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Friday, December 11, 2020—Drew Weissman, MD, PhD, an infectious disease expert at Penn Medicine, has been studying RNA for use in vaccines for over 15 years. He has dreamed about the seemingly endless possibilities of treating diseases with custom-made mRNA. However, he didn’t expect the mRNA technology he co-created with former colleague Katalin (Kati) Kariko, PhD, to become a critical technology used in some of the COVID-19 mRNA-based vaccines that are now in late stage development.

We sat down with Dr. Weissman to learn more about the science behind mRNA and his journey to creating the mRNA vaccine technology that is a critical component of Pfizer-BioNTech’s and Moderna’s mRNA-based COVID-19 vaccines and others being developed globally. 

What is different about an RNA-based vaccine compared to other vaccines, like the flu vaccine?

There are a lot of different kinds of vaccines, and they're all based on different platforms.

Most flu vaccines are an inactivated virus. They grow the virus in chicken eggs, and then they inactivate it so the virus is dead, and that's what they inject into your arm.

Other vaccines have live viruses where they attenuate the virus. They make it so it doesn't cause as bad a version of the disease. Then, they grow it, and they inject that into people – or they even spray it into the noses of little kids.

Some vaccines are called subunit proteins, which is one protein from the entire virus or bacterium. They usually grow those in mammalian cells, purify, and then inject it into people.

RNA is different. RNA is the producer of proteins. You can make an RNA that codes for a protein, and for COVID that's the spike protein found on the SARS-CoV-2 virus that causes COVID. When you inject the RNA that codes for the spike protein, the cells will take it up and produce the protein in large quantities. The advantage of RNA is that each RNA can make 1,000 to 100,000 proteins. So, there's a huge amplification when you use an RNA vaccine.

Where was the progress of RNA-based vaccines before COVID hit?

If you look back, RNA was first injected into an animal with the idea of using it as a therapeutic in 1990. It didn't go anywhere for therapeutics after that… until Katie Kariko and I started working on RNA to try and understand why it was so inflammatory. We figured that out, and then we figured out how to make it non-inflammatory. And after that, is when the vaccine field and other RNA fields took off, and people became interested again and started studying them.

Infectious disease expert Dr. Drew Weissman holding and looking at test tube

What piqued your original interest in RNA?

I'm not quite sure what actually piqued my interest in RNA. That was 23 years ago. It's actually funny the way Kati [Kariko] and I met. We used to fight over the copy machine. Back in those days, the only way you could read journal articles was to photocopy them out of the journal. And we would fight over the copy machine to be able to read articles.

We started talking and comparing what each other did. I was an immunologist, and she was an RNA biologist, and we got together and made a lot of great progress.

When you first started working on this RNA vaccine, what was your hope? Did you ever foresee the potential to save the world from a pandemic?

I’m a clinician and a researcher. Our big fear is always a new pandemic, but we expected it to be an influenza pandemic.

When we started this, we weren't thinking about curing pandemics. We were thinking about making new vaccines, making new therapeutics. We can use RNA to treat genetic diseases like cystic fibrosis and liver genetic diseases, use RNA to edit the genome and to fix genetic deficiencies. We had a lot of ideas for things that we could do with RNA – if we could get it to work.

My dream has always been to develop a new product, technology or drug that would actually go into people and help them. So, it’s exciting to see our technology being used in several of the mRNA vaccines currently being developed.

How are they able to expedite this vaccine processing? Why can it go so much faster than normal vaccine? And in what ways did your research help that?

There are a couple of answers to what has expedited its production. The first is that RNA itself is a very rapid platform. If you want to make a new influenza vaccine using the traditional methods, you have to isolate the virus, learn how to grow it, learn how to inactivate it, and purify it. That takes months. With RNA, you only need the sequence.

When the Chinese released the sequence of the SARS-CoV-2 virus, we started the process of making RNA the next day. A couple weeks later, we were injecting animals with the vaccine. RNA in itself is incredibly fast.

