So delighted to introduce our next speakers from GSK, Phil Dormitzer. Phil is Senior Vice President, Head of Vaccines, Research and Development. Have I got that more or less correct?
Yes, yes.
Excellent. I've also got Jeff McLaughlin from GSK IR. So thank you for joining us today. Unsurprisingly, and Phil, be reassured, this conversation is going to be about vaccines. It'd be a surprise if it was anything else. Obviously, from a commercial point of view, GSK is at a very important point because you're just launching Arexvy now, and shingles has obviously been a great success. You've got supply ongoing. Maybe to kick off just into the future expansion-
Yes
-of GSK's vaccines, we can talk about the Affinivax transaction-
Sure
-you did, and the MAPS technology. Now, from the outside, there's obviously an arms race going on with the number of valencies-
Yes
-with Strep pneumonia vaccines. And I've lost track of where we're up to. I know what you have, but-
Yeah
-I've had 30 valencies and so on and so forth. Could you talk to the regulatory mindset and the ACIP mindset in differentiation between invasive and community acquired? And then separately, how for a surrogate endpoint, which is effectively what we're talking about-
Mm-hmm
... how neutralizations are titrated, because this concept of interference as you increase the valencies is something which is made by your competitors.
Yeah.
There's a point of differentiation. Tie those together and say why the Affinivax is different. Why does it uniquely enable you to achieve this lack of interference, the expansion of coverage? Why is that expansion significant?
Yes.
Will that be recognized by the ACIP and FDA in their respective recommendations? Anyway, long, long question.
Sure.
Lots of things in there, but-
Sure
... it's a nice place to start.
Sure. So it is true, still, at the levels of valencies where we're achieving now, that increasing serotype coverage really does increase the overall coverage of invasive disease. At some point, when you get into well into the 30s, there may be a point of diminishing returns. But at the point where we are now, going from, you know, 13, 20, 24, 30, and 30+, you still really do get better coverage of existing disease out there. Now, why the MAPS technology allows you to get to higher valencies,
Maybe just before, for those of you, unfortunately, if you just give a little bit of background about the MAPS technology-
Sure
and just the Affinivax transaction.
Oh, absolutely. So, currently, you know, vaccines that require carbohydrates mounted on proteins, Prevnar being an example and Hib being another, rely on a conventional, glycoconjugation technology, in which the, carbohydrate is activated and can then undergoes a chemical reaction with the protein. And what we've seen is as you go to higher valencies, say, from 13 to 20 or so, although you do increase the level of coverage, the response to each individual serotypes tends to decrease. The MAPS technology is not a conventional glycoconjugation, which you chemically activate, the individual carbohydrates. Rather, the carrier proteins are genetically fused to rhizavidin, the carbohydrates are biotinylated. It's just a very simple non-covalent, but very strong interaction.
It does appear that as you get to the higher valencies, the MAPS technology, which is this non-covalent but strong technology, does appear to get—allow you to get to higher valencies without the same degree of diminution of response against the individual valencies. Scientifically, why that is? It's not as entirely clear. It's sort of an empirical observation that we see it, and indeed, the original interest in the MAPS technology was because it made manufacturing so, so easy. It turns out that it also allows you to get to these higher valencies with continued good coverage. There's another potential advantage of the technology, and that is that the carrier proteins themselves are pneumococcal proteins against which immunity may be elicited. We currently judge our these vaccines on the basis of anti-carbohydrate immunity.
The potential additional benefit of anti-protein immunity is potentially additive to that.
Mm-hmm. So just in terms of the, because when you're referencing immunity, you're talking about neutralization titers of monoclonals to that particular-
Opsonic phagocytic antibodies, typically, yeah.
Okay.
Yeah, yeah.
So then, you know, obviously, this is a surrogate.
Yeah.
But then-
Yes
... what I'm trying to get at is, is how much diminution of response is proportionate to a reduction in clinical efficacy in terms of infection?
