Good morning, and welcome to the 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 of Investor Relations at Moderna.
Thank you, operator. Good morning, everyone, and welcome to Moderna's conference call to discuss the interim Phase 1 data for mRNA-twelve seventy three, our vaccine against the novel coronavirus. You can access the press release issued this morning as well as the slides that we'll be reviewing by going to the Investors section of our website. Speaking on today's call are Stephane Bancel, our Chief Executive Officer Sal Zacks, our Chief Medical Officer Stephen Hogue, our President and Lawrence Kim, our Chief Financial Officer. Before we begin, please note that this conference call will include forward looking statements.
Please see Slide 2 of the SEC's earnings presentation and our SEC. Before we begin, please note that this conference call will include forward looking statements. Please note that this
conference call will include forward looking statements. Please note that
these are 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. With that, I will now turn the call over to Stephane.
Thank you, Lavina. Good morning or good afternoon, everyone, and thank you for joining our call. 1 hour ago, we reported positive interim Phase I data for mRNA-twelve seventy three, our development candidate against a novel coronavirus, as well as mouse challenge data. We believe that these two data sets will present an important step forward towards the development of a vaccine candidate against SARS CoV-two. We are encouraged by this interim data and they confirm our strategy to develop mRNA-twelve seventy three as fast as safely possible.
Let me briefly summarize the key takeaways from this morning press release before turning over to Tal to walk you through the supply data. After 2 doses, a prime and a boost, all participants across the 25 microgram and the 100 microgram dose cohort furoconverted with binding antibodies levels at or above levels seen in combatant sera, which is the level of antibody in human blood who have been infected by SARS CoV-two and recovered from SARS CoV-two disease. MRNA-twelve seventy three elicited neutralizing antibody type L levels in all eight initial participants across the 25 microgram and the 100 microgram dose cohort reaching or exceeding levels generally seen in combined sera. KAMALIN-twelve seventy three was generally well tolerated. We also announced between 25 preclinical mouse challenge study and of a successful vaccine candidate was run 1 for several animal challenge models.
This consists of vaccination of animals with the same dose regimen that's used in clinic, in this case, a prime and a boost. These are placebo controlled studies. After vaccination, the animals are exposed to high levels of a SARS CoV-two virus in order to mimic a natural infection. In this mass challenge study, we showed that mRNA-twelve seventy three provided full protection to 100% of the mice against viral replication in the lungs of the mice. The totality of the data released today, the interim Phase I data and the preclinical mass challenge model give us confidence that mRNA-twelve seventy three has a high probability to provide protection from COVID-nineteen disease in humans.
We'll know how much protection from the efficacy performance of a Phase 3 study. Currently, our plan is to start the Phase 3 study in July 2020. We could not be happier about these interim data. On Slide 4, we received a progression of mRNA-twelve seventy three program. The sequence of virus was made available to the world only 4 months ago.
It is humbling to already have this positive data and to be finalizing as we speak our Phase III protocol will be M2 start dosing in July. With this, let me now turn to Thad.
Thank you, Stephane, and good morning, everybody. Before I review the interim data, let me start with a reminder of the Phase I trial design, which as you know, was run is being run by the NIH. The study initially enrolled a total of 45 participants between the ages of 18 to 55 into 3 dose cohorts, 15 participants each in the 25, 100 and 250 microgram dose levels. The study was also recently expanded to include 2 additional age cohorts, 55 to 70 year olds and 71 and above. Enrollment into these cohorts is ongoing.
The vaccination regimen is a prime boost regimen, a month apart, totaling 2 vaccinations per participant. The first injection was given at day 1 and the second vaccination was given at day 29. The primary endpoints of the trial are safety and reactogenicity and tolerability and immunogenicity at day 57, although immunogenicity or titer levels were evaluated more frequently starting at day 15, day 29, day 36 and day 43. Today, we're sharing the top line interim analysis from the trial, safety and immunogenicity data from the 25 and 100 microgram dose levels are available after 2 vaccinations and safety and immunogenicity data for 1 vaccination at day 29 for the 2 50 microgram dose level. So let me start with the safety and tolerability profile.
Overall, mRNA-twelve seventy three was generally safe and well tolerated with a safety profile that's consistent with what we've seen in prior Moderna infectious disease vaccines in clinical studies. One incidence of a Grade 3 adverse events of erythema or redness around the injection site was reported in the 100 microgram dose cohort. But the most notable adverse events were 3 participants with grade 3 systemic grade 3 symptoms at the 2 50 microgram level that followed the 2nd vaccination at that dose. We did not see any of these after the first dose, and so I believe these flu like symptoms are really an indirect measure of a strong immune response. That said, all adverse events have been transient and self resolving.
No Grade 4 adverse events nor serious adverse events have been reported. Now let me talk about the immunogenicity. Similar to our other infectious disease vaccines, we observed a dose dependent increase in titer levels, both across dose levels and between the PRIME and BOOST injections within a dose level. All participants in the 18 to 55 age cohort across all dose levels seroconverted by day 15 the single vaccination, such that we could see antibodies in their blood. For the 25 microgram dose at day 43 or 2 weeks after the second vaccination, the level of these binding antibodies that the vaccine generated reached levels seen in convalescent serum from people who have recovered from COVID-nineteen disease.
