CII - David Martinez, PhD

August 28, 2023

David R. Martinez, PhD, Assistant Professor, Department of Immunobiology

“Immunologic approaches to pre-pandemic and pandemic coronaviruses”

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ID: 10650
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00:00So first, David Martinez.
00:02He joined the immunobiology
00:05department just three months ago,
00:07so welcome to Yale.
00:10So David grew up in El Salvador
00:12and he came to the United States,
00:14where he had the opportunity to work
00:17with very prominent scientists.
00:18So Sally Permars, who is a prominent
00:22immunologist and vaccinologist.
00:24She was his advisor during his doctoral
00:27studies at Duke University and then he
00:30joined Ralph Barrick's lab at UNC Chapel
00:33Hill from his postdoctoral studies.
00:35And David's core expertise
00:38is vaccinology and virology,
00:40focusing focusing on inflated
00:43viruses and coronaviruses.
00:44And I wanted to highlight that
00:46not only has he made very
00:48interesting observations for dengue,
00:50but he also has been very involved
00:54throughout the pandemic and
00:55he helps to understand.
00:57So to inform on the development
00:59of the vaccines,
01:01the Moderna and the J&amp;J,
01:03as well as the antibody,
01:05the antivirals from Eli,
01:06Lilly and AstraZeneca,
01:08which is really impressive.
01:09He's also a Hannah Gray,
01:11faculty fellow of the HTMI.
01:13And so please join me in welcoming
01:15David for his first talk at Yale as
01:17a tenure track assistant professor.
01:37All right, Well, thank you very much,
01:38Nicole, for that very kind introduction.
01:41Thank you all for joining the launch of the
01:43Yale Center for Infection and Immunity.
01:46I'm incredibly excited to be here
01:48enjoying such an outstanding but also
01:51incredibly friendly and supportive group.
01:54Also, thank you to the Dean for
01:56the support of the Center for
01:58Infection and Immunity and as well,
02:03Nicole, for planning this and and
02:05and just getting this set up.
02:07So I'd like to tell you a little bit
02:10about some of the approaches that we've
02:12been thinking about over the last really
02:143 1/2 years in terms of tackling these
02:17preemergent and pandemic coronaviruses.
02:22So this is I think, information
02:24that's hopefully familiar by now.
02:27But you know, we really have around,
02:29depending on who,
02:30how we define viral families, 24 to 26
02:33viral families that can infect humans.
02:35This is one of those viral families that
02:38includes members of the family Corona Verde.
02:41And from these family we really have
02:44a four genera that exists in in here.
02:46And from these four genera,
02:48two of them are more common
02:50commonly infecting humans.
02:51So these include the alpha coronaviruses
02:53that are shown here in in this cluster,
02:57as well as the beta coronaviruses that
02:59are shown here by these pink clusters
03:02from the beta coronavirus genus.
03:05We really have two major groups
03:07that are known to infect humans.
03:09These include the group to be
03:11sarbecoviruses or SARS related viruses,
03:13which of course include members of
03:15that we're familiar with including
03:16SARS COVID One which emerged in
03:182003 and SARS COVID 2A virus
03:21that now needs no introduction.
03:23We also have the group to see Merbeka
03:25viruses or MERS related viruses.
03:27So really it wasn't until the
03:29early 2000s that people began to
03:31pay attention to these groups.
03:33Whenever SARS coronavirus emerged
03:35and infected over 8000 people
03:38and caused around 800 deaths,
03:40so about 10% mortality rate.
03:43Some of these other viruses
03:44are more pathogenic,
03:45including MERS coronavirus.
03:46It's estimated to cause around
03:49a 30% mortality rate.
03:50And the reasons underlying the higher
03:53mortality rate of the virus are unknown,
03:56although it's speculated that
03:57some of the genes and the virus
04:00itself and the accessory orbs
04:02are potentially responsible for
04:03this increased pathogenesis.
04:05So in thinking about how to tackle
04:07these genetically divergent viruses,
04:09we began to look at one of these
04:14subgenera of the Sarbeca viruses.
04:16So these include the zoonotic,
04:17SARS like viruses.
04:19And this similarity plotter,
04:21still called Simplot,
04:22really depicts the genetic
04:24diversity within this subgenus of
04:27viruses throughout its genome.
