16 minutes News

16 Minutes #63: Malaria Vaccine Breakthrough, Beyond the Buzz

Jorge Conde, Rajeev Venkayya, and Sonal Chokshi

Posted May 1, 2021

Playing out against the backdrop of a global pandemic (including recent massive surges in regions around the world) is the news that came out a week ago that a candidate “malaria vaccine becomes first to achieve WHO-specified 75% efficacy goal”. While the findings are still in preprint with The Lancet, the resulting buzz and phrases quoted included everything from “unprecedented”, “groundbreaking work”, and “very exciting” to “high expectations”, “highly effective”, and “a hugely significant extra weapon”… A “weapon” in the war against malaria that is — a disease that is estimated to cause over 400,000 deaths each year globally, and predominantly in children under the age of five.

So in this special 2x explainer episode of 16 Minutes (also running on the a16z Podcast), we —Rajeev Venkayya of Takeda Pharmaceuticals, a16z bio general partner Jorge Conde, and Sonal Chokshi — dig into what’s hype/ what’s real about this news, beyond the headlines and beyond the buzz. What does the data tell us, what does the current study phase mean, and what’s left to get to widespread, real-world use? How does this candidate vaccine (R21 from Jenner Institute/ Oxford University) compare to the other malaria vaccine (RTS,S from GlaxoSmithKline)? How do, and don’t, advances in and around COVID vaccines play here? And why has it been so hard to develop vaccines for this particular disease?

Because we also cover (as is the premise of the show) where we are on the long arc of innovation… and this is an innovation story that’s been nearly a century in the making.

Show Notes

The urgency of finding a vaccine to combat malaria [2:45] and why malaria is so difficult to treat [5:12]

Discussion of the R21 vaccine candidate and its pending study [10:48]

Previous vaccine attempts, details around clinical trials [17:48], and the pros and cons of different vaccine approaches [24:27]

How vaccine effectiveness is measured [28:54] and possibilities for the future [33:35]


Sonal: Hi, everyone. Welcome to the a16z Podcast network. I’m Sonal, and this is a special 2x episode of 16 Minutes, which we’re also running on the main a16z Podcast as part of our ongoing such coverage — and it’s all about the recent news, science, technology, problem, and innovations behind malaria vaccines.

While the discussion includes contrasts and comparisons to COVID vaccines briefly – and also plays out against a broader backdrop of the massive recent surge of cases in India and South Asia, as well as new waves in Brazil, Turkey, France, Argentina and elsewhere — the big news that also came out this past week is that a new candidate malaria vaccine is the first to achieve the World Health Organization’s goal of 75% efficacy, according to the announcement from Oxford University

Just to give a sense of how big and buzzy this news has been, some of the keywords that have been quoted by experts in many of the releases and articles have included phrases from “unprecedented,” “groundbreaking work,” “very exciting,” to “high expectations,” “highly effective,” and “a hugely significant extra weapon.”

So, as is the premise of 16 Minutes (which, if you’re not already subscribed to, be sure to find, and follow, in your podcast app), we dig beyond the headlines for what’s hype/what’s real, as well as where we are on the long arc of innovation.

Our expert guests for this episode are Rajeev Venkayya, President of the Global Vaccine Business Unit at Takeda Pharmaceuticals, where he leads full-stack development of vaccines for tropical diseases like dengue, norovirus, and Zika. He’s also been trained as a medical doctor and served as Director of Vaccine Delivery at the Gates Foundation, and was previously at the White House in biodefense.

Rajeev has also shared how vaccine development works in general, including outlining the phases and what was accelerated for COVID vaccines in an episode the three of us did last year, with a16z bio general partner, Jorge Conde, who also joins this episode, and has, in fact, been on all of our vaccine episodes. I don’t know if you actually knew that Jorge, that you’ve been on every single vaccine episode. <Jorge: You keep inviting me back!> Yeah, well, sadly — and importantly — we’ve had to cover many different aspects of this topic over the past year and a half.

And, we’ve covered everything from vaccine nationalism and vaccine hesitancy to vaccine manufacturing and scaling and all about mRNA vaccines and much more. Listeners, you can find all of that at a16z.com/vaccines.