In fact, if you look closely, they're already above the median or the halfway point of the levels induced by or seen in convalescent serum. At the 100 microgram dose, also at day 43 or 2 weeks after the second vaccination, the level of binding antibodies now significantly exceeded the level seen in convalescent serum. I should say that convalescent serum used to benchmark these results were obtained within a month or 2 after the disease. Neutralizing antibody data are available only for the first 4 participants in each of the 25 and 100 microgram dose cohorts. Consistent with the binding antibody titers, mRNA-twelve seventy three vaccination elicited neutralizing titers in all eight participants as measured by plaque reduction neutralization assays against live SARS CoV-two virus.
The levels of these neutralizing titers at day 43 were at or above levels generally seen in convalescent syrup. Now I should say this is a difficult assay to perform for a live dangerous virus, and we're really indebted to NIAID and its academic partners for setting these up and running them. The important element here is that in general, neutralization correlates with total binding antibodies once you're above a certain threshold. So the relevance of these results for us is not just the direct confirmation that in these first eight subjects indeed we see neutralizing activity, but they really allow us to extrapolate what we expect to be achieving in all 45 subjects. Let me touch on the preclinical results from the viral challenge in mice that was conducted also in collaboration with NIAID and the institute's academic partners.
The results from the challenge study in mice show that mRNA-twelve seventy three completely prevented viral replication in the lungs of animals challenged with SARS CoV-two. Importantly, the neutralizing titers that we see in Phase I clinical trial participants at the 25 and 100 microgram dose levels are consistent with the titers that were protective in the mouse challenge model. So since early this year and in rapid succession, we, along with our collaborators at the NIH wind from selecting the antigen for mRNA-twelve seventy 3 on January 13 to vaccinating the 1st participant on March 16, a mere 63 days later. The FDA has given us clearance to proceed to Phase II on May 6, and the top line interim results today boost our confidence to move into Phase II shortly. NIAD plans to have these and full data from the Phase I trial in the public domain prior to the start of the Phase III, which we now anticipate will start in July of this year.
As mentioned previously, we will start the Phase II study in this quarter, and it will be evaluating the safety reactogenicity and immunogenicity of 2 vaccination, the PRIME and BOOST regimen of mRNA-twelve seventy three at 50 and 100 microgram. Based on the data that I've described, the study protocol is being amended and will no longer include a 2 50 microgram dose R. Since we're already potentially there at the lowest dose of 25 microgram, there really is no need to go to 10x that level. And especially when in the context of a pandemic, we expect demand to far outstrip supply. And the lower the dose, the more people we expect to be able to protect.
We intend to enroll 600 participants into age cohorts, 300 participants in adults aged 18 to 55 year old and 300 in older adults aged older than 55 year olds. Finalization of the Phase III protocol is ongoing, and we expect to begin the trial, as I said, in July. We'll come back and update once we have complete alignment on that protocol between us, our collaborators at the NIH and of course, the FDA. Let me now turn it over to Stephane for closing remarks.
Thanks, Utsal. We are excited and humbled by the opportunity to bring forward the vaccine against SARS CoV-two. The development of mRNA-twelve seventy three potentially accelerates our overall mission to develop a new class of medicines for patients. I would like to thank the entire Moderna team who have been working 7 days a week literally for 4 months now and the NIA team who helped us get to this place and all of our partners and suppliers. I would like to especially thank the many people who participate in our clinical studies, including patients, healthy volunteers, the physicians and nurses who work tirelessly to conduct this important clinical study in a very complicated environment with the pandemic going on.
With that, we're now happy to take your questions.
Our first question comes from the line of Matthew Harrison from Morgan Stanley. Your line is now open.
Good morning, everybody. Thanks for sharing these data and thanks for taking the question. I guess, two parts from me. First, if you're willing, could you provide us maybe a little bit more specificity around the specific titers you were seeing, whether that's what the titers you were getting with the vaccine or maybe specifically what the titers are that you're thinking about when you compare against convalescent sera? And then second, can you maybe talk a little bit more in detail about the longitudinal results here?
Were you seeing clear increase in titers after the boost? And how do you think about the need for a boost versus being able to use one vaccination? Thanks.
Thanks, Matthew. This is Todd. Let me take these two questions. I don't think we're being specific yet about the actual titers. I think we are going to defer to NIDA and its academic partners to publish these results.
And I think, of course, the relevant part here is not the absolute level of the titers, but actually how they correlate across between what we see the convalescent serum and any data in animal models. I think the other point that is worth noting is that these are still relatively early days, both for characterizing and standardizing clinical assays as well as for characterizing and standardizing what one sees in convalescent serum. So many people in many groups across the world are busy working at this. I think there's a concerted effort by NIAID that we are supportive and part of to standardize and qualify these assays. And I think all of that should emerge in the coming weeks months.
So I don't think it'd be appropriate to just give a number out there because what's relevant is not the number. It's our confidence in context of what that number means in terms of standardization and assays. In terms of longitude no results, thank you for that question. Indeed, as one would you can clearly see, that are real and there is a clear dose response among the doses. When you come in with a boost, that's where you really see an additional significant increase in those titers.
The early data that we have for neutralizing activity, these are the first four in each of the dose that we have. And so we focused obviously on the endgame here, which is 2 weeks after the boost. And at that level, if you look at what you get with the 25, as I said, you're already above the median and at the 100, there's no overlap in the confidence interval. If your question is what do you get after just one dose, I think you're starting to get antibodies at a dose of 100. You're starting to get to the level that you can see in convalescent serum.
