What do we know about long Covid?

Transcript

• 00:03Hello and welcome to the what do
• 00:05we know about Long Cove and how
• 00:07might a vaccine help webinar?
• 00:09Please put any questions for
• 00:10the speaker in the Q&A panel,
• 00:12and Please note that this session
• 00:14is being recorded. Thank you.
• 00:21Good morning everyone and
• 00:22thank you for joining us.
• 00:24For Akiko of Esaki's presentation
• 00:25on long COVID and how a vaccine
• 00:27may help as the director of Alumni
• 00:29Affairs at Yale School of Medicine,
• 00:31it gives me great pleasure to welcome
• 00:33you to our first and hopefully last.
• 00:36Virtual reunion weekend.
• 00:37For those who have not had the
• 00:40chance to meet or hear Akiko present
• 00:42before allow me a brief introduction,
• 00:44she joined Yale as a faculty member
• 00:47in 2000 and is currently the wall
• 00:49to more of an xet fits professor
• 00:51of Immunobiology and Molecular,
• 00:53cellular and developmental biology.
• 00:56The genealogy and my microbial
• 00:59diseases professor of molecular,
• 01:01cellular and developmental biology.
• 01:04The Howard Hughes Medical Institute.
• 01:06Her research is focused on
• 01:08understanding how viruses are
• 01:09recognized in eight community and
• 01:11how that information is used to
• 01:13generate protective adaptive immunity.
• 01:15She has received numerous honors
• 01:17during her career and most notably has
• 01:20been newly elected to the American
• 01:23Academy of Arts and Sciences.
• 01:25If you enjoyed her presentation
• 01:26and I have no doubt you will,
• 01:28please seek out more of her
• 01:30work and insights.
• 01:31She is very active on social media and
• 01:33gained a following on Twitter for her
• 01:35public health advice about COVID-19.
• 01:37Advocating for social distancing
• 01:38early in the pandemic.
• 01:39I will moderate our Q&A in the end,
• 01:42so please submit any questions you
• 01:43have in the chat feature and we will
• 01:46address as many as we have time for.
• 01:48I will now turn it over to Akiko.
• 01:52Thank you Aaron for the
• 01:54very kind introduction.
• 01:55I'm happy to be here today to give
• 01:58you a update and what we are doing
• 02:01to help people with long COVID.
• 02:04So I'm going to share my screen.
• 02:11OK, so today I want to tell you about
• 02:16long COVID an how might a vaccine help?
• 02:20And this is really an ongoing work
• 02:22that involves a large number of
• 02:25people here at Yale and elsewhere.
• 02:30So my laboratory has been collaborating
• 02:33with a large group at Yale to try to
• 02:37understand the outcome of COVID-19 disease,
• 02:40particularly from the standpoint
• 02:42of the immune response.
• 02:44We know that COVID-19 can
• 02:48cause asymptomatic infection.
• 02:51And all the way to fatal infection,
• 02:54and this really did depends on the host
• 02:58immune status as well as age and sex.
• 03:01So we know that the outcome of Cobett
• 03:0419 disease really differ between the
• 03:07different age group as well as sex as
• 03:10well as core mobility and pregnancy
• 03:13status and many other things that
• 03:15could affect the host immune response.
• 03:18And so, for instance,
• 03:20we've been looking at.
• 03:22Hospitalised patients immune response to
• 03:25COVID-19 from moderate to fatal disease
• 03:28and discovered so many different insights.
• 03:31For example,
• 03:32the severe COVID is really a company
• 03:35by a misfiring of the immune response,
• 03:39meaning that different parts of
• 03:42the immune system are engaged,
• 03:44normally reserved for fighting
• 03:46fungal or parasite infection are all
• 03:50being engaged in the severe COVID.
• 03:53And this becomes a maladapted immune
• 03:56response to fighting a viral infection.
• 04:00We also know that in fatal COVID cases.
• 04:04Things that should have happened earlier
• 04:07during immune response didn't happen,
• 04:09and that really results in uncontrolled viral
• 04:13replication and severe to lethal disease,
• 04:15and that is really seen for both the
• 04:19innate immune response which should
• 04:21happen within hours to days of primary
• 04:24infection to neutralizing antibodies.
• 04:27We found that people who don't develop
• 04:32neutralizing antibodies within
• 04:34the 1st 14 days of symptom onset.
• 04:36Are enriched in the lethal COVID group,
• 04:39so this kind of delay in the onset
• 04:43of appropriate immune response is
• 04:45really at the basis of our failure to
• 04:49cope with this virus and therefore
• 04:52succumb to infection.
• 04:53We've also done a lot of work on comparing
• 04:57sex differences in immune response,
• 05:00and this was really initiated by the
• 05:03support of Women's Health research
• 05:05at Yale here and has really taken
• 05:09off since then.
• 05:10Now there are numerous reports showing
• 05:14differences in male and female immune
• 05:17response to COVID and how that might explain.
• 05:21The risk factor for males being having
• 05:25a higher risk factor for lethal and
• 05:29severe COVID compared to female patients.
• 05:32And we've also been looking at the
• 05:36impact of COVID-19 in pregnancy,
• 05:39and have seen both subtle to severe
• 05:42consequences of kovit infection in
• 05:45pregnant women as well as impact on the
• 05:48placenta from a respiratory infection.
• 05:52Really highlighting that this
• 05:54particular virus,
• 05:55even though it's just a respiratory virus,
• 05:58has a huge impact throughout
• 06:01the body without.
