Scientists at the University of California, Riverside have developed a new, RNA-based vaccine strategy that could be effective against just about any strain of a virus, and can be used safely even for babies or the immunocompromised.

The new strategy would eliminate the need to create annual vaccines for viruses such as influenza, or SARS-CoV-2, because it targets a part of the viral genome that is common to all strains of a virus. “What I want to emphasize about this vaccine strategy is that it is broad,” said UCR virologist Rong Hai, PhD. “It is broadly applicable to any number of viruses, broadly effective against any variant of a virus, and safe for a broad spectrum of people. This could be the universal vaccine that we have been looking for.”

Hai and colleagues describe how the vaccine strategy works, and report on a demonstration of its efficacy in mice, in Proceedings of the National Academy of Sciences, in a paper titled “Live-attenuated virus vaccine defective in RNAi suppression induces rapid protection in neonatal and adult mice lacking mature B and T cells.”

“Global control of infectious diseases depends on the continuous development and deployment of diverse vaccination strategies,” the authors wrote. For example, every year, researchers try to predict the four influenza strains that are most likely to be prevalent during the upcoming flu season. And every year, people line up to get their updated vaccine, hoping the researchers formulated the shot correctly. The same is true of COVID vaccines, which have been reformulated to target sub-variants of the most prevalent circulating strains.

Traditionally, vaccines contain either a dead or modified, live version of a virus. The body’s immune system recognizes a protein in the virus and mounts an immune response. This response produces T-cells that attack the virus and stop it from spreading. It also produces “memory” B-cells that train your immune system to protect you from future attacks. However, as the authors noted, “Currently available live-attenuated and killed virus vaccines typically take a week or longer to activate specific protection by the adaptive immunity.”

The new vaccine also uses a live, modified version of a virus. However, it does not rely on the vaccinated body having this traditional immune response or immune active proteins— which is the reason it can be used by babies whose immune systems are underdeveloped, or people suffering from a disease that overtaxes their immune system. “… only a few approved vaccines (e.g., poliovirus and hepatitis B virus) are currently available for the protection of infants younger than 12 mo,” the team noted.

The reason viruses successfully cause disease is because they produce proteins that block a host’s RNA interference (RNAi) response. “A host—a person, a mouse, anyone infected— will produce small interfering RNAs as an immune response to viral infection,” explained senior study author Shouwei Ding, PhD, distinguished professor of microbiology at UCR. “These RNAi then knock down the virus.” The authors also explained, “Antiviral RNA interference (RNAi) is a recently recognized mammalian immune response to RNA virus infection …Consistent with its role in antiviral defense, the RNAi pathway is targeted for suppression by diverse mammalian RNA viruses.”

It’s this RNAi suppression by viruses that the new vaccine approach targets. Ding continued, “If we make a mutant virus that cannot produce the protein to suppress our RNAi, we can weaken the virus. It can replicate to some level, but then loses the battle to the host RNAi response. A virus weakened in this way can be used as a vaccine for boosting our RNAi immune system.”

The researchers tested this strategy in mutant mice lacking T and B cells, which were infected with a mouse virus called Nodamura. Much is already known about the induction and suppression of antiviral RNAi in mice by Nodamura virus (NoV), they pointed out. “The mosquito-transmitted Nodamura virus (NoV) is attenuated in mice by mutations that prevent expression of the B2 viral suppressor of RNA interference (VSR) and consequently, drastically enhance in vivo production of the virus-targeting small-interfering RNAs.”

Through their in vivo experiments in the genetically modified mice the team showed that one vaccine injection protected animals from a lethal dose of the unmodified virus for at least 90 days. (Some studies have shown that nine mouse days is roughly equivalent to one human year.)

There are few vaccines suitable for use in babies younger than six months old. However, even newborn mice produce small RNAi molecules, which is why the vaccine protected them as well. UC Riverside has now been issued a U.S. patent on this RNAi vaccine technology.

In 2013, the same research team published a paper showing that flu infections also induce us to produce RNAi molecules. “That’s why our next step is to use this same concept to generate a flu vaccine, so infants can be protected. If we are successful, they’ll no longer have to depend on their mothers’ antibodies,” Ding said.

Such a flu vaccine would also likely be delivered in the form of a spray, as many people have an aversion to needles. “Respiratory infections move through the nose, so a spray might be an easier delivery system,” Hai said.

The team acknowledges that more research will be required to see whether the same strategy can be applied to generate vaccines against other pathogenic viruses. “There are several well-known human pathogens; dengue, SARS, COVID. They all have similar viral functions,” Ding said. “This should be applicable to these viruses in an easy transfer of knowledge.”

The authors concluded, “Future studies are warranted to determine whether additional animal and human viruses attenuated by VSR inactivation induce similar protective immunity in healthy and adaptive immunity-compromised individuals … Human enterovirus-A71, influenza A, and dengue viruses all encode a similar RNAi suppressor, suggesting potential for developing a distinct type of virus vaccine to confer rapid and effective protection in infants and other immune-compromised individuals.”

Additionally, the researchers say there is little chance of a virus mutating to avoid this vaccination strategy. “Viruses may mutate in regions not targeted by traditional vaccines. However, we are targeting their whole genome with thousands of small RNAs. They cannot escape this,” Hai said. Ultimately, the researchers believe they can “cut and paste” this strategy to make a one-and-done vaccine for any number of viruses. “Compared to a few epitopes recognized by adaptive immunity, almost all regions of the viral RNAs are targeted for antiviral RNAi by a large pool of overlapping vsiRNAs produced during the immune response to VSR-disabled virus infection,” they wrote. “Consequently, it will be of interest to determine whether VSR-disabled live-attenuated virus vaccines confer a broad spectrum of protection against diverse virus strains.”

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