Research

The tale of mRNA

A decade of mRNA research helped scientists quickly develop COVID-19 vaccines.

mRNA
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A little more than a year ago, most of the general public had never heard of SARS-CoV-2, the virus that causes COVID-19. Now we have three vaccines in use — including two that use mRNA technology, made by Pfizer/BioNtech and Moderna — to fight the virus that has caused more than 535,000 deaths in the United States. For the first time in the realm of vaccine development, these vaccines were created, evaluated and authorized for emergency use in under a year.

Despite the accelerated timeline, the COVID-19 vaccines have been through every stage of clinical trials that would normally take place for a vaccine. So how did this happen so quickly?

The short answer

There are three major reasons why scientists were able to quickly create safe and effective vaccines against COVID-19, and none of them includes skipping safety protocols:

  • A lot of research on mRNA technology and on vaccines for similar respiratory viruses had been done in the past decade. Scientists were not starting from scratch at the beginning of the pandemic.
  • The federal government immediately addressed the typically time-consuming processes of clinical trial set-up, research funding and research publication. These processes were streamlined while maintaining clear focus on independent, expert review of all preclinical and clinical research results regarding both vaccine safety and efficacy. Securing funding typically requires a great deal of time investment.
  • We got a little lucky. SARS-CoV-2 is simply not as complicated as other viruses, such as HIV or the dengue virus, two viruses that have stumped vaccine developers for decades.

A deeper dive

When SARS-CoV-2 hit the scene in late 2019, scientists immediately sequenced its genetic code to learn precisely how this virus infects human cells to create an immune response. With this code in hand, vaccine developers plugged it into an experimental system that had already been investigated for other viruses, including respiratory syncytial viruses, or RSV, which can cause the common cold but also severe illness, especially in infants.

The creation of this system began more than a decade prior to the emergence of COVID-19, when scientists pinned down the detailed atomic structure of tiny proteins in RSV. These proteins are crucial for RSV to infect human cells, but the proteins change shape during the crucial infection process. Any vaccine for RSV had to spur the immune system to recognize a specific shape of the protein. Early vaccine candidates failed.

Then scientists used a new technology called X-ray crystallography to determine what the protein looked like at the critical juncture of infection. From this work, scientists stabilized the protein structure. They packaged it inside a molecule, and it wound up acting just like an antigen — a molecule that spurs an immune response. And it was 50 times more effective than anything tried for RSV previously.

This work on a vaccine for RSV laid the foundation for similar work on MERS, another respiratory disease caused by a coronavirus. This time, researchers used a new technology called cryo-EM to determine the structures of proteins and protein mutations needed to create a vaccine for MERS or any other kind of coronavirus vaccine.

Meanwhile, other scientists were investigating mRNA technology to create therapies for different diseases, including cancer. When the COVID-19 pandemic emerged, these two scientific worlds merged to join forces to create the first mRNA vaccines authorized for use against COVID-19.

How the mRNA vaccines work

“Traditional vaccines use weakened live viruses, dead viruses or a just some of the viral proteins, all of which are intended to prompt an immune response,” says UNC Health infectious diseases specialist Dr. David A. Wohl. “Some of these methods are under development for COVID-19 vaccines.”

But these methods involve time-consuming processes, such as growing and incubating viruses. It’s painstaking work, which is one of the primary reasons that until now, the quickest a vaccine had been developed was four years.

A solution was to use only one tiny part of a viral protein to create a vaccine that triggers an immune response. And a possibly even better way would be to use messenger RNA, or mRNA, a bit of genetic code crucial for cells to be able to make proteins we need every day.

“Think of mRNA as a text message to tell cells what to make,” Wohl says. “For a vaccine, we’ve been kind of clever and said, ‘what if we send our cells a text message so that they make some of the virus proteins. Then our body would see these proteins and react by making antibodies against them.’”

Thanks to earlier research, scientists could immediately determine the structure of the tiny spike protein on the surface of SARS-CoV-2 they needed to make. They learned which mRNA — or genetic code — was responsible for making that tiny spike protein. They synthesized this mRNA in a lab and began producing mass quantities of it for vaccines to be tested in cells and animal models of COVID-19. The results were astonishing.

