A new frontier is crossed in the battle against malaria. (AP Photo/David Longstreath)
Consistently ranked as one of the leading causes of death around the world, malaria doesn’t have an effective vaccine yet. But researchers have invented a promising new blueprint for one — with properties akin to the novel RNA-based vaccine for COVID-19.
Making a vaccine for malaria is challenging because its associated parasite, Plasmodium, contains a protein that inhibits production of memory T-cells, which protect against previously encountered pathogens. If the body can’t generate these cells, a vaccine is ineffective. But scientists recently tried a new approach using an RNA-based platform.
Their design circumvented the sneaky protein, allowed the body to produce the needed T-cells and completely immunized against malaria. The patent application for their novel vaccine, which hasn't yet been tested on humans, was published by the U.S. Patent & Trademark Office on Feb. 4.
“It's probably the highest level of protection that has been seen in a mouse model,” said Richard Bucala, co-inventor of the new vaccine and a physician and professor at Yale School of Medicine.
The team’s breakthrough could save hundreds of thousands of lives, particularly in developing nations. In 2019 alone, there were an estimated 229 million cases of malaria and 409,000 deaths worldwide. Of those deaths, 94% were in Africa, with children being the most vulnerable.
“It affects societies and populations that have the least amount of resources and expertise to manage these infections well," Bucala told The Academic Times. "We need new vaccines, and we need more tools."
Novartis Pharmaceuticals and the National Institutes of Health funded the work. GlaxoSmithKline is an assignee on the patent, which if approved, will allow the company to produce the vaccine and make it available to the public.
At present, the only vaccine to prevent malaria is called RTS,S. Approved two years ago, this vaccine is the result of nearly two decades of research, but is only about 30% effective. And after four years, that figure drops to 15%.
“It doesn't work very well,” Bucala said. “And the research studies all have the conclusion that the people who fail to mount a vaccine response, or who get reinfected, have poor memory T-cell responses.”
Along with Andrew Geall, a pharmaceutical researcher who developed the RNA platform that the duo used, Bucala found a way to prevent the unwanted protein in Plasmodium, called PMIF, from inhibiting T-cell generation.
“Our research studies indicate that it was this particular gene product, PMIF, that was responsible for this,” Bucala said. “It prevented memory T-cells from forming, and that's why one could not generate a memory response to Plasmodium.”
In a conventional vaccine, for instance the standard flu vaccine, an inactivated version of the virus is injected into a host. The body recognizes an intruder, fights against it, generates antibodies against the harmless virus, then returns back to normal.
However, once the virus has left the host, the body needs a way to remember how it fought back. Otherwise it will have to relearn the antibody generation — but perhaps next time with the actual, harmful virus infecting the host all the while. This is where memory T-cells come in: They remember how to generate the immune response and remind the body when the time comes. Plasmodium prevents the immune memory system from occurring by producing PMIF.
“Suppressing the T-cell response and immune memory is so important to the parasite that the parasite brings its own gene, PMIF, to do that,” Bucala said. “If you eliminate that factor, the body naturally develops memory immunity.”
The concept of the novel malaria vaccine accounts for the PMIF problem. Instead of injecting the actual pathogen, the vaccine presents the body with instructions, via RNA, on how to create the protein unique to the pathogen by itself in order to fight it — which is precisely how Pfizer’s COVID-19 vaccine works.
However, rather than an mRNA platform, Bucala and Geall use a self-amplifying saRNA platform. The key benefit of the latter is that it is effective at much lower doses because it can rapidly produce copies of itself inside the cell.
“For saRNA, one can potentially make a million doses of vaccine with a couple liters of synthetic production,” Bucala said. “It's much more efficient than the base-protected mRNA vaccines.”
The proposed saRNA vaccine tells the body to create the troublesome PMIF protein, generates antibodies against it and naturally produces the necessary memory T-cells, as Bucala had hoped.
“We thought we could combine RTS,S with a PMIF vaccine, but the mouse studies seem to suggest that just immunizing with PMIF is sufficient,” Bucala highlighted. “That's how striking the results were.”
Bucala and Geall have placed their vaccine in the hands of the Oxford University institution that facilitated the AstraZeneca COVID-19 vaccine. It is one of the only places in the world that is doing phase 1 studies in malaria, meaning researchers infect human volunteers with the disease after immunizing them.
“This is not in humans yet," Bucala noted, “but they are the group that can put it into humans, I think, best. We are doing those studies this year."
Beyond the saRNA technology's use for the malaria vaccine, Bucala believes it is an ideal method for immunization design in the future, including for COVID-19 prevention, because of its dual low cost and high yield. He says it could reach far and wide.
“The current mRNA approach is an important step in that direction,” he said. “But we are going to, I believe, need to do better. I hope that the saRNA opens that platform.”
The application for the patent, Uses Of Parasite Macrophage Migration Inhibitory Factors, was filed on Oct. 16, 2020 to the U.S. Patent Trademark Office with the application number 17/073006. The inventors of the pending patent are Richard Bucala, Yale School of Medicine and Andrew Geall, Novartis Pharmaceuticals. The assignees are Yale University and GlaxoSmithKline Biologicals SA.
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