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The job of making a vaccine is often described as thankless. In the words of Bill Foege, one of the world’s greatest public health physicians, “No one will thank you for saving them from a disease they never knew they had.”

But public health physicians argue that the return on investment is extremely high because vaccines prevent death and disability, especially for children. So why aren’t we making vaccines for more vaccine-preventable diseases? The reason is that vaccines must be effective and safe so that they can be used in healthy people, which makes the process of vaccine development long and difficult.

Before 2020, the average time from initial conception to licensing of vaccines was 10 to 15 years, with the shortest time being four years (mumps vaccine). Developing a COVID-19 vaccine in 11 months is therefore an extraordinary feat, made possible by years of fundamental research on new vaccine platforms, most prominently mRNA. Among them, the contributions of Drew Weissman and Dr. Katalin Kariko, recipients of the 2021 Lasker Clinical Medical Research Award, are particularly important.

The principle behind nucleic acid vaccines is rooted in Watson and Crick’s central law that DNA is transcribed into mRNA, and mRNA is translated into proteins. Nearly 30 years ago, it was shown that introducing DNA or mRNA into a cell or any living organism would express proteins determined by nucleic acid sequences. Shortly thereafter, the nucleic acid vaccine concept was validated after proteins expressed by exogenous DNA were shown to induce a protective immune response. However, real-world applications of DNA vaccines have been limited, initially because of safety concerns associated with integrating DNA into the human genome, and later because of the difficulty of scaling up efficient delivery of DNA into the nucleus.

In contrast, mRNA, although susceptible to hydrolysis, appears to be easier to manipulate because mRNA functions within the cytoplasm and therefore does not need to deliver nucleic acids into the nucleus. Decades of basic research by Weissman and Kariko, initially in their own lab and later after licensing to two biotechnology companies (Moderna and BioNTech), led to an mRNA vaccine becoming a reality. What was the key to their success?

They overcame several obstacles. mRNA is recognized by innate immune system pattern recognition receptors (FIG. 1), including members of the Toll-like receptor family (TLR3 and TLR7/8, which sense double-stranded and single-stranded RNA, respectively) and retinoic acid induces the gene I protein (RIG-1) pathway, which in turn induces inflammation and cell death (RIG-1 is a cytoplasmic pattern recognition receptor, Recognizes short double-stranded RNA and activates type I interferon, thereby activating the adaptive immune system). Thus, injecting mRNA into animals can cause shock, suggesting that the amount of mRNA that can be used in humans may be limited in order to avoid unacceptable side effects.

To explore ways to reduce inflammation, Weissman and Kariko set out to understand the way pattern recognition receptors distinguish between pathogen-derived RNA and their own RNA. They observed that many intracellular Rnas, such as rich ribosomal Rnas, were highly modified and speculated that these modifications allowed their own Rnas to escape immune recognition.

A key breakthrough came when Weissman and Kariko demonstrated that modifying mRNA with pseudouridine instead of ouridine reduced immune activation while retaining the ability to encode proteins. This modification increases protein production, up to 1,000 times that of unmodified mRNA, because the modified mRNA escapes recognition by protein kinase R (a sensor that recognizes RNA and then phosphorylates and activates the translation initiation factor eIF-2α, thereby shutting down protein translation). Pseudouridine modified mRNA is the backbone of licensed mRNA vaccines developed by Moderna and Pfizer-Biontech.

The final breakthrough was to determine the best way to package the mRNA without hydrolysis and the best way to deliver it into the cytoplasm. Multiple mRNA formulations have been tested in a variety of vaccines against other viruses. In 2017, clinical evidence from such trials demonstrated that the encapsulation and delivery of mRNA vaccines with lipid nanoparticles enhanced immunogenicity while maintaining a manageable safety profile.

Supporting studies in animals have shown that lipid nanoparticles target antigen-presenting cells in draining lymph nodes and assist the response by inducing activation of specific types of follicular CD4 helper T cells. These T cells can increase antibody production, the number of long-lived plasma cells and the degree of mature B cell response. The two currently licensed COVID-19 mRNA vaccines both use lipid nanoparticle formulations.

Fortunately, these advances in basic research were made before the pandemic, allowing pharmaceutical companies to build on their success. mRNA vaccines are safe, effective and mass-produced. More than 1 billion doses of mRNA vaccine have been administered, and scaling up production to 2-4 billion doses in 2021 and 2022 will be critical to the global fight against COVID-19. Unfortunately, there are significant inequalities in access to these life-saving tools, with mRNA vaccines currently administered mostly in high-income countries; And until vaccine production reaches its maximum, inequality will persist.

More broadly, mRNA promises a new dawn in the field of vaccinology, giving us the opportunity to prevent other infectious diseases, such as improving flu vaccines, and developing vaccines for diseases such as malaria, HIV, and tuberculosis that kill large numbers of patients and are relatively ineffective with conventional methods. Diseases such as cancer, which were previously considered difficult to deal with because of the low probability of vaccine development and the need for personalized vaccines, can now be considered for the development of vaccines. mRNA is not just about vaccines. The billions of doses of mRNA we have injected into patients to date have proven their safety, paving the way for other RNA therapies such as protein replacement, RNA interference, and CRISPR-Cas (regular clusters of interspaced short palindromic repeats and associated Cas endonucrenases) gene editing. The RNA revolution had just begun.

Weissman and Kariko’s scientific achievements have saved millions of lives, and Kariko’s career journey is moving, not because it is unique, but because it is universal. A commoner from an Eastern European country, she immigrated to the United States to pursue her scientific dreams, only to struggle with the U.S. tenure system, years of precarious research funding, and a demotion. She even agreed to take a pay cut to keep the lab running and continue her research. Kariko’s scientific journey has been a difficult one, one that many women, immigrants and minorities working in academia are familiar with. If you’ve ever been lucky enough to meet Dr. Kariko, she embodies the meaning of humility; It may be the hardships of her past that keep her grounded.

The hard work and great achievements of Weissman and Kariko represent every aspect of the scientific process. No steps, no miles. Their work is long and hard, requiring tenacity, wisdom and vision. While we must not forget that many people around the world still do not have access to vaccines, those of us fortunate enough to be vaccinated against COVID-19 are grateful for the protective benefits of vaccines. Congratulations to two basic scientists whose outstanding work has made mRNA vaccines a reality. I join many others in expressing my endless gratitude to them.