saRNA Vaccines Could Be Second R&D Revolution in as Many Months

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When the FDA greenlit Pfizer and BioNTech’s COVID-19 candidate in December 2020, it became the first mRNA (messenger RNA) vaccine approved for use in the United States. A week later, Moderna’s mRNA-1273 became the second. These two mRNA vaccines not only changed the course of the global pandemic, but general vaccine R&D as well.

Not three months later, however, the vaccine industry may be in for yet another revolution.

Yale University’s Richard Bucala, M.D., and co-inventor Andy Geall just filed a patent for a self-replicating RNA (saRNA) vaccine that can prevent malaria.

Traditional vaccines contain small or inactivated doses of the disease-causing organism, which are introduced into the body to provoke the immune system into mounting a response. Meanwhile, mRNA vaccines contain a synthetic version of the mRNA that a virus uses to build its infectious proteins. This mRNA is delivered into the human body, whose cells read it as instructions to build that viral protein, creating some of the virus’s molecules themselves. The immune system then detects these viral proteins and starts to produce a defensive response to them.

An saRNA vaccine is produced in essentially the same manner as its brethren RNA with the exception of the addition of a self-replicating RNA molecule, such as an alphavirus-derived RNA replicon. The vaccine can be delivered as viral replicon particles (VRPs) with the saRNA packaged into the viral particle, or as a completely synthetic saRNA produced after in vitro transcription. To generate harmless VRPs, envelope proteins are included as defective helper constructs during production. Therefore, resulting VRPs lack the ability to form infectious viral particles following a first infection, with only the RNA capable of further amplification.

These characteristics allow saRNA vaccines to overcome a common mRNA vaccine limitation—large dosing. Since it can rapidly produce copies of itself inside the cell, saRNA vaccines are effective at much lower doses and are much more efficient to produce.

It’s also these characteristics that make an saRNA vaccine so effective against malaria, the mosquito-borne disease that was responsible for 409,000 deaths in 2019. Malaria is caused by the plasmodium parasite, which is notoriously difficult to treat since it contains a protein that inhibits production of memory T-cells—the infection-fighting cells that respond to threats and protect the body against reinfection.

Seeing this as a window for exploitation, Bucala and Geall worked with Novartis Vaccines to design a saRNA vaccine that could target the protein, called plasmodium macrophage migration inhibitory factor (PMIF).

Using a strain of the malaria parasite with PMIF genetically deleted, they observed that mice infected with that strain developed memory T cells and showed stronger anti-parasite immunity. Next, the research team used two mouse models of malaria to test the effectiveness of a vaccine using PMIF. One model had early-stage liver infection from parasites carried by mosquitos, and the other, a severe, late-stage blood infection. In both models, the vaccine protected against reinfection. As a final test, the researchers transferred memory T cells from the immunized mice to control mice never exposed to malaria. Those mice were also protected.

With those results in hand, the scientists are now partnering with Oxford University for a Phase 1 study in humans. (Of note, it’s the same department of Oxford that worked with AstraZeneca on their COVID-19 vaccine candidate).

In unrelated preclinical studies, saRNA vaccines have shown protective immunization against other infectious diseases, including influenza, RSV, rabies, Ebola and HIV. Bucala said he believes his new approach may be generalizable to other parasitic diseases that also produce MIF-like proteins, such as leishmaniasis, hookworm, and filariais—all of which have no approved vaccine.

“The current mRNA approach is an important step in the [right] direction,” Bucala told The Academic Times. “But we are going to need to do better. I hope that saRNA opens that platform.”

Photo: The molecular structure of plasmodium MIF. Credit: Yale School of Medicine.