Good afternoon, and welcome to Moderna's Conference Call. At this time, all participants are in a listen-only mode. Following the formal remarks, we will open the call up for your questions. Please be advised that the call is being recorded. At this time, I'd like to turn the call over to Lavina Talukdar, Head Investor Relations at Moderna. Please proceed.
Thank you, operator. Hello, everyone, and welcome to Moderna's conference call to discuss results from in vitro studies against variants of the SARS-CoV-2 virus. You can access the press release issued today, as well as the slides that we'll be reviewing, by going to the investor section of our website. On today's call are Stéphane Bancel, our Chief Executive Officer, Tal Zaks, our Chief Medical Officer, Stephen Hoge, our President, and David Meline, our Chief Financial Officer. Before we begin, please note that this conference call will include forward-looking statements made pursuant to the Safe Harbor Provisions of the Private Securities Litigation Reform Act of 1995. Please see slide two of the accompanying presentation and our SEC filings for important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in these forward-looking statements.
We undertake no obligation to update or revise the information provided on this call as a result of new information or future results or developments. On slide three, please see the important indication and safety information for our COVID-19 vaccine, which has been authorized for emergency use in the U.S. and in many other countries around the world. Please review it at your own leisure. I will now turn the call over to Stéphane.
Thank you, Lavina. Good afternoon or good evening, everyone. Thank you for joining us. There has been a lot of question recently about the new SARS-CoV-2 strains and vaccine efficacy. For context, we have followed SARS-CoV-2 mutations since January 2020. The virus has mutated many times. It is an mRNA virus, and it will continue to mutate, and we will obviously continue to monitor closely mutations. We were pleased to announce this morning and post online a preprint of data generated by our teams in collaboration with Dr. Fauci's at the NIH. The vaccination with Moderna COVID-19 vaccine produces neutralizing titers against all key emerging strains tested, including B.1.1.7, first identified in the U.K., and B.1.351, first identified in the Republic of South Africa. No significant impact on neutralizing titers against B.1.1.7 variant relative to prior variants.
A six-fold reduction in neutralizing titers was observed with the B.1.351 variant relative to prior variants. Despite this reduction, neutralizing titer levels with B.1.351 remain above levels that are expected to be protective. Out of an abundance of caution, we also announced our clinical strategy to proactively address the pandemic as the virus continues to evolve with a new candidate, mRNA-1273.351, that Stephen will describe in a minute. With this introduction, let me now turn to Stephen.
Thank you, Stéphane, and thank you all for joining. What I'd like to provide a bit of an update on today that was covered in the preprint post online is some of our more recent data looking at the range of new spike protein variants that have been described in the public health community globally as we continue to follow the pandemic. This is an ongoing collaboration that we've had with the Vaccine Research Center at NIH and other collaborators to continually look at what's happening out there as the virus starts to evolve, and importantly, test the sera of people who've been vaccinated with our vaccine, mRNA-1273, and make sure that it is protective still against those variant spike proteins.
As you would see in the preprint that we posted online today, and on the slide in front of you, there's a large number of variants we've been following over time. In fact, this is activity that's really been ongoing continuously since we first started developing our vaccine. At least five of these variants involve multiple mutations and are highlighted on slide five. Against all of these, what we've done is we've tested the blood from peer people who were in our phase I study, as well as primates across a wider range of doses to see whether or not that serum is able to neutralize these variant viruses or these variant forms of the spike protein.
There are large number of ongoing variants that have been described, including, as you'll see at the bottom of this slide, P.1, which is also known as a Brazilian variant, and more recently, a California variant. Importantly, many of the mutations are gonna be common between these variants over time, and I'll try and cover that a little bit over the next couple of slides before getting into the data. On slide six, what I wanna highlight here are the three primary variants that seem to be getting a lot of attention right now. On the left is B.1.1.7. This is also known as the U.K. variant, where it was first described. In the middle, B.1.351, also known as the South African variant.
