| | Interview

Unwrapping the biological secrets behind Moderna’s Covid-19 vaccine

Tal Zaks, chief medical officer at Moderna Therapeutics (Credit: Moderna)

Tal Zaks, chief medical officer at Moderna Therapeutics which has become one of the front-runners in the race to develop a vaccine for Covid-19, is in fact an oncologist, and not a virologist by training. And so it’s perhaps no accident that the innovative “messenger RNA” (mRNA) technology upon which the company’s vaccine candidate is built, first got its foothold as a potential strategy for cancer treatment.

Moderna has nearly a dozen vaccine candidates in the pipeline, based on the same technology, including once for long-neglected tropical diseases like Chikungnya and Ebola. But the pandemic, in fact, created a big break the tiny startup biotech company needed.

Geneva Solutions – Moderna’s vaccine candidate operates on a wholly different technology than traditional vaccine technologies. Can you explain what that is and why you think it is better?

Tal Zaks – The central dogma of biology is that genetic material is stored in DNA, and the intermediary of translating the information from DNA to the cell to make a particular protein is mRNA.

mRNA is a transient copy of the instructions in our genes that instructs the cell’s ribosomes to make protein. Every cell has the same DNA. But what makes every cell unique is the fact that it actually has different mRNAs that translate different proteins. Now, what our technology does is it allows us to make a protein-based vaccine; instead of making the protein outside the body, we actually just set the messenger RNA as the vaccine, and that teaches our body's own cells to make the protein.

Is this the protein that fights the virus, or is this a protein that is a part of the virus?

The most common type of virus is an RNA virus. What we do though is we take just the information required to instruct the immune system to recognize the most important advantage of this virus - the distinctive spike protein [the crown, from which coronavirus gets its name].

An mRNA vaccine is not a virus, [or even a weakened virus]. It only gives the cells transit instructions to make that one piece of virus that we want to educate the immune system to recognize - [the spike protein].

It's essentially an instruction code. I inject it into the muscle. It gets distributed to the lymph nodes where the immune system works. The messenger RNA encodes for the spike protein and our cells start to make this spike protein.

Now the immune system sees a new protein it's never seen before. And it goes, ‘Oh, hold on a second. This looks like a foreign threat. I've never seen this protein before, let me go block it.’ And so the immune system starts to generate antibodies and T cells that recognize that spike protein. It focuses the attention of the immune system, just on that one protein.

What are the advantages of this technology compared with a traditional vaccine where you just inject a weakened form of the virus, or a part of the virus protein, into the body directly?

There are several.  The first is this is a relatively rapid enzymatic process, which can be done more rapidly from a manufacturing standpoint. Secondly, [we are doing the process inside the body], as opposed to a [more conventional recombinant engineering] technology where we take [artificial] cells, and have those cells make the virus [spike] protein for us outside of the body.

A bioreactor needed to make a batch of vaccine protein is typically a 30,000 litre affair that takes up three stories of a building and costs between half a billion and US$ 1 billion to build.  Whereas a bioreactor to make [the same quantity] of an mRNA vaccine is just 30 litres, not 30,000 litres.  That’s a huge difference.  It takes weeks, not months, to set up. And it can all be done in simple [bio]degradable plastic. And so from a production standpoint, there’s a tremendous efficiency here in time and capital to get it started.

The second advantage is that we mimic biology in a very profound manner. So there is no way [for our body] to make the wrong protein, because our cells are the factories that make the protein and we just give it the instruction set.  Whereas when you make a vaccine from recombinant protein in artificial cells, you always worry about, have you made the right protein? So there is a tremendous advantage in terms of the biological fidelity of your vaccine.

In terms of the efficacy you’ve shown in the Phase 2 trial for the COVID-19 vaccine, you provoked a neutralizing antibody response in all 45 volunteers that participated, correct - and those were all at different dosing levels?

In the first phase we tested at 25, 100 and 250 microgram levels - and already at the 25 microgram level we can get to levels roughly of those who have been sick.  But we wanted to be sure that we give the immune system the best chance to protect subjects. And so we were able to dose up to 100 micrograms and exceed the levels of antibodies that you see in convalescent plasma.  I think that’s important because if you can get to higher levels, your chances of protecting people are going to be higher and the duration of protection will hopefully be longer.  And the question of duration is obviously a big unknown.  Nobody knows how long you are going to be protected, either from having been sick, or from having been immunized, but I think it's a fair assumption to say that the higher the levels you start with probably the longer protection you're going to have.

Moderna facility.jpg
Inside one of Moderna's facilities (Credit: Moderna)

We're seeing a few reports of reinfection from other viral strains, as well as research indicating that the antibodies in people who have recovered don't seem to stay very long in the body. So could this be like the flu where we're going to have to get vaccinated every year unless or until we get rid of this virus?

The answer is we don't know, but I don't think it's going to be like the flu, let me tell you why. When you look at cases of reinfection, nobody has yet described a case of somebody getting sick a second time.