But for this malaria vaccine, I’d actually love to start by hearing from both of you what your reactions were to the recent news. And I’ll summarize the specifics of the news in a moment, but, would love to just quickly hear the big picture for why this matters, from your vantage point.

The fight against malaria

Rajeev: I think this is a really big deal, because malaria is one of the big three (as we call it) — HIV, tuberculosis, and malaria cause an extraordinary amount of suffering and deaths every year.

All three of them have proven to be very, very tough targets from the standpoint of vaccine development. There’s no vaccine yet for HIV, despite extraordinary global efforts for decades. We have a vaccine that leaves a lot to be desired in the BCG, that we give at birth for tuberculosis. And there is a malaria vaccine that was brought to the world a few years ago from GSK called RTSS — but, that vaccine, while efficacious, has some room for improvement, and this vaccine potentially could be that improvement we’re looking for.

Jorge: In addition to what Rajeev said, I would say two of my biggest reactions was number one, the fact that they seem to have early indications of a vaccine that’s highly efficacious against a parasite is no small feat in and of itself (a parasite is a tricky bug).

And the second one I would just point out is, you know, obviously, vaccines have gotten an incredible amount of attention over the last year or so, given the COVID pandemic. But this vaccine, first of all, has been decades in the making… <Sonal: Nearly a century, I heard!> …nearly a century of effort to try to find a vaccine against this parasite, and this breakthrough didn’t come from the same technology that gave us the COVID vaccine breakthroughs. And to me, what’s fantastic to see is, the dividends that come from decades of research that pay off using, sort of, “old-world” technology. What I mean is, you know, this was a vaccine developed using more traditional vaccine production methods, versus what we saw in the course of one short year with the mRNA vaccines that BioNTech and Pfizer and Moderna brought us for the COVID pandemic.

Rajeev: Yeah I think for a long time to come, we’re gonna think about vaccines in terms of “pre-mRNA” and “post-mRNA.”

This is technology that was developed well before mRNA vaccines came of age. The technology that was used is actually proven — it’s been used in the hepatitis B vaccine, as well as the human papillomavirus… <Sonal: HPV, yeah> …yeah, these virus-like particles that are very, very effective at “presenting antigen” to the immune system so that it can recognize it, and then develop an antibody and cell-mediated immune response to that antigen.

The challenge of finding a vaccine

Sonal: Well, let’s dig into what this vaccine is and how they work. But first, just to put this whole problem in scope, just quick statistics. Over 229 million cases of clinical malaria were reported the year before [2019], and the World Health Organization estimated that malaria causes over 400,000 deaths each year, globally. I mean this seems to be concentrated in Africa and South Asia, Southeast Asia, different regions, but it is important to just note the scope of the disease.

Jorge: A lot of these tropical diseases also happen to be “poor country diseases.” I have to wonder if this tropical disease was endemic in the richer parts of the world — had we, you know, gotten to this breakthrough sooner.

Sonal: I was wondering the exact same thing, Jorge. The fact that we got to a COVID mRNA vaccine in less than a year, versus this disease that people have been working on for nearly a century — it almost makes you wonder, like, if this were prevalent in the United States, we would have solved this like 20 years ago.

Rajeev: Possibly, possibly. There would have been a lot more R&D for sure.

Sonal: I frankly think this is also true for women’s health, but I will go on that rant later.

Jorge: I was about to say that.

Rajeev: Yeah. It’s important to note that almost all the deaths are happening in sub-Saharan Africa, and two-thirds of those deaths are in children under the age of five. This is a very, very significant global burden of disease that desperately needs a safe and effective vaccine.

Jorge: What some people don’t realize is, not only is the disease burden high, but malaria is something you can get infected with again and again and again. You don’t get sick once and then you’re immune. There are reinfections. And so that just adds to the burden.

Sonal: I’m really glad you’re bringing up the point that it’s not a one-and-done disease, like another type of disease. I actually read a statistic that the average in a lifetime is six times, that a person can get malaria six times in their lifetime.