Now, for the COVID pandemic, everybody has sped up their timelines. Everything was done in parallel, instead of sequentially. Despite the speed, no corners have been cut and no safety has been ignored in this process. 

What has been your role in the development of the Pfizer and Moderna vaccines?

Kati Kariko and I developed the nucleoside-modified mRNA technology and other mRNA vaccine-related improvements that both Pfizer-BioNTech and Moderna have used in the development of their vaccines. We've done a lot of research to figure out how the mRNA vaccine technology works and how to make it work better. Infectious disease expert Dr. Drew Weissman looking over colleague's shoulder in lab

If approved, these would be the first RNA-based vaccines approved for any disease. What are your hopes for the future?

Even before COVID hit, we had already set up clinical trials for mRNA vaccines for genital herpes, influenza, and HIV, and we're developing more pathogen vaccines right now. I think it's going to have huge applicability, especially for diseases where prior vaccines haven't worked well.

As a clinician, my first hope is that the vaccine can be efficiently given out to the world's population, so we can put this pandemic down – maybe not completely get rid of it, but certainly allow people to get back to a more normal way of life.

Beyond that, I think mRNA has huge applications to so many different diseases and so many different therapeutic applications. Now that there may soon be two modified mRNA vaccines that are approved, my hope is that other therapeutics and other applications using mRNA will move along much quicker and will get to people a lot faster.

A lot of people are saying, "Should I get this vaccine? How do I know it's safe? Am I going to get COVID from this vaccine?" What do you say to those questions?

What I can tell you is that the vaccine cannot give you the disease. There is no way; that's impossible. From all the evidence I have reviewed, the clinical trials were done correctly. No corners were cut. The trial results presented thus far indicate the vaccines are safe, and I believe that. 

I've been talking to a lot of people. People don’t say, "I'm not going to take it." They say, "I'm going to wait for other people to take it. And if they look fine after six months, then I'll take it." 

If that's the worst case and we can still get 70% of people to take the vaccine – even if it takes them six months, which is how long it could take for production anyway – then I'm fine with that. My big worry is that if only 50% of the population want to take it, then we're going to be stuck with this pandemic for a lot longer. And that would be a tragedy.

Can you tell us a little more about the safety of vaccine? Why is it good for people to take vaccines?

Vaccine safety has been something that has been studied since vaccines were first made. If you look at how they're studied, it's called a risk/benefit ratio, meaning, "Is the risk of the vaccine lower than the risk of the disease?" For every approved vaccine, the answer to this question is a resounding "yes."

For diseases like polio that have huge mortality and morbidity rates, the vaccine doesn't have to be a 100% safe, because you're saving millions of lives, but the polio vaccine is very safe.

The RNA vaccine is completely physiologic, meaning it's identical to the RNA that's in our cells. When a cell sees the vaccine, it thinks it’s itself.

There are no problems breaking the RNA down, and that's where a lot of drug toxicity comes from. The drug gets broken down into a toxic breakdown product. That won't happen with RNA. Most of the lipids used in the mRNA vaccine are also natural. 

From all the clinical data reported from the ongoing mRNA vaccines trials so far the vaccine safety profiles look very good. A large percentage of people who have received the mRNA vaccines experience side effects, such as soreness and swelling around the injection site, fever and headaches, but these side effects may indicate the vaccination is eliciting a strong immune response against the viral antigen.

How to convince people that the vaccine is safe, I think, is a matter of having people take it, see that they're not getting disease, and see that they're fine. 

How has working for Penn Medicine and in the city of Philadelphia helped you get to where you are today?

Philadelphia is really a great place for medical invention. The first hospital was built in Philadelphia. Philadelphia is the home of immunotherapies like CAR-T cell therapy and the first gene therapy. And now, Philadelphia is the home to critical mRNA technologies being used in COVID vaccines and hopefully many future vaccines and therapies.

Penn Medicine gave me a home, gave me lab space, gave me support, and helped me achieve this accomplishment. 

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