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A Malaria Vaccine Candidate

This story has been passed around a lot the last few days, and I’ve had several people ask me what I’ve thought of it. It’s on a really interesting possibility for a malaria vaccine, and part of the narrative hook is that it’s using mRNA technology, which is about as attention-getting a topic these days as we get in biopharma.

Let’s do a bit of malaria background, which will illustrate why every attempt to vaccinate for malaria has fallen short of what you’d want to see. The disease is not viral, and it’s not even bacterial: it’s caused by Plasmodium organisms that are part of their own phylum of unicellular parasites. It’s safe to say that we (and every other animal species) would not miss the lot of them if they were to suddenly disappear, but we’ve been stuck with them for tens of millions of years, and they’re not going away any time soon. Plasmodia have a complex life cycle that goes back and forth between our blood stream and their alternate insect hosts, and malaria is famous shared between us and the mosquitoes. Who frankly are another set of living creatures that would not be much missed if they were wiped out (to the point that I’ve seen serious estimates of how badly the food web would be disturbed if we ever found a way to do it).

Malaria has probably been a scourge of humanity ever since there were recognizable humans, and the number of people it has killed must be incalculable. There are at least five Plasmodium species that can cause the disease, but most of the deaths are due to P. falciparum. Like the coronavirus, this one appears to be an organism that jumped from another species to humans – in this case, the most closely related species is found in gorillas, and it’s believed that a strain of that one made the leap into humans and has been evolving from there. Sequencing suggests that this may be a relatively recent event, perhaps only around 10,000 years ago, and the timing of that with the development of agriculture (and its effects on the human-proximate mosquito population) may not be a coincidence.

So what makes malaria such a hard infection to treat (or to vaccinate against?) Their long history as obligate vertebrate parasites has unfortunately equipped Plasmodia with a whole list of strategies. Their multistage life cycle features different moves at different times, but once they’re out in the red blood cells, one trick is just the way that they live inside the erthyrocytes, which prevents direct contact with antibodies and with various immune-system cellular defenses. A second one is the notorious antigen-switching capability: the surface proteins in these organisms are extremely polymorphic and variable, and change with every stage of the life cycle. In P. falciparum, among those is a whole list of PfEMP-1 proteins that end up on the surface of the erythrocytes, and cause them to stick to endothelial cells and to other erythrocytes. This helps to spread the infection, and also leads to some of the severe circulatory consequences of malaria in general. This constantly changing surface presentation is a major challenge.

But there’s another nasty one that was discovered about ten years ago: it turns out that Plasmodia secrete a protein related to human macrophage migration inhibitory factor, and this PMIF protein blocks the formation of memory T cells against the parasite, and interferes with helper T cells in the development of a strong antibody response. Readers who have been following the twists and turns of immunology as it relates to the current pandemic will realize what low blows these are. Messing around with the formation of germinal centers and antibody development, while routing what should be the formation of memory T cells down a dead end: these severely impair the immune reponse, both in an immediate infection and in subsequent ones. It then comes as no surprise to find out that many Plasmodium species (and other parasites as well) seem to have similar MIF proteins as part of their weaponry.

In 2018, results of a study attacking this protein in mouse models of malaria infection came out, and the results were impressive. There were several experiments done, such as infection of animals with PMIF-deficient parasites and infusion of the generated T cells into other infected mice, as as well as attempts at vaccination against the PMIF protein itself. The authors concluded this way:

We suggest that the marked protection observed by PMIF immunization may prompt consideration of this antigen as a vaccine candidate, either as a standalone immunogen or in combination with other Plasmodium antigens, where it could act to ensure the development and maintenance of adequate memory responses in endemic settings.

And that is the malaria vaccine idea that has been in the news. The plan is to use a self-amplifying RNA vaccine, which is an idea that’s been looked at for the coronavirus but (to the best of my knowledge) not tried out in the clinic yet in the current pandemic. The two RNA vaccines we have work by injecting all the messenger RNA that you’re going to get, whereas a self-amplifying one needs far less of a payload. These are derived from one of several RNA viruses, with the coding instructions stripped out and switched. What remains is the code for your antigen protein of choice, and the machinery to produce an RNA polymerase that will crank out even more copies of it (thus “self-amplifying”).