04:29So these are fairly large RNA viruses,
04:31around 30 KB depending on
04:33which virus we're looking at.
04:35And these viruses on the right here
04:38are zoonotic viruses of bad origin,
04:40as well as human epidemic viruses
04:43or other zoonotic viruses.
04:44And what I want to draw your attention
04:46to in this particular similarity
04:48plot is that these viruses have a
04:50great degree of genetic diversity in
04:52various portions of their genomes,
04:53in particular the subunit one that is
04:57depicted here by the spike that I've laid,
04:59this ribbon model that have
05:02laid sort of parallel to this.
05:04So when we began to think about how
05:06do we begin to tackle these viruses
05:09that are genetically diverse,
05:10how are we going to deal with the
05:12genetic diversity of these viruses?
05:13So this depicted the bigger the dip,
05:15then the more genetic diversity
05:17we have among these viruses.
05:19So to begin to do this,
05:21we turn to patients that have
05:23been infected with the original
05:24SARS COVID from 2003.
05:26So this was a highly collaborative study
05:29spanning the NIAID Vaccine Research Center,
05:34UNC,
05:35Duke University and and other collaborators.
05:37So what we did is we got a hold of
05:41a convalescent PBMC samples and we
05:43began to study monoclonal antibodies
05:45from these from this particular patient.
05:47So this was a patient that I,
05:49like I said had been infected with
05:50SARS COVID in 2003 and by standard
05:54approaches that have been developed
05:56by others and also utilized by
05:58us and many others.
05:59Then we began to isolate antigen
06:02specific memory B cells by essentially
06:05taking an antigen bait protein,
06:08labeling it and then sorting
06:09those memory B cells and cloning
06:11out monoclonal antibodies.
06:12And we began to triage the antibodies
06:15and study them in a way that we could
06:17begin to map to where they bound on
06:19the spike protein on the SARS Kobe 2 virus,
06:22but also other SARS related viruses.
06:25And I'm going to tell you a little
06:27bit about those monoclonal antibodies.
06:29But first I want to just for the,
06:31so that my talk is clear,
06:32just want to introduce this other concept.
06:34So I think this is something that
06:36we're all familiar with by now just
06:38you know given what we've heard in
06:39the media over the last few years
06:41about antibodies to the coronavirus.
06:42But I think it's an important
06:44concept just for clarity of my talk.
06:47So antibodies have multiple functions.
06:49They can have antiviral functions
06:52like nonneutralizing functions like a
06:55BCC or various phagocytic functions.
06:57But one of the functions that they
06:59do not on the nonneutralizing side,
07:01but the other function is neutralization.
07:04So this is the literal ability of
07:05the Mal antibody molecule to stop
07:07the virus from delivering its its
07:09genetic cargo inside the cell.
07:11So for a lot of the data that I'm going
07:13to show you, when I say neutralization,
07:15I'm literally talking about this.
07:17So antibodies can neutralize by essentially
07:19stopping the conformational change of
07:21the spike protein which is, you know,
07:23essentially a spring loaded molecule.
07:25And in doing so,
07:26it can prevent the delivery of the viral
07:29cargo that the genetic cargo into the cell.
07:31So we screened over 1700 monoclonal
07:33antibodies that were isolated
07:35from this particular patient.
07:37And I don't have time to talk about
07:38all the 1700 monoclonal antibodies,
07:40but I want to draw your attention to
07:42four of these monoclonal antibodies
07:43that really caught our attention.
07:45So these were antibodies that could
07:47neutralize various SARS related viruses,
07:49including viruses of zoonotic origin
07:52from bat species as well as the
07:54SARS Co V2 pandemic virus and the
07:57original SARS coronavirus from 2003.
08:00So from these four monoclonal antibodies,
08:03what this data told us is that
08:05despite the genetic diversity within
08:06the subunit 1 portion of the spike,
08:08then clearly there were sites that were
08:11so-called Achilles heels within these
08:12viruses that could be targeted by the
08:14host immune response and in particular,
08:16the human immune response,
08:18which was not really known at the time.
08:21So we began to study these
08:23monoclonal antibodies,
08:23not just in vitro but also in vivo.
08:25So for for much of the data that I'm going
08:27to show you in this portion of my talk,
08:29then it really involves characterizing
08:31the antiviral functions of these
08:34monoclonal antibodies in mouse models.
