A new vaccine in the fight against malaria

In 2022, WHO’s African Region saw 233 million cases of malaria, with 580,000 deaths. 80% of those deaths are children under 5. The phase 3 trial of the new R21/Matrix-M malaria vaccine was published in The Lancet this month, and the results suggest a turning point in the fight against malaria. Gavin is joined by Professor Sir Adrian Hill, one of the creators of the vaccine, to discuss the process the vaccine went through, the history of malaria vaccine research, and what the future holds.

Read the phase 3 trial here:
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)02511-4/fulltext?dgcid=buzzsprout_tlv_podcast_generic_lancet

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Transcript

This transcript was automatically generated using speech recognition technology and may differ from the original audio. In citing or otherwise referring to the contents of this podcast, please ensure that you are quoting the recorded audio rather than this transcript.

Gavin: Hello and welcome to the Lancet Voice. It's February 2024 and we're very happy to have you with us. I'm your host Gavin Cleaver and today I'm talking to Professor Sir Adrian Hill about his recent work on a newly approved vaccine for malaria. In 2022, WHO's African region saw 233 million cases of malaria, with 580, 000 deaths.

80 percent of these are in children under 5, and the disease kills one child every two minutes worldwide. However, in 2021, the first vaccine for malaria was approved. That vaccine had an efficacy of 36 percent in children aged 5 to 17 months. The new R21 vaccine, Phase 3 results of which are published in The Lancet this month, has an efficacy of 75%.

It has the potential to be a game changer for countries affected by malaria worldwide, and I'm joined today by one of the creators of this new vaccine, Professor Sir Adrian Hill. He's the Lakshmi Mittal Professor of Vaccinology and Director of the Jenner Institute at Oxford University, and he was also one of the leads on the AstraZeneca COVID 19 vaccine.

Professor Hill, thank you for joining me today. There's been incredible progress in malaria vaccines over the last few years. Why have we seen this rapid progress? 

Adrian: Yeah, it has been pretty striking progress, as you say, in the last few years. The context, of course, is that people have been trying to make malaria vaccines since about 1908.

At least that's the first publication I can not find a record of. It hasn't been easy. There are no other parasitic vaccines for humans, or really any thought against any parasitic disease. So what, why is malaria being so difficult? It's not like there's been no funding for malaria. There's obviously been less than, say, for COVID, but it has taken a very long time, and it's an important disease that's killing well over half a million people a year.

Still, now in 2024. Firstly parasites are quite large at a molecular scale. There are over 5, 000 genes in the malaria parasite's genome. Scholars have argued for decades over which of those genes encoding a particular antigen might be best put into a subunit vaccine. And happily, there's a fairly good consensus now that one of those antigens is good.

In fact, both of the two new vaccines use a circumsporozoic protein as the antigen. So we're very much agreed on that. And of course, the parasite has multiple life cycle stages. It's not just like a virus where if you tackle it once and knock it out, you're there. With malaria, if you don't knock it out as soon as it gets injected by a mosquito, it hides in the liver.

for a week, where it's pretty untouchable by antibodies. And then those parasites come out, having multiplied 20, 000 times within a single liver cell, become blood stage parasites, and express completely different antigens. So if you have a very good vaccine against the first stage of the life cycle, it won't do anything against the blood stage.

So that's difficult. And then finally, the life cycles continue through a mosquito, where again the parasite has changed, and produced yet another mosquito. Again, different antigens. They've really been in parallel groups working on three different targets for malaria because the antigens are so difficult at different stages.

And the punchline at the end, having got to the finish is that it turns out you need extremely high antibody levels to protect at any of those stages. In COVID, we were getting tens of micrograms per ml and a useful vaccine. In malaria, you need hundreds of micrograms per ml, and that's just technically difficult.

Gavin: Given that both of these vaccines agree on the antigen, was there a particular kind of eureka moment, so to speak, when when both vaccines settled on this particular antigen? 

Adrian: I would say there were two Eureka moments. One was, the first thing to say is these vaccines are very different vintages.