• 06:03Infecting the Oregon it can have
• 06:05affect remote effect because of the
• 06:07information that's happening in the lung.
• 06:12There are others that Yale who are really
• 06:15investigating what happens in children.
• 06:18Doctor Kevin Harreld's group, for example,
• 06:21reported that there is a robust
• 06:24immune response that can control the
• 06:26virus in children and therefore most
• 06:30children recover with mild infection,
• 06:32whereas there are a handful of children
• 06:35who have multi organ involvement.
• 06:38Inflammatory diseases,
• 06:39which also is a mystery right now.
• 06:43Why do these handful of children
• 06:45become so severely ill from COVID?
• 06:47And that's a work of a doctor?
• 06:50Carrie Lucas in the same
• 06:52department looking at these issues,
• 06:54but today I really want to
• 06:56focus on long haul or disease.
• 06:59First of all,
• 07:00what is long COVID and what
• 07:02are the symptoms associated?
• 07:04How long do they last?
• 07:06What are the people affected?
• 07:08And finally,
• 07:09I want to start talking about
• 07:11potential therapy for lung COVID
• 07:16so long COVID was already detected
• 07:19last summer as people were experiencing
• 07:22very extended symptoms from COVID.
• 07:26And you know, some people even had very
• 07:29mild to asymptomatic infection but are
• 07:32beginning to develop very long term
• 07:36symptoms afterwards and so long COVID
• 07:39patients experience a large number
• 07:42of symptoms which I will go into.
• 07:47Weeks or months after infection
• 07:49for extended time period.
• 07:51So most common symptom is fatigue and
• 07:55this isn't just a little bit of fatigue,
• 07:59it's a severe fatigue that people
• 08:02become debilitated from this this
• 08:05disease and post exertional malaise is
• 08:08a second top symptom that long COVID
• 08:11patients experienced and cognitive
• 08:14dysfunction is also a large symptom.
• 08:18That longer population experience and.
• 08:22Majority have evidence of multiple
• 08:24organ disease, which I will get into.
• 08:27The long COVID,
• 08:29unlike the severe COVID that we
• 08:31study in the hospital,
• 08:33the long COVID patients are more
• 08:36dominated by younger female,
• 08:38so the Middle Age Group 30 to 50
• 08:41year old and that is really the
• 08:44most affected from long COVID and
• 08:48that also happens to coincide with
• 08:51the demographic most affected
• 08:53by autoimmune diseases.
• 08:54So the estimates of how many people develop.
• 08:59COVID vary between different studies,
• 09:01some of them say 5%.
• 09:03Some of them say 70%,
• 09:05but roughly about 10 to 20% of the
• 09:09COVID survivors develop Long Cove in,
• 09:11and this you know estimates about
• 09:145,000,000 cases of expected long
• 09:16COVID in the United States alone,
• 09:19which is a huge problem because
• 09:21these people are no longer able to
• 09:24function as they did before and would
• 09:27have a significant consequence,
• 09:29both economical.
• 09:30As well as health care costs
• 09:33associated with one COVID.
• 09:34And another study showed that the loan
• 09:37COVID percentages decline overtime,
• 09:39so it's not that everyone who has
• 09:42long COVID is going to suffer forever.
• 09:46The numbers and percentage decline overtime.
• 09:48So for example,
• 09:5013% of the participants had
• 09:52symptoms lasting over 28 days,
• 09:54but then that percentage drop after weeks.
• 09:58So after 12 weeks the percentage
• 10:00dropped about 2%.
• 10:02But there are people who are suffering.
• 10:05Suffering for more than
• 10:07a year with long COVID.
• 10:09And as I mentioned,
• 10:10it's a really debilitating disease.
• 10:1240% of cases require reduction in workload
• 10:15and 22% are unable to return to work,
• 10:19so this is a major crisis going forward
• 10:22even after we contain COVID with a vaccine,
• 10:25there will be millions of people
• 10:28suffering from long term consequences.
• 10:32And as I mentioned, long COVID is
• 10:35not just one organ, one symptom.
• 10:38It really has over 120 different symptoms
• 10:41that have been reported and that appear
• 10:44to involve so many organ systems.
• 10:47Systemic effects such as fever,
• 10:49fatigue, and post exertional malaise.
• 10:53Other symptoms that appear
• 10:55to just kind of be systemic,
• 10:58whereas there are distinct neuro
• 11:00psychiatric impact memory deficit,
• 11:02loss of ability to concentrate,
• 11:05and mood disorders.
• 11:06This is really, really severe in
• 11:09some people and there is dizziness,
• 11:12headache, blurry vision.
• 11:14Many different endocrine cardiovascular,
• 11:17pulmonary, musculoskeletal,
• 11:18and GI tract symptoms have been reported.
• 11:24And just to kind of reiterate,
• 11:27the demographic data being quite
• 11:29different from severe COVID.
• 11:31This is a study from a Mount Sinai
• 11:34group of Precision Recovery program
• 11:36that they have in in this group.
• 11:39Again, women are dominant at
• 11:4169% of the their patients are
• 11:44women and mean age is only 44,
• 11:47so 12 to 81. It varies,
• 11:50but mean is really is around 30 to 50.
• 11:54No, that range group.
• 11:56And the BMI it again.
• 11:58The BMI high BMI is a risk factor for
• 12:02severe COVID and for Long Cove it,
• 12:05it appears that the mean BMI is normal and
• 12:08then there are other sort of comorbidities
• 12:12that are associated with long COVID,
• 12:15but there's not a unifying.