The mRNA did exactly what it needed to do — create the piece of spike protein to trigger the creation of antibodies so that when the real virus showed up, the body was protected. Meanwhile, as the antibodies ramped up, the mRNA simply dissipated, as our cells do every day when our mRNA creates our own proteins. No viral mRNA enters our cell nuclei, where our DNA resides.

Understanding the vaccine clinical trials

Clinical trials often take years to complete, and the Moderna, Pfizer/BioNtech and other vaccines are still, technically, in clinical trials. The FDA has not approved these vaccines; the FDA issued emergency use authorization for Moderna, Pfizer/BioNtech and Johnson & Johnson vaccines because independently reviewed data for each was very strong. And clinical trial data show that these vaccines are safe.

“This is what we do,” says UNC Health infectious disease expert Dr. Cynthia Gay, who leads the Moderna and Novavax vaccine clinical trials at Carolina. “We run clinical trials and analyze safety and effectiveness data. It is truly amazing what we can accomplish when we apply new technology and if things like funding hurdles are removed.”

To ramp up the COVID-19 vaccine clinical trials, federal agencies leaned heavily on a network of academic medical centers, experts and pharmaceutical companies that was already in place nationally and internationally to run clinical trials for other therapies, such as for HIV treatments.

“As soon as there was enough phase 1 and phase 2 clinical trial safety data to review, the federal government relied on independent expert panels and the FDA to review that data immediately, Gay says. The data were compelling — showing the vaccines were safe and we could move forward with the next phase of evaluating these vaccines.”

Instead of waiting for the peer-review publication process to play out and then applying for funding for phase 2 trials, an independent panel recommended phase 2 trials to continue safety assessment while homing in on the proper dose. The government provided immediate funding. Phase 2 trials also were successful for the Moderna and Pfizer/BioNtech vaccines, so phase 3 trials with thousands of people began immediately.

Because of this streamlined process, we saved months if not years of time.

“Typically, outside of a global pandemic, each trial ends, data is analyzed, it is submitted for publication, and then hopefully accepted,” Gay says. “Then we search for funding. For COVID, we did not do the research hastily. All safety protocols were followed, but we collectively moved these studies along by cutting out the excess time, given the need. We are still following all the same steps in the same order with all the necessary review and input.”

This streamlined process, coupled with the fact that volunteers and networks of clinical researchers prioritized the COVID-19 vaccine research over other work, meant the Moderna and Pfizer vaccines could sail through clinical trials within nine months.

A stroke of luck

Scientists have been working on vaccines for all types of viruses and diseases — and failing — for many decades. Two notorious examples are vaccines for two of the world’s deadliest viruses — HIV and the dengue virus.

HIV hijacks the immune system itself, and even when drugs eliminate the virus, driving it down to levels that are nearly undetectable, some of the virus hibernates inside cells as if waiting for the cocktail of drugs to go away. Sure enough, when a person with HIV stops taking medications, the virus wakes up, multiplies and spreads. Finding a vaccine to protect against this diabolical virus has proven impossible so far.

Dengue virus, a mosquito-borne disease that infects millions of people each year, is actually composed of four different types of infections in one virus. It is a flavivirus, and so far creating sufficient antibodies for all serotypes through a vaccine has proven to be difficult.

As a respiratory pathogen, SARS-CoV-2 is nothing like either of these killer bugs, thankfully.

The COVID-19 vaccines in use now under EUA have been proven to be very effective so far, Gay says. “We’ve shown they are safe and there has not been any evidence of immune enhanced disease after vaccination after millions of people have been vaccinated. These vaccines are an important part of our strategy, along with masks and physical distancing, to help us end the pandemic as soon as possible.”

Read more stories from UNC Health.

Cindy Gay

 

Cynthia Gay is an associate professor of medicine in the Division of Infectious Diseases in the UNC School of Medicine. She is a practicing physician and the medical director of the UNC HIV Cure Center.

 

 

David WohlDavid A. Wohl is a professor of medicine in the Division of Infectious Diseases at the UNC School of Medicine. He is medical director of the UNC COVID-19 vaccine clinics at the Friday Center and Hillsborough Hospital.