On the far right-hand side, P.1, which is sometimes called the Brazilian variant, sometimes called the Japanese variant. In all three cases, what we're showing you is the spike protein, that is the key protein that we make in our vaccine, and that it allowed us to show 95% efficacy, or approximately 95% efficacy, in protection against COVID-19 disease. If you look across these different pictures, what you'll see is the trimer, the three different colored pieces, a light purple, a more tan color, and a pinkish color, are the three pieces of the trimer. Then highlighted in red are the mutations, the new variants that are starting to emerge. Now the virus will bind onto its host, bind onto cells, using the top end, which is denoted here as the receptor binding domain, or RBD, or the N-terminal domain, NTD.
That's the place where the virus really interacts with its human target. As you can see, the U.K. strain and all three of these strains, in fact, include many mutations across the protein. Many of these we've actually already described and tested before. In fact, you'll note in the middle something called D614G, which is a variant of the spike protein that was described extensively this summer as it was circulating. Over time, these strains have also developed a large number of other mutations, and as you can see, a decent number of them are now on the top of the molecule, near the RBD and NTD. These are of particular concern because when we develop antibodies that neutralize and protect against the coronavirus, we really find that the antibodies that bind at the top of the spike protein are particularly effective.
The good news is we get antibodies that are effective all over the spike protein, but we really want to focus on the following slide seven, on the receptor binding domain at the top of that molecule. If we zoom in there and look at the mutations that were on the prior slide, I want to highlight what that receptor binding domain looks like, what that part of the molecule looks like, and how mutations there might affect how it interacts with people as it tries to infect them. On the left-hand side with the UK strain, also known as B.1.1.7, what you can see here as denoted in yellow in the picture is the ACE2 receptor. This is the receptor that the virus tries to bind to.
Underneath it, now we're looking down on it, you can see the receptor binding domain of the spike protein in the U.K. strain. Specifically what we're highlighting N501Y, the N501Y, is one amino acid change, just one of the amino acids in the protein that changed in that receptor binding domain that's been described in that B.1.1.7 variant. That is the one that's on the receptor binding domain, but if you contrast that with the Brazilian strain in the middle, the B.1.351, what you'll note is there have been a few more mutations. In fact, three versus the wild type virus that are described in the Brazilian strain. In addition to the N501Y, you'll see a mutation called E484K. That is a second amino acid that's changed, and then a third in K417N.
What starts to happen as a virus evolves is it will acquire mutations, as you can see in that middle picture, that change the face of how that receptor or that virus will bind with its receptor, and also its appearance. As the virus changes its stripes, as it changes its appearance, one of the effects of that can be that you could see a decrease in immunity, that's either as a result of the vaccine or a prior natural infection. That's the thing that we most actively want to monitor for as a part of our ongoing monitoring about the efficacy of our vaccine and the evolution of this pandemic.
I will note on the right-hand side before moving to the next slide that the Brazilian strain does have some similar mutations, but in a couple of places, or specifically in K417, a different amino acid, so in this case K417T versus K417N, but on balance it looks more similar to the South African strain. We'll come back to that as we talk about why we think the South African strain is the right candidate for any booster activity. On the next slide eight, what I'd like to start to walk you through, given that overview, is some of the data on how is our current vaccine, how effective is it at neutralizing all of these variant viruses. The first thing I'll show on slide eight is just a wide range of mutants that we've looked at for which there has been no decrease in protection.
Quickly, these assays are assays where we take the blood of somebody who's been vaccinated with our vaccine, and we determine whether or not their blood can fully neutralize the virus when it expresses the variant spike protein. These are pseudovirus neutralization assays, so we're not using the live virus, but we're using a virus that's been engineered, as we do in all of our other publications and clinical studies, to express the spike protein from the mutant virus. Whether we look in panel A at the non-human primate serum, or on panel B in our phase I human serum, what I think you can appreciate is compared to the benchmark variant that we've been following for a while, which is D614 or D614G on the left-hand side, the gray bars, we see essentially the same sorts of neutralization in terms of titers of protection.
This is nearly well over 1,000, about 1,800, across all of these samples. That's good news, including the previously concerning mink cluster variant that had broken out in Europe. Initial data across all of these is very encouraging. If I move to slide nine, we conducted a similar analysis on the human sera. Here I'm going to focus just on the human sera, but the primate data showed a similar result as you saw in the preprint. Looking at the human sera against the U.K. strain, also called B.1.1.7, what you can see is on the panel A, the level of protection, the amount of neutralizing titers that we saw in this pseudovirus neutralization assay, was as high for the 1.1.7 variant as for the control, also denoted G here.