Yeah, yeah.
whether that is consistent across different serotypes, and whether it's consistent across different ranges, and has that been fully mapped and, predicted and taken into account by the agencies?
Yes, there's actually pretty intensive attention.
Sure
-paid to the individual serotypes. There's some, for example, serotype 3 is an example-
Mm-hmm
of a serotype that causes a considerable amount of disease in older adults. It is not that well covered by, by current vaccines. Some of these new generation vaccines do appear to elicit better responses against serotype 3. So, you do need to get into the details there a little bit because depending on what are the prevalent serotypes and what is the individual coverage of the individual serotypes, does determine that aggregate potential efficacy.
Oh, but I meant for, for any individual serotype.
Yes.
You know, whether a diminution of 10%, 15-
Mm-hmm
... 20%, and from what level?
Yes.
Whether the impairment on efficacy is identical by serotype.
Yeah, it is not, and that's why, for example—
Yeah
... Serotype 3 is particularly important.
Yeah, because it's.
And number-
takes relatively little to translate into
Exactly. It causes a lot of disease.
Yeah.
It does appear that immunity against serotype three, the bacterium appears to be able to escape more easily. In fact, serotype three appears that it can shed that carbohydrate more readily than it can shed some others. So there are some biological differences between these serotypes. They're not all the same in their behaviors, and serotype three is a particularly tricky one. At least in the data we have thus far, we do see quite good serotype three responses, which is important.
This is particularly relevant for invasive disease, yes?
Correct.
Okay.
Correct.
Let's talk from a competitive scenario of where we are-
Sure
... currently with Prevnar 20 and with Merck's equivalent brand name that I forget, but you'll remember.
The 15 valency.
Yes.
Yeah, yeah.
I can't remember what the brand name is. And also with Merck's new entrant. Well, that is Merck's new entrant, right?
Yes, yes.
V116, I think, is the code number. So just taking three, how do they compare? Do they address the problem, or they're still deficient in terms of what you think you could offer with Affinivax?
There are some different strategies that are being taken. The Merck product is really targeted specifically at older adults in its selection of serotypes. Whereas, both Prevnar 20 and the vaccines we're developing are developed - are targeted against the entire range. In fact, the highest burden of disease remains, at this point, still in infants. What we are seeing is that with the conventional glycan conjugation technology, at about 20, you're really starting to see this diminution. I think the MAPS technology enables us to get beyond 20, and even at 20 valent, there's still a considerable burden of disease left.
So I think what we're really looking at with the maps technology is the ability to target both adults and children, and to go to the higher levels of valency above 30, where we think that conventional glycan conjugation technology will have a real difficulty going. So I think we're gonna be highly competitive in, say, the 24 valency space, and I think we'll really start to really go where others can't go as we go up to the 30+ space, and that doesn't take into account the potential role of anti-protein immunity added to the anti-carbohydrate immunity.
The goal would be not only to provide vaccination to naive adults, but also to adults who have been previously vaccinated with an existing vaccine because of the breadth of coverage. The question is, do you have an indication that ACIP would buy into that? Because obviously, if you want to capture that the prevalent patient population-
Yeah
... is much greater than the incident patient population.
Well, I guess I don't want to try and predict what ACIP will do, but certainly there's precedent for that.
Mm-hmm.
As the valencies have gone up on other pneumococcal vaccines, that re-immunization has been recommended.
Okay. And then the separate last question was on, the immunity to the protein separate-
Yeah
... from the carbohydrate.
Yeah.
So in terms of, you know, immunologic mechanisms, are we delineating between B-cell and T-cell or just a broader, you know, innate adapter, or is there something? What are you thinking of? Because obviously-
Yeah
... your comments were underpinned-
Yeah
... by some-
Yeah. I mean, it could potentially, against the protein, it could potentially be either.
Yeah.
and I think certainly is directionally positive. How positive the addition of anti-pneumococcal protein immunity will be is to be determined, to what degree that will add to the anti-carbohydrate immunity. I think it's gonna be a good thing. How good a thing it's gonna be-
Yeah, it's-
... is gonna have to be de-
At this point, it's-
... is to be, to be determined. Yeah.
