Honors for mRNA Vaccines

2022 Warren Alpert Prize goes to mRNA research that enabled the design of COVID-19 vaccines

mRNA molecule, SARS-CoV-2 virus, syringe
Image: libre de droit/iStock/Getty Images Plus

 

The 2022 Warren Alpert Foundation Prize has been awarded to five scientists for transformational discoveries into the biology of mRNA, for its modification for medicinal use, and for the design of mRNA-based COVID-19 vaccines. The scientists’ collective efforts have not only saved lives and opened the door to ending the pandemic but set the stage for myriad mRNA vaccines and other mRNA-based therapies.

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The five award recipients are: 

  • Katalin Karikó, adjunct professor of neurosurgery, University of Pennsylvania; senior vice president RNA Protein Replacement Therapies, BioNTech
  • Drew Weissman, Roberts Family Professor in Vaccine Research, University of Pennsylvania
  • Eric Huang, general manager and chief scientific officer, Moderna Genomics
  • Uğur Şahin, professor at the medical faculty, Johannes Gutenberg University, Mainz; Helmholtz Professor for mRNA Cancer Immunotherapies, German Cancer Research Center, Helmholtz Institute Mainz; and co-founder and chief executive officer, BioNTech
  • Özlem Türeci, Helmholtz Professor for Personalized Cancer Immunotherapies, German Cancer Research Center, Helmholtz Institute Mainz; co-founder and chief medical officer, BioNTech

The $500,000 award, to be shared among the five winners, is given by the Warren Alpert Foundation in recognition of work that has improved the understanding, prevention, treatment, or cure of human disease. The prize is administered by Harvard Medical School. The award winners will be recognized at a hybrid (in-person and virtual) scientific symposium on Oct. 6, 2022, hosted by Harvard Medical School. For further information, visit the Warren Alpert Foundation Prize symposium website.

Significance of the work

Karikó and Weissman are being honored for pioneering work in the study of mRNA—the messenger molecule that carries DNA instructions from a cell’s nucleus to its protein-making factories—and for their design of a modified mRNA, which laid the groundwork for the development of the first two approved COVID-19 vaccines. Şahin and Türeci, as well as Karikó and Weissman, also studied and made other changes to mRNAs to help immune cells produce higher levels of protective proteins. 

Huang, Şahin, and Türeci made critical contributions to the design and testing of mRNA vaccines encapsulated in oily bubbles called lipid nanoparticles, which work as precision-targeted delivery vehicles that shield the delicate mRNA molecules while transporting them into the right immune cells. This collective work advanced fundamental molecular insights from the lab bench to the pandemic frontlines, proving that mRNA delivered in a lipid nanoparticle could be used as an effective vaccine against COVID-19. 

In total, the five researchers’ achievements have not only transformed the trajectory of the pandemic but propelled medicine forward, ushering in a new era characterized by mRNA-based vaccines and other treatments for a range of infectious and noninfectious diseases.

“The design of the mRNA vaccines is a triumph of basic science, clinical medicine, and public health, not only because of the record time in which these vaccines were taken from lab to clinic, and the untold numbers of lives they have saved and will continue to save, but because this work offers a breathtaking affirmation of the value of long-term investment in fundamental research and of its role in illuminating biological processes that inform the design of lifesaving therapies,” said George Q. Daley, dean of Harvard Medical School and chair of the Warren Alpert Foundation Prize scientific advisory board. 

“The pandemic blindsided us, but basic research that started decades earlier prepared us to quickly use earlier insights and deploy vaccines at a speed never before seen,” Daley added. “What a marvelous example of the power of collaboration between academia and industry and across scientific disciplines, across geographic boundaries.”

The Warren Alpert Foundation Prize recognizes the research of scientists throughout the world. Including the 2022 prize, the foundation has awarded more than $7 million to 78 individuals. Since the inception of the award in 1987, 12 honorees have gone on to receive Nobel prizes.

“The achievements of the scientists behind mRNA vaccines demonstrate the importance of investing in fundamental research—an investment that may yield surprising, at times unexpected, benefits years down the road,” said David M. Hirsch, director and chairman of the board of the Warren Alpert Foundation. “These five scientists embody the innovative spirit that Warren Alpert sought to support when establishing his foundation, and we are delighted to recognize them with this prize.”

A long, sinuous journey 

The code of life is stored in DNA, which sits coiled tightly inside the nucleus of a cell. DNA contains the instructions for making proteins, which fuel life and drive all basic molecular processes inside cells, tissues, and organs. The critical connection between genetic code and functional proteins is messenger RNA, or mRNA, which ferries DNA’s instructions to the protein-making factories of the cell. As far back as the 1990s, scientists were captivated by the therapeutic potential of mRNA, hypothesizing that lab-made mRNA, loaded with the right set of instructions, could induce cells to temporarily make any protein, including proteins that are absent or deficient as well as those present at normal levels but misfolded and malfunctioning. 