Importantly, as we look at individual groups of mutations, including the N501Y, which I showed on that picture before, as a standalone or any of the others, we didn't see any substantial decrease in the levels of neutralizing titers. The panel C, which shows that compared for the eight individuals, shows that all eight individuals had essentially similar levels of protection between the wild type virus for which we previously developed the vaccine and the U.K. strain. This is obviously very good news, because it suggests that the U.K. strain should be well-protected or well-covered by the neutralizing antibodies and responses that we've been developing with our Moderna COVID-19 vaccine. As we move to slide 10, we'll look at the Brazilian strain. Sorry, South African strain, I should say, also known as B.1.351.
In this case, again, the good news is we were able to demonstrate that the blood from people who've been vaccinated with the Moderna COVID-19 vaccine was able to completely neutralize the virus. As you'll note on the panel on the left in B, with the 3.5.1 strain, the level of neutralizing titers had declined about sixfold, and that's also visible on the panel in the middle with D. That sixfold reduction happened in all of the subjects in a fairly consistent way. Now, the good news, again, is that the level of neutralizing titers that we saw in this assay suggests to us that we are still effective at being able to protect against the South African strain, the 3.5.1 strain of the virus that is now circulating.
Importantly, as you can see on panel B, as we go look at just those mutations, 501Y, 484K and 417N that I had referenced before that are also related to what's happened with the Brazilian strain, again, we saw good protection in these neutralization assays. However, it's obvious also that we saw a sixfold decrease, and so while we think the vaccine is likely to continue to be effective, it just highlights the importance for continuing to be vigilant in screening against strains. With that, on slide 11, we did announce today a clarification in our strategy proactively to continue to maintain high degrees of efficacy against SARS-CoV-2 as it continues to evolve.
Now the virus isn't going to stand still, and while the current strains appear to be well protected by our COVID-19 vaccine, as we continue to follow the story in the weeks, months, and perhaps the years ahead, it's important that we remain vigilant and develop potential tools and countermeasures that would allow us to continue to beat back the pandemic. Today we announced two parts of that strategy. The first is testing an additional booster of Moderna's COVID-19 vaccine, mRNA-1273, to further increase titers against the emerging strains. As we've published in the past, our vaccine is very good at developing and boosting those titers, and we believe an mRNA vaccine or potentially a third dose of an mRNA vaccine is a way that if it becomes necessary in the future, we can raise those titers again.
That's particularly important as we think about over time, waning or decreasing immunity specifically to some of these new emerging strains if it were to pass. The second strategy that we announced today is advancing an emerging strain booster candidate, which we've called mRNA-1273.351, after the South African strain variant that we just described, against those variants first identified. We would seek to determine whether this new booster candidate can be more effective at boosting the titers specifically against this new emergent strain. We have every reason to hope and believe that mRNA-1273, the authorized vaccine, will be able to do it, but if possible, to increase those titers even further with adaptation of mRNA-1273.351, the strain-specific booster, we think it's prudent to plan to do that and evaluate that today, as it will give us more tools in the future.
We're excited to announce today, as I said, the key messages are that the vaccine appears to be fully effective against all strains we've tested. Importantly, as we continue to monitor strains and where we identify the potential emergence of decreasing neutralizing protection, as we did with the B.1.351 strain from South Africa, we will develop a strategy both boosting with our 1273 Moderna COVID-19 vaccine and moving forward, if appropriate, with strain-specific boosters. With that, we'd like to open it up to the operator for any questions.
As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from the line of Matthew Harrison from Morgan Stanley. Your line is now open.
Great. Good afternoon. Thanks for taking the questions. Stephen, I guess I have two that I wanted to ask. First, can you just address, would you expect any differences if you run these experiments in the live virus assay versus the pseudovirus assay here? I guess, second question is just around, as we think about correlates of protection, and we think about what you guys view as the lowest level of antibody that could be protective. [audio distortion].
