- mRNA, as a vaccine delivery platform, had been dissed in the past but is now proving to be the safest, most effective COVID shot
- Doctor-inventor Drew Weismann is known as the “father" of mRNA vaccines
- He worked with Katalin Karikó, biochemist who immigrated from Hungary 1985 with a few hundred dollars in her pocket, and is now dubbed as the "mother" of mRNA vaccines
- Dr Weissman holds many patents, including those that pertain to modifications required to make RNA suitable for vaccines and other therapies
- These patents were licensed to Gary Dahl who founded and is CEO of CELLSCRIPT; Dahl subsequently licensed the technology to Moderna and BioNTech to ultimately use in their COVID-19 vaccines
- Today, mRNA is the leading weapon in man’s arsenal against COVID-19
Dubai: About 30 years ago, a handful of scientists started exploring ways to make vaccines more simple. Most viruses have either RNA (ribonucleic acid) or DNA (deoxyribonucleic acid) as their genetic material. The researchers had one lofty aim then: know the exact structure of the messenger RNA that made the critical piece of a virus’s protein surface.
But when Dr Drew Weissman first started injecting mice with genetic molecules with his messenger RNA molecule, he faced a wall. His first formula overwhelmed the animals with inflammation — and some died. He did not give up, tried ways around it.
Miraculously, he solved that problem together with a colleague, with a bit of clever biochemistry. The breakthrough came in 2005, when Weismann met Hungarian biochemist Katalin Karikó at the University of Pennsylvania (Penn).
It was a fluke: their collaboration started with a chance meeting in a photocopier. What happened next was dubbed as “groundbreaking”. Their lab work captured in a paper entitled “Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA” was peer-reviewed and published in Immunity. It shook the scientific world.
Excerpts of Gulf News interview with Dr Weissman:
Please share with us about your work with mRNA:
I started working with mRNA when I moved to the University of Pennsylvania (Penn) in 1998. Prior to that, I was doing a fellowship at the US National Institutes of Health in Tony Fauci’s (director of the US National Institute of Allergy and Infectious Diseases, NIAID) lab.
When I got to Penn, my interest was in using dendritic cells. These are better known as "antigen-presenting cells". They’re the cells that start immune reactions. And the interest was using these cells in vaccines. And the question then became: How do you deliver the antigen — the antigen is the part of the pathogen that you want an immune response against.
My interest was in using dendritic cells. These are better known as 'antigen-presenting cells'. They’re the cells that start immune reactions.
So we looked at many ways of doing this. And I started collaborating with Katalin Kariko and chose the RNA as the delivery vehicle.
He received his graduate degrees from Boston University School of Medicine. Dr. Weissman, in collaboration with Dr Katalin Karikó, discovered the ability of modified nucleosides in RNA to suppress activation of innate immune sensors and increase the translation of mRNA containing certain modified nucleosides.
Many people are confused about mRNA vaccines. Compared to traditional vaccine platforms (inactivated, attenuated) what are they, really?
The way mRNA works is, in our cells, there’s the nucleus that contains the DNA. The DNA encodes every protein that makes our cells and our bodies work. The RNA is the intermediate. So when a cell wants to make a protein, a messenger RNA (mRNA) is made in the nucleus that copies the code for a protein.
That mRNA then transports to a machine in the cell that reads the code in the RNA and produces a protein. And the code from the RNA that it got from the DNA, determines the protein that will be made.
So the way an mRNA vaccine works is that, we put the code for the spike protein (of the SARS-CoV-2), the virus that causes COVID-19, into the mRNA, and deliver it to a cell. The cell reads it, makes the spike protein, and the body recognises the spike protein as “foreign” — and makes an immune response against it.
Many people are afraid about the so-called "unknown side-effects" of mRNA vaccines. How would you address their fears?
I think what they have to understand is that this isn’t a brand new technology. mRNA has been given to patients for 15 years. This is not brand new. It was not invented last March (2020) when the pandemic started to “blossom”. It’s not a new technology. It’s been in patients for many years. Those patients have done very well.
We haven’t seen any adverse events. Over 187 million doses of mRNA vaccines have been administered so far (in the US alone, as of April 12, 2021). And we’re not seeing any unexpected or any unusual adverse events.
People have to consider that the mortality rate from COVID-19 ranges anywhere from 0.5% to 35%. That’s a pretty high mortality rate. We see that in our elderly, the infirm, or patients with other medical conditions.