The GSK vaccine is mid 1980s. That's the so called RTSS vaccine, whereas our vaccine was conceived in 2011. It existed to vaccinate mice by 2012. So you know it's 25 years younger than the GSK vaccine, and we argue that there have been some. Improvements and the data do that. So I guess the first Eureka moment was in the mid 90s when the RTSS vaccine was being tested for the first time.

And in the next couple of years, it was clear it was actually protecting maybe half the people who were vaccinated. That was in adults. It was in what we call a challenge model where we deliberately infect individuals and of course treat them if they do get malaria. That was a big step forward. Nobody had really shown any efficacy before the mid 90s with any malaria.

Vaccine for humans and people were hopeful that if you can get 50%, you can push it up towards 70, 80, 90 percent you would usually get with a vaccine. And that turned out really not to be the case with RTSS, it did improve a bit with different immunization regimens. But, overall in its phase three trial, the efficacy was 50 to 55 percent.

You can't. And then, very unluckily in 2015, that GSK vaccine appeared to have an important safety problem in the children it was used to vaccinate. And that was a very odd doubling of mortality in girls compared to boys. And compared to the controls, which looked odd. And some people didn't believe it and said it could have been chance, but the regulator is at WHO.

Insisted really on a very big safety trial that took delayed things eight or nine years. And of course it was not for it. So in the meantime, of course, vaccinology advances, as you've seen recently with COVID, new types of vaccine. We use a particular nanoparticle based based on the hepatitis B vaccine.

So there's actually some of the vaccine against hepatitis B in the malaria vaccine. And it's used as a scaffold to turn the malaria vaccine into a sphere. Or a nanoparticle, as we call it. The other key ingredient is an adjuvant. You need a very potent adjuvant that will make those antibody responses. As high as possible, and we used an adjuvant from a company called Novavax that had been around for several years was somewhat related to the GSK adjuvant, but distinct, and that's been very important for our program, but the most important development really was finding a manufacturer who happens to be the world's largest vaccine manufacturer, the Serum Institute of India in Pune in India.

Who do very large scale manufacture of many vaccines, particularly childhood vaccines, particularly for lower income country markets. And they were very keen on malaria and visited us in 2017. And we've been working with them since. So this has been a very much a partnership with the two companies and the University of Oxford.

Gavin: In simple terms, what's the difficulty in translating a vaccine that shows efficacy in adults into a child population such as the one largely affected by malaria? 

Adrian: Yeah, the first thing you have to do is to show that the vaccine is safe in children and we are vaccinating infants, not not toddlers.

That's a slightly higher bar, has to be very safe. We were using an adjuvant that had not been given to young children before, and we were able to show safety very early on in our initial trials in children in Africa. But the other thing that's a bit unpredictable is why Immune responses, and I mentioned that we need very high immune responses, very high antibody levels, how they vary by age, and what we've learned in the malaria field is the best age to vaccinate is between 5 and 12 months of age.

If you go in earlier, the antibody responses are really much weaker, so you can't vaccinate at 1, 2, and 3 months of age. And if you delay till two or three years of age, the antibody titers aren't as good again. So we are deploying this year in really five, six, seven holes to get the antibody responses as durable as possible.

Gavin: How difficult was the deployment, like how difficult is it to organize a phase three on this scale? 

Adrian: Yeah, there, funnily enough, coming second was an advantage. RTSS had used 11 different field sites. We decided that wasn't really necessary and picked four of the best, if you like. Two in East Africa, two in West Africa.

We also chose sites that differed in their seasonality. Sometimes when The rains are very seasonal, say in West Africa, you get the peak of malaria transmission a few weeks, a few months later. And we managed to find both seasonal and we call it perennial non seasonal sites, just to show that the vaccine could be deployed in all of those different settings in sub Saharan.

Gavin: How important is it to have working scientific partnerships with these countries in the, in testing? 

Adrian: It's crucial, because most of the hard work in a clinical trial is done on site, in the field sites. You need trained staff, you need ideally experienced principal investigators, and we had a total of five sites, two of them were elite sub sites.