Matthew, thanks for the question. Let me try and do the first one, which is would we expect a difference in live virus assay? Not at present, ultimately the prudent thing to do is get a hold of particularly the South African strain B.1.351, and run live virus assays and confirm that result.
I think we wouldn't expect a priori that we would see that all of a sudden, as a result of the live virus, that you'd see breakthrough. If anything, I would hope that the live virus might have an even more reassuring result. We'll ultimately have to run that experiment to confirm, and those experiments are ongoing. The second, I would just, final point on that is that I would note that we have seen, in general, very good concordance across all of the live virus assays and the pseudovirus assays across all of our prior publications, including phase I, phase II, and phase III, where we've done live and pseudovirus neutralization assays. I think we have reasons for confidence there. The second question, which is what's the level of protection? Look, I think that is the $64,000 question.
I think we have confidence right now. I would say based on a few things. The first is it's clear that we saw with the vaccines at 95% efficacy, a very high level of efficacy. Sufficiently high that we don't know whether we would lose very much, even with a titer that fell sixfold as we're seeing here in the B.1.351 strain. It's quite plausible with that level of efficacy, you've got a lot of room to give. If you ask the question from another direction and say, "Well, now what can we develop as correlates prior to we have them?" We don't have clinical correlates of protection. We do have animal model surrogates.
As we develop data over the last year, I think we've all begun to believe that some of the challenge models, including, for instance, the primate challenge models, are reasonably predictive of what we ultimately were able to demonstrate in the clinical experience. In that sense, the levels of titers that we have shown and published to be protective against viral challenge in primates is usually just above the level of detection in our pseudovirus neutralization assay. Down slightly below 100 is sufficient to modify disease. In fact, the levels that we published in the New England Journal in primates where we gave primates a 10 microgram prime and boost, the levels of titers they had were even below the levels that you see against the pseudovirus assay for B.1.351 strain, and even there we were able to protect against disease.
As we build more confidence in those surrogates, and obviously we have more work to do and confirm that against the new strains, but as we build more confidence in those surrogates, I think it continues to give us reason to believe that we're still well above what we need from a protection perspective. Ultimately, we'll have to run those challenge models in primates again with the new strain and confirm it, just like we will with the live virus assay. Thank you.
Thank you. Our next question comes from the line of Ted Tenthoff from Piper Sandler. Your line is now open.
Great. Thank you, guys, and thank you for taking my question. Thank you for this update. I think it goes without saying, but it's just very reassuring all of this work that you're doing and not just hanging up the gates and claiming victory on the success of mRNA-1273 , but I think this is really important work. I wanted to get a sense for this prime or this boosting strategy, and obviously there's still a lot of work to do on the preclinical side and the early clinical side. Can you give us a sense from the antibody data that you have to date what that schedule might look like? Are we talking three months after, the same four weeks after? Would it be even further out? Any just early ideas of what that might look like would be really helpful. Thanks.
Ted, this is Tal. Let me try and take that one. Look, I think the levels of neutralizing antibodies that we see after the primary series, as you'll recall, are quite high, and judging by everything that Stephen has described, I expect they're gonna be protective in the near term, even against the South African strain. Our thinking at this point is to start to study a third booster shot out 12 months, maybe 6-12 months, but not sooner, as the way to demonstrate the utility of that third dose.
Yeah. That makes a lot of sense. Obviously you'll be getting more information from the antibody as you kind of collect that. Very cool. That's helpful to start. Again, thanks for all the hard work you're doing here in keeping us safe.
Thank you, Ted.
Thank you. Our next question comes from the line of Salveen Richter from Goldman Sachs.
Good afternoon. Thanks for taking my questions. With regard to the work that was done here, did you look at any higher doses, including the prior 250 microgram dose? Secondly, as you think about the vaccine on the forward here, how are you or where is your updated thinking with regard to durability of protection as well as this lever of novel strains that are coming out and how you might think about creating a new vaccine, and over what period? I guess if I could add another layer into that, how you would think about younger population versus older population, and how this might play out?