But I think we anticipate going forward, at least at the doses that we're talking about today, with a PRIME boost regimen into Phase III.
Thank you. Our next question comes from the line of Salveen Richter from Goldman Sachs. Your line is now open.
Good morning. Nice to see this data. So two questions for me. How do you get confidence here as to what is protective for the binding and neutralizing antibodies levels seen in covalent serum? And then secondly, based on everything you've seen to date, what do you see as the risks on the forward as you look to the Phase II and Phase III?
Thank you, Sylvain. So what is how do we get confidence as to what is protective? I think it is a measure of really two elements. One is understanding the how these correlate with convalescent serum. And I think while these data give us great confidence that we've got now the right dose range for Phase III, Just being at convalescent sera could be enough.
We know or at least we believe, and I think most experts would agree that once you've had disease, at least as we know it in the past 5 months, with relatively short follow-up, but once you've had disease, we've not seen really cases described with getting disease again. And I suspect we would have seen those descriptions if that were a real problem. So we anticipate, I think, like most experts, that having disease is protective and therefore, having antibodies by extrapolation is likely protective. And so if you get to the level of people who've had disease, that should be enough. The other point that I think is going to give us confidence is the various animal models.
We're describing just the first one here today. I should qualify and say that the virus here is actually a virus that had been slightly altered so that it binds to the mouse ACE2 receptor. But it's a valid model in the sense that you see the full gamut of replication in the organs you care about, which in this case is lung. And to the degree that you can correlate generating antibodies to the same level and consistent with that, you then challenge animals and they do not get replication of the virus in their lungs, I think that all increases our confidence. I think what you'll see in the weeks months ahead is more data, both in terms of animal models and in terms of the validity and standardization of these assays that would allow this confidence to continue to increase.
Ultimately, we're going to have to pick a dose for Phase III. And as I said, we believe that it's going to be somewhere between 25 100. I think whenever you're a vaccine developer, you always want to make sure that you've got a margin and that you've got higher immune response than what you absolutely need because you expect to see some variability in the population there inevitably always is. But here, we're going to have a very difficult math because the higher the dose, the fewer people were going to be able to immunize. So I hope I've answered that.
The risks going forward, well, it's a good question. I think the biggest risk as I see it is actually in being able to see enough cases. So what do I mean by that? The success of the Phase III trial depends on only 3 factors. Number 1, can we or 2 factors.
Can you get enough cases in the placebo arm such that in the vaccinated arms, if you avoid those cases, you can actually speak to it statistically. And that's a function of how good is the vaccine and how protective is it to immunize against this spike protein. I think the totality of science tells us that this is the right antigen and that we should be protective. The challenge for me then shifts to how do I ensure I have enough cases to be able to demonstrate that as quick as possible. And I think that's a function of being able to conduct a Phase III trial that's large enough, but more importantly, that actually goes and vaccinates people who are then at risk for getting disease in the ensuing months.
Because if I vaccinate a whole bunch of people, it doesn't matter how many, if there is no circulating virus in the places that I chose to vaccinate, then we won't have the cases, and it will be a long time before we know. So I think really, as I look forward, I think this these data today take off the table the risk of not being immunogenic or the risk of the antibody type being wrong. No, it works and it's you see demonstration of neutralizing activity. So I think the major risk as I look ahead is just operationally being able to demonstrate clearly that there's safety efficacy in a large randomized trial. So we'll get there.
It's just it's really a question of time.
Great. Thank you.
Thank you. Our next question comes from the line of Cory Kasimov from JPMorgan. Your line is now open.
Hey, good morning, guys, and really great to see this latest very encouraging step. So two questions from me as well. First, can you provide additional details around the systemic Grade 3 safety events that we're seeing at the 250 dose? And was there any evidence of this in lower dose cohorts even sub Grade 3? And then secondly, how much do you want to see to select for that go forward dose in Phase 3?
Will this be coming from will this information come from Phase 1 since you're now including the 50 microgram dose? Or is it going to be based on preliminary Phase 2 data as well? I guess, what else is left to finalize that decision? Thank you.
Hi, Cory, it's Saul. Thanks for the questions. The systemic Grade 3 were sort of your typical solicited adverse events. I think it was a case of fever. We had some muscle pains, a headache, fatigue.
Among those symptoms is what you see. They were all gone by the next day, and they're sort of typical solicited adverse reactions for vaccines. We didn't see anything that we didn't expect, frankly. You do see some grade 1s and 2s. We haven't reported the exact numbers.
You'll see that all come out in the table, but nothing surprising and nothing that we believe would prevent 1 from fully developing and vaccine. What additional data do we expect prior to Phase III? I think it's going to be the totality of the data from the Phase I. It's going to be the emerging safety, the very initial safety profile from Phase II to just confirm safety profile, and I think that's it. We're talking a matter really weeks before we hope to be launching the Phase 3.
There will continuously be data coming out of this Phase I. And of course, we'll do our best to accelerate any learnings we have from the emerging Phase II. I also think it's important to continuously look at the assays, their performance and continuing to characterize and standardize what convalescent serum is that we're all comfortable with the choices that we're making here.
Okay, great. Thank you and good luck with the ongoing work.
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. One question from me. In the Phase 1 study for CMV, neutralizing antibody titers were around 10 to 40 times that of seropositive patients.