On the other hand, the adverse event rate from the vaccine is very tolerable. People get a sore arm for a day, some people get flu-like symptoms and feel lousy for a day — and then they’re better. So comparing the risk of dying, anywhere from 0.5% to 35%, versus a sore arm for a day, to me, isn’t much of a comparison.
Some people question the efficacy of mRNA-based COVID shots due to the "warp speed” with which vaccine was developed. What would say to those people?
The vaccines have been in development for many years. They’ve been given to different animal models — mice, macaques, monkeys, pigs, chickens, rabbits and guinea pigs. And it’s been tested in humans for a bunch of years.
It’s worked incredibly well in all of the animal models and in humans — 95% efficacy for symptomatic infection, 100% efficacy against severe disease and death. Those are pretty good results. It’s had enormous amounts of testing. It’s a very safe and effective vaccine.
Q: What’s makes mRNA a truly “revolutionary” technology?
We understand some of that. It’s a little science-heavy. But I’ll try to break it down. There’s really a couple of things that make it revolutionary.
One: the speed that a vaccine can be made. For most vaccines, you have to isolate the virus that causes the disease. You have to figure out how to grow it. Once you do that, you have to figure out how to inactivate (kill) it. And then determine whether or not it will make a protective immune response.
All of that takes time. With mRNA, you only need the genetic sequence, the code of the protein of interest. For the coronavirus, that’s the spike protein. So on January 12 (2020), and we had the sequence, and we started making the vaccine that day. So speed is one thing.
Two: RNA works well because the RNA produces protein for a couple of days. And why that’s important is that our immune system wants to see antigen protein for a couple of days. When you inject an inactivated virus or a protein sub-unit vaccine, the proteins clear very rapidly. But when you get infected, the virus grows in your cells for days. That’s what the immune system wants to see in order to make a good immune response. That’s what the RNA vaccine does.
Third: The lipid nanoparticle (LNP) — the fat droplet that the RNA is encapsulated in — is also an adjuvant. An adjuvant boosts the immune response, it stimulates the immune system to make a better immune response.
The mRNA based COVID-19 vaccines show a 90%+ efficacy. How was it arrived at?
It’s part of a phase-3 clinical trial. What a phase-3 trial does is it splits people into two groups: one group gets a placebo, the other group gets the vaccine. And you follow both groups and ask: ‘Do they develop infection?’; ‘Do they develop severe infection?’; ‘Do they end up in the hospital?’; ‘Do they die?’. You compare those two groups. And what they found was that the group that got the vaccine had 95% less of the disease, compared to the placebo group.
How long do you think will the immunity from COVID-19 conferred by mRNA shots last?
We don’t know that. What we know so far is that it’s lasted six months. Studies from both Pfizer/BioNTech and Moderna have recently shown the antibody levels are still high, six months after the vaccine.
The responses after six months are very good. So there’s high hopes that it will be at least a year, if not longer.
We’re gonna keep having to follow over time — to see how long they last. Some vaccines last a short amount of time. Others last a lifetime. We don’t know where mRNA-LNPs (lipid nanoparticles) are gonna end up being, but it’s lasted six months. The responses after six months are very good. So there’s high hopes that it will be at least a year, if not longer.
How many days or weeks would it take to re-program vaccines to address the new COVID-19 variants?
I think the first thing to consider is that there are many variants. People talk about the South African, the UK, the Brazilian, the California — there are many, thousands and thousands of variants that keep appearing. So it’s a concern. What we know so far is that the RNA vaccines, both the Pfizer/BioNTech and Moderna, protect against all of the known variants.
The concern is that, at some point in the future, a variant might appear that a vaccine doesn’t protect against.
And at that point in time, we’ll have to make an update. For RNA vaccines, as I mentioned, you just need the sequence (of the target antigen/virus) and you can make a vaccine. I was talking with Uğur Şahin, the BioNTech CEO, who said it would take them 6 weeks to make a new vaccine — and have it in the arms of people for a new variant. That’s very quick. And that’s what’s expected of the RNA vaccines.
Besides COVID-19, what other diseases could be touched by mRNA technology?
It’s really enormous. Before COVID hit, we had five phase-1 clinical trials in planning for different vaccines. Moderna has clinical trials for for CMV (cytomegalovirus, related to the herpes viruses), Zika that were ongoing. There are clinical trials for RNA therapeutics, delivering monoclonal antibodies with mRNA. In the future, I think the big opening or advancement for RNA is going to be in gene therapy — treating diseases like cystic fibrosis, sickle-cell anaemia, and other liver genetic disorders.
What do you tell people in the anti-vax camp, and those who engage in vaccine scaremongering?
