COVID-19 vaccine: what does RNA research have to do with it? (2023)

December 14, 2020

A coronavirus uses a protein in its membrane - shown here in red in a molecular model - to bind to a receptor - shown in blue - on a human cell to enter the cell. Once inside, the virus uses the cellular machinery to make more copies of itself. (Juan Gaertner / Source of Science)

Rochester's research on the structure and function of RNA provides important information for developing treatments for the coronavirus.

The US Food and Drug Administration recently granted an emergency use authorization for aCOVID-19 vaccine developed by Pfizerand the German pharmaceutical company BioNTech.

The vaccine made history not only because it reported a 95% effectiveness rate in preventing COVID-19 in clinical trials, but because it is the first vaccine to be approved by the FDA for human use and based on RNA technology.

"The development of RNA vaccines is a great boon for the future of infectious disease treatment," he says.Lynne Maquat, J. Lowell Orbison Distinguished Service Alumni Professor of Biochemistry and Biophysics, Oncology and Pediatrics at Rochester and Director of the Rochester Center for RNA Biology.

COVID-19, short for "Coronavirus Disease 2019", is caused by the novel coronavirus SARS-CoV-2. Like many other viruses, SARS-CoV-2 is an RNA virus. This means that the SARS-CoV-2 genome is encoded in ribonucleic acid (RNA), unlike humans and other mammals. Viral RNA is sneaky: its properties cause the human protein synthesis machinery to mistake it for the RNA produced by our own DNA.

For this reason, several of the leading vaccines and treatments for COVID-19 are based on RNA technology.

A contingent of researchers from theUniversity of Rochesterstudy the RNA of viruses to better understand how RNAs work and how they are involved in disease. This RNA research forms an important foundation for the development of vaccines and other drugs and therapies to stop the virus and stop infections.

"Understanding the structure and function of RNA helps us understand how we can throw a therapeutic wrench into what the COVID-19 RNA is doing - creating new viruses that can infect more cells of ours and of other people as well."

As scientists have realized in recent decades that genetic material is largely regulated by the RNA that encodes it, that most of our DNA makes RNA, and that RNA is not only a target but also a tool for disease therapy," o The world of RNA research has exploded," says Maquat. "The University of Rochester understood this."

Maquat was founded in 2007The Center for RNA Biologyas a means of interdisciplinary research on the function, structure and processing of RNAs. The center includes researchers from the River Campus and Medical Center and combines expertise in biology, chemistry, engineering, neurology and pharmacology.

“Our strength as a university is our diversity of research expertise combined with our highly collaborative nature,” she says.Drache Fu, Associate Professor of Biology at River Campus and member of the Center for RNA Biology. "We are surrounded by outstanding researchers advancing our understanding of RNA biology and a medical center that offers a translational aspect where knowledge gained from RNA biology can be applied to therapeutics."

How is RNA related to disease?

AChart created by The New York Timesillustrates how the coronavirus that causes COVID-19 enters the body through the nose, mouth or eyes and attaches itself to our cells. Once the virus is in our cells, it releases its RNA. Our hijacked cells serve as virus factories, reading the virus's RNA and producing long viral proteins to weaken the immune system. The virus makes new copies of itself and spreads to other parts of the body and to other people through saliva, sweat and other body fluids.

“Once the virus is in our cells, the entire process of infection and reinfection depends on the viral RNA”, says Maquat.

One of the reasons viruses pose such a challenge is that they change and mutate in response to drugs.

This means that every time a new strain of virus emerges, new treatments against the virus and vaccines must be developed. Armed with groundbreaking research into RNA fundamentals, scientists are better equipped to design and test therapies that directly target RNAs and processes critical to a virus's life cycle.

How do RNA vaccines work?

Conventional vaccines against viruses like influenza inject inactivated viral proteins called antigens. Antigens stimulate the body's immune system to recognize the specific virus and produce antibodies in response, in the hope that these antibodies will fight off future viral infections.

RNA-based vaccines - such as those developed by Pfizer/BioNTech and the American biotechnology company Moderna - do not introduce an antigen, but inject a short sequence of synthetic messenger RNA (mRNA) encapsulated in a specially designed lipid nanoparticle. This mRNA instructs the cells to produce the virus antigen themselves.

For example, once a vaccine mRNA is in our body, it "instructs" the protein synthesis machinery in our cells, which normally makes proteins from the mRNAs derived from our genes, to make a piece of the SARS virus. -CoV-2 spike protein. Since the SARS-CoV-2 virus spike protein is foreign to our body, our body will produce antibodies that inactivate the protein.

“If the virus enters our body from an infected person, these antibodies bind to the virus and inactivate it, binding to its spike proteins, which coat the outside of the virus capsule”, says Maquat.

An RNA-based vaccine therefore acts as a code, instructing the body to make many copies of the viral protein - and the resulting antibodies - on its own, leading to an immune response.

Unlike more traditional vaccines, RNA-based vaccines also have the benefit of eliminating the need to work with the real virus.

"Working with a live virus is expensive and very labor intensive, requiring researchers to use dedicated biosafety labs and wear bulky personal protective equipment so that the virus is 'biocontained' and nobody gets infected," says Maquat.