And for the COVID-nineteen Phase 1, it seems to be much lower. So could you provide some color around this and what it means in terms of conferring protection, particularly since the patient's staging an active immune response may yield higher titers than what can be assayed in convalescent plasma?
Thanks, Alec. Let me try and answer that. I think the salient comparator, as we look at the data, is that, at the 100 microgram after the boost, we far exceed what you see in convalescent serum. The confidence intervals do not overlap. I think at the 25 micrograms, as I described, we're already at that level.
I think the relevance for me here is the convalescent serum. We're still only with a few months of history from this disease. So we're talking about convalescent serum that were obtained at 1 to 2 months after disease, which is sort of their peak. So I think it's an appropriate benchmark. I think CMV is a different story because CMV, you're talking about a chronic latent infection and these are antibodies that people live with them constantly.
So I think you're comparing apples to oranges here. Your second question, I think, is the one that everybody is sort of wrestling with, which is, okay, what level are you shooting for and what is protective? And as I said, I think that determination is going to be a function of a full quantitation and standardization of the assays in convalescent serum and seeing more data as it relates to the preclinical models. What do I mean by that? Well, if you look at this mouse study that we described, so after a prime and a boost at a dose that completely protects the animal, we see neutralizing activity that is the same as what we've described here after a prime and a boost.
But one of the salient points is that at that dose in the mouse, after just the prime, the mouse was already protected. And so I think we're getting a comfortable margin here to know that we're at the right level that one needs to be in to protect people. I think the question is going to be, okay, how much higher above that do you want to have a margin of safety.
Great. Thanks and congrats on the progress.
Thank you, Alex.
Thank you. Our next question comes from the line of Hartaj Singh from Oppenheimer. Your line is now open.
Great. Thank you for the questions and all the progress. Really kudos there, Tal and Stephane. Just taking a step back, one of the things that I think some investors are struggling with is how quickly Moderna has moved. I think Moderna has been pretty transparent about how they're moving you're moving quickly.
Stephane, if you can take a step back and maybe talk a little bit about how the platform, all the manufacturing investments you've made, the persona there have that you have have gotten you to a point where you could essentially do in 1 year that normally takes 5, 10 years? Of course, it's a pandemic and regulatory authorities are being more helpful. And then secondly, how this new sort of approach using this platform approach with these investments and all the preclinical work you've done across all the modalities could also help in different modalities of Moderna? Thank you for the question.
If I think about kind of how did we get there, how could we go from the sequence in January to having the interim Phase I data in May, green light from the FDA in May and saying that we believe our current path is to start the pivotal Phase III in July. I think there are maybe 5 things that come to mind. The first one is, of course, the platform. Messenger RNA being an information molecule, we could not have done that with other technology like neurocombinant, like attenuated diarase technology or others. The fact that we are really dealing with an information platform that we can work directly from the genetic information of a virus and literally drop that into our vaccine cassette from the sequence of a virus, I think, is really a unique feature that creates extraordinary leverage and network effect.
The second piece for me is that this was not our first vaccine. I think there has been a lot of question we have asked ourselves, a lot of scientific unknown, process unknown during manufacturing that I think one of the next where we got lucky, but we were prepared for it is the progress we have done 9 vaccine in clinical trial before that. And so we have been actually doing vaccines first in human for the H10 flu was December 2015. That's more than 4 years ago before we started 1273. And as you can imagine, we've been working a couple of years on the science and CMC readiness for manufacturing on the vaccine.
And we always keep on learning. We keep on working. The teams in the science develop new lipids, more potent mRNA constructs. And on the process side, Ron and his team keep on inventing new processes, making the process better yield more potent mRNA. And as you know, we will never stop.
We still believe we're in the early days of mRNA science. We still believe we have a lot to learn and we still believe we are the best company positioned in this space to keep growing and keep learning and keep making better and better products. The first piece that enabled us to move very quickly is that we were prepared because we had been working with NIAID, Doctor. Tony Fauci Department on the Middle East respiratory syndrome, which is another corona, which as you can imagine in those few hours when we saw the sequence of SARS CoV-two and the team had to really kind of analyze and understand which protein to pick, how to go at developing the vaccine. Those are, of course, fundamental decisions because if you get this wrong, then the vaccine is not going to work.
We were, of course, massively informed by all the work that has been done by our teams and NIAID over the last couple of years. So that's also very important. I think it might have been a very different situation if you had never worked on the coronavirus before. The 4th one is Norwood. As I've said many times, and I won't stop repeating because I believe it is a competitive strategic advantage of a company, having our own manufacturing facility from raw materials to shipping vials to clinical trials, having our own teams who understand the process, who can make judgment about decisions is really fundamental.
If we had had contract manufacturers, we could never have moved so fast because one would have had to call 4, 5 CMOs around the world and the chance they all had an empty slot for us waiting was, of course, very thin. And so being in Norwood with our own team, own equipment, own facility allowed us to tell the team this is very important. This one needs to move through the system much faster than usual and people knew the importance of this and as this virus was spreading, our determination just grew stronger with the days. And the last thing for me is the team. We have been very fortunate over the years to assemble a team across the company and not talking only about the executive of the entire company.
A team of scientists, engineers, clinicians, women and men, who I think believe in the mission of a company. This is once in a lifetime opportunity that we have in our carrier to be able to collectively together figure out how to build a new technology that could help so many people. And I think today, the company is 9 years old. It's just getting to a place where all those pieces are coming together. So it's more of a network effect of all the investments we've made, of the science, of what we have done before that got us prepared for this moment.