The saRNA idea has a lot of appeal, but it comes with its own delivery challenges since you’re trying to use a much larger RNA construct, with the instructions for the added polymerase and all. But as that last link shows, there’s been a lot of preclinical work done on this class, and the hope is that the saRNA candidate against the malaria parasite PIMF protein might see first-in-human dosing later this year.

It’s a long shot, but it’s a good one to try. The mouse model results for this target were indeed good, and going after PIMF is a fundamentally different mechanism than the other things that have been tried against malaria so far. And we already know that those don’t work very well – the only existing vaccine (RTS,S) is better than nothing, but it still has rather modest efficacy even after a four-shot regimen (which poses significant practical challenges, as you can imagine). And there’s a long list of other vaccine ideas that haven’t even made it to that level of usefulness. So I’m very glad to see another shot on goal coming from a new direction – good luck to everyone involved, and I hope that PIMF turns out to be at least part of the answer. If it does, there are plenty of other infections that could benefit as well!

23 comments on “A Malaria Vaccine Candidate”

  1. John Wayne says:

    This is an exciting development, and I hope they have some good luck in the clinic. Malaria is another example of an organism that will evolve around whatever therapy you deploy against it; the more tools at our disposal the better off we will be.

    One minor nitpick … the life cycle of malaria is cyclic and is typically described as having three primary stages: liver, blood, and insect. There are a lot of details in each stage. For example, vivax malaria can be very hard to clear from liver cells.

    1. Alvaro Baeza Garcia says:

      That is a good question. We have pre-published a study in bioRxiv, where we show that the absence of PMIF impacts the survival of infected hepatocytes by inhibiting p53 apoptosis of infected cells is a protection mechanism to infection. In the case of P.vivax would be logical to think that PMIF also increases the survival of hepatocytes, so by inhibiting this mechanism, we could decrease infection and then clear P.vivax.

  2. Brett says:

    (to the point that I’ve seen serious estimates of how badly the food web would be disturbed if we ever found a way to do it).

    It wouldn’t even be that big of a deal – they’re been seriously testing it with the “gene drive” stuff. There’s like 4 species of mosquitoes responsible for transmitting diseases to humans out of hundreds, and they’re an invasive species basically everywhere outside of Africa.

    1. Lars says:

      But malaria is a huge problem precisely in Africa (and other places).

      1. metaphysician says:

        I think the argument is that it would be ecologically benign to annihilate the offending mosquito species, since they are few and in most of the world invasive. Its not that Africa doesn’t matter, but that Africa is the only place where you would have to consider ecosystem knock-on effects much ( and it still would almost certainly be worthwhile ).

    2. Tatil Sever says:

      Even with a gene drive, there is a chance a few mosquitoes may evolve a way around it and the species may come back some years later. For that reason, I’ve heard a suggestion to use it in areas where we have a way to treat the sick patients effectively. With mosquitoes out of the way at least for a few years, we may have time to eradicate the disease in that area by treating and isolating all of infected people. After that even if the mosquitoes come back they wouldn’t be biting anybody carrying the parasite, so they disease would stay locally eradicated.

      1. Jim Hartley says:

        That’s a pretty cool idea. Would have to be 100% effective? Or good contact tracing? What would herd immunity look like?

        1. DataWatcher says:

          “Swarm” immunity, perhaps?

      2. > I’ve heard a suggestion to use it in areas where we have a way to treat the sick
        > patients effectively… After that even if the mosquitoes come back …

        Malaria, unfortunately, hides itself away in the human body even when the patient has fully recovered; the patient can then experience the disease again months or years later, even after returning to the developed world where re-infection probability is nil. This is called “malaria relapse” and is a distinct phenomenon from both re-infection and also from normal “we almost killed the disease but not quite all of it” thing that can happen with many pathogens. Malaria is special, and it does special things that viral and bacterial and even fungal infections can’t do.