Okay, I've got it.
Yeah.
If there are any questions in the audience, then please raise your hand. I'm more than happy to take them. Otherwise, I'll just keep going with my list. So, Shingrix.
Yes.
So this is very successful, there was been some recent data on prevalence of dementia in patients-
Yes
... that were vaccinated or not.
Yes.
It's not entirely surprising. It's consistent, perhaps, with what one might expect. The problem is what you do with it-
Yes
... because you're never gonna be able to run a trial in order to demonstrate this prospectively.
Yes.
So it's a kind of interesting observation that builds in our limitations, but what do you do with it? Unless I'm missing something, I'm just gonna stop there and say: Well, then let's segue to look at different targets, but also with long time, long-term sequelae, like Epstein-Barr virus.
Yes.
That would seem a more interesting prospect.
I think they're both interesting. First thing we want to do is understand the effect with dimentia, which was actually observed initially with Zostavax-
Mm-hmm
... rather than with Shingrix. And Shingrix is a much more effective antiviral zoster vaccine. So certainly, we now want to extend the observations that were made with Zostavax and make sure and confirm that they're there with Shingrix as well.
And has that. It was a preprint from memory. Has it been subject to peer review yet, or is it still a preprint?
I don't think it's subject to peer... I say there's a lot of interest in it, so that's there. There are multiple studies-
Mm-hmm
... looking at existing databases. Dementia, it takes a while to develop, so there's certainly interest in looking at surrogate markers that maybe, you know, may be able to get indication earlier. Trying to understand what is the mechanism? There's an association that was observed with Zostavax, but trying to understand the mechanism is very important. Certainly looking at the principle of Shingrix, which is different from that of most antiviral vaccines. Most antiviral vaccines target the entry apparatus, whereas Shingrix appears to target the immune evasion apparatus. And we're certainly very interested in seeing tools beyond just current Shingrix to other pathogen, including Epstein-Barr virus as well.
So we're very interested in understanding what we see with the current candidates as well, and also about generating additional candidates that could target other herpes viruses using the same basic principles.
Mm-hmm. And do you have a Herpes simplex virus? Not currently.
Oh, oh, yeah, yeah, yeah, in the investigational, but, but yes.
In which phase in-
And I would say that would be a immunotherapeutic.
Yeah.
So that'd be a little bit different-
Yeah
... in that we are looking at people who already have genital herpes.
To prevent the recurrent cold sore.
To prevent the recurrences, which gives you, unlike the, trying to prevent, in fact, for people who have herpes, genital herpes, a lot more power to be able to show an effect.
Yeah, it's much more manageable-
Yes
... monetizable asset. MenABCWY.
Yes.
You're also doing a gonorrhea.
Yes.
So, there was some interesting data that I hadn't previously seen that regards one of the two that, and whether there's any indication that the regulator is, you know, gonna consider that, or whether that's just an interesting, and the focus should be on gonorrhea. And then maybe talk to-- because obviously, you know, MenB is available as a vaccine-
Yes
... including one of yours, and ACWY is available as a vaccine.
Yes.
So the merits in terms of-
Yeah
... commercial uptake, of having an all-in-one, and how that-
Sure
... fits into the schedule.
Sure.
Two things.
So some of the epidemiological observations that link receipt of Bexsero to reductions in gonorrhea are very interesting. Now, those are not randomized controlled trials to look at the outcome on gonorrhea, but we do have an actual gonorrhea vaccine that is targeted. And that's another one of these cases where if we go into a high-risk population, attack rates can be high enough that you can start to generate genuine efficacy data. So it is certainly of interest that we see reductions in gonorrhea associated with Bexsero, but that's not randomized placebo-controlled trials. And maybe my-
Well, just before-
Yeah
... before moving on to that.
Yeah.
From a translational medicine approach-
Yes
... why should in mind that should trigger?