Such an approach could use natural cellular processes to turn human cells into the body’s own medicine-making factories. But that tantalizing prospect remained out of reach for two reasons. First, experiments showed that mRNA could spark aberrant, inflammatory reactions in animal models. Second, it is an unstable molecule that gets rapidly destroyed once inside the body, which in turn reduces its ability to trigger sufficient levels of protein production. 

Understanding the biology and function of mRNA builds on the work of numerous scientists over many years. However, through their relentless pursuit to develop mRNA-based therapies and vaccines, Karikó and Weissman as well as Şahin and Türeci, overcame these two critical hurdles, paving the way for the first mRNA vaccines.

Starting in the late 1990s, Karikó and Weissman sought to understand the molecular basis for the immune responses to RNA and to develop ways to avoid them.

The researchers not only identified the immune cell receptors that interacted with mRNA but pinpointed the mRNA component responsible for triggering abnormal hyper-inflammatory responses in animal models. To circumvent this, they used an approach that mimicked a natural chemical tweak to one of mRNA’s building blocks—its nucleosides—that made mRNA less conspicuous to the immune system. This tweak allowed the modified mRNA to slip into cells and do its job without causing aberrant immune reactions. Karikó’s and Weissman’s discovery laid the foundation for the development of mRNA-based therapies for the treatment of a range of diseases, including cancer and cardiovascular illness, among others.  

Packaging and delivery 

Although researchers succeeded in making mRNA both less inflammatory and better capable of producing the right kinds of proteins, two significant problems remained: how to keep this fragile molecule from being destroyed rapidly once injected into the body and how to deliver it precisely into the right types of immune cells. It was a problem of both packaging and delivery. Could tiny, oily bubbles—lipid nanoparticles—be the right delivery vehicle? This approach had been used already by others to sheathe nucleic acids and deliver them into animal models. Huang and colleagues at Moderna, and Şahin, Türeci, and colleagues at BioNTech used lipid nanoparticles to preferentially deliver mRNA into various target cells that stimulate the immune system in a precision-targeted manner.

Taken together, these efforts provided the blueprint for the development of highly effective mRNA vaccines. They also precipitated a number of advances and have now opened the door for mRNA technology to be used both for prevention and treatments for other diseases. The insights generated by these scientists formed the basis for a number of experimental therapies undergoing both clinical and preclinical testing for multiple conditions, including various forms of cancer, heart failure, stroke, anemia, bleeding disorders, asthma, cystic fibrosis, autoimmune diseases, and more.

From labs to arms

Unlike traditional vaccines, mRNA vaccines do not deliver viral proteins directly into the body. Instead, they carry protein-making instructions and deposit them inside human cells, coaxing the cells into making their own protein fragments mimicking parts of the invading pathogen—in this case, the spike surface protein of SARS-CoV-2, the virus that causes COVID-19. This approach offers a controlled way to prime the immune system to recognize and disable the real virus during an eventual encounter. 

The development of such vaccines represents the culmination of efforts by multiple researchers, each of whom made important contributions to the science underlying this achievement. 

However, Huang at Moderna, and Şahin and Türeci at BioNTech, performed the seminal translational work that harnessed and advanced the basic biological insights of mRNA science and used them to design lifesaving vaccines. Long before the pandemic, these three researchers were already working on mRNA-based therapies for a range of diseases, but in January 2020, with the then-novel coronavirus spreading rapidly across countries, their focus changed. Following the publication of the fully mapped SARS-CoV-2 genome by Chinese researchers on Jan. 10, 2020, these scientists pivoted quickly to develop COVID-19 vaccines, shepherding the candidate vaccines through preclinical experiments, clinical trials, regulatory approval, and, eventually, to large-scale manufacturing for rapid inoculation of billions of people.

At BioNTech, Şahin and Türeci had been working for more than a decade to develop an mRNA vaccine platform to treat cancer. Their goal was to design individualized mRNA vaccines that would use the patient’s tumor antigens to induce the patient’s own cells to vanquish the tumor. For this work, they also used lipid nanoparticles to encase mRNA molecules and deliver them into specific immune cells. Building on this earlier work, Şahin and Türeci were able to swiftly switch gears and focus their existing knowledge of mRNA biology and their clinical-stage vaccine platform for use against a novel pathogen—SARS-CoV-2. The BioNTech mRNA COVID-19 vaccine went on to become the first approved COVID-19 vaccine for use in humans. BioNTech scientists continue to explore the use of this technology for many other conditions.At Moderna, Huang had been working on mRNA-based therapies for intravenous infusion for an array of diseases since 2013. He spearheaded Moderna’s efforts on several fronts, including development off mRNA-based vaccines using lipid nanoparticle technology against a number of viral pathogens and to enhance anticancer immunity. In 2020, capitalizing on these prior advances in vaccine development, Huang’s team quickly moved to design Moderna’s COVID-19 vaccine. Building on Huang’s earlier work, Moderna has now developed a vaccine pipeline for conditions including cytomegalovirus, Zika, influenza, respiratory syncytial virus, HIV, and cancer. 

A collage of the Warren Alpert prize winners
Clockwise from top left: Eric Huang, Katalin Karikó, Uğur Şahin, Drew Weissman, and Özlem Türeci