The world’s first malaria vaccine: one year since the WHO recommended its widespread use

Since 2015, global progress against malaria has stalled, and some high burden countries are seeing increases in cases of the disease. The WHO estimates there were 241 million malaria cases and 627,000 malaria deaths worldwide in 2020. This is about 14 million more cases and 69,000 more deaths than in 2019.

One year ago, the WHO recommended the widespread use of the world's first malaria vaccine – a tool that, when used alongside other interventions, can help change the trajectory of malaria control and save lives.

We spoke with Dr. Mary Hamel, the WHO's Lead for Malaria Vaccines, about the vaccine and its potential impact.

It has been more than three years since the launch of the pilot implementation for the world’s first malaria vaccine, RTS,S, and one year since the WHO recommended its widespread use. What has happened in that time?

Dr. Hamel: The pilot implementation for the RTS,S malaria vaccine started three years ago, in 2019, in Ghana, Kenya, and Malawi. Since those ministries of health launched the vaccine in pilot areas, they have delivered more than three million doses to more than one million children.

In that time, we’ve learned a few key things about the vaccine.

First, that the vaccine has a very strong safety profile.

Second, there is high demand for the vaccine. Even during the pandemic, parents brought their children in for this vaccine and continue to do so. The evidence for demand is important because the vaccine has a different schedule from most childhood vaccines. It's a four-dose schedule with the first three doses given monthly from about five months of age, and the last dose given at around age two. The schedule begins a little later than most childhood vaccines begin and finishes a bit later. But parents came in, demand was very high, and coverage very rapidly reached good levels in all three countries.

We saw that parents understood that even when the child is vaccinated, the child can still get malaria, so it is important to continue using the other recommended interventions against malaria, including insecticide-treated nets, and that when their child gets fever, parents still need to bring them in for diagnosis and treatment.

We also learned something that was bit of a surprise: that the vaccine is reaching children who weren't reached by other preventive tools, such as bed nets or indoor residual spraying. In fact, the data indicate that the vaccine is reaching more than two thirds of children in the pilot areas who were not sleeping under a bed net, improving coverage overall for malaria- preventive interventions.

And then finally, we have looked at what is happening at hospitals since the vaccine was introduced, among children who are the age that could have received the vaccine. This is an important point, so I want to be sure to be clear: during the first two years of introduction, we know that only 65 to 70 percent of the children in these geographies had been vaccinated against malaria because the vaccine was still scaling up. But even with the vaccine reaching 65 to 70 percent of children, we saw a 30 percent drop in children who are presenting to the hospital with severe malaria. This is really important because, tragically, about a third to half of children who develop severe malaria die of it. We are also seeing an impact on mortality, among children who are the age that could have received the vaccine – again same caveat here that 65 to 70 percent of children in this area received the malaria vaccine. Nonetheless, we've seen about a 10 percent reduction in all-cause mortality. This is because in addition to the risk of dying from malaria, children with malaria are more susceptible to poor outcomes from other childhood illnesses and diseases. So, when you prevent malaria, you are also preventing deaths from other diseases.

The data and experience generated in these pilots informed the October 2021 WHO recommendation for broad use of the vaccine in areas where children are at risk of malaria illness and death.

Since then, Gavi, the Vaccine Alliance, announced in December 2021 that it would fund the rollout of the vaccine in sub- Saharan Africa. This was followed by UNICEF’s announcement in August that it would buy 18 million doses of the vaccine from GSK for US$170 million over the next three years.

How many lives are being saved by the vaccine?

Dr. Hamel: In Africa, malaria was responsible for nearly half a million deaths in 2020 alone. Mathematical models indicate that if the vaccine is rolled out across Africa, in areas of moderate to high transmission, tens of thousands of lives will be saved every year. Another way to understand this is that for every 200 children vaccinated, one child’s life is saved.

What are the next steps?

Dr. Hamel: Ghana, Kenya, and Malawi will expand access to the malaria vaccine later this year or early next year, doubling the number of children who have access to the vaccine in those countries. 

In early 2024, new countries beyond these three will begin introducing the vaccine.

First, these new countries need to develop their plans for introducing the vaccine and apply for support from Gavi. Gavi estimates demand will eventually exceed 80 million doses per year – that far exceeds the supply available in the coming few years.

The WHO anticipated this supply gap and while working with partners to support increased supply, we worked with expert advisors, primarily from the African continent, to advise on how the initial limited supply should be allocated in a fair and transparent way. The initial supply will go across countries, to children living in areas of highest need. These areas of highest need are being defined by countries, using their own data on where the children at highest risk live. The implication is that each country will introduce the vaccine in a subnational and phased way, beginning in the areas with children at highest risk, and then as more supply becomes available, they will roll out to other areas in the country.

At the same time, the current manufacturer, GSK, is scaling up manufacturing production to 15 million doses per year and is completing a product transfer to Bharat Biotech of India, which has the capacity to further scale up vaccine supply. GSK recently announced that they have committed 30 million doses of the AS01 adjuvant to match the RTS,S antigen that will be manufactured by Bharat Biotech.

That's one way to increase supply to meet demand, but the other is to have a second vaccine come to the market.

Tell us about the second vaccine, R21. How quickly might this become available and how different is its efficacy or use?

