mRNA vaccine technology makes headway via Pitt, Penn State research

A new kind of mRNA vaccine developed by researchers at the University of Pittsburgh and Penn State University could be cheaper to produce and offer a greater level of immunity across multiple variants of the virus.

The news comes as mRNA vaccines have been targeted by the Trump administration's recent funding cuts, and Health Secretary Robert F. Kennedy Jr. fired all members of the expert vaccine panel the Advisory Committee on Immunization Practices, which advises the Centers for Disease Control and Prevention on vaccine safety and eligibility guidelines.

Results of the Pitt study, tested in a small group of mice, were published in npj Vaccines, a journal associated with Nature, on June 3. It's considered a proof-of-concept study and will require more research until human clinical trials are possible.

Continual mutation of the SARS-CoV-2 virus — the virus that causes COVID-19 — has presented challenges for scientists' ability to forecast a dominant variant and tailor vaccines effectively, requiring recalibration each year depending on what is currently circulating.

"This study demonstrated two key aspects," said Suresh Kuchipudi, senior author on the paper and chair of infectious diseases and microbiology at Pitt's School of Public Health, "that we can produce mRNA vaccines with much less mRNA required, that will significantly lower the cost of the vaccines."

And, he said, "It is also possible that with mRNA vaccines, we can provide broad protection across multiple versions of the virus without needing to constantly update."

This was possible because of a design called a trans-amplifying vaccine. In traditional mRNA vaccines, a single molecule of RNA — a kind of code that creates viral proteins in the body — is included to help the body recognize and fight off viruses.

Amplifying RNA vaccines use two components: that viral protein, as well as another component that helps enhance the mRNA signal. In trans-amplifying mRNA vaccines, those two components are encoded separately, allowing for more flexibility in design and potentially fewer side effects, though the latter needs further study.

And instead of using code from one circulating variant, the trans-amplifying vaccine uses code from a "consensus spike protein," meaning it includes mRNA that is conserved across multiple variants, allowing it to provide broader immunity.

"After several years, we have seen multiple variants emerge," said Kuchipudi. "If you look at the genetic sequence of the spike protein among all these variants, certain parts are conserved across all. We can design a spike protein that can broadly cover known variants."

The new formulation also includes a component called a replicase, which helps to generate a signal in the body with a lower dose of mRNA. Researchers used a replicase based on the Venezuelan Equine Encephalitis Virus (VEEV).

"We chose the VEEV replicase because it's a well-studied enzyme known for its ability to amplify target mRNA efficiently," said Kuchipudi in an email. "In our system, it boosts the expression of the vaccine antigen (SARS-CoV-2) without requiring a high starting dose."

They also conducted safety studies and found the VEEV replicase did not affect the body's original cells in a negative way.

Scientists then measured the presence of antibodies in the injected mice to see how their new vaccine formulation compared to the traditional mRNA vaccine.

The mice showed immunity comparable to the original COVID-19 mRNA vaccines and with 40 times less mRNA used.

Moderna's current Spikevax formulation is given at 50 micrograms per dose for adults, and Pfizer/BioNTech's Comirnaty contains 30 micrograms (ug) per dose. This could be why many people who received the Moderna vaccine reported more side effects.

The trans-amplifying vaccine, by contrast, was given at 20 ug of the VEEV replicase and 0.5 ug of the consensus spike protein mRNA, as well as a lower dose formulation at 20 ugs and 0.05 ugs, respectively.

This vaccine could offer greater flexibility and be more cost efficient than the existing COVID vaccines, said Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine and co-director of the Texas Children's Hospital Center for Vaccine Development.

"I think it's a worthwhile study," he said.

The study is also an example of how much research goes into a product like a vaccine before it becomes available to the public — and this one is still early in the developmental process. Kuchipudi said the team wants to delve deeper into learning more about potential side effects.

"We did some early mouse studies and saw no apparent side effects," said Kuchipudi. "We plan to conduct more in-depth safety studies in mice next, focusing on immune responses, inflammation, and any potential off-target effects," or unpredictable side effects that might occur other than at the injection site, or what's typically associated with getting a vaccine.

But in the current political climate, it may be harder for scientists to further their research on these kinds of vaccines.

On May 28, President Trump rescinded its contract with Moderna, per Reuters reporting. That included more than $700 million in federal monies for vaccine research and development for diseases like bird flu.

In a statement to Reuters, an HHS spokesperson said that "after a comprehensive internal review, the agency had determined that the project did not meet the scientific standards or safety expectations required for continued federal investment."

Although mRNA vaccines have been around since the 1990s, they have been the face of intense scrutiny after their development was fast-tracked via Operation Warp Speed, the government-backed push to get COVID-19 vaccines into the hands of the public during a deadly pandemic.

To date, they have saved 3.2 million lives, said Hotez.

"What you should be focusing on, if there are ways you think you can improve the technology, that's what you have to incentivize," he said.

The Pitt and Penn State study is illustrative of that, he said. "This is an example of heading toward 2.0."

But Hotez is worried about deprioritization of this kind of research in the coming years, especially as infectious disease surveillance infrastructure, including staffing, has been cut, leaving officials in a weaker position to understand and defend against future viruses.

"I think the FDA is prematurely shutting down mRNA technology when it has enormous promise," he said. "It's a relatively safe vaccine. Every vaccine technology has strengths and weaknesses ... to toss it out the window for ideological reasons makes no sense."

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