Unwrapping The Biological Secrets Behind Moderna’s COVID-19 Vaccine Technology Inside View 02/09/2020 • Elaine Ruth Fletcher Share this:Click to share on Twitter (Opens in new window)Click to share on LinkedIn (Opens in new window)Click to share on Facebook (Opens in new window)Click to email this to a friend (Opens in new window)Click to print (Opens in new window) Tal Zaks, chief medical officer at Moderna Tal Zaks, chief medical officer at Moderna Therapeutics since 2015, which has become one of the front-runners in the race to develop a vaccine for COVID-19, is in fact an oncologist, 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. Currently Moderna has nearly a dozen vaccine candidates in the pipeline, based on the same technology, including ones for long-neglected tropical diseases like Chikungunya and Ebola. But the pandemic, in fact, created a big break the tiny startup biotech company needed. Zaks sat down with Elaine from Geneva Solutions’ health stream, produced in collaboration with Health Policy Watch, to talk about the technology and why he believes in it. Geneva Solutions: Moderna’s vaccine candidate operates on a wholly different technology than traditional vaccine technologies. Can you explain in a nutshell 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. GS: Is this the protein that fights the virus, or is this a protein that is a part of the virus? TZ: 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 distinctive spike protein from which coronavirus gets its name]. 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. mRNA serves as a template for cells to produce the coronavirus spike protein, which then triggers the body’s immune system to produce neutralizing antibodies against the protein. GS – To recap, you’re sending an instruction to the body to make a spike protein, which is only one part of the virus, and so it’s not really dangerous. But the body’s immune system will see that spike protein and say, hey, this is dangerous and start making antibodies and T cells, which will protect the body if the same spike protein starts to invade as part of a real virus. TZ: And because that spike protein is what the virus uses to attach itself to a cell, if you can generate an antibody that recognizes those [spike proteins], a good proportion of them will end up blocking the virus, and therefore neutralizing its ability to infect cells. And that’s where the concept of “neutralizing antibodies” comes from. GS: Yes, we said that a successful vaccine must not only produce “antibodies” but it must produce “neutralizing antibodies”. What’s the difference? TZ: When the immune system sees the spike protein, it doesn’t know which part of that protein is actually the critical part for the virus to attach, so it starts making antibodies against all sorts of different components. What’s important is that you have enough it starts making antibodies against all sorts of different [viral] components. What’s important is that you have enough antibodies that some of them actually now combine to neutralize the virus. GS: So they bind with the protein and neutralize it. TZ: Correct. They neutralize the virus’s ability to infect cells. When you measure antibodies in the blood, you can either measure the total amount of antibodies that can bind to anything. Or you can actually set up an assay to see the level of neutralizing activity in the blood. The more you’re able to dilute the blood, and still block the virus, the higher the level of neutralizing activity, or neutralizing antibody “titres” in that blood, which will block the virus. Bioreactors for mRNA vaccine production are smaller and cheaper than those used for making traditional vaccines. GS: What are the advantages of this technology, as compared to a traditional vaccine where you just inject a weakened form of the virus, or a part of the virus protein, into the body directly? TZ: 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. GS: You are also testing the same technology on many other viruses, correct? TZ: The COVID-19 source code is the tenth virus against which we have demonstrated the ability to generate neutralizing antibodies in the clinic. And that’s out of ten viruses that we have tried, so our hit rate has been pretty good. That being said, we are less than five years out from having dosed the first ever subject on an infectious disease vaccine. So it’s a relatively young technology. [Before COVID-19 came along] our most advanced program was the vaccine for CMV (cytomegalovirus) one we’ve completed enrollment in Phase 2, and are on track to start a Phase 3 trial next year. So in a way, we got lucky because we had already been planning and thinking ahead of how one scales up this technology. And it’s one of the reasons that overall, we’re pretty advanced in our cold chain distribution and some of the other manufacturing components here, because we’ve been at it for a few years. But COVID-19 is going to be the first, I think, to get the market. GS: In terms of the efficacy you’ve shown in the Phase 1 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? TZ: 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. Early phase clinical trial results show that volunteers who received 2 100 microgram doses of Moderna’s COVID-19 vaccine candidate produced the same levels, or higher levels, of neutralizing antibodies [blue box] compared to people who were naturally infected with the virus [red background]GS: In terms of length of protection, 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? TZ: 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 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. And it’d be really surprising if somebody got really sick, and six months later got really sick again – we as a species wouldn’t survive. The immune system has served us well throughout its evolution, so that when we recover from an infection, we tend not to get sick a second time. So the data today are that if you’ve been sick, you don’t get sick a second time at least after five six months. If I can achieve the same level of neutralizing antibodies with the vaccine, or in fact, if I can exceed them, which I can now do across all age groups, including the older people, [as the most recent Moderna study has shown] then