Universal vaccine strategy boosts body's RNAi response to virus

Scientists at the University of California, Riverside have developed a new RNA-based vaccine strategy that is effective against nearly all strains of the virus and is safe for use in infants and immunocompromised individuals.

The new strategy targets a part of the viral genome that is common to all strains of the virus, eliminating the need to create vaccines every year for viruses such as influenza and SARS-CoV-2. “What I want to emphasize about this vaccine strategy is that it's broad,” said UCR virologist Dr. Ron Haigh. “It's broadly applicable to any number of viruses, broadly effective against all variants of the virus, and safe for a wide range of people. This could be the universal vaccine we've been looking for.”

Hai et al. describe how the vaccine strategy works and report on demonstrating its effectiveness in mice. Proceedings of the National Academy of Sciencespublished in a paper entitled “A live-attenuated virus vaccine defective in RNAi inhibition induces rapid protection in neonatal and adult mice lacking mature B and T cells.”

“Global control of infectious diseases depends on the continued development and deployment of diverse vaccination strategies,” the authors write. For example, each year researchers try to predict the four influenza strains that are most likely to circulate during the upcoming flu season. And every year, people line up to get the latest vaccine, hoping that researchers got it right. The same is true for coronavirus vaccines that have been reformulated to target subvariants of the most prevalent strains.

Traditionally, vaccines contain killed or modified live viruses. The body's immune system recognizes the proteins within the virus and mounts an immune response. This reaction produces T cells that attack the virus and stop it from spreading. It also produces “memory” B cells that train the immune system to protect against future attacks. However, as the authors pointed out, “Currently available live attenuated and inactivated virus vaccines typically take more than a week to activate specific protection by adaptive immunity.”

The new vaccine also uses a live, modified virus. However, this vaccine does not rely on the vaccinated body having this traditional immune response or immune active proteins. This is why it can also be used in infants with underdeveloped immune systems and people suffering from illnesses that overtax the immune system. “…Currently, only a few approved vaccines (such as poliovirus and hepatitis B virus) are available for prevention in infants under 12 months of age,” the researchers noted.

The reason viruses can cause disease is because they produce proteins that block the host's RNA interference (RNAi) response. “The host (human, mouse, infected person) produces small interfering RNAs as an immune response to viral infection,” said Shuwei Ding, senior author of the study and distinguished professor of microbiology at UCR. The doctor explained. “These RNAi knock down the virus.” The authors also note that “antiviral RNA interference (RNAi) is a recently recognized mammalian immune response to RNA virus infection…its role in antiviral defense. Consistent with its role, the RNAi pathway is targeted for suppression by a variety of mammalian RNA viruses.

It is this viral suppression of RNAi that new vaccine approaches are targeting. Ding continued, “We can weaken the virus by creating a mutant virus that cannot produce the protein that suppresses RNAi. It can replicate up to a point, but after that it loses the battle against the host's RNAi response.” Viruses weakened using the RNAi method can be used as vaccines to strengthen the immune system.”

The researchers tested this strategy in mutant mice lacking T and B cells, infected with a mouse virus called Nodamura. They pointed out that much is already known about the induction and suppression of antiviral RNAi in mice by Nodamura virus (NoV). “Nodamura virus (NoV), which is transmitted by mosquitoes, is attenuated in mice by a mutation that prevents the expression of the B2 viral suppressor RNA interference (VSR), resulting in the in vivo release of small interfering RNA that targets the virus. Production is greatly enhanced.”

Through in vivo experiments using genetically modified mice, the research team showed that a single vaccine injection can protect animals from a lethal dose of the unmodified virus for at least 90 days. (Some studies have shown that a mouse's 9 days is roughly equivalent to a human's 1 year.)

Few vaccines are suitable for use in infants younger than 6 months of age. But newborn mice also produce small RNAi molecules, so the vaccine also protected them. The University of California, Riverside has been awarded a US patent for his RNAi vaccine technology.

In 2013, the same research team published a paper showing that influenza infection also induces the production of RNAi molecules. “So our next step is to use this same concept to produce a flu vaccine so that it can protect infants. If we're successful, they won't have to rely on their mother's antibodies. will disappear,” Ding said.

Because many people have an aversion to needles, it is likely that such flu vaccines will also come in spray form. “Respiratory infections are transmitted through the nose, so the spray may be easier to spread,” High said.

The research team acknowledges that further research is needed to see if the same strategy can be applied to generate vaccines against other pathogenic viruses. “There are some well-known human pathogens: dengue fever, SARS, and the new coronavirus. They all have similar viral functions,” Ding said. “This should be applicable to these viruses by easily transferring knowledge.”

The authors wrote, The study was justified…Human enterovirus A71, influenza A, and dengue virus all encode similar RNAi.'' This suppressor suggests the possibility of developing a distinct type of viral vaccine that would provide rapid and effective protection to infants and other immunocompromised individuals. ”

Additionally, researchers say there is little chance of the virus mutating to evade this vaccination strategy. “The virus can mutate in areas not covered by traditional vaccines. But we use thousands of small RNAs to target their entire genome. They can't escape this. I can’t,” High said. Ultimately, researchers believe this strategy could be “cut and pasted” to create a one-time vaccine for any number of viruses. “Compared to the few epitopes recognized by adaptive immunity, nearly all regions of viral RNA are targeted for antiviral RNAi by the large pool of overlapping vsiRNAs generated during immune responses to VSR-disabling viral infections.” “,” the researchers wrote. “Therefore, it will be interesting to determine whether a VSR-disabled live attenuated virus vaccine confers broad-spectrum protection against diverse virus strains.”