• 12:18A picture of what people had
• 12:21before they developed long COVID.
• 12:25And if you look at the symptoms,
• 12:28severity and the number of symptoms overtime,
• 12:31what you see is something like this
• 12:34where vast majority of this severity
• 12:37score that goes extends to seven
• 12:40months are the moderate group,
• 12:42whereas a severe and very severe.
• 12:45They tend to decline over time,
• 12:47which is great.
• 12:49People are kind of converting to
• 12:52from CV or two a moderate to mild.
• 12:55Disease overtime.
• 12:56And then very mild goes up
• 12:59and then no symptoms.
• 13:01These are the people who stayed low.
• 13:04And if you look at the average
• 13:07number of symptom as I mentioned,
• 13:09everyone has a variety of symptoms,
• 13:12but the ones that don't
• 13:14recover for up to 90 days,
• 13:16they really do have numerous
• 13:18symptoms ranging in the teens.
• 13:20So meaning that they have numerous
• 13:23different organ involvement and symptoms
• 13:25that last for extended time period,
• 13:27whereas those that recovered with an
• 13:30acute or recovered within 90 days.
• 13:32They are symptom number declines.
• 13:35Quite rapidly and within three
• 13:37months they are devoid of symptoms,
• 13:39so really we're interested in this kind
• 13:42of people who are unable to recover
• 13:45over 90 days with numerous symptoms.
• 13:50So what is long COVID?
• 13:52What is how is it cost?
• 13:54We have a couple of hypothesis.
• 13:57One is that there is a viral reservoir
• 13:59that is remaining in these people even
• 14:02though they cannot detect any PCR
• 14:05positive virus from their nasopharynx.
• 14:07There may be virus in different tissues
• 14:10that cannot be accessed by such a
• 14:14nasal swab and that may be causing
• 14:16a chronic in long term symptoms.
• 14:20And the other possibility hypothesis
• 14:22is that there is autoreactive immune
• 14:25responses that are occurring,
• 14:27so these are the T&B cells of the
• 14:30immune system that are now attacking
• 14:32the various different cells or
• 14:35factors within different organs,
• 14:38and that might be leading to the
• 14:41multi organ symptoms that I explained
• 14:44to you before,
• 14:45and so both of these possibilities
• 14:48are still remaining valid.
• 14:50And there is ample evidence for
• 14:53both of these types of disease
• 14:57to be happening with COVID.
• 14:59And so just share with you a couple of these.
• 15:03This is a study that biopsied
• 15:05intestine of patients with COVID.
• 15:08This is a 92 days from the symptom onset,
• 15:12so months after they have had started
• 15:15the symptom and looking at what this is
• 15:18looking at is really source code V2,
• 15:21which is the virus that causes
• 15:24COVID new nucleocapsid protein,
• 15:26which is indicated in green here and
• 15:28you can see that these intestinal
• 15:31sections contain cells with.
• 15:34Very distinct patterns of the nuclear
• 15:36protein that you can see within the
• 15:39cytosol of these cells and this is
• 15:42from the terminal ileum and this
• 15:45is from the duodenum.
• 15:46You can see that there are these
• 15:49nucleocapsid positive cells that
• 15:51are mostly epithelial cells that
• 15:53are in the intestine,
• 15:55and they found five out of 14
• 15:57people who had positive staining.
• 16:00For SARS Co V2 antigen.
• 16:02After an extended time period.
• 16:04Indicating that the viral reservoir could
• 16:07be happening in the long COVID patients.
• 16:13Another possibility is the autoimmunity
• 16:15and this is a work that we published
• 16:19very recently where in collaboration
• 16:21with Doctor Aaron Rings Laboratory,
• 16:24we dissected the existence of auto antibodies
• 16:28and COVID-19 and I want to take you through
• 16:32some of the key data from this study.
• 16:36So doctor ranks laboratory developed a new
• 16:39tool called rapid extracellular antigen.
• 16:42Profiling rape this is a powerful new
• 16:46technology in which you can assess the
• 16:50ability of a patients antibody to bind
• 16:53to variety of self antigens that are
• 16:57about 3000 different human EXO proteome,
• 17:00which means that proteins that are either
• 17:03extracellular or secreted are included
• 17:06in the in this East library and each
• 17:10cell expresses different type of human.
• 17:13Conditions and when you bind your antibody
• 17:17to these cells and you can pull down the
• 17:21cells that are bound by the antibody,
• 17:24and then you can figure out what
• 17:27kind of antigen was expressed by
• 17:30such east by doing deep sequencing.
• 17:33And this enables doctoring to determine a
• 17:36wide variety of autoantibodies from a patient
• 17:39in a very high throughput and comprehensive,
• 17:43unbiased manner.
• 17:44So with this his group and we
• 17:47collaborated to look at auto
• 17:50antibodies and COVID-19 patients.
• 17:52These are hospitalized patients
• 17:54who had severe disease.
• 17:56Here moderate disease,
• 17:57mild to asymptomatic who are not
• 18:00hospitalized in negative controls.
• 18:02And the brighter the yellow,
• 18:04the more autoantibody there is in a
• 18:08patient and each patient is a column here.
• 18:12And what we found was quite striking
• 18:15that there are auto antibodies against
• 18:17so many different host proteins over
• 18:20120 different host proteins are bound
• 18:23by COVID-19 patients antibodies,
• 18:25and here particularly prominent are
• 18:28the antibodies against interference,
• 18:30which are the very factors that
• 18:32the host immune responses used to
• 18:35fight a viral infection.