08:36And just to give you a brief overview
08:39of how the experiments are being set up
08:41and they're essentially two different
08:42ways that we evaluated these antibodies,
08:44either in a prophylactic or preventative
08:47setting or in a therapeutic setting.
08:49So in these various animal models
08:52of coronavirus pathogenesis,
08:53then peak virus replication is around
08:562 days post infection or 48 hours.
08:58So we want to evaluate the antibodies
09:00in a manner that we can test whether or
09:03not viral replication and the relevant
09:06tissues of these mice like the lung or
09:08the upper Airways can in fact be dampen.
09:10So we either treated the mice at 12
09:13or or 12 hours before infection or 12
09:15hours post infection or even at times
09:18later post infection to determine
09:19whether or not the antibodies had any
09:22efficacy against these various viruses.
09:25So looking at this data,
09:27we first began to evaluate the
09:30antiviral function of four of these,
09:32you know,
09:32broadly neutralizing crossreactive
09:34antibodies against the original SARS.
09:36So this is SARS Co V1 and a highly
09:39pathogenic mouse model.
09:41So from this data,
09:42whenever we compared the ability
09:44of these antibodies to block virus
09:46replication in the lungs of these
09:49animals compared to a negative
09:50controlled flu monoclonal antibody,
09:52then only one of these antibodies was really
09:56able to fully suppress virus replication.
09:58So for the remainder of this
09:59particular part of my talk that I'm
10:01going to focus on telling you about
10:02that particular monoclonal antibody,
10:04which is called DH1047.
10:05So we wanted to know whether
10:07or not this antibody could not
10:09only prevent disease in these mice,
10:11but could it also dampen virus
10:13replication in a therapeutic setting?
10:15So once the mice are infected,
10:16if we treat them with
10:18this particular antibody,
10:19can we mitigate signs of viral pathogenesis?
10:22And that is in fact what we saw
10:25whenever mice were treated with
10:27DH1047 in a therapeutic setting,
10:29then we could reduce lung virus
10:31replication as well as other
10:33measures of viral pathogenesis.
10:36We then wanted to expand our breath
10:39of studying this monoclonal antibody
10:41and also evaluate the ability of this
10:43particular antibody isolated from
10:45a human and blocking these various
10:48coronaviruses and mouse animal models.
10:50So we looked at A2 zoonotic
10:53preemergent viruses that I'll note
10:56that whenever you take these two
10:58coronaviruses that are shown here,
11:00they're isolated from a bat and
11:02you put them in human primary
11:03airway epithelial cells,
11:05they grow efficiently well and they
11:07can evade many of the commonly used
11:09countermeasures at least against SARS
11:11COVID and and also against SARS,
11:13COVID too.
11:14So but this,
11:15this monoclonal antibody that we
11:17isolated from a human then could not
11:19only prevent the virus infection
11:21and pretreated mice,
11:22but could also treat the virus
11:24infection in these mice.
11:25Suggesting that within these
11:27highly genetically diverse subunit
11:291 portion of the spike then this
11:31was again pointing to an Achilles
11:34heel within these various viruses.
11:36And then also in looking at again
11:38looking at more breadth of this
11:40virus as we also evaluated another
11:43SARS related virus called WIV 16.
11:45And then we could similarly treat
11:48these mice in a preventative or or
11:50therapeutic setting and also against
11:52a SARS two related virus that was
11:54isolated from an animal called a pangolin.
11:57So clearly the,
11:59the footprint bound by this
12:01monoclonal antibody then it's highly
12:03must be highly conserved.
12:04So we were interested in also
12:06testing the ability of this antibody
12:08against the SARS 2 variants,
12:10at least the variants that
12:11were prevalent at the time.
12:13So you know,
12:15this was totally unexpected
12:17because what we found was that
12:19this monoclonal antibody could not
12:21only have this wide diverse breath
12:23against these zoonotic viruses,
12:25but it could also block all
12:27the various variants.
12:29At the time that we published a study,
12:31the delta was sort of the prevalent
12:32variant but it could potently
12:34neutralize these various variants
12:37at I see 50 levels in the sub
12:39100 microgram levels.
12:41And then finally in collaboration with
12:43Primavera Chara at Duke University
12:45who's a structural biologist.
