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A multi-site team of Cleveland Clinic researchers has developed new methods to increase the strength and duration of COVID-19 mRNA vaccines. The researchers found inspiration by turning to viruses themselves.

Current COVID-19 mRNA vaccines need to be replenished with regular boosters to protect against reinfection. The new findings published in The Journal of Medical Virology provide a blueprint to improve this protection and potentially increase the time needed between booster shots, learning from strategies employed by the herpes virus.

"mRNA vaccines give our bodies the genetic instructions they need to build pieces of the pathogen that our immune systems can respond to. In this way, mRNA vaccines act a lot like the viruses we fight against," says corresponding author Jae Jung, PhD, Director of Infection Biology and the Sheikha Fatima bint Mubarak Global Center for Pathogen & Human Health Research.

While viruses have their own genetic material, they have no way to carry out the instructions written in their genes. Instead, they trick infected host cells into reading the foreign genetic material and making proteins for the virus. The research team believed they could exploit their knowledge of how this happens to improve how host cells read the genetic material in mRNA vaccines.

"Viruses have evolved so many clever ways to make host cells read their genetic material really quickly and effectively," says co-first author Dokyun "Leo" Kim, a graduate student in the Jung Lab. "If we want to use the same genetic material to fight these viruses with mRNA vaccines, maybe we should take a page out of their book."

Exploiting how the herpes virus bypasses "spelling differences"

Dr. Jung, who also leads the department of Cancer Biology, has previously studied some of these strategies. Because viral genes use different DNA and RNA sequences than human genes, it can be difficult for host cells to produce the protein the virus is asking for.

"Think of it like using different spellings of the same word when writing out instructions," says Kim, "Infected cells can figure out what protein the viral genes want them to make, but the spelling differences mean it's a little harder to read the instructions."

Dr. Jung's old team had found that the herpes virus had developed a tool called a "trans-inducer" to avoid this loss of efficiency. Kim and co-first author Chih-Jen "Jonathan" Lai, PhD, a postdoctoral fellow in the Jung Lab, compare the trans-inducer to reading glasses for the host cells. It helps host cells read viral genes well enough to overcome any differences in genetic instructions. The two asked whether the tool could also help our bodies read the information in the COVID-19 mRNA vaccine.

Adapting viral tricks for vaccine development

The researchers teamed up with Kun Li, PhD, to make and test alterations through the Florida Research and Innovation Center's high containment core. They found that adding the "efficiency element" from the herpes virus to the COVID-19 mRNA vaccine greatly improved the immune response and protected against lethal levels of infection in preclinical trials. This protection lasted up to 20 weeks after vaccination.

"We still aren't quite sure how the element works, but its effects are clear," Kim says. "In cases where the virus's gene 'spelling' differs from the host's, this element helps the host read the viral instructions efficiently."

Then the researchers took things a step further – they made a COVID-19 mRNA vaccine without the efficiency tool, using gene sequences with "herpes virus spelling." Preclinical tests confirmed that even this small change in vaccine configuration improved the strength and duration of protection it provided against infection.

"mRNA vaccines are a relatively new technology that gained traction during the COVID-19 pandemic, so there's still a lot of room for improvement." Kim says. "The work didn't end the second a safe and functional COVID-19 vaccine became available. Now we can take our time to push the limits of what the vaccine can do."