The component-
If we-
... of the vaccine that's thought to be most biologically plausible to bring that about is what's called the OMV, the outer component. And that, that's a component of bacteria that has multiple antigens in it. You can come up with other reasons why there might be associations as well, both biological and behavioral, in terms of who gets immunized against Bexsero, who's most likely to get gonorrhea. So certainly interested in this is actually analogous to what we talked about before. There's certainly interest in pursuing the association.
Mm-hmm.
I'm most interested in well-controlled trials-
Breakthrough gonorrhea, what development plan, and with the idea to displace, you know, the existing or the soon-to-be-approved MenABCWY with the gonorrhea component, or would it be left out there?
No
... as alternate option, or would you be using it to target-
Right
... high-risk groups?
Right.
Obviously, you have your V franchise-
Right
... which means that you have an access into-
Yeah
... patients who may have a high risk.
I mean, the MenABCWY vaccine, it could be tremendously important, ultimately, both for, you know, but also in infants as well. So I'd say that the value of a gonorrhea vaccine is, you know, separate and potentially superimposable on the value of, of MenACWY. In other words, this association with, could be added, but, vaccine.
And potential separate points as well.
And, and-
Potentially separate point as well.
Potentially.
One thing I didn't ask on Shingrix is this issue of revaccination and when and which patients in particular.
Mm, mm.
Now, from the follow-up we have-
Yes
... I think we have 10-year follow-up with very high, right?
Yeah.
So-
Yeah
... are there subgroups of patients that we can identify, either by function of age-
Mm-hmm
... or there are viral therapy before?
Immunity will be necessary. It is impressive that we get up to 10 years-
Mm-hmm
... after a primary immunization series, that we still have some immunity, but eventually, chances are, a boost will be required. Likely to be sooner in those who are immunocompromised-
Mm-hmm
... than in those who are not. There is some degree of trade-off between going for boosters or indications in terms of the age range. So right now, we have ongoing studies where we continue to monitor people and from the original trials for longer and longer periods of time, that will inform those decisions about how much do you prioritize re-immunization, how much you prioritize expanding age ranges. At this point, one of the things we're doing is continuing to monitor, because you just don't see a very rapid drop-off in immunity yet.
You have a deal with CureVac-
Yes
- the German mRNA company. Could you talk and bring us up to date with your efforts, both through influenza and-
Yeah
... I can't remember whether you're still engaged with-- I think you are still engaged with COVID.
We are.
With COVID too.
Well, on both. Yeah.
So just bring us up to speed in where you are versus your somewhat two other mRNA late-stage sponsors.
Yeah. So we are in the clinic-
Mm
At this point, with CureVac, with both influenza teams. The test is going well now, and trying to apply it back. Currently, which marks COVID much in that they would take self-out or not. So, we have a long history in our GSK. Of course, we have through our collaborative efforts as well. So, you know, the Novartis acquisition, GSK is actually one of the original RNA vaccine companies. Well, I was at Novartis many years ago when we started playing then primarily with self-amplifying RNA. We have found that the reliability of nucleoside-modified RNA makes it a very attractive candidate for additional vaccines.
We can see this in the influence playing now, but go to forward restraint, else will be when?
We haven't released a specific date. What I can say is that we are very pleased with the phase I data that we're seeing, and we do intend to progress these candidates.
And given... So I know CureVac initially had non-modified mRNA from memory.
Right.
And then there's Next Gen, which was modified, which is the one you're talking about.
That's right.
And so when we think about the immunogenicity-
Yes
... and comparatively, on the basis of if the modification is what may be contributing to the immunogenicity or not, I mean, where I'm going is this-
Yeah
... is basically, is there any reason to believe that the profile, the AE profile, is gonna differentiate from BioNTech and Moderna in terms of the flu vaccine?