Hi, Salveen. Let me try and take those. 250, we don't have, I don't think, data on the small cohort that got the 250, but I think the extrapolation here should be pretty clear. I should say that the data between the different assays correlate pretty well. I think you can extrapolate there. In my mind, from what I've seen to date, the most straightforward way to raise somebody's neutralizing titers is to just give them another booster shot. That immunologically makes more sense to me than increase any given dose. In terms of durability, our sense is, the three months data have been out there. I think the six months data should be out shortly. I anticipate that the decay of antibody levels should be relatively consistent with other antibody responses, consistent with having a very strong T cell response that boosts immunity to begin with.
I continue to maintain that I expect the durability of the primary series to be out to one year, if not longer, based on the kinetics so far. There is the concern that these data raise that if there's a higher sensitivity to this strain or the B.1.351 strain, because potentially the levels required are higher because you generate relatively less neutralizing antibody to them, does that mean that protection against that specific strain may wane sooner? That could be. I think time will tell, and this will require an ongoing evaluation, both of the antibodies in people, but frankly also of the clinical reality of what happens in the real world, i.e., do people previously immunized or infected with prior variants actually get reinfected with this variant? I think that's to be determined. Your question about younger versus older.
I think by and large, it's true that it's often difficult to generate the titers you want in older people. That being said, I think at the 100 microgram dose, we've pretty conclusively shown that the levels we get are indistinguishable between younger adults and older adults. So far, I don't have a significant concern for them waning sooner in the elderly, but they may, and we're going to have to follow that. I still believe that the boosting strategy, whether it's six, 12 months later, should be applicable to both younger and older adults. Based on the totality of the data that I've seen to date, I don't think we're about to develop two different dosing recommendations to younger and older people. At least that's my sentiment today. Over.
Thanks, Tal. Maybe with regard to the last question, I was just more wondering if the frequency of another vaccination would be different between adults and children versus different vaccines.
I don't think so. This variant that we're putting into production is really meant to help us evaluate whether what we need to do is sort of plug an immunological gap in case that a different variant requires a slightly different immune response or just to boost the levels. I think we just don't know the answer to that yet. Once we have a better understanding of the relative immunogenicity of the different vaccines, I think we can be wiser about what the actual recommendation is. I think it's too early.
Thank you.
Thank you. Our next question comes from the line of Michael Yee from Jefferies. Your line is now open.
Hey, guys. Good afternoon, and thanks for hosting this call. I think I have two important questions. One is what you think the FDA or the agency or what your conversations are like around approvals for future variants, and whether you think antibody titer levels could be at, what's the threshold level? Maybe make some comments on that, because I think that's super important. The second question is also related, which is, now that you have all this capacity, how do you think about how fast you could actually ramp things? Maybe we could do some math around that, but I think those are two super important questions. Thanks.
Thank you, Michael. This is Tal. I agree with you. They are important questions. Let me take the first one. As it relates to FDA, let me preface by saying I don't know, I've yet to have our first deep dive conversation with them around this. That being said, I think they're on record as stating that should we need a variant, the path to approval is there. While they need to be fleshed out, they should not involve repeating efficacy trials. I think there is a regulatory paradigm that's been established around flu, albeit with many more years of experience. Look, where we are at the end of January of 2021 in terms of understanding the relationship between neutralizing antibodies and antibodies in total and prevention of disease is not where we were in January of 2020.
There's unmistakable, unimpeachable evidence for a very strong correlation, at least for two mRNA vaccines done independently, that high levels of neutralizing antibodies do correlate with protection. I think extrapolating that understanding into a new variant is a very different framework than establishing the initial proof of principle that indeed such a vaccine can prevent disease. More to come on that, but we have to have a chance to have that dialogue, and I expect FDA, like before, will be ahead of us and provide clear thinking and guidance as to what would be required. I'll defer to Stéphane to talk about the manufacturing piece.
Thanks, Tal. Good afternoon, Michael. Indeed, manufacturing ramp is a very good question. I think there are two parameters to think about. One is that potential strain booster, mRNA-1273.351, is a single dose, of course, as a boost versus 2 dose for the initial vaccination treatment with the current COVID-19 authorized vaccine. That's already 2X right there. The second dimension is the dose. It's unknown at this stage, Tal and Stephen are going to run the clinical study to understand what dose is required. For example, if we were to try three doses, 25, 50, 100 microgram. Those are just examples. No decision has been made yet.