    3. Ben says:

      I once went drinking in the scottish highlands during midge season. I woke up with (many) bites and a fairly convincing action plan for gene-drive crispr based midge extinction saved in my phone notes

      1. Some idiot says:

        🙂

        One of my (Scottish) friends tells me that Scotch Whiskey is good here… It doesn’t stop the midges biting, and it doesn’t lessen the effects of the bites, but at least you don’t worry as much about them…!

        And for those of you thinking “hey, midge bites can’t be that bad”, well, I’m happy for your sake that you haven’t been up in the Highlands in midge season…!

        1. jbosch says:

          Scotch could b the actual reason why the midges come and bite you. Ever thought of that?

          It will be really interesting to follow this efforts for a new disrupting Malaria treatment, now that I have been working on Pf for about 20 years and the last 5 on Pv.

  3. gcc says:

    This is really fascinating. I hope it works!

    About self-amplifying RNA vaccines for COVID-19, one of the four initial BioNTech/Pfizer vaccine candidates (BNT162c2) was a self-amplifying RNA. It looks like it went into Phase I/II trials in Germany, although it didn’t end up being the one they moved forward with for larger trials. Some details here: https://covid19.trackvaccines.org/vaccines/39/

    1. A Nonny Mouse says:

      The Imperial one was tested on about 600 people (including my daughter). Initial doses for the first 300 were too low as they were very cautious with this new approach.

      They seem to have abandoned it as they are too late for the party, but it is said that they are looking at modified versions for new variants.

    2. Hannah Bowman says:

      Arcturus Therapeutics is also trying a self-replicating mRNA vaccine for COVID. It’s apparently in Phase II trials. https://arcturusrx.com/

  4. Barry says:

    Recent data show that the two mRNA vaccines are the market each elicit more complete immunity than does surviving infection w/ SARSCoV2. It’s likely that this is because the virus blocks Interferon-1 signalling (and thus t-cell response) It’s possible that a malaria vaccine could elicit more complete immunity than does infection w/ malaria because it–analogously–lacks the PMIF. But that hasn’t been seen in the last century of efforts.

  5. Mike says:

    While Vaccine development is welcome, failure to use DDT which effectively cleared malaria in the Americas and Europe is a missed opportunity in Africa.

    1. Rob Z says:

      The idea that there was a missed opportunity to used DDT to clear malaria from Africa is simply wrong.

      Scientists realized that if DDT was applied without restriction, insects would become even more resistant to it and some bird species would likely die out. They recommended that it no longer be sprayed on fields for insect control but it is still widely used for bed nets in Africa.

      This is all very widely known.

      1. metaphysician says:

        Also, mosquito and malaria extermination programs predated DDT. IIRC, malaria was eliminated from Panama during the construction of the Canal purely through vector control infrastructure work. You don’t need DDT, or any specific pesticide, to eliminate malaria, you “just” need a sufficiently stable prosperous and organized society to support a large scale campaign to eliminate its habitat. Sadly, most of Sub Saharan Africa is poor and unstable. Hence the work on things like gene drives which can work even if you can’t do vector control.

        1. aairfccha says:

          It worked, however it also was a bit of a herculean effort in a relatively small area. Today’s environmentalists probably would drop dead at the thought of implementing it on a continental scale.

          https://en.wikipedia.org/wiki/Health_measures_during_the_construction_of_the_Panama_Canal

  6. Ken Gross says:

    Interestingly, some people have adaptive immunity to malaria. Not everyone who is infected by P. falciparum gets the infection.

    1. Barry says:

      yes, falciparum is mostly a scourge of children and of travelers. Immunity or partial immunity is common among survivors.

  7. Julian R. says:

    How do you stop the ssRNA from self-amplifying all the way to, y’know, infinity?

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