Nucleoside modification is a huge step change-
Mm
As of being able to immunize tolerably with RNA, and that certainly remains true. Beyond that, the details of sequence optimization, composition, production, details of mRNA manufacturing quality. Well, you do have incremental, additional incremental, differences in terms of tolerability and immunogenicity. So no question, moving from non-nucleoside-modified to nucleoside-modified RNA made a huge difference. This is further room for differentiation based on the fine, both composition and manufacturing. Yeah.
For both efficacy and safety?
For both. And, you know, they're linked because, you know, it's the balance between tolerability and immunogenicity that you can adjust by really optimizing your RNAs.
And how much is-
deliver lipid delivery systems.
How much is volume? I mean, obviously, the self-amplifying, or is that... I don't understand what are the-
Oh, sure, sure.
-the drivers of reactogenicity.
Sure.
Maybe you can help me.
Oh, yeah. So, for self-amplifying RNA, nucleoside-modified RNA, I like to think of nucleoside-modified RNA as kind of a, sort of a plow horse, a very reliable technology. And although there are differences in terms of the ratio that you get of reactogenicity to immunogenicity, just depending on composition. In general, the more RNA you give, the more immunogenic it is, but also the more reactogenic it is. With our clinical model is doing very well. The issue there is, can you scale it up, manufacture it reliably, stay intact enough so that it really is a reliable product at large scale? And so in the long run, I still have an interest in self-amplifying RNA, but for today, the nucleoside-modified RNA is much more practical.
As you think of novel targets that you wish to pursue, so we spoke about, herpes simplex, current genital herpes. We mentioned EBV, but I don't think you've anything-
I'm sorry?
EBV, do you have anything on that?
Oh, oh, very interested in EBV. Yes. I mean, certainly the link that's been shown, between-
With MS.
Yeah, with MS-
Yeah
- is interesting. Of course, there are other, nothing quite as big as MS in terms of, of total impact, but EBV has other potential.
Buckets and-
Yeah, exactly.
Yeah.
Cytomegalovirus remains a huge, as yet undefeated challenge, with tremendous disease burden.
And so where are you? I don't think you've got an IND for EBV. So that's good. But you have something preclinically, it sounds like?
We have, yeah. We have definitely, we have research efforts around EBV efforts as well, since finger effect might in others as well.
Okay. And Lyme disease, if obviously, GSK had a Lyme disease withdrawal, and I seem to remember that the one that Pfizer licensed, which you will remember from Valneva-
Yes.
- that came from GSK originally.
I think it was originally. Yeah.
Yeah. But you know, this is still a major and growing-
Yeah
significant monetizable opportunity. So, is there are you working in that space or not?
It is not a current focus.
Okay.
Yeah. Yeah.
And when you look at the, there are only a limited number of vaccine players, because historically, the manufacturing, I'm not sure if the right word is, maybe democratized it, because the barriers to entry are somewhat lower than perhaps they were before.
Low.
But still, you need to have a certain amount of CapEx and skills.
Certainly.
And therefore, the number of bidders is less, and therefore, it's been an attractive area to go fishing from a BD perspective. Hence, you got Affinivax. I'm not expecting you to give names, but are there novel platforms, targets, vaccines out there in the biosphere which are of interest to you? And are they increasing, or is there a fairly stagnant, shrinking pool, which means the growth opportunities with external growth opportunities are finite, and therefore, all the innovation has really got to come from what you can attain internally?
I think there's still lots of room for innovation, both internally and externally. Certainly, we think that one of our strengths is having multiple platforms. We're not reliant on any single platform. Of course, we've been discussing the most innovative vaccines. We have over 20 licensed vaccines right now, many of which have life cycle management programs as well. So the fact that we have everything from conventional glycoconjugates to MAPS bioconjugates in terms of the conjugation space, we have E. coli expressed and mammalian expressed subunits, extensive structural engineering of subunits-
Adjuvants.
... a whole adjuvant portfolio, as well, historical live attenuated vaccines, which some of which actually still have life cycle management possibilities. It's that breadth of that breadth that I think remains important. And even within categories, such as nucleic acid-based vaccines or carbohydrate-based vaccines, there remain many opportunities for innovation within the categories as well.
