A vaccine against malaria: five minutes with . . . Richard Bucala

“It’s been next to impossible, historically, to create a vaccine against malaria. The reason it’s been so difficult is because the infection is not associated with sterile immunity. In other words, once you’re infected, you’re always infected at some level, and even if you become cured of the infection with antibiotics or other measures, you are constantly at risk for being reinfected. The main problem seems to be the lack of effective protective memory, particularly T cell memory. We have a seasonal flu vaccine, for instance. We’re exposed to the antigen and whether or not we’re infected in the subsequent few months, we produce memory cells which persist in our bodies for many years. And if 10 or 20 years later, we’re exposed to that same strain of influenza, we have the cells that could mount an effective immune response and perhaps won’t eliminate the infection but will make the infection much less severe. In the case of malaria, successful T cell memory does not develop, and it’s been challenging to understand why.

“In the early 2000s, it was discovered that every malaria species encodes within its genome a very close homolog of macrophage migration inhibitory factor (MIF), a cytokine. This was extremely puzzling and difficult to understand. Malaria is a protozoan parasite. It encodes about 6200 genes. There are no cytokines in the genome, no real orthologs or homologs to host proteins except for one, and that’s MIF. Our training in medical graduate school has been that parasites survive in their host to complete their life cycle by evading immunity, circumventing the immune response, and shielding themselves from immune destruction. So the idea that a parasite would have its own immune hormone or inflammatory hormone seemed contradictory.

“We then studied a strain of malaria that was produced in the laboratory which lacked MIF. In experimental models, the strain infected mice had some disease, but we observed that in the absence of MIF a memory T cell response occurred. And so, the function of this protein MIF is that it kills memory T cells. We thought vaccinating against this protein would allow other vaccine antigens to be more effective. But, in fact, the results were so striking that we believed it would be useful as a standalone vaccine.

“A former student in my laboratory suggested that we use RNA technology as the vaccine platform. This was completely new to us and it was hard to interest anyone in it. And this is what has changed in the past year with the success of the Pfizer BioNTech and Moderna vaccines. Everybody knows about RNA vaccines now. The vaccine platform that we developed with Novartis is not a naked or base protected RNA molecule, which is what the Pfizer and the Moderna vaccines use. It’s something called a self-replicating, self-amplifying RNA or saRNA. It’s an RNA molecule in front of which there are genes that encode for replication proteins. By combining the saRNA with the MIF antigen, we were able to demonstrate full protection in mouse models.

“We are now collaborating with the Oxford Vaccine Group to evaluate it in comparison with their best malaria vaccines. Based on this advanced preclinical evaluation there may be a pathway to phase I testing in humans and it may be at Oxford. But all this work is going to unfold over the next several months. It’s extremely hopeful.”