• 18:37So obviously if you have auto
• 18:40antibodies against your own weapon.
• 18:42Then you cannot deploy those weapons
• 18:44well to fight a viral infection,
• 18:47and that's really what's happening in
• 18:49the severe cobett COVID patients that
• 18:52these patients are unable to fight
• 18:54the viral infection because of their
• 18:57autoantibody against the very protein
• 18:59that's needed to combat viral infections.
• 19:01But in addition to these,
• 19:03there are so many other yellow
• 19:06boxes you see here,
• 19:08which are autoantibody against variety
• 19:10of different immune cells themselves.
• 19:12Which is kind of scary,
• 19:14which means that these autoantibodies
• 19:16are actually dampening our own
• 19:19ability to fight a viral infection.
• 19:21Just to give you a couple of examples,
• 19:24this is looking at cumulative autoantibodies
• 19:27that exist in COVID-19 patients and a
• 19:30severe moderate patients who are in the
• 19:32hospital developed a large number of
• 19:35auto antibodies against all of these
• 19:38different immune factors and cell types.
• 19:41And when you look at the functional
• 19:44consequences of these autoantibodies,
• 19:46it is quite striking that,
• 19:48as I mentioned,
• 19:49the top left box corner that had these
• 19:53interferon specific autoantibodies.
• 19:55If you look at those patients ability
• 19:58to control the viral load over time,
• 20:02inbred the patients with these
• 20:04interferon specific autoantibodies
• 20:06were unable to clear the virus,
• 20:08whereas those patients without work.
• 20:11Able to decline in viral load and
• 20:14ultimately control the virus infection.
• 20:17Indicating that these
• 20:18autoantibodies are not only there,
• 20:20but it's functionally impairing our
• 20:23ability to fight a viral infection.
• 20:27And one more example of autoantibody
• 20:30against different immune cell types.
• 20:32So you've probably heard
• 20:34a lot about antibodies.
• 20:35Antibodies are really important
• 20:37to fight a viral infection,
• 20:39and the cell types that produce these
• 20:42antibodies are known as B cells and
• 20:45B cells themselves are absolutely
• 20:47critical for making the antibody.
• 20:49And yet in some people we found that
• 20:52COVID patients developed an antibody
• 20:54against the B cells themselves.
• 20:57So it's like a real like a suicidal
• 21:00antibody that you know bind to the
• 21:02B cells and then then kill them.
• 21:05And these antibodies interesting Lee.
• 21:07Those people who had these peaceful
• 21:09specific anybody have very low B cells
• 21:12as well as inability to mount and a
• 21:14antibody response against the virus.
• 21:17So really,
• 21:18indicating that these autoantibodies
• 21:20have a impairment induced impairment
• 21:22in the immune system so that people can
• 21:25no longer fight the viral infection.
• 21:28And in addition to these immune
• 21:31factors and cell types,
• 21:33we found auto antibodies to a wide
• 21:35range of tissue associated antigens
• 21:38that are in the brain vasculature,
• 21:41connective tissues, cardiac tissues,
• 21:43hepatic tissues, saliva skin,
• 21:45GI tract, and many others.
• 21:48So this really paints a picture of a
• 21:52diverse autoantibody causing all kinds of,
• 21:55you know,
• 21:55immune mediated damage across
• 21:57variety of different organs.
• 21:59And that was my second hypothesis of
• 22:02how along COVID might develop now.
• 22:05These are really patients who had like
• 22:08severe disease enough to be hospitalised,
• 22:11so it's not really the typical
• 22:13loan COVID patients were right now
• 22:16looking at long COVID patients SERA.
• 22:19To see if we see a similar kinds
• 22:22of autoantibodies an if So what the
• 22:24nature of these autoantibodies are,
• 22:26you know what kinds of tissue
• 22:28or antigens are they binding?
• 22:32So it seems that there is very little that we
• 22:36can do right now to help long COVID patients.
• 22:40We don't have a therapy, we don't even
• 22:43have a great diagnosis for the long COVID.
• 22:47Finally, the CDC has a guideline for
• 22:49COVID diagnosis for the long COVID,
• 22:52but there is one kind of ray of hope here
• 22:56because I've been looking and hearing
• 22:59from people on Twitter that patient.
• 23:02Patient based group reporting.
• 23:04About 40% of the long haulers.
• 23:07Feeling better after vaccination.
• 23:09And so, as I mentioned,
• 23:12long COVID may be caused by
• 23:14persistent viral reservoir or and or
• 23:17autoantibody or autoimmune response.
• 23:19And so we think that the vaccine may
• 23:22improve long covered symptom by inducing
• 23:25robust antibodies and T cells against
• 23:28the virus to clear the reservoir.
• 23:31Or it may temporarily sort of suppress
• 23:35the autoreactive cells ability to cause
• 23:38toxic immunopathology in the patients,
• 23:41and So what this means is that,
• 23:45for instance, the M RNA vaccines.
• 23:50Induce both innate and adaptive immune
• 23:52responses and the innate immune
• 23:55response cytokines combined two and
• 23:57suppress the autoreactive cells and
• 24:00therefore improve the symptoms or the
• 24:03adaptive immune responses that are
• 24:05engaged by the vaccine with antibodies
• 24:08and T cells that are attacking the
• 24:12virus of our and controlling the
• 24:15persistent virus in these patients,
• 24:17and maybe both of these things are happening.