12:47Then we solve the structure for
12:52DH1047 bound to the source Kobe 1RB.
12:54DI don't have time to tell you,
12:55tell you all about the details,
12:57but what I want to just briefly
12:59tell you is that the DH1047,
13:01this broadly neutralizing and broadly
13:03protective antibody against our
13:05Becca viruses then actually binds to
13:07the inner side of this or Becca virus RBD.
13:10So in a more detailed paper that
13:11was published by Eric Holman,
13:13Sapphire and colleagues then an
13:15antibody that they described called
13:17RB D6 or COVID 250 then actually has
13:20almost the identical footprint of this
13:22particular antibody that I told you.
13:25So not only did we demonstrate that a
13:28DH1047 has his broad activity in mice,
13:29but on a more practical level,
13:31we think that the epitope or the
13:34footprint bound by this antibody
13:35is actually a rational target
13:38for panzerbecovirus vaccines.
13:39And we're actually interested in utilizing
13:41this knowledge for deploying and
13:43developing optimal vaccination strategies
13:45against this group of SARS related viruses.
13:50In fact, that some of our
13:51work also spans this area.
13:53So I think it's also clear that no
13:56universal vaccines exist against
13:58this group of SARS related viruses,
14:00although we have a number of
14:02individuals that are working on
14:04approaches that have so far proved
14:05to be successful in animal models.
14:08So we designed a vaccine approach
14:10that we were interested in really
14:12based on a heterologous boost to
14:13try to harness the immune system to
14:16target these cross reactive B cells
14:18to these conserve sites including
14:20the site that is targeted by DH1047
14:22or even more conserve sites within
14:24the machinery of the S2 domain.
14:26So the subunit 2 or the stock
14:28that is shown here in green.
14:30So some of these conserve sites include
14:33the fusion peptide as well as the
14:35stem Helix loop that have now been
14:38described by David Weissler and colleagues.
14:40And these sites can actually are
14:42highly conserved among these viruses.
14:44And not just within these viruses,
14:46but the fusion peptide is sort of a,
14:47you know, this,
14:49you know,
14:51general type of protein motif on
14:55type 1 membranes of these various
14:58infectious viruses that infect humans.
15:01So I don't have time to tell you
15:03all about the details of this data.
15:04But utilizing the design of
15:06these chimeric spikes,
15:08then we aim to boost mice in a manner
15:10that could direct their immune systems
15:12to these highly conserved areas.
15:15And we aim to try to increase
15:17immune coverage against these
15:18genetically divergent Sarbeca
15:19viruses that are shown here on the
15:22left by this phylogenetic tree.
15:23So just to tell you a little
15:25bit of the details of this data.
15:26Then the chimeric spike boosted mice
15:28that I I am telling you about are
15:32actually shown in Group one or group 2.
15:35So they were either given to the mice in
15:37a Multiplex manner or boosted separately.
15:40And the what I want to draw your
15:43attention to is that Group 4 is
15:46actually AM RNA vaccinated mouse
15:48group that received a similar vaccine
15:50to the Pfizer and Moderna vaccine.
15:52So whenever we vaccinate these mice
15:54and begin to compare the neutralizing
15:56activities of these various
15:58vaccines including our vaccines,
16:00then what we observed with our
16:01vaccines is that we were able to
16:04elicit broadly neutralizing antibodies
16:05not just against the original SARS
16:07and SARS Co V2 but also against
16:10these more genetically divergent
16:12preemergent SARS related viruses.
16:14More importantly and I think a
16:16far more stringent test is that
16:18whenever we introduce
16:19viruses that were not included in
16:21the vaccine cocktail to these mice
16:23including a heterologous WI V1 or
16:25even a very hard to neutralize at
16:28the time the so-called beta variant,
16:30then our vaccines can fully
16:32protect mice against both lower and
16:35upper airway virus replication.
16:36So we think that this could be a
16:39potentially a strategy among many strategies.
16:41So this is by no means you know that
16:43one of the by no means the only approach
16:46that different individuals are pursuing.
16:48But we think that this could be a
16:52strategy to to have a tool in our
16:54armamentarium for dealing with these
16:55genetically divergent viruses that
16:57could emerge at a later point in time.
16:59And we think that this could perhaps
17:01be a strategy for preventing,
17:03God forbid,
17:04a future starts Kobe 3 virus emergence event.