I would expect the duration of protection from a vaccine to be as long as the duration of protection from having been sick, because we believe that protection is a function of the immune system recognizing the spike protein as manifest by these neutralizing antibodies. GS: But is it possible that two years down the road, that protection wanes and we need another dose? TZ: 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. And by the way, one of the utilities of a messenger RNA technology is that you can actually get very effective booster shots. And that’s not true of all technologies. In fact, the problem people have with adenovectors, like the Oxford/AstraZeneca candidate, CanSino and others, is that it’s very difficult to give a booster shot with an adenovector. And the reason is the immune system recognizes the entire adenovector, and so when you come in a second time, it very quickly neutralizes it. Because the spike protein is just one small component of everything else [in the vaccine], you don’t get much of an opportunity to show that antigen a second time. With an mRNA, when we give the injection, the immune system doesn’t recognize the messenger RNA, it only wakes up when the body starts to make the protein. And so we can boost as many times as we need. So, to summarize it – so far we’ve seen [natural] protection for at least five to six months. I anticipate that vaccination should give as much durability as [actually] being sick. And should we need booster shots in the future, I think we’re well positioned with an mRNA technology to do that. Moderna’s clinical development manufacturing facility in MA, USA. GS: And what about the comparison to flu? TZ: The reason we need a vaccine every year is not that the immunity wanes. It’s because there’s a new viral strain that has escaped. So today, in fact, our SARS-COV-2 vaccine generates antibodies that are able to neutralize the strains that are in the population. And this type of coronavirus actually has a proofreading engine so it’s less mutation prone. Now, of course, it can mutate, it’s already proven its ability to mutate, but if SARS-CoV-2 mutates to something that the immune system doesn’t recognize we’ll probably be calling it SARS-CoV-3. In which case, if we have a proven mRNA technology that can indeed prevent disease, and we will have set up a manufacturing platform to enable millions of doses to be produced quickly, we’ll just put in the new sequence into an mRNA platform and turn out a new vaccine [if we run into SARS-CoV-3]. GS: And in terms of the speed with which a vaccine could be adapted? TZ: I do think that this platform can do better than traditional flu technologies, which take six months between the time the WHO releases the strain [to making a vaccine]. And the problem with that long [lead] time is that every few years, we end up immunizing ourselves against something that’s less relevant or not as protective. So if [in the case of SARS-CoV-X], your turnaround time is 2-3 months, then your ability to actually make sure that you produce the right stuff is much higher. And so, even if if these coronaviruses start to behave like flu, and cause significant morbidity with rapid mutation rates and strains that emerge at a higher pace, hopefully we’ll be able to immunize ourselves better in the future by having established technology like an mRNA platform. GS: You also mentioned that the mRNA vaccine sparks the creation of neutralizing antibodies against the spike protein, and isn’t the spike protein pretty much the same in all of these SARS-CoV-2 strains? TZ: Exactly. There’s one mutation -the d 614g – that allows the spike protein to, to improve the infectivity of the virus, but it doesn’t change anything in the recognition domains and so the same neutralizing antibodies that worked against the original Wuhan strain are also as effective against this more infectious strain – and that’s the one that is currently circulating. GS: Let’s turn to the policy questions. Moderna has signed up to a long-term contract with the Swiss manufacturing firm, Lonza, which can manufacturer as much as a billion doses a year? TZ: Including Swiss, US and UK manufacturing, that’s the total globally. Moderna TX’s manufacturing partners for its COVID-19 vaccine candidate. GS: You have more than the US, Switzerland and Israel that have signed pre-orders, can you tell us how many countries you have. TZ: At this point, no. GS: But you are part of the [WHO-led] COVAX facility? TZ: We are in discussions with them, yes. GS: Because you were funded by CEPI (Coalition for Epidemic Preparedness Initiative), partly, correct? TZ: 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. GS: Having said that, are you positive about trying to make some of your amazing vaccine available through the COVAX facility to low and middle income countries? How will Moderna be playing that hand? TZ: 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 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. GS: OK, 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 the COVAX Facility, will there be a price differential? You talked about how much cheaper and easier this is to manufacture than a regular vaccine. TZ: 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. GS: 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? TZ: Moderna is now a publicly traded company on the US stock exchange. I have a 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. GS: 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? TZ: 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. —————————————- An oncologist by training, Zaks was previously head of Global Oncology at Sanofi and prior to that, built the oncology translational medicine team at GlaxoSmithKline’s genetics research group. He received his MD and PhD from Israel’s Ben Gurion University of the Negev, and then conducted post-doctoral research at the U.S. National Institutes of Health, while completing his clinical training in internal medicine at Temple University Hospital. He also is an associate professor of medicine at the University of Pennsylvania. Image Credits: Moderna TX, Moderna TX, Miller J. (2020). ACIP COVID-19 Vaccine Presentation. Moderna TX, Moderna TX. 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