Jorge: At some point, you do develop immunity. Like, the reason why people catch malaria an average of six times and not an average of the number of years that they’ve lived — because eventually you become more resistant to it.

Sonal: Right. It’s like my parents, they never get stung or sick. But when we were kids, my brothers and I used to count and compare our mosquito bites, and we’d have, like, competitions for, like, how many we had. I would have (I’m not exaggerating), hundreds of bites on my body. And we did everything by the way. Nets, the coils, everything, you name it. The anti-malarial drugs — although I didn’t take mine, which is why I got sick. I was a young kid. I spit mine out. It was disgusting, and no one watched to see if I swallowed it.

Jorge: And by the way, the way that these anti-malarial pills work (at least some of them), is they essentially poison your blood so that the parasite…

Sonal: They taste poisonous. They taste like poison.

Jorge: Yeah, the parasite can’t survive in your bloodstream.

Sonal: So, why has this disease been so difficult? And in general, is there a difference when you’re designing a vaccine to target a parasite versus a bacteria or other viruses? The reason I’m asking is because, Jorge, you mentioned the malaria parasite — it has a complex life cycle, and can mutate. <Jorge: It’s wild> It’s crazy. I mean I’ve experienced a very mild form of it when I was a child, and just a little anecdotal bit of detail (that I don’t know if people who have never experienced this would ever know this), but in my experience, I had like the highest fever one day; the next day, it was as if I were a completely healthy person. And then the third day, I had a super high fever again. I don’t know if that’s a normal thing, but that was bizarre to me. Like, I had no idea why that even happened.

Jorge: Well, part of the reason why that probably happened is this sort of funky lifecycle of the parasite. So, you know, an individual gets infected when they are bitten by a female mosquito that’s carrying an infectious form of the parasite. That goes to your liver, where it continues to reproduce. Then it gets released to your bloodstream, where it attacks your red blood cells. And, it replicates within your red blood cells, and, when your red blood cells get too full of parasite, they burst, release a bunch of parasites into your bloodstream — that’s what causes the fever to spike. And then, it gets tamped down, and then when there’s another burst (of another set of red blood cells), the fever spikes again.

And then, to complete the life cycle, you now have a sort of premature version of the parasite floating around in your bloodstream, and you get bitten by a mosquito — and now that goes back up into the mosquito (to complete its sexual maturation). So it actually comes full circle. A lot of people think about parasites having a host. You know, in the case of malaria, malaria is being raised in sort of like shared custody between man and mosquito.

Sonal: That’s an incredible explanation.

Do you have any thoughts specifically on what it means to target malaria, as a disease?

Rajeev: Well, it’s almost a self-fulfilling situation, because the fact that a person can have malaria multiple times tells us that the immune system is having a tough time with this parasite. The immune system is not able to identify the parts of the parasite that it can then attack when it gets reinfected to prevent the illness from recurring.

And so, if the immune system, which is super sophisticated, is not able to do that, then almost by definition, it’s going to be a tough vaccine problem. One of the reasons is, the parasite can be quite effective at evading the immune system in the way that it grows in a person’s body. The parasite’s life cycle involves transmission through a mosquito that bites a person who gets infected — but then once that parasite is in a person, it has multiple stages of its growth that can be difficult to target. And so, that’s another unique feature of malaria.

A promising vaccine candidate

Sonal: So, let’s talk specifically about this vaccine. To summarize, the candidate vaccine here, it’s called R21. It was developed by scientists at the Jenner Institute at Oxford. And the reported findings are that they demonstrate a high-level efficacy of 77% over 12 months of follow-up, in a study with African children. Specifically, 450 participants aged 5-17 months, all from the country of Burkina Faso. Most of the doses were administered before the peak malaria season there (three vaccinations were administered at four-week intervals), and then a fourth dose came one year later.

So, that’s a super high-level summary. One more quick note, this was all part of the phase 2b trial — randomized, controlled, double-blind — the findings are still in press with the medical journal The Lancet (and I will include all links and sources that are mentioned in the show notes as always).