Now many of us wished we already had a big manufacturing plant where we could be able to make 20,000,000 or 50,000,000 doses in the 1st month from January, that would have been amazing. Unfortunately, this caught us a bit too early in company's history. But this is what I think has made this opportunity unique. And to your second question, I think the read across the platform is going to be extremely valuable, both internally in how we think about study design, how we think about translating products from preclinical to clinical. There are a lot of learnings.
As you can imagine, this is a very special moment for the company. And if you look at it at a more global basis,
assuming we
start in July as planned in our Phase III for 1273, we have not yet shared the size of the study because we have to discuss and align with the FDA as everybody can appreciate. But this is going to be a large study because as Tal said, the biggest risk of the study is the attack rate and how quickly are we going to get enough people infected to get to efficacy data. Well, one of the ways to solve for that is you just have a lot of people enrolled in the study because I just smiled. And so that is going to enable us to get a very big safety that are going to benefit all the vaccine programs. And then the question, because so far if you look at it, we have said we are in 18 to 55 years old, 5570, 71 and above.
There are still a lot of subpopulation that we have not talked about yet that might be accelerated through a Phase III study. And this would be, of course, extremely valuable across the platform. So I think I hope this answers both of your questions.
Great. Thank you, Stefan.
Thank you. Our next question comes from the line of Yasmeen Rahimi from Roth Capital Partners.
Congrats team on the amazing progress and thank you for your tremendous dedication for working on this incredibly urgent matter. Two questions for you. The first question is, can you share with us what was the median age of the cohort that just read out? Did you look at age dependency on neutralizing antibodies and immuno genicity data? And maybe some color on reasons for moving forward with the micro 50 microgram dose group in the new cohorts of the Phase I study?
And then I have a follow-up. And thank you for taking my question.
Hi, Yasmeen. Thanks for the question. It's Paul. I don't have data yet on the median age or any of those other analyses. These, I think are things that we'll be looking at.
In due course, I think the salient point for age is going to be very deliberately testing the immunogenicity in older and elderly adults, which is part of the Phase I that has been hit by the NIH. You asked about reasons for moving forward in the 50. I think as we described, we think the Phase III dose is going to be somewhere between 25 100. The question is how much of a margin do you want above already exceeding the median of convalescent serum. And with that in mind, the Phase II is really meant to expand the safety database and enable us to start the Phase III.
So that's why we have amended the Phase II instead of 102.50 to be 150. There's no reason to go higher. But it is important to continuously expand our understanding both of safety, tolerability and eventually immunogenicity of the dose range that we think is the relevant one for Phase III and eventual deployment.
And then another question is, can you shed some light in regards to maybe the level of viral load reduction you saw
in the
challenge model or to an extent to the T cell responses in the mouse model? And thank you again for taking our questions.
Yes. So when you look in the mouse models, I think the relevant organ where you want to see decrease in viral replication is the lungs, right? That's where the virus causes its pathology. And there we see complete elimination of viral replication at the dose that we described that has the same level of neutralizing antibodies. Don't have any T cell data yet to share.
I would make 2 observations. 1, whenever we look across our platform, whether it's preclinical or in clinical trials, we do see strong T cell activity, and you would expect that based on the fundamental scientific principles of how an mRNA vaccine works because it teaches the body, our body's own cells to make the protein from within the cell and that's how you stimulate T cell responses as well. It is not a recombinant protein. The other element is when you see such a strong, what we call an amnestic response with a boost that is your you mount an immune response faster and stronger when you boost, that tells you that you've got T cell health. That's how the immune system works.
You have a collaboration between T cells and B cells to stimulate the second response to happen quicker. So I think based on places where we have other data, based on the fundamental science and based on the magnitude and kinetics of the immune response we see here, I have little doubt that we are eliciting T cells. Measuring T cells is a tricky thing, especially in clinical trials and often is not very useful as a way to either predict immunity or find a correlate of protection. And so we're really focusing here on the antibody assays as the relevant measures of what we're achieving.
Thank you, again.
Thank you for the questions, Yasmeen.
Thank you. Our next question comes from the line of Alan Carr from Needham and Company. Your line is now open.
Hi, thanks for taking my questions and congratulations on your progress. Tom, can you go into a little more detail about the target group to be enrolled in Phase II and Phase III? You mentioned at risk and Have you and government agencies come to any conclusions on which groups that maybe it's by age? And then also can you give us an update on manufacturing capacity? Do you think you'll be entering into more production agreements?
And then where do you what sort of production capacity do you think you'll have towards the end of the year? Thanks.
Thanks, Alan. Let me take the first question and then I'll defer to Stephane or Juan to take the second one. The Phase II is still subjects that we anticipate not being at risk, at least as far as the local epidemiology of the centers where we're going, although that's, of course, very hard to predict these days in the U. S. And it will have both old adults and older adults.
The expectation for the Phase III is that we will enroll people at risk. We will enroll people at risk both based on their age, based on their comorbidities and based on their, occupations and other sort of parameters that put people at risk. I think the goal here is to have a fairly large trial that will look across different ways of how one defines that risk and leave some of that decision making to the local investigators who understand their local population better. But the exact discussion on what that would look like from a protocol perspective and then in real life, I is still ongoing between us and the NIH and FDA. I think FDA has an expectation that the Phase III trial will indeed include people at risk and will include a population that would be representative of the population where we ultimately expect to apply this vaccine.