• 24:22Depending on what the patients
• 24:24have with respect to long covin.
• 24:27And so we thought that this would be a
• 24:31great place to look into the underlying
• 24:36mechanism along COVID as well as
• 24:39potentially defined therapy against it so.
• 24:43We formed a Yale COVID recovery study
• 24:46and when I say we it's really a superb
• 24:51leadership of Harlan Krumholz and his
• 24:54post grad associate Daisy Massey,
• 24:56who really put this forward.
• 24:59And now we have a study up and
• 25:02running where we are recruiting among
• 25:05COVID patients with who have not
• 25:08gotten the vaccine yet,
• 25:10and then we're following
• 25:12their immune response overtime
• 25:14after they become vaccinated.
• 25:16To see what kind of changes occur in the
• 25:20immune response in the long haulers and
• 25:23what those changes mean with respect
• 25:26to their recovery from the symptoms.
• 25:29And this is again of a large
• 25:33collaboration between Charles de la Cruz,
• 25:35Natalie Lambert Arm Ring,
• 25:37who I already mentioned is the
• 25:40creator of the Reed technology.
• 25:42Erica spots as well as these other
• 25:45younger investigators who are really.
• 25:48Recruiting and consenting
• 25:49and studying the patients.
• 25:51And so I'm very fortunate to be involved
• 25:55in this large group who are really
• 25:58looking at the impact of vaccine on
• 26:01long hauler with respect to every
• 26:04immune parameter that you can imagine,
• 26:07we're throwing everything at this disease.
• 26:10Whatever the cutting edge technology
• 26:13we have on hand.
• 26:16So the mission is really to understand
• 26:19the immunological determinant of
• 26:20disease pathogenesis of long COVID.
• 26:22In order to inform rational therapy.
• 26:25And we're very excited to to
• 26:28carry on with this effort.
• 26:31So I want to acknowledge
• 26:33the number of people here.
• 26:35First of all, I was able to only
• 26:37discuss a little bit of our research
• 26:40today that has to do with the diverse
• 26:43autoantibodies in patients with COVID-19.
• 26:45But I also mentioned some of the misfiring
• 26:48of the immunological responses that
• 26:50happen in severe COVID with fatal COVID.
• 26:53I also mentioned there's a delay in
• 26:55the neutralizing antibody titer and
• 26:57then sex differences in immunity
• 26:59that I mentioned earlier.
• 27:01And these are the are the real heroes.
• 27:04They're the ones that really
• 27:06carried out the study.
• 27:08The names are listed here and my
• 27:10lab members who have been absolutely
• 27:12amazing over the entire pandemic period,
• 27:15not only looking at the immune responses,
• 27:18but also creating an animal model
• 27:20to study COVID as well as really
• 27:23getting involved in the surveillance.
• 27:25The PCR testing for the health
• 27:28care workers which were able to
• 27:30pick up some early exposure cases.
• 27:32Back in the spring of last year,
• 27:35when testing was quite limited
• 27:37and this entire set of work that
• 27:40are listed here is enabled by the
• 27:42impact deal BIOREPOSITORY,
• 27:44which is run by Doctor Albert Co at
• 27:47the school public health as well
• 27:50as all the others listed here.
• 27:52And I want to thank the funders for
• 27:55allowing us to carry on this research,
• 27:58so I'm going to stop sharing here
• 28:01and take any questions.
• 28:15Still no.
• 28:21OK, can you hear me now?
• 28:23Yes yes wonderful ekigho sorry everybody.
• 28:25We're having some technical difficulties
• 28:27on my end so thank you for your patience.
• 28:30Wonderful presentation.
• 28:30Thank you very very much.
• 28:32This is just extraordinary work and I
• 28:34appreciate you giving kudos to the team.
• 28:37'cause as everyone knows,
• 28:38this is a true team partnership and we're
• 28:41so excited that you're leading the way.
• 28:43I am actually shocked to see that we
• 28:45don't have any questions in the chat.
• 28:48So please, I know this group.
• 28:50This is not a shy group of alumni.
• 28:52Submit your questions and luckily
• 28:54we did have a couple people submit
• 28:56to me just a few days prior because
• 28:58they were so excited they couldn't.
• 29:00They couldn't wait to ask you, Akiko.
• 29:01So let me let me jump right in with
• 29:04some of our pre submitted questions.
• 29:06The first is why do you think women
• 29:08are more at risk of getting lung COVID?
• 29:11Yeah, so that's a very interesting question
• 29:14because as I mentioned in the seminar there,
• 29:18the demographic for the long COVID
• 29:20is quite distinct from what we see
• 29:24with the hospitalized patients who
• 29:26are much older and males are more at
• 29:29risk for severe disease with COVID,
• 29:32whereas the long Cove it is really
• 29:35dominated by younger women 30 to 50 year
• 29:39old there dominated in that group so.
• 29:42There are a couple of reasons
• 29:44why this might be.
• 29:46One is what I alluded to,
• 29:48which is this group of women are
• 29:50also a high risk for developing
• 29:53autoimmune disease such as lupus,
• 29:55arthritis and many others,
• 29:57and so if that's the group that's
• 30:00sort of developing a long COVID,
• 30:02it's potentially possible that
• 30:04the autoimmune disease is the 2nd
• 30:07hypothesis that I have about long COVID
• 30:09may be happening in those patients.