Just as an example, if we ended up to learn in the clinic that because people have been extremely well-protected with the initial vaccination, that 25 micrograms of the strain booster is enough, that's right there an eight times more mass of product that you can do. Sorry, with the same mass of product produced, which is a bottleneck, you can make eight times more doses. As we've said, we are building the capacity for 2021 for 1 billion doses of capacity. We currently have a plan to deliver at least 600 million doses of supply. We're trying as hard as we can to get to 1 billion doses of supply. We've said that next year, because of a ramp, we should be around 1.2 billion doses, assuming 100 micrograms. You can do the math right there.
Yep. Perfect. Peter Marks, Director CBER, made the comment that Tal was referring to. That could be good news for you guys.
Correct. Peter made that comment in a public setting.
Yep
The manufacturing ramp, maybe to add, Michael, is what could be the competitive landscape? As we learned, recombinant protein take very long to develop. We mean very long to adapt to a new strain. There's, I think, an open question on the adenovirus in term of as you keep injecting people the virus, do you mount an immune response to the vaccine that will actually wane efficacy over time? I think mRNA technology, Moderna's mRNA technology, is very well-positioned if that were to be used again. As we've said in our introduction, in our conclusion, we are taking this new product to the clinic because we want to be prudent and to be ready if it is required to boost, especially I would say people at risk of the elderly, but we will figure this out in the coming months. Over. Thanks, Michael.
Thank you much.
Yeah.
Thanks.
Thank you. Our next question comes from the line of Gena Wang from Barclays. Your line is now open.
Thank you for taking my questions. I have two questions regarding animal data. You tested 30 microgram and 100 microgram in non-human primates. That translates to roughly 100 microgram and 300 microgram in human. We did see the fold drop was higher at the higher dose, at the 100 microgram. Just wondering if you can give some explanation on that. Second question is, have you done the third boost in non-human primates to see if that can generate sufficient or improve neutralizing antibody against the new strain?
Thanks, Gena, for the questions. They're very astute. I'll just take the second question first very quickly. The primates are very important for us because they give us a lens into what's going to happen perhaps as we boost humans. Those experiments are experiments we're going to be conducting very quickly in the near term. We haven't done that third dose yet, but we'll be looking to do that, as well as testing the new mRNA-1273.351 booster. On the question of sort of the relative immunogenicity, it's actually expected if you're going to continue to boost with an antigen, for instance, if you're boosting with the wild type virus spike protein as we were with mRNA-1273, that as you give higher in doses, you'd see more and more exaggerated responses, and so higher and higher levels of neutralizing antibody titer.
In that sense, it's not surprising that at the 100 microgram level in a primate, you saw the relative difference between what you were seeing with the wild-type virus versus what you see with the, in this case, the B.1.351 strain, would start to get a little more exaggerated. That's the effect of boosting. I think the important point on those is that as you start to get those really high exaggerated numbers in the primate, as we'd expect to be in humans, the relative importance of that comparison probably goes down in import. When you start talking about neutralizing titers well above 300, maybe even above 500, against even the South African strain, you're starting to get to very, very high levels of neutralizing titers, and it's fine distinctions that you're chasing between them.
I wouldn't over-interpret the difference as you were pointing to it on the 100 microgram versus the 30 microgram in the primate in the paper.
The good news is, first, even at the lower doses, we're seeing neutralization against the pseudovirus for the new spike protein. As we boost with the 1273, we see increasing titers both for the new strain, the emerging strain, and for the original strains. That's expected. There may be a slight decrease in the rate of increase. We might see more increases in boosting in the old strain. That's what you'd expect immunologically.
The last thing I'd say is that these primates, pre-clinical systems, as Tal referenced a moment ago, they become really good systems for us to understand how to develop strain-specific boosters and evolve and hopefully even work with regulators to get approval to update to the vaccine in the time ahead, because we do think they really do start to predict, or hopefully they start to predict our prior experiences and don't require extensive clinical studies. I hope I answered that question. A good catch but nothing there that's unexpected from our side.