17:07So this is clearly one of the
17:09approaches that we think is successful.
17:11But there are other approaches
17:13that not only us,
17:14but others are pursuing in the field.
17:16And one of the approaches that I
17:17want to sort of end with in terms of
17:20the coronavirus aspect of my talk is
17:22to tell you a little bit about how
17:24we're thinking about dealing with
17:26more of the breadth of these various
17:29highly pathogenic coronaviruses.
17:30So in a collaboration with Duke University,
17:33then what we began to do is to engineer
17:37nanoparticles by including various RBD's.
17:39So the RBD remember is a site that
17:41contains these Achilles heels on
17:43these various viruses and one of the
17:45areas that we're interested in is to
17:47be able to expand the immune breath,
17:49the protective immune breath
17:51against these various viruses.
17:52So in a proof of concept study that I'm
17:55going to just tell you about real quick,
17:57then what we decided to do was to expand
18:00the breath of our our vaccine that
18:03I'm going to tell you about not just
18:05against group to be Cerbecca viruses,
18:07but also group,
18:08group to see Marbecca viruses.
18:10So we engineered A ferritin nanoparticle
18:14vaccine and tagged three of these
18:16various receptor binding domains
18:18from not only group to obese,
18:19but also group to C sarbacoviruses.
18:22And we began to study the immunogenicity
18:24and the ability of the epitopes on
18:26the receptor binding domains to
18:28be presented in a manner that the
18:30immune system immune system could
18:32see them and generate optimal immune
18:34responses in at least in mouse models.
18:36So I don't have time to tell you
18:38all about the details of that data,
18:39but I'll show you some of the data
18:42that we think is important and and
18:44being able to guide universal vaccine
18:47approaches.
18:47So the first question that we asked
18:49is whether or not this multimeric
18:51nanoparticle RBD vaccine could elicit
18:53this protective immunity against
18:54these genetically divergent not
18:56just SARS related virus,
18:58but also MERS related viruses that
19:00we know are poised for emergence
19:03since MERS coronavirus continues to
19:05emerge each year in the Middle East.
19:07But we wanted to test these viruses,
19:10test these this vaccine against
19:12these viruses not just in stringent
19:15in vitro assays but also in highly
19:18pathogenic animal models of of disease.
19:21So when we evaluated the ability of these
19:23of the vaccine to elicit protective
19:26immunity in particular neutralizing
19:27antibodies against authentic viruses.
19:30So this this is not pseudovirus
19:32but actually authentic virus.
19:34Then this Multimeric RBD vaccine not only
19:37elicited high levels of neutralizing
19:40antibodies against zoonotic viruses,
19:43also the original sarscovy from 2003,
19:46but we could also elicit whenever
19:49we begin to add more relevant RBD's
19:53neutralizing antibodies against
19:55this other group to see MERS, MERS,
19:58coronavirus as well as a whole
19:59host of other MERS related viruses.
20:02Which I don't have time to tell you
20:04about that data and a more stringent
20:06test whenever we evaluate the vaccine
20:09and not just protecting against
20:11mortality and a highly pathogenic
20:13SARS Co V1 mouse model,
20:14but what we what we see is that.
20:17The multimeric vaccine can not
20:19only protect against lung virus
20:21replication relative to a control,
20:23but it can also protect against
20:26upper airway virus replication.
20:27And then similarly whenever we evaluate
20:29the ability of this trivalent or
20:32multimeric vaccine to protect against
20:34MERS coronavirus then we see fairly
20:36stringent protection against both lower
20:38and upper airway virus replication.
20:41So I'm in conclusion then this is another
20:44approach that we're excited about.
20:45So the so-called multimeric vaccine
20:48expressing various Group 2B and
20:50Group 2C receptor binding domains
20:52to elicit these types of broadly
20:54neutralizing antibodies.
20:55And we think that this could be one
20:58of the many strategies that not only
21:00us but in other individuals that
21:02are pursuing similar strategies.
21:03In particular,
21:04I'm David Viessler from the University
21:06of Washington and Howard Hughes
21:08Medical Institute as well as Pamela
21:10Bjorkman who also have other really
21:12promising approaches.
21:12So I would be remiss not to
21:14mention their work in this area,
21:16which I think is also critically
21:20important and some future directions,
21:21at least for this particular part of my talk.