And of course, that should include everybody.
Thanks, Tal. So, Stefan, let me maybe take a stab at the manufacturing capacity question and whatever I miss, I'm sure Ron will add to it. As we've shared in the past, we are currently scaling up our manufacturing capacity as fast as we can. Partnership with Lonza help us to be able, assuming a 50 microgram dose, to potentially get to 1,000,000,000 dose per year. And as you understand, we are basically expanding from the Norwood plant, which was our only manufacturing capacity before the Lonza partnership to enabling GMP suite at Lonza with new CapEx, new teams and so on.
And so the way to think about it is a ramp. It's a ramp between Norwood, which was not kind of fully staffed and without the process of a larger scale that we think we can get to, that the teams are working on as we speak. And so the way to really think about it, I think, is that in terms of monthly output. And so what we've said in the past is the monthly output is going to start, obviously, making millions of vials doses sorry per month going into tens of 1,000,000 of doses per month and just keep ramping that number until we get to around €1,000,000,000 annual run rate on a monthly basis. And that's how you want to think about it.
So it will take several quarters obviously to get there, but the team is already working really hard both in Norwood. As we said, one is transferring the process to the Lonsai and New Hampshire plant in the U. S. As a first step with a goal to start making product there in July. So we'll give you more updates as time goes by.
There are so many moving pieces right now. Just be assured that Juan and his team are highly aware that every additional million doses will make a big difference in many people's lives. And so we'll make sure while not compromising quality, because of the product that we're injecting in people, so quality is priority number 1. While not compromising quality, the team knows the role they have to play to protect a lot of people. So we get as much as we can out of our system.
Thanks. One last one. Tal, with respect to animal models, what do you think is is there a best animal model for respiratory infections? You've used a mouse one here, but what are your thoughts on that? Is there might we get you mentioned there's more animal models in progress?
Sure.
Paul, do you want to take that? Please go ahead, Stephen. Thanks.
Yes. So Alan, thanks for the question. I think the answer is always virus specific. And because this is such a new virus, we just don't know. We don't have enough information to say which particular models are most predictive.
There are several under development. Obviously, you start in rodents and there are also primate models that have been put in place. Our intention is to test in a pretty broad set of models, so eventually across most of them, just to confirm the activity of the vaccine and its potential to generate protective immunity in those models. But I don't think we have a
clear sense of which one
is going to be more or less predictive. Obviously, the most encouraging thing to find will be that across any model across primate and rodent models, that we're able to show this sort of protective immunity that we showed today or that we announced today in just the rodent.
Thanks.
Thank you. Our next question comes from the line of George Farmer from BMO Capital Markets. Your line is now open.
Hi, good morning. Thanks for taking my questions. I wanted to talk about the difference between immunogenicity and neutralizing antibodies. I guess the 2 aren't necessarily the same. At what point do you get comfortable with whether immunogenicity is actually predictive of the generation of neutralizing antibodies?
Are we there yet? And is it necessary to keep on doing these kinds of high risk assays on patients to determine such?
George, it's Tal. Thank you. The short answer is yes, I think we're there. In other words, there is in people who are looking at it, there's a clear, linear correlation between total binding antibodies and neutralizing activities. I think that's true once you cross a threshold.
We're clearly here at or beyond that threshold with the data that we've described. I think the one caveat is that these assays need a certain level of qualification and standardization before we can just use binding as the correlate. So there are several assay formats that are being developed. There's the neutralization assay that's PRINT, which is looking at reduction of plaques. That is the one that's most complicated but is the gold standard because it's a live virus and it's the full viral life cycle.
There is, on the other end of the spectrum, just measuring antibodies, which is what we are describing here. In the middle, there's something called a pseudo neutralization assay, which is where you develop a pseudo virus, one that has all the components necessary to bind and get into a cell but don't have a replication cycle and are not dangerous to work with, and you can adapt these to high throughput. There's work ongoing by many labs to correlate all of these assays so that the simplest one and the one that's the most high throughput can be put to use to develop a correlate of protection, a surrogate of protection, a way to actually be able say, yes, if you achieve this, then you should be protected and make vaccine development ultimately easier. So I think to summarize my question, I think we're there in terms of the confidence we have that the antibodies we're eliciting are the right ones. I think there's work to be done to standardize these correlations so that the simpler assays can be adopted for more high throughput use.
Great.
And then a couple more. Recognizing the urgency of developing the vaccine, what is the rationale for layering Phase 2 and Phase 3 so close together? I mean, do you need don't you need to get some sufficient information out of the Phase II trial before comfortably starting the Phase III? And then also, how do these how does the potency of this vaccine compare to, what you've seen with the CMV vaccine?
Yes. So two good questions. I think the Phase II was envisioned with 2 goals in mind. Number 1 was to substantiate the safety, at least in the initial month or 2, of what we are proposing to take into Phase III in a larger number than just 15 subjects per dose level before you go vaccinate 1,000. So I think that's a reasonable expectation from the agency and that was always the number one driver to do this Phase 2.
