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!