So those five principal investigators had all done a phase three trial for malaria before, which was fantastically helpful. And not least because we essentially got our good phase two efficacy results in just 450 children in January of 2020. So we were planning the phase three trial just as COVID exploded.

And wasn't entirely clear whether that would even be possible, but thanks to video technology and Comms working very well without us having to travel to the field sites or being allowed to travel to the field sites. The trial was able to go forward. 

Gavin: Taking a step back and in very broad terms how impactful is the kind of sheer burden of malaria in these areas?

Adrian: In about 2000, there were of the order of a million children dying each year in Africa alone from malaria. And then the world woke up a bit. A lot of more money went into global health, there hadn't been nearly enough going in the 1990s. Bed nets started to be used more widely, insecticide treated bed nets helped out.

Drugs were looked at again to give preventatively to young children, and they've made a contribution. And spraying as well had been around for a long time. So really fairly traditional measures were deployed much more successfully. So that by 2015, we were down to about half a million deaths. That was costing money, billions a year, but it was cost effective.

And then the numbers started to creep up again, not just due to the pandemic, but of course populations are growing in Africa all the time. From 2017 till now, the numbers have been pretty similar, about 600, 000, 650, 000 childhood and adult deaths a year. Mainly children in Sub Saharan Africa. Really points to what the impact of these vaccines could be.

If you can roll them out successfully and the regiment is a four dose regime, with three doses close together and a booster a year later. If you could do that, we think you could save hundreds of thousands of lives. 500, 600, 000 to maybe 100, 000 deaths. Just by Implementing one of those vaccines widely.

That's what the modelers can estimate. That points to what's really crucial with malaria vaccine. You've got to have enough of it to impact on disease in Africa particularly. And that was one of the challenges for the RTSS vaccine where currently they can provide 6 million doses a year. 6 million doses, 4 doses per child means 1.

5 million vaccinees. And there are at least 40, maybe 50 million children who live in high transmission, moderate to high transmission areas of malaria and really need vaccination. So that vaccine on its own can't deal with the problem. The huge advantage of partnering with the Serum Institute is that, remember for COVID, they did billions of doses of the Oxford AstraZeneca vaccine manufactured there in one facility.

I think for malaria, they can make as much as the market requires. And I'll come back to that in a minute. But initially, that's going to be 100 million to 200 million for those 50 million children. So we're very confident that should be manufacturable and will be deployed from probably April of this year after all the approvals have now been given.

But, the other key point is there are other populations who need a malaria vaccine. For example, pregnant women in Africa can die of malaria. Very often they have. Stillbirths because the parasite really bizarrely likes to live in the placenta. So the stillbirth rate is high. We're starting a trial in the coming weeks on women in Africa who intend to become pregnant to see if we can protect them.

There's the other important malaria parasite, Plasmodium vivax. We're partnered with Serum Institute to make that vaccine as well. There are candidate vaccines coming along for the other stages, like blood stage. As I mentioned earlier, they're looking promising and then most important of all, this is a disease we should be able to eradicate.

There have been attempts in the past, they were under power, there was no vaccine, there were less effective tools, but certainly in the next decade, I think if we provided the money needed to control malaria very efficiently with new tools, we should be able to eliminate in many countries soon. and eradicate globally by the mid 2030s.

Gavin: It would be a huge step. How important still is the kind of breadth of tools, things like bed nets as well as these vaccines? 

Adrian: Yeah, so let's be very clear. There's no suggestion you should stop using existing tools and just use a vaccine. The vaccine individually is probably more effective than any of those single tools.

But the combination is at least additive. That's shown in clinical trials. If you give drugs and bed nets as well as vaccines, if you can get 70 percent efficacy with each, the two together combine arithmetically, so you're up in the 90 percent range. So the key question is, what can we afford?

And not many people know that last year, for the last five years, about 4 billion a year, Is spent not on malaria research, but on deploying tools like bed nets and insecticides. When a vaccine comes along, you can do the calculation that our vaccine is 3. 9 a dose. If you're distributing 100 million doses of that, you're still at less than half a billion and 4 billion is being used on the other tools.