Thank you. That's very helpful.
Thank you. Our next question comes from the line of Cory Kasimov from JP Morgan.
Hey, good afternoon, guys. Two questions from me as well. First of all, I'm just curious, for the patients in the phase III study that were vaccinated and still got COVID, have you been able to sequence their virus, and did you find any of these variants there? Secondly, are you interested in potentially multiplexing variants, or do you have any pre-clinical work that suggests that might be effective in the future if it becomes necessary? Thank you.
Cory, let me take those. Thanks for the questions. In phase III, we don't know yet. That work is ongoing, but I still don't have any news to share on the sequence of the breakthrough infections. In terms of multiplexing, I think we're looking at that. For me, putting this B.1.351 is the first one. Of course, we'll do a whole bunch of pre-clinical evaluations to see the utility of multiplexing versus more simply just a heterologous prime boost to, over time, close any immunological gaps that a monomeric vaccine may engender. These are good questions, but they will require more data that we don't yet have. Over.
Okay, appreciate it. Thank you.
Thank you. Our next question comes from the line of Geoff Meacham from Bank of America. Your line is now open.
Hey, guys. This is Alec on for Geoff. Thanks for taking our questions. When you're thinking about the boosting study, would you expect your ability to boost to be stronger in individuals receiving a non-mRNA based vaccine first? What, in your mind, could limit an individual's ability to receive a booster? Would this be maybe hypersensitivity or vaccine-neutralizing antibodies? When you look at the structure of the spike protein, are there any other regions, I know you mentioned E484K, but any other regions where mutations that we maybe haven't seen yet could uniquely detract from the efficacy of mRNA-1273? Or do you think it's really more of a cumulative effect of maybe not 10, but maybe 15 or 20 mutations across the spike protein?
Let me take it. Alec, thanks for the question. Let me take the first one. I'll let Stephen comment on the structural one. I don't see necessarily a difference in the ability to boost whether somebody got a primary series of an adenovector or a recombinant protein for that matter, or an mRNA. I think whatever specific immunity you have, which is encompassed in memory B cells, et cetera, that's the basis upon which you're boosting. I think we do have data from our CMV vaccine showing that when you come in with a third dose, you get a further very nice increase in titers. Since the immune system can't see the LNP specifically, our vaccine platform has the inherent advantage that it should be able to boost irrespective of how you have become immune.
By the way, that should also apply to boosting people who have been infected previously with a wild-type virus, whether they were symptomatic or not from that infection. Certainly, we know on the safety side that even if you had been infected, we had 600 of those individuals in our 3,000 phase III trial, then there's no adverse safety. There's no problem in giving somebody from a safety perspective another boost, and as evidenced by the fact that we had people with high levels of antibodies because of infection, and they were fine. Along those veins, I see no reason to have any contraindication for a boost that is different in the third dose than it would be in the second dose.
The only contraindication to date that we have for boosting somebody, giving them a second dose, is if they had true anaphylaxis to the first, and those are really, really rare events. If you look at the MMWR report just last week, it seems like our event rate is not clear that it's even above background rates of the rates you see just with flu vaccines. I think I feel very confident on that. I'll let Stephen talk to the structural elements here. Yeah
Yeah, thank you for the question. I think the short answer is yes, it's probably a totality of many acquired mutations that are going to be required. I remind you that the difference between a vaccine, especially one with a full spike protein like ours, is that you get a really broad polyclonal response against all parts of the protein. That ensures that there's many different places you can develop neutralizing immunity too. That's been our experience, and that's the advantage of the full-length spike protein. What that means is that single mutations or maybe small handfuls are unlikely to completely evade. I think even to this point now where we're looking at the B.1.351 strain and seeing a large number of mutations present, we're still seeing that we have good neutralizing activity, at least in these in vitro assays.
That's encouraging. It's definitely true that in a few mutations that you pointed to do start to create specific concern because they seem to be individually driving some of the difference. I think the E484K variant, as well as N501Y and 417, are things that we're all going to be watching as a public health community very closely as those play out across the strains. I think the good news is we're still in good shape. It does require a lot of mutations in order to create a gap. As of right now, we don't think we have a gap with the vaccines using our spike protein. Frankly, the same may be true for others.