If you look at those people, they break them down into different groups. There are the true anti-vaxxers — the people that, through no science at all, have made up their minds that vaccines are bad. What they believe in is nonsense.
There is no data that vaccines cause autism and that vaccines cause infertility. All this is made up social media nonsense. The problem is that you can’t present science to those people to convince them otherwise. However, the majority of people break down into those that are just nervous. What they want is that they want to see other people get the vaccine to make sure they’re OK, before they take it.
There are the true anti-vaxxers — the people that, through no science at all, have made up their minds that vaccines are bad. What they believe in is nonsense. There is no data that vaccines cause autism and that vaccines cause infertility.
And for those people, I point out that more than 100 million people have received the vaccine so far. And those people don’t die from the disease. They don’t have a bad illness from the disease — 95% of them don’t have any (coronavirus-related) illness at all. The risk of not getting the vaccine is high, it’s 0.5% to 35% mortality. There’s high levels of long-term effects from having COVID. It is a bad disease. The mRNA vaccines have been proven to be safe, more than 100 million people had taken it. That’s what I try to explain to the people who are nervous about the vaccine.
What about sharing of mRNA technology (patent) to the developing world in order to speed up vaccine production/distribution so that we can come out of the pandemic sooner?
What the pharmaceutical companies Moderna and Pfizer did early on, is they started to develop facilities to make RNA vaccines. Such facilities did not exist for producing large amounts of vaccine, billions of doses.
We need to vaccinate a large portion — 70% to 80% of the people worldwide in order to stop this pandemic. If we don’t, we are going to run into the problem where variants will keep appearing. And variants will, or they already have for certain ones, can re-infect people.
So early on, they started making it. They started figuring out how to make it at high levels and high amounts, they bought and leased GMP (good manufacturing practices) facilities. And they ran into the problem with raw materials…so they had to go to the people who made the raw materials to increase production. All of that has taken time. That’s why it took months to increase production. But what we are going to see, going forward, is that production is going to keep increasing. And that’s what we need to vaccinate the world.
In summary, what key insights would you like to tell people about mRNA vaccines, and vaccines in general.
I think people need to realise is that RNA vaccines and all COVID vaccines are effective and safe. The only way to stop this pandemic is to vaccinate the entire world. We need to vaccinate a large portion — 70% to 80% of the people worldwide in order to stop this pandemic.
Weissman hopes he can make a vaccine that would protect against all such viruses, instead of just one at a time. “There have been three coronavirus epidemics in the past 20 years,” he said.
“You would have to be foolish to think there isn’t going to be a fourth and a fifth and a sixth,” he told US media in November 2020.
Dr Weissman’s lab continues to develop other vaccines that induce potent antibody and T cell responses with mRNA–technology. It also develops methods to replace genetically-deficient proteins, edit the genome, and specifically target cells and organs with mRNA-LNPs, including lung, heart, brain, CD4+ cells, all T cells, and bone marrow stem cells.
We need to vaccinate a large portion — 70% to 80% of the people worldwide in order to stop this pandemic. If we don’t, we are going to run into the problem where variants will keep appearing. And variants will, or they already have for certain ones, can re-infect people. So it may turn into an influenza, where every year. there is a variant of influenza that can infect the world. We need to avoid that. We need to stop that. And the way to do that is to vaccinate the world.
That changed their scientific journey. By then, Kariko had already been working for several years on RNA, specifically on ways to solve some of the main technical barriers to introducing messenger RNA into cells.
Weissman, for his part, had been working on an HIV vaccine. They decided to collaborate. Specifically, their aim was develop a way of allowing synthetic RNA to go “unrecognised” by the body’s immune system. Countless hours of lab work had passed.
Then in 2005, their endeavour succeeded. Other scientists in the field hailed their work as a "breakthrough”. They didn’t stop there. As research work progressed, they succeeded in placing RNA in lipid nanoparticles — a coating that prevents them from degrading too quickly — and facilitates their entry into cells.
Along the way, they obtained patents for their work. The techniques that Kariko and Weissman developed are now used in both the Pfizer/BioNTech and Moderna shots against COVID-19. Both companies use the same strategy — introducing genetic instructions into the body to trigger the production of a protein identical to that of the coronavirus, thereby eliciting the desired immune response — without adverse reactions.
For their mRNA work, Kariko and Weissman are now seen as frontrunners to win the Nobel Prize for Medicine.
For their mRNA work, Kariko and Weissman are now seen as frontrunners to win the Nobel Prize for Medicine.