So this is very good value for money. So if you add that all together, yeah, we're going to be spending 4 to 5 billion over the next five years, I estimate, on all of those tools combined. But, if you can eradicate malaria You get your money back. You won't be spending money on any insecticide treated bed nets or on vaccines or other interventions.

So if it costs twice as much per year to mount an eradication campaign and that were likely to be successful, that's a bargain because you would stop spending the five billion dollars from That day onwards it's human eradication. 

Gavin: Is that an argument that is easy to make to, to funding bodies and especially to governments in Africa?

Are they on board with the kind of upfront cost and then the eventual savings? Or is it a more difficult conversation? 

Adrian: We don't know yet because in the last few months, the entire focus has been on rolling out a vaccine to an age group that don't typically get vaccinated in some of the poorest countries in the world.

Getting through all the approvals at WHO and getting Gavi and UNICEF and other international organizations to accelerate the deployment. And in the next year, we will know how that has gone. That I think is the stage with new vaccines coming along, as I've said, to think about combination of vaccines and about elimination and eradication.

And what will probably happen is that there will be pilot studies in individual countries. And even with our malaria vaccine, R21, at the moment, there are two countries. In West Africa and one in Asia, who are going to test the vaccine not to see if it prevents disease, we know it does, but to see if you can knock down parasite rates in the population.

In other words, go a long way towards eradication. And even in the trial data we have so far, there's evidence that vaccine, just given to young children, halves the level of infection in the childhood population. I think it will help, but we will need Other tombs as well. 

Gavin: While we're talking about funding, you mentioned earlier that there was a big change in funding between the 1990s and the 2000s.

Was there a particular moment where the kind of funding for malaria, for tackling malaria, for malaria eradication changed? Was there anything that particularly caused that? 

Adrian: Yeah, a few things happened around then. There were rock concerts and they'd rock stars saying global health is something that we I've been neglecting a need to invest in.

So Bono and others made a difference related to disasters in particular countries and so on. The other very important thing was that the Gates Foundation, the, then one of the richest men in the world said, I'm going to spend most of my money on global health. And the Bill Gates, Bill and Melinda Gates foundation was started and they are very scientifically clued up and impressive.

And they've been pretty good at picking vaccine candidates to support. They've been very supportive of our program and that was a new money into the system. And then international organizations like UNICEF and Gavi, which didn't exist before the Global Alliance for Vaccines and Immunization, were able to start supplying vaccines to all countries in Africa at very low prices.

Mainly because Very large manufacturers in South Asia and to an extent in East Asia simply scaled up their facilities and were able to make vaccines at a dollar a dose rather than 10 or 20 a dose. And that transformed vaccine supply. So the average child in rural African countries now gets up to 10 vaccines in the first year of life.

That was unimaginable in the 1990s. So all we're trying to do with malaria is add one more. How difficult 

Gavin: in low income countries actually is keeping those regimens, especially as this is a multi dose vaccine. Are there any kind of challenges over time? 

Adrian: It's remarkably impressive what is happening today.

So the best measure, of course, is you go back and see what percentage of children have had three or four doses of those common childhood vaccines. And frankly, the rates in rural Burkina Faso are higher than in some parts of London. Which is a little bit better off than Burkina Faso, which is an ugly statement.

So yeah, there's a very good system in place, of course it's challenged by, all sorts of things that, that, that happen in, in, in many countries, whether there's a coup or the, or there are other logistic challenges, the numbers speak for themselves. We have more than halved childhood mortality in 15 years from From 2000, I'll be very disappointed if we haven't have childhood mortality from malaria in the next five years.

We should be able to do better. And then once you're down to, five figure numbers rather than six figure numbers, I think agencies will be more enthusiastic about putting money in to try and finish this off. 

Gavin: And the results for your vaccine look promising in efficacy over time as well, right?

Adrian: They do. And what we're seeing, the general measure is efficacy over the first year after vaccination in five to 17 month olds. And we're very close to 80 percent with this vaccine. And that's pretty good, compared to other deployed vaccines. And that remember is just the vaccine on its own.

