“It’s thrilling for me to see this. All of the things we were thinking would happen back then—it’s happening now.”
- Philip Felgner, Ph.D., biochemist, director, Vaccine Research Center, UC, Irvine
“I often compare doing science with my daughter’s rowing: you are in a boat going backward without a clear view of how far the finish line is. So, I think, passion, single-minded focus, and a sense of mission are the key ingredients for fulfillment in a research career."
- Katalin Kariko, Ph.D., Hungarian-American biochemist, co-inventor of modified mRNA technology used in development of COVID mRNA vaccines
The National Institutes of Health (NIH) is the largest publicly funded biomedical research center in the world, and for fiscal year 2020 its annual budget was $41.68 billion. If you’ve ever wondered whether investment of this kind of money in basic (fundamental) research is worth it, consider the astonishingly successful development of the two mRNA COVID-19 vaccines released at the end of that same year. By November 2021, it was estimated that the COVID-19 vaccination program in the U. S., largely propelled by these mRNA vaccines, prevented 1,087,191 deaths and 10,319,961 hospitalizations. The development of these mRNA vaccines drew on the decades of work of hundreds of researchers, many funded by the NIH. In today’s Germ Gems post, I review the background of mRNA vaccines and discuss how they will usher in this new era of vaccinology.
What is RNA? Before reviewing the steps that went into development of mRNA vaccines that specifically target the RNA virus that causes COVID-19, namely, SARS-CoV-2, a little background on ribonucleic acid (RNA) and its cousin deoxyribonucleic acid (DNA) may be helpful.
Some readers may have heard more about DNA than RNA. DNA is composed of two polynucleotide chains that coil around each other to form the famous double helix. DNA carries genetic instructions for the development, functioning, growth and reproduction of all known organisms and many viruses. About two decades ago, an extraordinary international effort called the Human Genome Project determined the sequence of the human genome and identified the estimated 20,000 to 25,000 genes it contains.
Biologically, messenger RNA (mRNA) is transcribed from DNA. mRNA is essential in various roles in coding, decoding, regulation and expression of genes. It is the workhorse in making cell proteins, such as the spike protein that adorns the surface of SARS-CoV-2 and the antibodies that the cells of our immune system make to thwart the virus.
But RNA is more than just DNA's lesser-known cousin. In fact, RNA may even have helped get life itself started. (Some experts believe that RNA was the first molecule of heredity, so it evolved all the essential methods for storing and expressing genetic information before DNA came onto the scene.)
mRNA COVID-19 vaccines. The Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines teach our cells how to make the spike protein that will trigger an immune response resulting in antibodies directed against SARS-CoV-2.
While it ordinarily takes four or more years to develop a vaccine, the fact that both Pfizer’s and Modena’s mRNA vaccines were launched in less than a year’s time from the discovery of SARS-CoV-2 is astonishing. And it belies the several decades-long painstaking effort on the part of many scientists who worked on various aspects of mRNA vaccines that made this ultimate achievement possible. For an excellent review, I recommend the October, 2021 Nature article, “The tangled history of mRNA vaccines.”
Despite some nay-sayers, we can cheer the Food and Drug Administration’s recent authorization of both mRNA vaccines for children as young as 6 months. Also, studies have shown that scaling up mRNA vaccination in low-income countries saves lives and money. We should therefore continue to advocate strongly for universal vaccination against COVID-19, and mRNA vaccines should be prioritized.
mRNA vaccines to prevent other infections. Given the unprecedented success of mRNA vaccines directed against SARS-CoV-2, it is not surprising that academic and pharmaceutical partnerships are springing up that target other challenging RNA viruses. At the top of that list are influenza virus and HIV, but research programs aimed at preventing Ebola virus, Zika virus, respiratory syncytial virus, and rabies virus infections are also underway.
Intriguingly, last month Moderna initiated a phase 3 clinical trial testing a mRNA vaccine in women ages 16 to 40 years old to prevent fetal infection by cytomegalovirus (CMV), a DNA virus. CMV is the Number One cause of congenital infections in the U.S. And, this past November the first-ever mRNA vaccine against Lyme disease showed promise in animal trials involving guinea pigs (the vaccine targets the immune system to respond to tick saliva—the vehicle for the bacterium that causes Lyme disease, that is, Borrelia burgdorferi).
mRNA vaccines to treat cancer. In addition to application of mRNA technology to prevent a wide variety of infections, mRNA researchers are discovering that mRNA vaccines can potentially be used to treat (not prevent) some very serious cancers. In clinical trials, researchers have found that these mRNA cancer vaccines work by helping one’s immune system find and destroy cancer cells.
Moderna is studying at least four cancer vaccines in clinical trials targeting melanoma, non-small cell lung cancer, colorectal cancer, and pancreatic cancer. The University Medical Center Groningen is collaborating with BioNTech on an mRNA vaccine for ovarian cancer, and BioNTech is also collaborating with Regeneron Pharmaceuticals on an mRNA vaccine for advanced melanoma. Additionally, BioNTech is working with Memorial Sloane Kettering on a mRNA pancreatic cancer vaccine, and early trials show promise.
The bottom line. With more than two years of global experience with the Pfizer-BioNTech and Moderna mRNA vaccines behind us, it can be concluded that, by and large, they both continue to hold up well in terms of safety and efficacy. (A recent review of the U.S. data can be found in the May1 issue of Clinical Infectious Diseases, “Effectiveness of Severe Acute Respiratory Syndrome Coronavirus 2 Messenger RNA Vaccines for Preventing Coronavirus Disease 2019 Hospitalizations in the United States.”) But because SARS-CoV-2 keeps mutating, it’s not surprising that neither vaccine is perfect. For example, even double-boosted, Dr. Anthony Fauci, President Biden’s Chief Medical Advisor, reported a mild case of COVID-19 on June 15, and COVID-19 reinfections continue to mount as new Omicron subvariants crop up.
Nevertheless, the response to SARS-CoV-2 has shown the general public what science at its very best can accomplish. And I think that the American taxpayer can be proud of their investment in the NIH that played a pivotal role in realization of mRNA vaccines.
