Messenger RNA, or mRNA, vaccines entered the public consciousness when they were introduced during the COVID-19 pandemic, and both Pfizer-BioNTech and Moderna used the technology in developing their highly effective vaccines to fight the virus.

Since then, scientists have been fine-tuning this vaccine delivery system to make it more effective. A Yale research team has now developed a technology that improves both the power of mRNA vaccines and their effectiveness against a host of diseases.

The new technology offers the promise of expanding the reach of these vaccines, including for the prevention of other diseases, including cancer and autoimmune diseases.

The results of their study are published in Nature Biomedical Engineering.

Unlike traditional vaccines, which typically deliver an inactivated or weakened version of a virus to stimulate a person’s immune response, mRNA vaccines deliver genetic instructions that create a bit of a virus inside the individual’s cells. The cells then make the protein needed to create an immune response.

“Everyone is very familiar with mRNA vaccines from the pandemic,” said Sidi Chen, associate professor of genetics and neurosurgery at the Yale School of Medicine, who served as the study’s senior author. “But we wondered why the vaccine was working so well in COVID, but not so much in many other diseases that it was being tested on.”

The answer, it turns out, lies in the body’s response to antigens. Antigens are the substances that the immune system recognizes as foreign or possibly harmful, which then triggers an immune response.

But if the body doesn’t recognize an antigen, it can’t mount a good immune response. To be recognized by the body, antigens must attach to the surface of cells, where they are more easily detected. The problem, Chen explained, is that some antigens created by mRNA vaccine are unable to make it to surface. They get stuck deep within cells, evading the body’s immune response system.

To solve this challenge, they developed what they called a molecular vaccine platform (or MVP), which attaches a sort of “cell-GPS” module to the proteins that mRNA vaccines deliver to cells. This, in turn, guides the proteins to the cell surface where they stimulate greater antigen expression and can be seen by the immune system.

Researchers created these “GPS” modules from natural membrane proteins, such as signal peptides and transmembrane anchors that help antigens travel to the cell surface. (Signal peptides are short amino acid sequences that direct a protein to its correct location in a cell, and transmembrane anchors are segments within amino acids that secure proteins to cells, allowing them to move and to communicate.)

In a series of laboratory experiments, researchers tested the new platform on mpox (formerly known as monkeypox,) human papillomavirus (HPV, which is inked to cervical cancer,) and varicella-zoster virus (shingles.) In all cases, the platform produced stronger immune responses with dramatic improvements in antigen expression, antibody production, and T cell activation, Chen said.

The new platform could make future mRNA vaccines more reliable and effective against a host of different viruses, as well as other diseases.

“We’re taking an important step forward to allow us to broaden what the vaccines can be used for,” Chen said. “We’re trying to expand this type of technology to other diseases, such as cancer, HIV, and autoimmune conditions.”

Chen is also a member of the Systems Biology Institute at Yale’s West Campus and an affiliate of Yale Cancer Center, Yale Stem Cell Center, and Yale Center for Biomedical Data Science.

The study included 11 Yale-affiliated authors, with postdoctoral fellow Zhenhao Fang and Ph.D. candidate Valter Monteiro serving as first authors. In addition to Chen, senior authors were Carolina Lucas, assistant professor of immunobiology, and Daniel DiMaio, the Waldemar Von Zedtwitz Professor of Genetics, professor of molecular biophysics and biochemistry, and professor of therapeutic radiology.