If you add in the bed nets and you add in spraying and so on and maybe other interventions to, to come. You really should be, reducing the background malaria rate that you would had if you had no interventions by well over 90%. Were there any 

Gavin: kind of additional challenges during this trial on 0 to 17 months old versus, previous trials went all the way up to, I think, 36 months.

Is that correct? 

Adrian: Yeah. We we divided our group into two cohorts, really 5 to 17 month olds and 18 to 36 month olds. Mainly because we realized that, there will be one year olds and two year olds who could benefit from this vaccine. And that's what we found. Yeah, the efficacy was a little bit lower, about, maybe 5 percent lower, but still very useful to have.

And, it's a bit difficult to go to a family in their house and say, we see you have a five month old, we've come to vaccinate them. And the mother says, what about my one year old and two year old? And actually the age you're most likely to die of malaria at is one year of age. Data are very clear on that.

So you'd like to vaccinate the one year olds and do a catch up campaign. But at the moment, we're just focused on getting, 15 million doses out this year and use the vaccine as, as wisely as possible. So are those kind of, those are the immediate next steps? Absolutely. Yes. And remember that country teams not outsiders, vaccinate children in Africa.

So there's a bit of training to be done. There's a lot more record keeping to be done. If you're vaccinating children at 6, 10, 14 weeks of age initially, then 5, 6, 7 months for malaria, then 9 months for yellow fever and and measles, and then a booster dose in the first year of life. It's really quite impressive what happens, but what's been really reassuring in the last year or two are the data from a huge implementation study run by WHO in three African countries with the old RTSS vaccine.

And the uptake rates were really high we've had villagers asking our researchers, where is the malaria vaccine? We've heard about it on the radio. We'd like it now. And frankly, if you're a mother in an African village. And let's say your neighbor's one year old dies, the chances are extremely high that child has died of malaria, and those mothers know that.

So you know, having got what were very expensive pneumococcal vaccines, for example. It's widely distributed in young children in Africa, along with the other eight or nine vaccines. Malaria has been the really important missing one, and now we're in a position to, to make that widely available. 

Gavin: Yeah.

How did you feel when the efficacy data came back from this phase three trial? You must've been pretty excited. 

Adrian: We were reassured, but remember when we were, I think most excited was here in Oxford when our healthy volunteers. Who were vaccinated and then deliberately infected by mosquito bites showed around about 70 75 percent efficacy way back in 2017.

Then we had the phase two trial in Burkina Faso, a really high transmission zone there. And the efficacy was 77 percent over a year. We were reassured when we saw the phase three data, but it would have been very surprising if suddenly it dropped to, 30 or 50 percent in having been in the mid seventies.

But vaccines do fail at phase three sometimes, right? They do. But the difference about malaria is we get an answer much faster in malaria, sadly, because that reflects how common malaria is as a disease. Contrast that with tuberculosis, where you can't do a trial in a few hundred children and then get an answer.

Thousands or tens of thousands. So we had narrow confidence intervals on the point estimate in the Phase 2 trial. And that was within 1 percent of what we saw in the Phase 3 trial. And that just reflects the number of episodes in these very malarious areas. And we had a lot of statistical power, as I said.

Gavin: It's all very fascinating. Is there anything that you would like to add that you feel like we haven't discussed about the vaccines or about, treating malaria in general? 

Adrian: Yeah, just a couple of words about immediate plans. I mentioned that this vaccine should be useful for adults. Women who plan to become pregnant in West Africa will be the next target population.

We do think the efficacy here is high enough to make a useful traveler's vaccine. That has not been our priority because of the death rate in young children, but we are planning to develop this as a traveler's vaccine. And we are also hoping to add in a VIVAX component to that traveller's vaccine so you don't have to get the right malaria vaccine for wherever you're going.

So still plenty of work to do and it'll keep us busy, but it's very exciting the point we're at. 

Gavin: Well, Professor Adrian Hill, best of luck with the next steps and thank you so much for coming on the podcast. Thank you for covering it. Thank you to Professor Hill, and thanks to you for listening to this episode of The Lancet Voice.

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