Biopharmaceutical Science

Pieter Cullis
2022

Never in the history of biopharmaceutical science has the impact of rapid translation of extraordinary basic research to clinics been so profoundly felt by the public. The successful development of SARS-CoV-2 vaccines by Pfizer/BioNTech and Moderna took less than 12 months and the vaccines have already saved millions of lives worldwide. As one nominator wrote, “No other recent scientific discovery had a higher and more positive impact on humans than the COVID-19 mRNA vaccine”. This rapid medical advance, however, does not come by easily and is the result of arduous and sometimes, under-appreciated efforts of the brilliant and perseverant scientists involved. We are honoring three of them, Drs. Katalin Kariko, Drew Weissman, and Pieter Cullis as recipients of the 2022 Tang Prize in Biopharmaceutical Science. The new platform they developed is a nucleoside-modified mRNA-based vaccine, delivered by lipid nanoparticles. The challenges of delivering RNA into the human body are two-fold. First, RNA triggers innate immune responses, and second, it is easily degradable, and hence difficult to reach the target cells or organs. The breakthrough discoveries of the three laureates and the ingenious approaches they developed to overcome these issues are keys to the rapid and successful development of the SARS-CoV2 vaccines. These techniques not only revolutionize vaccinology, but also usher in a new era of RNA-based therapies.

 

Dr. Katalin Kariko was educated in Hungary and moved to the US in 1985 to pursue her interest in RNA-based vaccines and therapies. More specifically, she was interested in RNA and its chemical synthesis for efficient protein expression in cells in vitro/ in vivo. With systematic rigor, Dr. Kariko has solved several problems related to the use of RNA in vaccinology and therapy. During the 1990s, as a research associate Professor at the University of Pennsylvania, she became interested in the development of in vitro-transcribed messenger RNA (mRNA) for protein therapies. For that, she needed to understand the mechanism of the immune response mediated by RNAs. Together with her colleague, Dr. Weissman, she showed that mRNA is recognized by Toll-like receptors, thus participating in the innate immune response, and injection of mRNA into animals caused severe inflammation. However, they found that if the nucleosides of the mRNA were modified, the mRNA did not elicit such responses. They reasoned that selected nucleosides in naturally occurring RNA, such as tRNA, are often methylated or modified, and hence not recognized by the innate immune receptors. They demonstrated that indeed Toll-like receptors do not recognize RNAs with modified nucleosides such as m5C, m6A, m5U, s2U, or pseudouridine. Their critical finding is the creation of stealth RNA that cannot cause inflammation, as described in the journal of Immunity (Immunity. 2005;23(2):165-175). They also developed the necessary techniques for purifying RNA preparations in sufficient quantities free of oligonucleotide fragments or double-stranded RNA. Dr. Kariko founded a biotech company, RNARx, with Dr. Weissman, and was the CEO from 2006 to 2013. Since 2013, Dr. Kariko has been associated with BioNTech RNA Pharmaceuticals, first as a vice president and then as senior vice president in 2019, while continuously being an adjunct professor at the University of Pennsylvania. She was involved in the development of the COVID-19 vaccine as a coauthor of the BNT162-b2 paper, describing the current clinically approved vaccine developed by BioNtech (Nature. 2021;595(7868):572-577). Drs. Kariko and Weissman, hold U.S. patents for the application of nonimmunogenic, nucleoside-modified RNA. Their work was a foundation for BioNTech and Moderna to create therapeutic vaccines for COVID-19 that were produced by Pfizer (developed by BioNTech) and by Moderna (US8278036B2 & US8748089B2). Clearly, her pioneering work is critical for the development of both BioNTech and Moderna vaccines.

 

Dr. Drew Weissman is the Roberts Family Professor in Vaccine Research at the University of Pennsylvania, where he started his laboratory in 1997 to develop vaccine against HIV. Prior to that, he worked at NIH in the group of Dr. Anthony Fauci on HIV-related research (Nature. 1997;389(6654):981-985). In collaboration with Dr. Kariko, he started studying RNA as vaccines. Dr. Weissman and Dr. Kariko first collaborated on the studies of mRNA transfection of dendritic cells which induced inflammatory responses (J Immunol. 2000;165(8):4710-4717; J Biol Chem 277:12689-96, 2002). Then they published the pivotal discovery in 2005 as described above. Subsequent to the discovery that nucleoside-modified RNAs are nonimmunogenic, Dr. Weissman has been actively engaged in the application of this technology to the development of RNA vaccines against infections by viruses such as HIV and Zika Virus (Nat Commun 8:14630, 2017; Nature 543:248-251, 2017). Obviously, all the important discoveries are a team effort, with Dr. Weissman contributing significantly to the projects, especially providing the immunology insights.

 

Dr. Pieter Cullis is a pioneer developer of lipid nanoparticles and a professor at the University of British Columbia. He is a leader in the studies of membrane structure and function at the molecular level for the development of effective therapeutic agents. His lab showed that cationic lipids used for transfection can induce non-bilayer lipid structures in biological membranes, leading to the basic understanding of how transfection reagents facilitate intracellular delivery of DNA and RNA-based macromolecules. This is critical in the development of RNA-based vaccines, as RNA is quite unstable and difficult to be efficiently delivered into the cells. For his entire career, Dr. Cullis has focused on understanding membrane structure and function at the molecular level and advancing this information for therapeutic purposes. Mostly he has focused on the roles of lipids in membranes by using model membrane systems which led to engineered liposomal nanoparticulate (LN or LNP) systems to deliver conventional and nucleic acid-based drugs. His interest lies in the delivery of siRNA into new particles with cationic lipids in vivo, delivery of immune-stimulating drugs, such as CpG, for cancer and vaccine adjuvant, and encapsulation of chemotherapies. His classical papers have garnered over 2000 citations each, and, a great percentage of FDA-approved or emergency medical usage of lipid nanoparticles have relied on his technology. With his novel technology, Dr. Cullis is the founder of 11 companies, and among them, he co-founded Acuitas to develop lipid nanoparticle pharmaceuticals. In 2014, he started a collaboration with Dr. Weissman, who was working with BioNTech on RNA vaccines, and Dr. Cullis’ expertise was crucial in a delivery system. In 2019, Pfizer joined their effort to produce an mRNA influenza vaccine with LNP. When the COVID pandemic hit, the Pfizer-BioNTech vaccine was made. It is clear that without the delivery system developed by Dr. Cullis, the mRNA-based COVID vaccines would not have such success and impact on human health.

 

The SARS-CoV-2 mRNA vaccine could not have been advanced without the use of
(a) Nucleoside-modified RNA to escape immunity (contributed by Drs. Katalin Kariko and Drew Weissman) (b) RNA encoding stabilized Spike protein (contributed by Drs. Barney Graham and Kizzmekia Corbett) or (c) lipid nanoparticle technology (contributed by Dr. Pieter Cullis). In addition, the clinical teams at BioNTech and Moderna should share significant credits for developing the vaccines at a record pace. Due to the limitation of awarding number of laureates, while recognizing the contributions of others, the Tang Prize in Biopharmaceutical Sciences selection committee selects Drs. Kariko, Weissman, and Cullis as the most deserving and representative of the contributors.

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