Rajeev: One thing I do want listeners to know is that the data we’re discussing today and you’ve seen in the media comes out of a preprint — which means this is not yet a peer-reviewed publication. Other experts will look at the study design and the results and they’ll ask critical questions of the researchers that they’ll then have to address in their responses, ultimately resulting in a peer-reviewed publication. Now of course we do hope that the essence of the findings will remain unchanged, and that the conclusions will largely be the same — but we can’t say that for sure until the peer review process is actually concluded.

Sonal: I mean, the preprint — lately “science-by-press release” is definitely a thing that’s accelerated in the last year for sure. I’ve seen it at a whole new scale that I’ve never seen before.

Rajeev: Yeah, and you know some would say that given that we’re living in COVID times, where literally every day matters in science, that we have to accept science-by-press release, hopefully followed very quickly by peer-reviewed publications. But the peer review and publishing process just takes too long, frankly, for COVID. And so we often end up having to rely on press releases and preprints.

But, I do want to point out that the preprint came out right around World Malaria Day, which is April 25th. And I think that’s probably why these guys released the preprint when they did.

Jorge: Wait, it’s April 25th you said? <Rajeev: Yeah> So World Malaria Day is the same day as DNA Day. That’s interesting.

Sonal: Oh, that is interesting!

Rajeev: I didn’t realize we observed DNA Day. That’s…

Jorge: Yeah, because April 25th was when the Nature article [was published] that Rosalind Franklin published her Photo 51, and Watson and Crick published their one-page, structure-of-DNA paper. And then, in an act of symmetry, the tie between Francis Collins and Craig Venter in sequencing the human genome was announced by Bill Clinton on April 25th.

Rajeev: Oh my gosh, I didn’t realize we were — there was a World DNA Day. Thanks for sharing that.

Sonal: So, back to the point about malaria. Anything more to say on the specifics of malaria as a disease that’s relevant here?

Rajeev: Well, there are a couple of things to think about when you are looking at vaccine development. And one reason, and perhaps the most important, is to prevent the severe illness that comes from it. But there is another objective with malaria vaccines, which is blocking transmission. Now, we’ve all heard with COVID, that one of the goals of vaccines is to reduce transmission in the community to help us get a handle on the pandemic. The same concept applies when it comes to malaria, but the vaccine approach is very different.

And — this will blow your mind — when we think about blocking transmission of malaria, the way it’s being approached from a vaccine standpoint, is to prevent a mosquito from picking up malaria from a person that has it. And the way you do that is by designing a vaccine that will generate antibodies that are taken up by the mosquito, along with the parasites, and preventing the parasite from reproducing inside the mosquito.

So, you’re giving a person a vaccine that’s not going to prevent their illness, it’s going to prevent the parasite from reproducing in the mosquito, so you’re actually indirectly vaccinating the mosquito (and not the person), because that person could still get malaria illness.

Jorge: The fact that we’re vaccinating mosquitoes, I think is wild.

Sonal: That’s fascinating. Let’s actually talk about the findings.

Rajeev: So, basically what the researchers did is, they took this group of children that are in a place with a very, very high incidence of malaria, right before the malaria season, and they gave them three doses of vaccine with another dose a year later.

They then counted cases of malaria, so they monitored for fevers in the children, and when a child came in with fever, they would do a set of diagnostic studies, and if they were found to have malaria, then they would be classified as being a malaria case. And then you compare across the three groups, and the three groups were a control group that received the rabies vaccine, there was a low dose adjuvant group, and a high dose adjuvant group. And both of those had the same amount of the protein that makes up the vaccine.

Sonal: Can you quickly explain what an adjuvant is and why it matters, because everyone always mentions that and how that plays in with the way the vaccine works.

Rajeev: Adjuvants are what you might consider immune boosters. And so, for any given amount of let’s say protein that you’re giving somebody to train their immune system to recognize a virus or bacteria, or in this case, a parasite, you can get away with a smaller dose of that protein if you give somebody an immune-boosting adjuvant.

The adjuvant that is used in this trial is the same adjuvant that a company called Novavax is using for its COVID-19 vaccine. And this is an adjuvant that is chemically related to an adjuvant that is used by GSK in their vaccine against shingles that is currently on the market.