Even if the time line is abridged, it is still some information that's relevant, that I think makes us all more comfortable. I think the second reason to do the Phase II is that it will allow us to substantiate and better quantify the immune response. And in a world where our understanding of the immune response continues to evolve as to what is relevant and how much is relevant, There's a potential down the road that the Phase II with 100 subjects now per arm with very tight error bars will give us confidence as to the level of antibodies that is then relevant as measured both by standardized assays on standardized convalescent serum and animal models that the scientific world is developing and will feel is predictive of what's likely to happen in people. And so the Phase II continues to increase our data. Even as the Phase III is launching and ongoing, I think the Phase II will generate data that is relevant for continuously increasing understanding of what it is we're trying to achieve here.
And relative to CMV vaccine?
Yes. So I think the dose here, if you do the math of the CMV vaccine, remember, CMV has 6 different mRNAs in every construct. So if you take a look of at 180 microgram of our CMV vaccine, which was near the top end of the dose, I mean, the highest dose we've tested was 300, and you divide that the mass by 6, then you realize that the per antigen level in any one of those constructs was between 30 50 microgram at the highest doses that we've tested. And here, we're talking about 25 to 250 of just one antigen. So that's one way of thinking about it.
Of course, that is not all of biology. The every construct is going to get translated and expressed depending on the biology of that construct and that mRNA and its sequence, the promoter, everything else that goes into it. So it's not a one to one, but at least it gives you sort of a rough sense of a ballpark estimate of what we think where we think the potency of this vaccine lands relative to others that we have been developing.
Great. Thanks again.
Thank you.
Thank you. Our next question comes from the line of Jonathan Miller from Evercore ISI. Your line is now open.
Hey, guys. Thanks for squeezing me in here. I guess I wanted to ask more about neutralizing antibody levels in CONVUS sera. And I understand that you're not giving numbers here, but when we look at CONVALCANTEZ sera, we see huge variability in the reported levels of neutralizing antibodies. You've spoken a little bit about the need for standardization of those assays.
But I just wanted to clarify, when you say you're at or above those median levels, are you using a particular reference or a particular source that's already been published? Or is that internal data taken from patients that haven't been published yet?
Yes. Thanks, Jonathan. That's an excellent question. These are internal data that have been generated by our collaborators at NIAID.
And you're just looking at convalescent sera broadly speaking. You're not thinking about, for instance, I know the FDA and has put out guidelines for the use of convalescentira as a therapeutic, which has minimum bars for expected neutralizing antibody titers, sometimes that seem much higher than what we see in the broader population. But you're just talking about observed in the broader population of recovered patients.
That is correct. Although I would note that NIAID does put that bar of sort of their monoclonal antibody control. And if you look at where we get to at the 100 microgram post boost, we're well above that level as well. Okay. Well, we will totally We will be above that level
as well.
So if that helps you visualize the graphs, then we're above there.
No, absolutely. And we look forward to seeing that published. I was also going to ask a little bit more about cellular responses. You said you haven't gotten that data. I think I was confused.
Have you not gotten that data from the animal models? Did you have any data of cellular responses in patients yet? Or are we still Okay.
Fair enough. I'm not sure to what degree we actually expect to see several of our responses in the clinical data. It's easier to play around with that in the nonclinical models. I personally find in the clinical trials that these are complicated finicky assays that really for an antigen like this and a disease like this, I don't expect them to add that much of the significant information as it relates to vaccine development. They're always reassuring to see, but you can deduce their presence based on the first principles that I alluded to.
And I struggle to see how that data is actually informative to concrete vaccine development, frankly.
Cycle. Makes sense. And one final one. As you talk about the amendment to the Phase 2 with the new doses being 50 100 as opposed to going up to 250, you've spoken a little bit about wanting to get as many doses as possible out of the manufacturable stock and that makes perfect sense to me. But you also said that there was dose dependency in effect observed across those doses.
Do you see a delta in first dose efficacy? Obviously, you don't have BOOST data, but in prime efficacy between 1 100 and 250 micrograms? And how big is that delta?
That's a very astute observation. The answer is yes. We still see a delta to the 250. I think that delta pales in comparison the bump you get with the boost, and that's why we're comfortable with the prime boost. We should be able to go much lower.
All right. Thank you very much.
Thank you. Our next question comes from the line of Geoffrey Forges from SVB Leerink. Your line is now open.
Thank you very much for taking my questions and congratulations on getting so far, so fast, really remarkable in the history of vaccines. A few short questions. First, Hal, could you talk about do you have any information about the number of epitopes that you're seeing antibodies develop to? And a little bit about the isotypes, but I presume it's all IgG. Secondly, in your conversations with regulators, could you give us a sense of what duration of safety you'll need to see in vaccine subjects, both in the Phase 2, obviously, you're moving quickly to Phase 3, but particularly in Phase 3.
And do you envisage needing to give longer term reboosting, particularly if the virus isn't circulating and providing any natural boosting? And then Stephane, could you give us a sense of whether your expectations are that this vaccine will be profitable for Moderna? Because a number of your competitors are talking about giving product away. But obviously, if you're at the 1,000,000,000 dose level, just wondering how you're talking to investors about what that profitability might look like or whether it should be profitable.
So Jeffrey, this is Tal. Let me take your first three questions. A number of epitopes, we haven't mapped it yet. Isotypes is a total IgG we're talking about. Duration of safety, I think in Phase 2, we expect just the preliminary prime boost to get a sense of the tolerability as enabling to get into Phase 3.
I think the duration of safety for Phase III will be your typical vaccines. It will be a total follow-up of, I expect, a year or 2. I would make a distinction between safety and tolerability. You get a good sense of the tolerability just up to 7 days after the dose. You don't expect anything after that.