• 30:12In that you know they they were sort
• 30:14of prone to developing autoimmunity.
• 30:17But this virus kind of tipped
• 30:19the balance forward to developing
• 30:21a severe autoimmune disease,
• 30:23in which in which case you know they
• 30:26developped these autoantibody to variety
• 30:28of cell types in you know that may
• 30:31be causing these multiple symptoms.
• 30:34So that's one hypothesis.
• 30:36There may also be some you know factors
• 30:39that are related to sex hormones or.
• 30:43Other issues that we haven't
• 30:45been able to tackle yet,
• 30:47which may be also happening in this group.
• 30:51OK, great, thank you and the second
• 30:53question is do people who are severely
• 30:55ill from COVID also get lung COVID?
• 30:59Yeah, that's a really good question.
• 31:01In fact, as I mentioned that the percentage
• 31:04of long haul or disease really differ
• 31:07between different studies and one of
• 31:09the key differences in these studies
• 31:11is that when you follow patients who
• 31:14were sick enough to be hospitalized,
• 31:16and some of them got, you know,
• 31:19mechanical ventilation and so on.
• 31:20These sort of the patients who sustained
• 31:23lung damage in other organ damage,
• 31:25which tend to be very long
• 31:28lasting because it's.
• 31:29Really hard to repair these tissues,
• 31:31especially because these people are
• 31:33also in the older age group whose repair
• 31:36functions have declined over time.
• 31:38So you know if you ask these people,
• 31:41do you still have lingering symptoms?
• 31:43The answer is vast.
• 31:45Majority is yes, so about 70 percent.
• 31:4875% of people who've had sort of
• 31:50severe enough COVID to be hospitalized.
• 31:53They still have lingering symptoms.
• 31:54That's different from what we're calling
• 31:57a long COVID, which is people with.
• 31:59Milder disease who are never
• 32:01hospitalized who are developing these?
• 32:03You know,
• 32:04very long term symptom after either
• 32:06asymptomatic or mild infection and
• 32:08that tends to be the the group that
• 32:11is more dominated by younger women.
• 32:13And so I think the Long Cove it.
• 32:16It's easy to kind of bunch
• 32:18everything into one basket,
• 32:20but it in terms of pathogenesis we
• 32:22really need to separate these groups
• 32:25and so I would say that the long Cove
• 32:28it is really referring to this milder.
• 32:31Infection that's causing long
• 32:32term symptom as opposed to the
• 32:35hospitalized patients who are still
• 32:36feeling ill from the damage that
• 32:39they sustained from the COVID.
• 32:40So I hope that answers that question.
• 32:44Absolutely thank you through all answer.
• 32:45So we are starting to get some
• 32:47questions in the chat, which is great.
• 32:49I'm going to send the first one
• 32:52over to you and. Read it verbatim.
• 32:55So given autoimmunity likely
• 32:56plays an important role in the
• 32:59pathogenesis of long COVID,
• 33:00I want to find out if these patients
• 33:02have an increased prevalence of
• 33:04family history or personal history
• 33:06of autoimmune diseases like collagen,
• 33:09vascular disease preceding
• 33:10the diagnosis of COVID-19.
• 33:13Yeah, that's an excellent question,
• 33:15so I'm not sure how much the kind
• 33:17of inherited susceptibility to
• 33:19autoimmune diseases were known in
• 33:22the long haulers right now we are
• 33:25collecting this kind of information.
• 33:27First. We have this very extensive
• 33:30survey of symptoms and history.
• 33:32You know whether they've had any
• 33:35autoimmune disease in the past,
• 33:37what kind of medications they were giving,
• 33:40so we should be able to collect
• 33:43some of these.
• 33:45Important information soon,
• 33:46but obviously our family history
• 33:47of all the different diseases that's,
• 33:49I think the next next step we're
• 33:51going to have to reach out to
• 33:54these patients and find out.
• 33:56Great, thank you.
• 33:57The next question is has the REACH
• 34:00technology been applied to other
• 34:02viral illnesses and if So what sort
• 34:04of differences in number and or
• 34:06diversity of responses are seen?
• 34:09Yeah, another very excellent question,
• 34:12so we don't think that COVID is
• 34:15alone in inducing these types
• 34:18of auto mean oldani bodies.
• 34:21So we are currently testing or in the in
• 34:24the midst of planning a test for other
• 34:27acute respiratory viral infections and
• 34:30potentially other types of infections,
• 34:33so we don't know the answer yet.
• 34:36This brief technology is quite knew.
• 34:38It's really the first of
• 34:40many application was kovid,
• 34:42but I believe Doctor Ring is going to be
• 34:45expanding his analysis to other diseases,
• 34:48and in fact he has done reap analysis of.
• 34:52Known autoimmune diseases
• 34:54and have found that lupus,
• 34:56the diversity of antibodies that are
• 34:59found in COVID exceeds that of lupus,
• 35:02so it's really kind of a remarkable picture
• 35:05of autoimmune activation happening in Kovan,
• 35:08and whether that happens
• 35:10after flu infection and virus.
• 35:12Other kind of viral infection.
• 35:14We are really in the midst of
• 35:17doing this kind of research.
• 35:20Great, thank
• 35:21you so the next one is.
• 35:24Are there any emerging therapies
• 35:26that show early promise?
• 35:28Yeah, so the only only glimpse we
• 35:31have of anything helping long COVID
• 35:33really appears to be this vaccines.
• 35:36There are other anecdotal reportes of people
• 35:39feeling better with other medications.