So, it’s an adjuvant that has been proven (at least in that vaccine) to be very efficacious. And at least based on the phase two data that we have, with the combination with this — what we call “virus-like particle” — it also appears to be quite effective at generating a protective immune response.

Jorge: I understand why you’d have a high dose and a low dose arm. Why is the control arm a rabies vaccine versus saline?

Sonal: Yes, I was wondering.

Rajeev: Yeah, well, you know, when you’re looking at the immediate safety of a vaccine — meaning sore arms, fevers, or chills that you might get after a vaccine — you’re gonna see that to some degree with many vaccines. And so, we want to do a “fair or appropriate comparison.”. And so, using another licensed vaccine that would be appropriate for the population that’s in the study is an approach that’s often taken to have the control group even out between.

Previous attempts and clinical trials

Sonal: I see. You’re sort of controlling for the variables you’re trying to measure. <Rajeev: That’s right> That makes a lot of sense. So, why — this is the real question here, the big-picture question — why has it been so hard to develop a vaccine for malaria? Now, we’ve talked already about the difficulties of the disease, but, like, if you look at the arc of it — Rajeev you said there’s one vaccine I think right, the GSK one, RTSS, and I think the last thing that I read was that they demonstrated 55.8% efficacy in African children.

Can you explain that vaccine, and tell us more about — I’m really trying to dig into, like, why it’s been so damn hard to actually get here, and why this milestone is so significant.

Rajeev: Well, it was a big deal when GSK showed that their malaria vaccine worked a few years ago in a phase three trial. Now they showed that initially they had about 56% efficacy in the first year. Unfortunately, that efficacy wore off over time. And so, if you looked at how efficacious it was after four years, it dropped down to 36%.

And so, that vaccine is not yet widely recommended. There’s a pilot program rolling out in a handful of countries that’s happening as we speak.

Sonal: And by the way when you describe the pilot program, you were involved with that organization, Gavi (I believe) is the one that’s sort of helping the World Health Organization pilot the GSK vaccine in Kenya, Ghana, Malawi, I believe.

Rajeev: Yeah previously, I served on the Gavi board, which is the primary financing entity for vaccines for low-income countries. The data coming out of that program will inform the future implementation of that vaccine. Based on that level of efficacy that was seen with that first malaria vaccine, the WHO later came out with a target efficacy of 75% for future malaria vaccines. That was what presumably these researchers were going for when they tested their vaccine, and they were actually able to hit that target.

Sonal: So, the GlaxoSmithKline vaccine has been through lots of clinical trials — a lot more clinical trials than this one has — and this particular vaccine, going back to this specific news, of the Oxford vaccine news. This is a phase 2B trial, it’s not phase three yet. Can you quickly explain what it means to be in phase 2b and what comes next in phase three?

Rajeev: Sure, sure. So when we take vaccines through clinical trials in people, we start out with the studies to assess the safety of the vaccine to pick up any significant problems in small numbers of people before you go into bigger trials. And that’s done typically in phase one. In those phase I trials, you’re also assessing what the right dose of the vaccine could be. So you might have high, medium, and low doses of the vaccine to give you a sense as to what the right dose is to take it to further clinical development.

In phase II development, you’re often going into [a] larger number of individuals, and confirming that you are at the right dose. You might even still have different dose levels in your phase two. In a standard phase two trial for infectious diseases, you’re not actually looking to see whether you’re preventing infection, because there’s a relatively small number of people in phase two trials, and that wouldn’t be enough to actually be able to statistically measure a difference in the vaccine group versus the control group.

phase 2B trial is a little bit different: You have an even larger trial than a standard phase two, and these are often powered statistically to give you a sense as to whether the vaccine is actually working. This is a way that a company might de-risk the vaccine program before they go into a very large, very expensive, sometimes very long phase-three clinical trial.

So, this is that type of trial, where given the high incidence of malaria in this region and this population, they were actually able to show whether or not the vaccine works at preventing malaria.

