Unlocking new therapies after Covid-19 vaccines.
The mRNA vaccine technology now in widespread use in new COVID-19 vaccines is built on research at Penn Medicine. It has extraordinary potential in the prevention and treatment of numerous intractable diseases.
The spike protein is the entry key for a coronavirus to attach to and infect a human cell. But when the body can make that key for itself, it can learn to lock the virus out. Such is the promise of the first two COVID-19 vaccines produced by Pfizer/BioNTech and Moderna.
The week before both vaccines were approved by the Food and Drug Administration for emergency use in December 2020, the Washington Post editorial board lauded the remarkable science behind them—and two major advances in that science begun decades ago at Penn—as “an extraordinary advance in technology, never before used on such a scale, with great promise for the future, and some uncertainties.”
These vaccines involve injecting modified synthetic messenger RNA (mRNA) molecules that code for the SARS-CoV-2 spike protein into the body. The cells use the mRNA as a template to build the spike protein to which the body then mounts an immune response to learn to fight the virus, should it ever encounter the real thing.
It is the first time approved human vaccines have used mRNA to teach the body to make viral proteins, rather than introducing a viral protein or weakened virus itself to prime the immune system as in most traditional vaccines. The vaccines are new—but the technology has been long in development. And now mRNA has a promising future for countless new vaccines and therapies.
The vaccine’s story begins in the early 2000s, when Drew Weissman, MD, PhD, a professor of Infectious Diseases at the Perelman School of Medicine, and Katalin Karikó, PhD, an adjunct associate professor, began working together at Penn.
One major advance they made was to modify the mRNA molecule itself so that it could avoid attack from the immune system and the inflammatory response in the body that was seen in early animal studies. The other advance was enclosing the mRNA in a lipid nanoparticle envelope to deliver mRNA safely and efficiently into the body—a delivery mechanism that is already part of multiple approved drugs at higher concentrations and one that, fortuitously, turned out to also function as an adjuvant to enhance the effectiveness of the COVID-19 vaccines.
The discovery has been hailed by some as Nobel Prize-worthy. “If anyone asks me whom to vote for some day down the line, I would put them front and center,” Derrick Rossi, PhD, co-founder of Moderna, told STAT News. “That fundamental discovery is going to go into medicines that help the world.”
Penn Medicine scientists first began exploring the possibility of using mRNA vaccines for HIV more than 20 years ago, and in recent years have turned to developing them for malaria, influenza, and other infectious diseases. Cancer immunotherapy researchers are investigating ways to make personalized cancer “vaccines.”
In Weissman’s lab at Penn, he and Norbert Pardi, PhD, a research assistant professor, are developing new mRNA vaccines for 30 different infectious diseases. Five are already being tested in humans—against HIV, the genital herpes virus, and the influenza virus. The team is also involved in a clinical trial for a universal flu vaccine to replace an annual one.
Weissman also anticipates opportunities to develop pan-coronavirus vaccines to address not only newer variants of SARS-CoV-2, but also any future related viruses that may cross over into humans from other species—a possibility to take seriously, considering that it has happened three times in the last 20 years, with SARS, MERS, and the current pandemic.
Therapeutic uses of mRNA are yet another new possibility opened by the success of the platform in COVID-19 vaccines. The same technology could be used as a basis for gene therapies that could target stem cells and fix genetic mutations, or as a treatment method for acute and chronic diseases—enabling the body to produce therapeutic proteins within specific organs or cell types where they are needed.