21:24Then you know,
21:25we're of course interested in
21:26evaluating whether or not we can
21:28begin to boost some of these conserved
21:30epitopes within the S2 machinery.
21:32So in particular the fusion peptide
21:33as well as the same Helix loop,
21:35irrelevant animal models,
21:37as well as these more multimeric vaccines.
21:40And not just their ability to
21:42prevent mortality and highly
21:43pathogenic disease in mice,
21:45but also the ability to prevent
21:47the transmission of these highly
21:49transmissible SARS Cov 2 variants.
21:52Another area that I'm actually
21:53just super interested in and will
21:55be an area that the lab will be
21:58expanding into is understanding
22:00sort of more fundamental mechanisms
22:02of the induction and generation
22:05and maintenance of plasma cells.
22:07And in particular long lived
22:08plasma cells and relevant tissues.
22:10Not just in the bone marrow,
22:11but also in relevant areas including
22:14the lemon appropriate or even
22:17in the upper and lower airway.
22:19Utilizing this really nice and
22:22elegant system for time stamping
22:24and being able to track the
22:28generation and longevity of
22:29these cells in various tissues.
22:31So in the last couple minutes then
22:33I just want to just briefly tell
22:35you about another group of viruses.
22:36So I I mentioned very early
22:38in my talk about, you know,
22:39the 26 viral families that can infect humans.
22:42So Corona Verde is one of those
22:43families that I just told you about.
22:45But another of those families
22:47includes the Flavy Verde,
22:48which as we also know has been a a major,
22:54you know, source of human infections.
22:58And in particular,
22:59including members from from from
23:01this group have made many important
23:04contributions whenever Zika virus which
23:06is a flaming virus emerged in 2015.
23:09But a virus that I'm actually really
23:11interested in is dengue virus.
23:13And the reason why I'm interested in
23:15this virus because it actually breaks
23:18the many of the canonical immunological
23:20rules that we typically think of in
23:23terms of understanding antibody responses.
23:25So this virus is transmitted
23:27by a many vectors.
23:29One of these vectors includes 80S aegypti
23:32and it's highly prevalent in tropical
23:34areas including my very own El Salvador.
23:37And it infects upwards of
23:39400 million people each year.
23:41And the group that's most afflicted
23:43by the most severe forms of
23:46the disease includes children.
23:48And one of the areas that I'm interested
23:50in studying Danga virus is really
23:52more on the immune side of things.
23:54So and now a published paper as well
23:58as other epidemiologic papers in
24:01the New England Journal of Medicine.
24:03Then it's become increasingly clear
24:06that in zero negative children that
24:09received the only FDA approved vaccine,
24:11the socalled Invaxia,
24:12then these children have higher
24:15incidence of hospitalization in very
24:17young children compared to children who
24:20have had a prior dengue virus infection.
24:23So if you have,
24:23if you're a zero negative child,
24:25you live in an endemic area,
24:27you cannot actually get the vaccine.
24:29It's actually contraindicated
24:30in this particular group.
24:32So Aravinda De Silva is one of my
24:36postdoc mentors and he's actually
24:39supporting my program by letting me
24:42access PBMC samples from a cohort from
24:44the Philippines that which contains 0
24:47negative and 0 positive children who
24:49were vaccinated with being vaccia.
24:50So I'm actually really interested
24:53in understanding the fundamental
24:54properties of those monoclonal
24:56antibodies from these by basic groups
24:58of of children in terms of their
25:01baseline status and understanding what
25:03is particular about these antibody
25:05properties and these children that
25:07could potentially lead to enhanced disease.
25:10So just again,
25:12not really give you everything,
25:13but just to give you a little bit
25:15of the flavor of the things that
25:16we're interested in for the future.
25:18So with that,
25:19I'd like to acknowledge members who
25:21contributed to the to these studies,
25:22including members from UNC particular,
25:26my postdoctoral advisor Ralph Barrick
25:28and Aravinda De Silva from Duke University,
25:32Bart Haynes,
25:32Kevin Saunders.
25:33And then our collaborator on all
25:36the mRNA work,
25:37Drew Wiseman and also a nascent
25:40collaborator who's also assistant
25:42professor at University of
25:44Pennsylvania Norbert Party,
25:46who did his post for Drew.