One area that we get questions on is the Vaxcite. You obviously decided you want to go to Affinivax.
Yeah, we did.
So, why—what was the rationale? Was it the platform value of Affinivax? Was there some other—and please bear in mind, this is not my core area of competence-
Yeah
... or I suspect many other peoples in the room. So maybe just give us a little bit of detail on why you went for Affinivax rather than the Vaxcite approach.
Sure. And I'll focus more on Affinivax than on Vaxcite. I think one of the original things that appealed to us so much about Affinivax was the manufacturing practicality of it. Conventional glycan conjugation has been around for a long time, and clearly, you know, Prevnar has been a very successful vaccine. It's a very complicated technology. There's always the complication of having to make all these different carbohydrates. But in addition, with conventional glycan conjugation, you have a chemical reaction for each that then allows this covalent interaction with the carrier protein. What impressed us initially was how simple the MAPS technology was from a manufacturing point of view.
You take your carrier, and you genetically fuse it to rhizavidin, and then you simply biotinylate the carbohydrate and add it, which is then a quite simple reaction, where you really mix the two, and through a very strong non-covalent interaction, they come together. You don't have to get into a very novel processes to make the protein itself. And although it, one of the initial appeals was the manufacturing simplicity, the discovering that you actually get better responses per carbohydrate as you go to higher valencies, was not intuitive that that would be the case, but it just turned out to actually be the case. And that does not yet take into account the additional benefit of actually having a potentially protective immunity against the carbohydrates themselves.
So it's the combination of the ability to go to higher valencies, have strong responses against individual valencies, combined with a great degree of manufacturing practicality, that made Affinivax so appealing to us.
We anticipate the first data in terms of just the catalyst for seeing the strep pneumonia vaccine. Just remind us the timelines, and then when we're going to see the next project using that platform.
Yeah. So, there are already some phase II data in adults. We will be, we're starting infant trials in 2024, and in 2024, we also anticipate starting the first in-human trials for the 30+-valent vaccine as well. So these will be important, although due to a fill finish issue, we ended up stopping the infant trial, and it allowed us to get a preliminary look. We're very pleased with what we're seeing, and it encourages us to go forward.
Mm-hmm.
And also allows us to refine the way we're going forward as well. So in other words, being able to tailor as we pick up the infant trials and progress the adult trials.
Aside from the Affinivax, you know, strep pneumonia vaccine, what other pipeline projects that maybe not be so well known to the investors in the room are you most excited about within your vaccine portfolio?
I, I-
One thing I didn't mention, given, you know, the ownership or majority ownership of ViiV, HIV.
Yes.
Is this still of live interest, or is it in the backseat?
Oh, yeah, yeah. Very, very much so. Now, ViiV is primarily focused on antivirals rather than vaccines.
Oh, I just meant just because the organization is-
Oh, well, overall, there's a synergy of having ViiV for HIV, a very active infectious disease division that's producing both, you know, antibodies, antibiotics as well.
mRNAs.
Yes, our...
Hep B.
for hep B, chronic hep B, RNA-based therapeutics as well. Of course, the vaccine portfolio, also global health portfolio as well, with Mosquirix as just one example. The fact we have now sort of a quite comprehensive infectious disease offering across these areas gives us strength, and I think that actually some deep subject matter expertise really does make a difference. And the fact that we can so work together across the various modalities of anti-infective treatments and prophylactics is important.
On HIV, do you have anything in the clinic?
For a vaccine?
Yes.
No. I would, I would love to make an HIV vaccine. We do need to see something that looks more promising than the HIV vaccines that have been te tested to date.
Yeah, so at what point?
So we remain open-minded, have not found a HIV vaccine to seize on at this point.
I've exhausted my questions. I'm looking in the room if there are any add-ons. It seems not. So on that note, Phil, I'd like to thank you and Jeff for joining us today. Much appreciated.
Oh, thank you.
Pleasure.
Pleasure speaking with you.