The next step after this would be a large phase III trial. We can benchmark against GSK’s phase three trial of their malaria vaccine, which had about 15,000 children in it. And as we all know from COVID, the phase three clinical trials there have ranged from 20,000 to 60,000 individuals in any given phase three. So, this is smaller than that. And the main reason they were able to get away with a smaller trial is because the incidence of malaria was so high in the places where they were testing the vaccine.

Sonal: And for specifics, what I understand is that the recruitment of the phase three trial has already started, and they’re recruiting 4,800 children aged 5-36 months across four African countries. But here’s a little twist. So, you mentioned Novavax — so they’re one of the partners that’s collaborating with Jenner. But the other is, of course, the dominant player, the Serum Institute of India. They are obviously going through a massive COVID — so they’re actually delaying this a little bit, from what I understand.

Rajeev: Yeah, you know, it’s worth talking a little bit about that comparison between this vaccine and the GSK vaccine. Actually, they’re quite similar. They use similar adjuvants or immune boosters. The adjuvant used in the GSK vaccine is their proprietary adjuvant called AS01. In the case of the Oxford vaccine, it’s called Matrix-M, which is the Novavax vaccine. They’re both derived from tree bark (believe it or not) and so the chemical construct between the two, of the adjuvants, is quite similar.

The other parallel between these two vaccines is the virus-like particle approach is the same one taken between the two. They both use the hepatitis B surface antigen, which forms the core (or the base particle) for the vaccine.

The primary difference is that there is less of the hepatitis B surface antigen protein in the new Oxford vaccine. So there is proportionally much more of the malaria protein on the particle, than there is in the earlier GSK vaccine. And that is thought to be (potentially) a contributor to the difference that we’re seeing in efficacy with this vaccine, versus what GSK saw.

Sonal: And to be clear — I just want to kind of take the bottom line on that. Basically, what both of these vaccines are doing is targeting the parasite in that sporozoite phase of the lifecycle, which is when it enters the human body from the mosquito. And, the vaccines you’re saying — the main difference between the two vaccines — the R21 includes a higher concentration than the GSK. But that’s the primary difference. Other than that, they’re relatively similar underlying mechanisms.

Rajeev: That’s right, these two vaccines are quite similar insofar as they use a similar adjuvant, and they also have a similar structure.

Different vaccine approaches

Jorge: You know, in the case of this malaria vaccine, when we look at SARS-CoV-2/COVID as an example, the vaccine makers all sort of thought the spike protein was the best target or the most likely target, and that’s where the major players focused. Is there a similar consensus in malaria as to what the right targets are, or has that in and of itself been an odyssey?

Rajeev: Great question. There’s a lot of consensus around what’s called the circumsporozoite protein, let’s just say it’s CSP — which is the protein that is used in both the GSK RTSS vaccine as well as the Oxford R21 vaccine that we’re talking about today. And given that we’ve had limited efficacy with the vaccines against CSP — it’s not to say that something else won’t turn out to be better in future vaccine clinical trials.

Sonal: What happens if the bets we’re making with these vaccines — and this, I think, is the underlying thrust of Jorge’s question — is that it’s not actually effective at that sporozoite phase, do you have any thoughts on that? When we put all our bets on the coronavirus that hey we’re gonna focus on the spike protein, we’re taking a good bet — and so far it seems to have borne out, given that even with the new strains, that it’s still targeting the spike.

Rajeev: Well, it’s possible that we won’t be able to get there with this protein as the primary target, and that we would have to perhaps add a second target to the vaccine in the future. And it’s possible that we would have to add a second protein, or go after a different protein, in order to get efficacy against the parasite in this stage of its lifecycle. There are a lot of other proteins that one could target on this parasite.

Sonal: Got it. And actually, quick question for Jorge — is it naive of me to ask whether an mRNA approach would be more efficient? You guys put it really well, like, the old world/the traditional world versus a new world we’re in. Would a different approach to vaccines do a much better job? Because when I think of how we are thinking of these new batches of vaccines that we have in our bodies as, like, “software as a service,” are we able to do more with that — like, is that even on the horizon for malaria, or is that like just a pipe dream?

