you most. We must change mindsets. It’s time to start addressing malaria with the same urgency as COVID-19.

One of the potential benefits of monoclonal antibodies is that they could be given as a single shot, and primarily before periods of risk during times of high transmission. In highly seasonal settings, where most of the malaria occurs over four to five months, the idea is that you could get a single monoclonal antibody shot just before the malaria season, and it would protect you through the whole season.

We all respond differently to vaccines, but with monoclonals, you’re taking out that variable because you’re just putting the agent (the antibody) in the body directly instead of asking your body to develop it. Compared to vaccines, monoclonal antibodies also could potentially have higher efficacy.

Monoclonal antibodies for malaria are in clinical trials in sub-Saharan Africa. The initial proof-of-concept studies look encouraging. However, the challenges now are to translate this promising research into products that work in real-world settings, that can be delivered effectively, that are accepted by communities that could benefit from them, and that are affordable.

I’d have to go back to WHO’s 2021 recommendation for widespread use of RTS,S. It’s been a long journey and a lot of trailblazing, but the first malaria vaccine is here, and it’s starting to have impact and save lives.

This achievement is very important not only in the context of this first malaria vaccine but also for what it means for future malaria vaccines: the learnings and the opportunity to move faster to impact, in terms of challenging the status quo on development and introduction timelines.