It does point to a place, particularly as you were referencing some of those mutations that are showing up in the South African strain, where you want to get ahead of it, and you want to start developing countermeasures in case they're necessary in the future. Certainly right now it doesn't feel like they are.
Okay, great. Thank you.
Thank you. Our next question comes from the line of Hartaj Singh from Oppenheimer and Company. Your line is now open.
Great. Thank you. I just got two quick questions. One is as there's debate between extending the duration between the first and the second vaccine of the two mRNA vaccines that are approved, any thoughts on what this new data gives you any additional insights there or how to go about proceeding going forward in that context? The other is, as we've seen more mutants and these variants, there's another couple of adenovirus vaccines that should be getting on the market soon, AstraZeneca, Johnson & Johnson. I don't expect you to comment on them, but could you give any insight as to how these new mutant variations could make sort of drug development more complicated? Will it? You don't think so? Just any thoughts there. Thank you for the questions.
Hi, Hartaj, it's Tal. Let me start with the first one. Look, I think that our data are clear and unimpeachable and only obtained with a four-week difference. On trial, it was three to five weeks. You want to extend it to six, I get it. I think the more people extend the window between the first and the second dose, the more we're operating in the land of conjectures as opposed to hard data. There's good immunological arguments to be made of why boosting two or three months later immunologically still should be as robust. There's also a concern I have personally that during that period, people are sub-optimally protected. It's totally within the jurisdiction of any given regulatory or healthcare framework to make that decision for their population. Our job is to generate the data.
The data to date that we have point to a four-week window between our vaccines is the one that's been studied. In the future, I think we'll look for opportunities to study and provide data for wider windows. By and large, I think this is a function in the immediate future because of limited supply. You're asking me a question about do mutants make the future of development more difficult every other vaccine that will be out there. Actually, in a roundabout way, quite the opposite because there's been a wonderful convergence of science here.
I think the science for understanding that the spike protein is the antigen of interest has been so robust that it really, if you look back at 2020, if there was one unifying theme to all these vaccines, the protein that they all encode, either ex vivo or in our own body is pretty much similar, if not even identical. I think many of these vaccines, as it relates to the specificity of the immune response, will be very similar. In a way that makes it quite straightforward to then conduct experiments that either have to do with heterologous prime boost with a different protein or a different platform. We've developed assays, and we'll continue to develop assays and look at specific neutralization against these different strains, as you can see from today's preprint.
I think in between that concordance of what the community we're reaching for, what these vaccine encodes, and the availability of the assay as a vaccine developer, they actually make, I think our life more straightforward.
Yeah. Maybe, Hartaj.
Thank you, Tal.
If I just add one thing to that, which is just to draw a link between the two comments, I think really. The virus is going to evolve as long as it's infecting. The key thing we need to do is stop it from infecting. We need to break that transmission cycle. We need to stop those infections from lasting a very long time. I think when you get to the questions of sort of the dosing regimen, where I think we have the highest degree of confidence is obviously the dose that we studied for which there's data which shows that two doses approximately 28 days apart of 100 micrograms of our vaccine stops that disease. We hope is ultimately therefore suppressing transmission and infection.
Once we start in a world where we're say only giving one dose and then waiting a long period of time, we start to, as Tal said, start to experiment with that and create opportunities for the virus to continue to evolve. Now, we don't know whether that's an issue or not with missing a dose, but it doesn't seem prudent right now to be providing that kind of a fertile ground for those things to happen as opposed to doing everything we can to continue to follow public health guidelines, do everything we can to vaccinate as supported by the data, and ultimately try and beat this thing back for good.
Great. Thank you all. Thanks for the comments.
Thank you. At this time, I'm showing no further questions. I would like to turn the call back over to Stéphane Bancel for closing remarks.
Well, thank you very much, everybody, for jumping quickly on the call. I hope those data and the answers to the questions were helpful. We wish you a nice evening, and please, everybody, stay safe. Bye.
Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.