Dr. Hamel: The R21/MatrixM vaccine candidate has had promising results from a phase 2 trial conducted in an area of highly seasonal malaria transmission, and is currently in a phase 3 trial to confirm efficacy and safety, to measure efficacy when malaria transmission is year-round (rather than limited to four or five months of the year), and to show duration of protection. We anticipate that if all goes very well, and the phase 3 results on safety and efficacy are positive, the R21/MatrixM candidate vaccine could be available for use in highly seasonal areas as early as 2024 or 2025.

There has been a lot of excited reporting that efficacy rates for R21/MatrixM in the phase 2 trial reached 75 percent. It is important to understand that this level of efficacy was reached when the vaccine was given in a particular way, with the three primary vaccine doses given a month apart to all children just before the peak malaria transmission season began, and then a fourth dose was given just before the next high transmission season. And importantly, this trial was conducted in a particular setting, an area of highly seasonal malaria, where malaria transmission is largely limited to five months of the year, with few cases outside of that peak season. The high efficacy is achieved because the vaccine is most efficacious just after the vaccine is administered, and there is little or no malaria transmission when efficacy wanes. RTS,S/AS01 was shown to have similarly high efficacy when provided before the peak malaria transmission season in such a setting in a phase 3 trial published last year [Editor’s note: this trial compared three malaria prevention strategies – RTS,S/AS01 alone, Seasonal Malaria Chemoprevention alone, and the combination of RTS,S/AS01 plus Seasonal Malaria Chemoprevention]. We are looking forward to seeing the phase 3 trial results for the R21/MatrixM, to confirm the efficacy in highly seasonal areas, but also to measure efficacy in areas where malaria occurs year-round. 

Right now, we don't know if R21/MatrixM will be more efficacious than RTS,S, the first malaria vaccine. But we know that a vaccine with efficacy similar to RTS,S can be life-saving, and we look forward to having a second malaria vaccine at similar or higher efficacy to RTS,S.

Some have said the RTS,S vaccine is notable because it was able to bridge gaps in product development, sometimes called the 'first valley of death' and the 'second valley of death.' What does that mean?

Dr. Hamel: Bringing a vaccine from discovery to licensure to reaching the population at risk can be a long, expensive, and risky process. And when the vaccine is meant exclusively for low- or middle-income countries, the risks are even higher because there is no high-income market to buy [enough] vaccine so that the manufacturer can be assured they will recover costs. In the case of RTS,S, GSK worked for 35 years to move the vaccine from discovery through clinical development and testing, to recommendation, and finally to reaching children and saving lives.

There are two major periods of risk in vaccine development, referred to by researchers as the first and second “valleys of death.” The first valley of death refers to the period from drug or vaccine discovery, when a laboratory or academic institution identifies a promising intervention, through the first stages of clinical testing. Without sufficient resources, a vaccine candidate may never get through these initial stages and what might have been an important life-saving vaccine, might never make it to clinical trials.

But even if it overcomes this first hurdle, there is the second "valley of death” – ensuring the vaccine reaches the target population. In the case of RTS,S, this second valley of death is being bridged with the support from Gavi, which is financing the rollout of the malaria vaccine in countries with moderate to high malaria transmission.

RTS,S, which is targeted solely to low- and middle-income countries, is overcoming these two hurdles and reaching children should send a positive signal to vaccine developers and encourage the development of future vaccines, including those with different targets on the parasite, or maybe different target populations like pregnant women or a transmission-blocking vaccine. 

Why is this signal important?

Dr. Hamel: Because vaccine development is so costly – both financially and in time and commitment – developers and manufactures need to have confidence that if they develop an efficacious and safe vaccine with important potential health impact, that their vaccine will be purchased, and will reach the target populations. 

In the case of RTS,S, there were academics who were very global health minded and worked for decades developing a vaccine because they wanted to help children who are suffering from this disease.

But then, when RTS,S was developed in 1987, there was concern that it might never reach people and save lives. There was a gap between the lab and getting it to the point of manufacturing and delivery – and considerable funding support would be needed to bridge that gap. 

For the RTS,S vaccine, it was the Gates Foundation that supported and worked with PATH’s Malaria Vaccine Initiative and GSK to bring this vaccine forward through the large and costly phase 3 trials. Then Gavi, Global Fund, and Unitaid stepped up to fund the pilot implementations which generated the key findings that informed the WHO recommendations. Without the foresight and commitment of Gavi, Global Fund, and Unitaid, we would not have a malaria vaccine today – after 35 years of development, it would have been scrapped – and the lack of progress after so much work would have been extremely detrimental to the development of future malaria vaccines. Developers would have seen this area as high-risk. So, the commitment to fund the phase 3 trials and pilots were critical interventions that may have changed the future of malaria vaccines. Ultimately, the vaccine was successfully piloted and the important benefit on child health and survival was shown. But then, the question remained: who's going to buy this? There's not a wealthy market for malaria vaccines.

This is just the reason Gavi was established, to help ensure life-saving vaccines reach children living in resource-poor areas. That’s why the recent announcements from Gavi and UNICEF are such an important signal. They are showing researchers and manufacturers that we are bringing this vaccine into health systems and we can do the same for other effective vaccines and life-saving interventions that are developed in the future.