SEDI is, of course, something that you monitor for a longer duration. I think, I expect the agency is interested in seeing, as long as safety is reasonable to follow these people, given the size of the trial that we anticipate to launch and the fact that it will be the largest and first such experiment for our platform. Longer term reboosting, I think, is a good question. I don't think we have any idea today either what natural infection you in terms of long term immunity, let alone what a vaccine would do and how relevant waning immunity over the course of months years is to a pandemic that may or may not circulate. So great questions, but our entire history on the relevance of anything having to do with durability here is no longer than 4 months since the start of following subjects, certainly in the U.
S, maybe 5 in China. So these are all good questions that we will need to collect data on, but I think our your prediction here is as good as mine. Let me transfer your last question over to Scott's line.
On. So as we've said in the past, we have not finalized our analysis on pricing. As you said, we have moved so fast in January. We have been usually focusing on the clinical plan, and Talend and his team have done a remarkable job. And on the manufacturing plan, because trust me, it was not part of the business plan to be having a line of sight of how we're going to make even a 100,000,000 dose for 2020, '21, not even talking about €1,000,000,000 So that has really been our focus and will remain for the coming weeks.
We want to do a detailed analysis of value. When you think about the health care cost and the health care system, we want to understand the value of this vaccine. And when we have this analysis done and button up, we will, of course, share it with our investors and our analysts.
Great. Thanks for the answers. Appreciate it.
Thank you. Our next question comes from the line of Jim Birchenough from Wells Fargo. Your line is now open.
Yes. Hi, guys. Congrats on all the progress. A few questions, maybe just starting with the preclinical data, the mouse model. So SARS CoV-two doesn't bind very well to the ACE2 receptor.
And I know you referenced a modified virus, but could you speak to the binding affinity to ACE2 with the modified virus? And then did you look for any other areas of infectivity, upper airway as
an example? And then kind of follow-up. Thanks.
Vin, do you want to take that more?
Yes, sure. So this is done with an academic collaborator with the NIAID. It's the work I'm describing as theirs. They have modified the SARS CoV-two virus, particularly the receptor binding domain, so that there is good infection of mouse ACE2 receptors, have demonstrated that. And so the negative control in the study, you obviously have a viral infection, both in the lower tract and the upper respiratory tract.
I think the we looked at a range of dose levels across that study And I'll wait for the data to come out, but we did see suppression of viral replication both in the upper airway and lower respiratory tract. Our primary focus though, as Tal described, is what's happening in the lower respiratory tract. That's the disease that causes COVID-nineteen, as opposed to sort of just nasal replication or things like that. So the assay itself, at least the negative controls, give us a high degree of confidence that it's replicating a good productive infection in the mice, and that the vaccine is able to completely eliminate viral replication in the lower risk tract in the lungs.
And then maybe just on the clinical side, just in terms of confidence in these results being replicated in older adults,
Is there
anything to reference in your CMV experience that would suggest you can get to immunogenicity that's comparable in older adults to younger. And just wondering, a bit of a controversial area, but challenge studies. Is your sense that that's going to be difficult to pursue and you feel there's enough infection out there to really conduct an appropriate Phase III study?
Yes. So the older adults, let me just say that where we have experienced, which was, I think, our first RSV program, we did not see a difference between older adults and adults. So we look forward to carefully seeing the results here. I'm sorry, your second question?
Just in terms of regulator appetite for a challenge study.
The challenge study, yes. Yes.
And just whether there's enough infection out there to do an appropriate Phase III.
Yes.
I guess what you're seeing me is having a bit of a Floridian block there. The issue with the challenge study, as I see it, is threefold. Number 1, for us, by the time it ever gets established, it would likely be irrelevant. I mean, we're about to launch a Phase II, and we'll be in an efficacy trial, I think, before anybody is able to launch a challenge study. Number 2, on the fundamentals of it, the challenge study, if you read sort of the expert opinions and people are continually looking at this, it's not going to replace our ability or the need, I'm sorry, to do a safety and efficacy trial for a very simple reason.
A challenge study is not going to give you a good enough sense of the efficacy because you'll be measuring a vaccine's ability to limit very minimal disease in relatively healthy people, where what you really want to know is that the vaccine can eliminate really severe disease in older people and people with comorbidities. That's really the benefit that we hope for a vaccine to do. And so your confidence that the vaccine can do it, let alone your confidence that you have the right dose, I think it's going to be very hard with from a challenge study. And your sense of safety of the vaccine is also going to be very hard to extrapolate from a limited number of subjects in a challenge study. So it's I don't think it's really possible to get the full assurance of safety and efficacy from a challenge study.
And if it doesn't eliminate the need to do an efficacy trial, then at least for us, the benefit that our development would obtain from putting people in harm's way, I don't think outweighs the risk for those individuals. Now all that being said, if the right institutions develop and qualify and set up the ability to do such a challenge study and regulators believe that such information would be materially useful
Great. Thanks for
taking the questions.
Thank you. At this time, I'm showing no further questions. I would like to turn the call back over to Stephane Vanzel for closing remarks.
Well, thank you very much everybody for being with us today on a quick notice and for your excellent questions. We look forward to talking to you in the coming days. And just to remind you, our next big rendezvous is on June 2. We have Stephen, Melissa and the team will share with you all the new things they have been working on in the science. It will be a very exciting day.
Speak to you soon and Mr. Sage. Thank you.
Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.