Jorge: I don’t think it’s a naïve question at all. You know, I — the vaccine producers that have mRNA technologies are looking at a broad range of infectious diseases for their next areas of focus. So, influenza is — you know, the flu is going to be an area of focus. The common cold is potentially, you know, on the table. So, viruses like that, clearly are sort of a next-horizon focus for these companies producing mRNA-based vaccines, and I don’t think it’s unreasonable to assume that their focus will expand beyond that.

I don’t know, technically, if an mRNA-based vaccine against malaria is feasible, but if you’re looking at surface proteins, arguably, you could theoretically develop an mRNA vaccine against the malaria parasite.

Rajeev: I agree with what Jorge said. I don’t think we can say that just because mRNA is a new technology that it’s more likely to be effective against malaria; however, I do think we can say that we need to give it a shot, because there’s so many advantages of mRNA approaches relative to more traditional approaches of developing vaccines.

One of the really interesting possibilities is that you could combine vaccine approaches into a single mRNA product. So, for example, you could have a CSP part of the sequence in your mRNA vaccine — which is the same protein that is targeted by these first two malaria vaccines that we’ve been discussing. And then you could have a second sequence or set of sequences that are targeting that sexual form of the parasite that the mosquito takes up when it has a blood meal, and then goes on to transmit the parasite to somebody else.

Remember, one thing that we need to realize is that second vaccine target where you’re trying to prevent the mosquito from going on to transmit the parasite — a vaccine like that would not prevent the actual illness associated with malaria. So, if you had a vaccine that was just focused on that, you’d be giving it to somebody and telling them “Look, this isn’t going to keep you from getting sick from malaria, it’s going to keep you from passing the malaria parasite onto somebody else.” That’s not a very attractive vaccine for someone to take. But if you combine that with something that also prevents them from getting sick in the first place — which could be this other part of the mRNA vaccine — then you’ve got a vaccine that everyone’s gonna want to take, and helps us to reduce malaria transmission, and maybe even eliminate malaria long term.

Measuring vaccine effectiveness

Sonal: Wow. Okay. In general, for context, over 100 malaria vaccine candidates have entered clinical trials in the past decades. But none has shown this level of efficacy that’s been targeted by the World Health Organization.

Now, again, to be clear, we’re talking about phase 2B. It hasn’t done large scale yet. But, one of the people who heads the World Health Organization malaria vaccine implementation program, argues that even modest efficacy would have a high impact precisely for the reason that people get the disease over and over again.

So, can we quickly talk about what the numbers of efficacy mean? They evaluated the vaccine safety, efficacy, etc., over one year — and what it means in, like, real-world practice?

Rajeev: Yeah, let me touch on the three parameters of vaccine performance that we often look at. One is immunogenicity. This is the easiest to measure. It’s simply the antibody response to the vaccine. We measure antibody levels in the bloodstream, and that becomes a measure of what we call immunogenicity. The reason that’s important is because the level of antibodies you generate with a vaccine might correlate to that vaccine’s ability to protect you from getting infected or contracting the illness associated with that infectious disease.

A second term we use in late-stage clinical trials is efficacy. And what that typically means or measures, is the ability of a vaccine to prevent the illness associated with an infectious disease. That term “efficacy” is very specific to the context of a clinical trial. So, there is usually a point estimate (let’s say 70% efficacious), and it’ll have a confidence bound around that, which represents kind of the error range given the size of the sample of your study.

The third measure we often talk about is effectiveness. Another way to think of this is real-world effectiveness. So, this is the assessment of how well the vaccine functions outside of a clinical trial, when you’re in the real world. You’ve launched the vaccine into a population (like we have with our COVID vaccines), and now we’re measuring how much illness and disease there is in a population.

Outside of the very controlled environment of a phase three clinical trial, where you may be telling people to do a number of things in order to protect themselves from the infectious disease. And so, you might see that a vaccine performs very well in the context of a phase three clinical trial. Then once you actually roll it out to the population, it doesn’t perform quite as well because these are real-world circumstances where people aren’t doing all the same things they wouldn’t be in the context of a clinical trial.