• 35:41I you know we don't have enough
• 35:44number to conclude what other
• 35:46therapies might be working there.
• 35:48There may be some clinical trials that are
• 35:52ongoing that's going to inform us soon,
• 35:54but this is an important question because.
• 35:58You know, depending on the hypothesis,
• 36:00if the reservoir the viral
• 36:02reservoir is causing long COVID,
• 36:04we really need to go after that virus,
• 36:07which means we can treat these patients with
• 36:10monoclonal antibody cocktails or antivirals.
• 36:12Or, you know, fear on something like that.
• 36:15They really get the virus,
• 36:17whereas if it's really caused by,
• 36:20you know autoimmune disease,
• 36:21then we really need to be
• 36:23dampening the immune response.
• 36:25So therapies that are used in
• 36:28autoimmune diseases can be used for.
• 36:30More COVID may be potentially more targeted.
• 36:32Approach can be developed based on what kind
• 36:35of autoantigens that they were detecting,
• 36:37so there's a lot of different
• 36:39ways to go about therapy,
• 36:41but we really need to know the disease
• 36:44pathogenesis before we can engage in those.
• 36:47I thank you for the next writer.
• 36:50Has had two doses of the Pfizer
• 36:53vaccine and lives in Georgia and
• 36:55is reluctant to go out in public
• 36:58and was wondering if you could
• 37:00speak to is anyone working on
• 37:02neutralizing antibodies and antibody
• 37:04test or CMI test for vaccines?
• 37:06He's a little concerned about the
• 37:09neutralizing antibodies
• 37:09or cell mediated immunity.
• 37:11Yeah, that's also a common,
• 37:13you know concern that people even
• 37:15though they got the two doses.
• 37:17There are rare cases,
• 37:19a breakthrough infection that happen,
• 37:22and that's with all vaccines.
• 37:24Fortunately,
• 37:25the M RNA vaccines like the Pfizer one
• 37:28that the question or just indicated.
• 37:31I have really high efficacy and
• 37:34effectiveness against infection,
• 37:35so that's really great news,
• 37:38but the breakthrough does occur
• 37:40in rare cases and we don't
• 37:43know why some people with fully
• 37:46vaccinate status are getting.
• 37:48Infected again,
• 37:48it could be that there there was an
• 37:51underlying immune deficiency in these people,
• 37:54or it could be that they got exposed to
• 37:57a variant that you know wasn't quite
• 38:00well neutralized by their antibodies,
• 38:02and so I agree with this person 100%.
• 38:05I think we need a neutralizing antibody test.
• 38:09It's right now to do this with the
• 38:12real virus. It's a huge endeavor.
• 38:14We do this in the lab,
• 38:16but it requires the biosafety Level 3.
• 38:20Days and days of hard work.
• 38:22And so to do this in millions of
• 38:25people would not be possible.
• 38:27However,
• 38:27I hope that the companies are coming
• 38:30up with similar approach where it's
• 38:33a little bit more more streamlined
• 38:35and less less cumbersome to be able
• 38:38to look at the neutralizing titer,
• 38:40and one of the proxy for the
• 38:42neutralizing titer is the anti RBD
• 38:45antibody these so they sort of
• 38:47receptor binding domain of the spike protein.
• 38:50That's being targeted.
• 38:51Bispecific antibodies and that tend
• 38:53to have a pretty good correlation
• 38:56with neutralizing titer.
• 38:57So one way to get around the entire
• 38:59sort of cumbersome neutralizing assays
• 39:01to use anti RBD Eliza to monitor antibodies.
• 39:06But I just wanted to reiterate
• 39:08that the Pfizer vaccine Moderna
• 39:10these are extremely effective.
• 39:12So vast majority of people are
• 39:14going to be protected and so I think
• 39:18the the person should be able.
• 39:20Little bit more comforted by that.
• 39:22Thank you.
• 39:23I'm
• 39:23going to read this one verbatim.
• 39:25It's a little long when you mentioned
• 39:27the multisystem nature of long COVID-19
• 39:29and a potential reservoir of the virus,
• 39:31and many of the different tissue types.
• 39:34Do you? Do we have any idea of how
• 39:36the virus reside in these tissue?
• 39:39My understanding is that some of
• 39:41these tissue types mentioned do
• 39:42not express ace two SP receptors.
• 39:46Yes, so I think the consensus is that this
• 39:50virus obviously uses a Stew as a receptor.
• 39:54It also has other requirement like TEMPRESS,
• 39:57which is a protease that enables entry
• 40:00process and so there there are different
• 40:04types of host cell requirement for
• 40:07infection and if you survey the literature,
• 40:10vast majority of the target cells
• 40:13are epithelial in nature so.
• 40:16Nasal cavity the long the
• 40:18intestinal tract kidney.
• 40:19The epithelial cells appear to
• 40:21be a major target of infection,
• 40:24so that's number one and that they
• 40:27have high levels of ACE 2 and #2
• 40:30is that there are some reports
• 40:33including our own that detected
• 40:35virus in the neurons in the brain.
• 40:39And so there's controversy about
• 40:41whether it's two is expressed well in
• 40:44the neurons or the brain, and in fact,
• 40:47if you look at the M RNA level for a Stew,
• 40:51it's quite low.
• 40:52However, if you look at the protein,
• 40:54it's there an we've also demonstrated
• 40:57a functional requirement phase two
• 40:59by neutralizing ace two or blocking
• 41:00a Stew and showing that the virus
• 41:03not lingering effects these cells,
• 41:05indicating that it is it is possible
• 41:07to have these kind of persistent
• 41:09infection in organs that are.
