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.)