So what does that mean? Well, let's say that I've got antibodies to the virus and I walk down the streets and somebody sneezes on me. And there's a lot of SARS-COV-2 in what I've just inhaled. Okay, so now that virus is in my nose, and my antibodies are starting to fight it. Now if somebody says, Hey, let me put a swab in your nose and do a PCR test to see if you've got the virus, well guess what they're gonna find some virus. It doesn't mean that the virus is going to make me sick. It doesn't even mean I can shed enough of that virus to make somebody else sick. So the fact that we've been able to detect reinfection so far. I have no idea what it means.

Except, nobody has yet even shown one case of somebody who was sick, and got sick a second time. And that tells you that at least with the experience we've had to date, in 5-6 months, immunity is pretty robust.

But is it possible that two years down the road, that protection wanes and we need another dose?

Sure it is. But in terms of what we're trying to achieve for society, if we can get everybody immunized in the next year or so, then, we will make a big dent in this pandemic. And if we need to get booster shots to remind the immune system, well, I think that'll be a problem for 2022-2023 and beyond.

Let’s turn to the policy questions. Moderna has signed up to a long-term contract with the Swiss manufacturing firm, Lonza, which can manufacture as much as a billion doses a year?

Including Swiss, US and UK manufacturing, that’s the total globally.

You have more than the US, Switzerland and Israel that have signed pre-orders, can you tell us how many countries you have.

At this point, no.

But you are part of the [WHO-led] COVAX facility?

We are in discussions with them, yes.

Because you were partly funded by CEPI (Coalition for Epidemic Preparedness Initiative), correct?

There was a very small, initial first seed funding that just allowed for that first lot that went into Phase 1. That is the total extent of funding we've received from CEPI.  There has not been significant funding from CEPI for scaling up or for supplies.

Having said that, are you positive about trying to make some of your vaccine available through the COVAX facility to low and middle-income countries? How will Moderna be playing that hand?

Absolutely. I hope to be able to do so. I am not in a financial position where I can simply donate vaccine supplies. I think people need to recognize that I'm not an established pharmaceutical company.

And I'm hoping through that facility that the rich countries step up to the plate, and support the poor countries in their ability to access vaccines.  I don't think it's reasonable or realistic to expect the pharmaceutical company to shoulder that. So having said that, I do hope that through COVAX and other like-minded bodies, we will be able to enable access to our vaccine to countries and individuals that currently are unlikely to afford it.

You say that you can’t be expected to donate as a young biotech company. What about a concessionary price?  If supplies are made available to COVAX, will there be a price differential? You talked about how much cheaper and easier this is to manufacture than a regular vaccine.

That will be in the future once we actually get there.  Remember this is the first scale-up of production. Anytime you do something for the first time for a technology, it is expensive. We have a line of sight in the future, you know 10-15 years from now, this will be much cheaper. But compared to the cost of the first recombinant proteins that were made back in the 1990s, and their current cost of production today, you'll see logs of decreasing cost. So I think we anticipate a decrease in costs but I don't think that's the reality today.

And I think it's too early for me to talk about differential pricing. I think we've made pretty clear what our pricing strategy to date is, and that pricing strategy is fair and equitable across everybody, broadly speaking. The only concessions we've made are for much higher volumes, so far.

And what about the Swiss connection. Can you say anything about this? Will we need to ask the Swiss investors that are backing Moderna to accept a lower dividend in order to make the vaccine cheaper to low and middle-income countries?

Moderna is now a publicly-traded company on the US stock exchange.

I have tremendous respect for and I very much like my Swiss colleagues and investors. Obviously we've also been talking to Swiss Medic [the Swiss drug regulatory authority] and Swiss physicians in terms of specific interest in this vaccine for the Swiss population. And I'm happy that some of the smartest people who understand not just finance and investment, but also biology and how the two come together, are in Switzerland and I think we have benefited from their foresight.

Do you think that you can credit Switzerland for having helped really leverage the funds that allowed you to do some of this? Was it the investment community or was it the IPO that really launched you?

The current investment in manufacturing specifically for COVID is the use of proceeds for the fundraising that we did earlier this year in May, right. So we raised over a billion dollars on the US public markets, specifically to invest in manufacturing ahead of time, at risk. The Swiss investors, I think, were early and long term backers of our company in the sense that they saw the potential of this company in the early days and you should recognize that.

Whether it’s this last billion or whether it's the close to a billion dollars that the United States has been investing or has promised to invest in supporting us, that was actually made possible - I mean, nobody could actually make those investments were it not for the billions of dollars of private investment in the last decade that public investors have made in building Moderna. So, it's both capital and money, and time and talent of people who've been at this for the past 10 years almost, that enabled in 2020, additional investments on top of that, which is just a fraction of the total investments that went into making this enterprise possible. And I think the Swiss, I give a lot of credit for their role in those early investments to make all this to make 2020 possible for Moderna.

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The full version of this article is available to read on Health Policy Watch