Earlier this month, the Nobel Prize for Physiology or Medicine was awarded to Drew Weissman, M.D., Ph.D., and Katalin Karikó, Ph.D., for their groundbreaking, decades-long work on messenger RNA (mRNA) that enabled the unprecedented rapid development of the mRNA vaccines that stemmed the COVID-19 pandemic. Both Nobel laureates have connections to the National Institute of Allergy and Infectious Diseases (NIAID) and the NIH. Dr. Weissman, an immunologist and professor of vaccine research at the University of Pennsylvania, was a postdoctoral fellow from 1991-1997 in NIAID’s Laboratory of Immunoregulation, led by former NIAID Director Anthony S. Fauci, M.D., and a grantee of NIAID and the National Heart, Lung and Blood Institute (NHLBI). Dr. Karikó, a biochemist who currently works as a research professor at the University of Szeged in her native Hungary and adjunct professor at the Perelman School of Medicine at the University of Pennsylvania, has received funding from NHLBI and the National Institute of Neurological Disorders and Stroke.
In announcing the award, the Nobel Prize Assembly cited Dr. Weissman and Dr. Karikó for their “groundbreaking findings, which have fundamentally changed our understanding of how mRNA interacts with our immune system,” and added, “the laureates contributed to the unprecedented rate of vaccine development during one of the greatest threats to human health in modern times.”
In his congratulations of the two Nobel winners, acting NIH Director Larry Tabak, D.D.S., Ph.D., said, “While the lifesaving benefits of mRNA vaccines are now clearly realized, Karikó and Weissman’s breakthrough finding in 2005 was not fully appreciated at the time as to why it would be significant. However, their dogged dedication to gaining a better understanding of how RNA interacts with the immune system underscores the often-underappreciated importance of incremental research. Following where the science leads through step-by-step investigations often doesn’t appear to be flashy, but it can end up leading to major advances.”
Traditional Vaccines
In general, vaccines work by stimulating the immune system to produce a response to protect against getting infected or very sick from a specific virus or other pathogen. This gives the human body some lead time to fight against disease if later exposed to the virus or pathogen. Historically, most vaccines, such as those against measles, polio, and yellow fever, were made from killed or weakened whole viruses. In more recent years, vaccines based on viral components rather than whole viruses have been developed. These types of vaccines, such as those for hepatitis B and the human papillomavirus, use viral genetic material to make proteins designed to stimulate the creation of antibodies to block the virus. Other types of vaccines, such as those against the Ebola virus, use a harmless virus as a carrier or vector to carry a part of the disease-causing virus into the body to instruct cells to produce viral proteins that stimulate an immune response against the pathogen.
Each of these types of vaccines, however, have manufacturing requirements that make them less suitable when vaccine production is needed quickly to address a disease outbreak or an entirely new pandemic virus.
The Challenges of Early mRNA Vaccine Science
In the early 1990s, researchers began exploring vaccines that use mRNA transcribed in a laboratory (in vitro) to teach the body’s cells to make a protein or piece of protein to trigger an immune response. This approach, however, had several scientific challenges to overcome. Specifically, transcribed mRNA was unstable and challenging to deliver and caused substantial inflammatory reactions. As a result, scientific enthusiasm for the technology was initially limited. During this time frame, Dr. Weissman was working as a NIAID postdoctoral fellow focusing on dendritic cells and their effect on HIV in connection with HIV vaccine development. In this work, he recognized that mRNA’s interaction with dendritic cells caused unhealthy inflammation in the body but remained curious as to its potential. When he began his appointment at the University of Pennsylvania in 1997, he formed a collaboration with colleague and assistant professor Dr. Karikó, who had found limited interest in her proposed research to test mRNA for treatments. The two scientists began focusing their efforts to determine how different RNA types interact with the immune system.
The Scientific Breakthrough
In their work, Drs. Karikó and Weissman found that dendritic cells recognized in vitro mRNA as a foreign substance, which resulted in inflammation. However, this effect didn’t occur in mRNA from mammalian cells. By inserting chemical modifications to the lab-transcribed mRNA, the inflammatory response was eliminated, the researchers discovered. Their finding, which represented a major change in understanding how cells recognize and react to different forms of mRNA, was published in 2005. In additional studies published in 2008 and 2010, Karikó and Weissman showed how this modified mRNA could significantly increase protein production.
Applying mRNA Vaccines to a Historic Pandemic
Scientists at NIAID’s Vaccine Research Center (VRC) and several biopharmaceutical companies began exploring the use of mRNA technology in the mid-to-late 2000s for use against Zika virus. In the 2010s, scientists at NIAID’s VRC began to study the coronavirus responsible for Middle East Respiratory Syndrome (MERS-CoV), a close relative of the SARS-CoV-2 virus. These studies, and others on additional coronaviruses, provided an important foundation for the development of immunogenic vaccines against coronaviruses. Once the COVID-19 pandemic began in 2020 and the genetic blueprint for the virus became available, two investigational mRNA vaccines containing antigenic designs developed at the VRC were developed and rapidly began human testing: one co-developed by NIAID’s VRC and Moderna and the other from Pfizer in collaboration with BioNtech where Karikó then worked as a senior vice president—were developed and rapidly began human testing. Both vaccines, which encoded the modified by design SARS-CoV-2 spike protein, had protective effects of roughly 95% and were authorized for use by December 2020—an unprecedented feat in vaccine development. Today, the two COVID-19 vaccines have been used in at least 164 countries and have been credited for saving millions of lives and preventing severe disease.
The Future of mRNA Vaccines
Through Karikó and Weissman’s work and the success of the COVID-19 vaccines, scientists can now use mRNA to tailor proteins for specific virus vaccines. NIAID is testing several mRNA vaccines for other diseases, such as HIV and influenza. The increased flexibility and speed with which mRNA vaccines can be developed also led scientists to believe that the technology may be used to play a future role against other emerging infectious diseases and in treating sickle-cell disease, multiple sclerosis and some forms of cancer.