Developing a vaccine from a live virus also takes much longer than making an mRNA-based vaccine, but "no one should think the process is easy," says Maquat of Pfizer/BioNTech Vaccine. "As it's the first of its kind, a lot had to be worked on."

How is the Rochester RNA research applicable to COVID-19?

Maquat has been studying RNA since 1972 and was part of the first wave of scientists to recognize the important role that RNA plays in human health and disease.

Our cells have multiple ways of fighting viruses, which can be seen as an "arms race" between the host and the virus. One of the weapons in our cells' arsenal is an RNA surveillance mechanism discovered by Maquat called Nonsense-Mediated mRNA Decay (NMD).

"Nursery-mediated mRNA degradation protects us from many genetic mutations that could cause disease if NMD were not active to destroy the RNA that harbors the mutation," she says.

Maquat's discovery has contributed to the development of drug therapies for genetic diseases such as cystic fibrosis and could be useful in developing treatments for the coronavirus.

"NMD also helps us fight viral infections, which is why many viruses inhibit or bypass NMD," she adds. “The genome of the COVID-19 virus is a positive-sense single-stranded RNA. Other positive-sense single-stranded RNA viruses are known to avoid NMD by having RNA structures that prevent NMD from degrading viral RNAs.”

Maquat's lab collaborated with a lab at Harvard University to test how viral proteins can inhibit the NMD machinery.

His recent work focuses on the SARS-CoV-2 structural protein called N. Laboratory experiments and datasets from infected human cells indicate that this virus is unusual in that it does not inhibit the NMD signaling pathway, which controls many of our genes and some of the Viruses regulate the genes. Instead, the viral N protein appears to promote the signaling pathway.

“SARS-CoV-2 reproduces its RNA genome much more efficiently than other pathogenic human viruses,” says Maquat. “Perhaps there is a connection; we will see."

At the Faculty of Biology, Fu andJack Weren,Nathaniel and Helen Wisch, Professor of Biology, received accelerated grants from the National Science Foundation to apply their expertise in cellular and evolutionary biology to the study of proteins involved in COVID-19 infection. The funding was part of NSF's Rapid Response Research (RAPID) program to mobilize funds for high-priority projects.

Werren's research will be important in alleviating some of the possible side effects of COVID-19 infections, including blood clots and heart disease, while Fu's research will provide insight into the potential effects of viral infection on human cellular metabolism.

"Our research will provide insight into the possible effects of viral infection on host cellular processes," says Fu. "Identifying which cellular functions are affected by the virus could help reduce some of the negative effects of COVID-19." Green = said twice.

Douglas Anderson, an assistant professor of medicine at the Aab Cardiovascular Research Institute and a member of the Center for RNA Biology, studies how RNA mutations can cause human disease and found that alternative therapies such as CRISPR gene-editing technology could also "lead a new approach to the way we fight and fight infectious diseases”, he says.

In recent years, Anderson's lab has developed tools and delivery systems that use RNA-targeted CRISPR-Cas13 to treat human genetic diseases that affect muscle function. CRISPR-Cas13 is like molecular scissors that can target specific RNAs for degradation using small, programmable guide RNAs.

When the health crisis became apparent in Wuhan, China, researchers in Anderson's lab focused on developing a CRISPR-Cas13 therapeutic targeting SARS-CoV-2. Using already available knowledge about coronavirus RNA replication, they developed unique CRISPR guide RNAs capable of targeting any viral RNA produced in a cell infected with SARS-CoV-2. Using a new cloning method developed in Anderson's lab, multiple CRISPR guide RNAs can be packaged into a single therapeutic vector (a genetically engineered transporter) to simultaneously target multiple viral RNA sites. The multipronged targeting strategy can be used as a therapy to protect against virus-induced cellular toxicity and to prevent the "flight" of viruses that may have mutated.

"Infectious viruses and pandemics seem to come out of nowhere, which has made it difficult to quickly develop and track traditional small molecule therapies or vaccines," says Anderson. "There is a clear need to develop alternative targeted therapies such as CRISPR-Cas13 that can be rapidly reprogrammed to combat emerging pandemics."

Although many new treatments are being considered for the new coronavirus, one thing is certain, says Maquat: "Targeting the RNA or proteins it produces is essential to therapeutically combat this disease."

What role will RNA play in the future of vaccines and disease treatments?

Most people living in the US today have only read about the 1918 flu pandemic and the relatively new RNA viruses like Ebola or Zika that are prevalent in other countries.

"RNA treatments are likely to be a wave of the future for these and other emerging diseases," says Maquat. "Epidemiologists know that new infectious agents are emerging because of how small the world has become due to international travel, including to and from places where humans and animals are in close contact."

Bats, in particular, are reservoirs of viruses.. Given bats' unusual physiology, many bat species can live with viruses without suffering ill effects. However, if these bat viruses mutate so they can infect humans, new diseases will emerge, says Maquat.

“It's just a matter of when it will happen and what virus it will be. The hope is that with the new pipelines in place for COVID-19, we will be ready and able to develop vaccines against these new viruses.”

This story was originally published on April 28, 2020 and updated on December 14, 2020.

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Tag: RNA Biology Center,COVID 19,Institute of Biochemistry and Biophysics,Department of Biology,Douglas Anderson,Drache Fu,featured post,Lynne Maquat,medical Center,School of Arts and Sciences

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