Sonal: So is there anything important to note about the question of effectiveness when it comes to this vaccine? Now again, it’s not in deployment yet, etc., but what are the considerations. One that of course comes to mind here is like, there’s like multiple doses.

Jorge: Multiple doses, yeah, I think that’s the biggest one.

Rajeev: That’s a big one. Multiple-dose is a big one. But there’s also, you know, in the clinical trial, people may have been very good about using bed nets at nighttime at home to prevent mosquitoes from biting. But in the real world, they may not keep up with their bed net use. They may not keep up with their indoor residual spraying of insecticides, which is often used to reduce biting in mosquitoes.

So, there are a variety of things that could increase the likelihood of getting infected in a real-world setting, which could correspondingly reduce your measured effectiveness.

Sonal: So, the other promise of this candidate vaccine from Oxford, is also the potential to get more high-volume, affordable vaccines. I read that it’s easier to make than the one that’s being used with the GlaxoSmithKline one, suggesting that it could be cheaper. Do you know if that’s true or not?

Rajeev: I’m not aware of the differences in the cost of making the two, because they’re quite similar. But it is using a pretty standard method of making vaccines. It’s manufactured in yeast (which is a tried-and-true way of manufacturing protein) — and the fact that Serum Institute of India has done this, means almost best-in-class in terms of efficiency, plus very high quality of vaccine manufacturing, given Serum Institute of India’s great track record here.

So, that’s also good news because this is a vaccine that is going to have to be priced at a level that is affordable for the poorest countries in the world, and can be purchased by Gavi. The fact that the cost structure is likely to be very low, helps to ensure that we’ll have a low price for this vaccine (at least for poor countries).

Possible next steps

Sonal: There hasn’t been a EUA for a vaccine in malaria, especially given the fact that malaria kills more people in Africa than COVID does currently. Do you think it’s possible that they might do some kind of EUA-type of situation for this?

Rajeev: I don’t think so. I would expect them to go through a standard (although accelerated) review process. One of the things that you are able to do in a standard review process is make sure that the manufacturing processes are all very well worked out, and validated, and reproducible with high quality.

It’s important for any vaccine, but certainly a vaccine like this that’s going to be going into vulnerable infants, you want to make sure that you do absolutely everything. And hopefully in the fastest time period possible.

Sonal: Right. I mean, we don’t even have a vaccine for kids for COVID yet, in fact, right, so.

Rajeev: That’s right, that’s right. One of the things that may be coming out of COVID is that we’re all a lot more attentive to global health problems that affect everybody in the world.

Jorge: I have to believe that we’ve also now developed capability, capacity, and political will in terms of vaccine production to do these things at the scale and speed necessary to hopefully benefit the entire world. My hope is that not only have we developed new technologies — you know we are now in a post-mRNA vaccine world (as Rajeev mentioned) — that have the potential to be um pointed at other infectious diseases, and hopefully give us other future breakthroughs.

When it comes to malaria, we’ve been pointing all of our guns at this for a long time. So, we’ve not only been looking for a vaccine, but as folks know, there have been philanthropic efforts to get bed nets out there. There’s of course tons of efforts in terms of insecticides, to reduce the population of mosquitoes. And there’s even, you know, engineering biology approaches to create genetically modified mosquitoes that are resistant to malaria. So, this is one weapon in what is a pretty deep armament to try to beat this thing.

Rajeev: Yeah, it’s absolutely true that this could be a critical tool in our toolkit. I look forward to seeing the peer-reviewed publication and hope that we’ll be seeing just as good results when the vaccine goes into phase three.

It’s also exciting to think about the end game. There is a day when we could imagine eliminating malaria from many more parts of the world, and possibly even eradicating it from the face of the Earth. Now, that’s not going to be easy, as smallpox and polio have proven (and certainly malaria is very different from those other diseases which are caused by viruses) — but it is something we can hope for.

Jorge: I was gonna say, we know the date of eradication will be April 25th, we just don’t know what year.

Sonal: Thank you so much, you guys, for joining this week’s episode of 16 Minutes.

Rajeev: Thanks a lot for having me, Sonal.

Jorge: Thank you, Sonal. Thank you, Rajeev.