25:48We're also going to be collaborating
25:50with him on on mRNA approaches
25:51to emerging flaving viruses.
25:53So more to come on that.
25:55Also my funding acknowledgements from
25:57the Howard Hughes Medical Institute.
25:59Thank you very much for your attention. So
26:11you're good with time. So we can take
26:13some questions from the audience.
26:23So I have the microphone.
26:31Excellent talk. Thank you, David.
26:33My question is about the
26:35conserved epitope to you.
26:37You found that the monocle
26:39Ronnie body binds to has that.
26:41How is it resistant to evasion
26:44and is that there's some kind
26:46of a critical function that
26:47the virus has to preserve?
26:49And is it also preserved
26:50in the Omicron linear?
26:51Yeah. So if if you incubate the
26:54antibody with Omicron and this
26:57various lineages for longer,
26:58you can have some neutralization.
27:00So even though many of the Omicron
27:04lineages haven't necessarily mutated
27:06the footprint of the antibody,
27:07then additional mutations within the
27:09RBD that are distal to the actual
27:12footprint epitope can actually alter
27:14the accessibility of the epitope.
27:16So you know much like many of the
27:20monoclonal antibody therapies then
27:23Omicron and its various lineages
27:25including you know the latest XBB
27:271.5 and its various lineages then
27:29have demonstrated the ability
27:31to evade this DH1047 antibody.
27:34So that's unfortunately,
27:35you know, just a a,
27:37a problem that the field has and and
27:42something that the virus has figured out by,
27:44you know,
27:45mutating sort of these distal and
27:47outside parts within the footprint,
27:49not even necessarily the footprint
27:52but but you know we're still excited
27:54about the ability of this to,
27:57you know,
27:57retain its function against these number
28:00of different zoonotic viruses that
28:02we know are poised for human emergence.
28:05David. Hey David, great talk.
28:06Thank you.
28:07I'm
28:07curious what your your choice of
28:10nanoparticles and is it important for the
28:12these multivalent vaccines
28:13for them to actually
28:14be attached to a a particle or
28:17that's is that advantageous compared
28:19to just having mix of proteins injected.
28:22Yeah, you know we think it we we
28:24think it might be and you know this
28:26this is certainly on on you know
28:28the more practical side is this is
28:29reflected by the by the potency and
28:31the amount of immune response we see.
28:33In particular you know the levels
28:36of serum neutralizing antibodies are
28:39greatly exceeded whenever we couple
28:42you know whatever protein of choice
28:44in this case that receptor binding
28:46domain in a multi in a multimaric form.
28:49You know for probably for reasons
28:51of you know activating you know
28:54besyl receptors in a in a better way
28:57potentially or in a more potent way.
28:59But that seems to be a feature that confers,
29:03you know, these B cells to to make far
29:06more potent levels of antibody responses.
29:09And this is not something that
29:10we just see with coronaviruses,
29:12but also with other viruses that are
29:15genetically divergent like HIV for example.
29:17So let me just quick follow up.
29:19That's really interesting.
29:20Is it important that individual
29:22particles be multivalent or if
29:25you took a mixture of particles,
29:281 coated with this receptor binding domain,
29:31another particle coded with that one,
29:34mix them together and then inject it,
29:35would that work equally well? Yeah.
29:37So that's that's a great question.
29:38So you know based on data that from
29:42from our group actually you know with
29:45the with the chimeric mRNA vaccines
29:47when you give them all together
29:50even though you may have breath you
29:52actually lose some of the potency.
29:53You know and you know we could go
29:55on about you know like theoretical
29:57reasons underlying this actual you
29:59know phenotype you know but it
30:01could just be that you just have
30:03you know multiple different clones
30:04of B cells that are being selected
30:06against the various antigens as
30:08opposed to you know more potent and
30:11higher affinity clones against the
30:13the the single particle with say
30:15like a single protein for example.
30:18But we we definitely lose some of
30:20the potency when we include more
30:21antigens and and give them all at once.
30:25So but but but definitely I that's an
30:27interesting question and something
30:28that we've thought about a lot
30:30in optimizing these strategies.
30:31Thank you.
30:32That's a great talk and great discussion.
30:34I am fascinated by these same topics.
30:36So we'll be sure to continue
30:38over the lunch break asking you.