• 41:11Not positive for S2 by M RNA in the
• 41:14standard way of looking at things.
• 41:16But if you look at the protein,
• 41:19they're actually quite positive and
• 41:20that also goes for the placenta.
• 41:23Placenta also has very low levels
• 41:25of the M RNA,
• 41:26and yet if you look at the protein
• 41:28expression it's quite positive there.
• 41:39Hear me OK, OK Now I can hear yes
• 41:41just a little bit. It's good.
• 41:46OK. Are there pediatric cases
• 41:49of lung COVID either post?
• 41:53I'm sorry I don't know the acronym ISC
• 41:56or in children who have not had this an
• 42:00ISC right? So the MISC like I
• 42:03mentioned earlier is a rare event
• 42:06that happened in some children.
• 42:08It is very severe.
• 42:11That requires hospitalization and treatment,
• 42:13whereas there are pediatric
• 42:15cases of long COVID.
• 42:16Again, I want to distinguish that from MI.
• 42:20See is these are the children who
• 42:22have mild to asymptomatic COVID
• 42:24infection and then develop overtime.
• 42:27This long term symptoms an I know that
• 42:30many children actually suffer from
• 42:32lung COVID people who are athletes
• 42:35in our very active in different
• 42:38sports no longer able to run.
• 42:40You know, because they,
• 42:42they they they they get post exertional
• 42:45malaise as well as shortness of breath.
• 42:48They just can't engage in these
• 42:50kinds of sports anymore.
• 42:52There are people who are getting anxiety,
• 42:55depression,
• 42:55and other mental issues as a
• 42:58result of long COVID in the
• 43:01in the pediatric population.
• 43:03You know,
• 43:03and then there are these very
• 43:05severe cases that happen.
• 43:07The Missy kids,
• 43:08so it's a range of different things,
• 43:10but the long Cove is a very
• 43:13distinct phenotype from the
• 43:15Missy and as as far as I know,
• 43:17I haven't heard of anyone
• 43:19with Missy developing long,
• 43:20Long Cove it,
• 43:21but it's such a rare intersection
• 43:23that you know maybe future
• 43:26investigation will reveal those.
• 43:28Thank
• 43:28you, how can a long hauler determine
• 43:30whether there is an issue with viral
• 43:33reservoir problem or an autoimmune problem?
• 43:36Yeah, excellent question,
• 43:38and that's precisely why we're doing
• 43:41this deep immunological dive into
• 43:43these patients because I believe
• 43:45that these two possibilities may
• 43:47be happening either in subset of
• 43:50patients having one or the other,
• 43:53or another subset having both.
• 43:55Or maybe it's a varying degree that's
• 43:58happening in within a patient.
• 44:00So in order to we would love
• 44:03to find a biomarker for either.
• 44:06A person having a persistent infection
• 44:09or those who are having autoimmunity
• 44:11and with this deep dive we will be able
• 44:14to determine if there are these two
• 44:17different baskets of disease and what
• 44:19parameters are correlating with each.
• 44:21And so you know,
• 44:23I I've actually seen the first
• 44:25glimpse of the data from the long
• 44:27holders and it's really striking.
• 44:30I would love to report this.
• 44:32It's such a such an early look that
• 44:35I I can't even talk about it, but.
• 44:38But I know that there is a signature
• 44:41so very excited to be able to.
• 44:43You don't figure this out soon
• 44:45and report it and to help people.
• 44:49It's really exciting to hear
• 44:51there's more to come in that area.
• 44:53I'm going to read this
• 44:55one verbatim split along.
• 44:56You said earlier that if a virus
• 44:58reservoir is causing long COVID,
• 45:00you'd have to hop up immune system.
• 45:02On the other hand,
• 45:03if the immune system response is
• 45:05causing it by attacking antibodies,
• 45:07you need to slow the Union system down.
• 45:10What happens if both are
• 45:11true went that greatly
• 45:13complicate treatment.
• 45:13Yeah, very tricky, right?
• 45:15But I think there is a way to do this so.
• 45:19The fact that, OK,
• 45:21let's assume a person has both a
• 45:24viral reservoir, an auto, anybody.
• 45:26We could tackle the viral reservoir
• 45:28using synthetic treatment like
• 45:30monoclonal antibody cocktail an.
• 45:32If we get rid of that reservoir we
• 45:35get rid of that part of the disease
• 45:38and then for the autoimmune part
• 45:41we can basically use treatments
• 45:44that are immunosuppressive,
• 45:46which will dampen the autoreactive
• 45:48cells in those patients so.
• 45:50I think combination combination of
• 45:52different approaches and therapy
• 45:54that are not going to be interfering
• 45:57with each other is possible.
• 46:01OK, great and we're getting
• 46:03low on questions folks,
• 46:04so if you have anymore we
• 46:06have a few more minutes.
• 46:09Why wouldn't vaccine?
• 46:10Why wouldn't vaccines cause immune
• 46:12mediated COVID like symptoms
• 46:13like the natural one does?
• 46:15Yeah, another very good question.
• 46:17So the natural infection has a myriad of
• 46:21different effects on the immune system.
• 46:23One of the things that we saw very
• 46:26early on in the COVID patient is
• 46:29a severe decline in the T cells.
• 46:32So the virus infection causes a rapid
• 46:35drop in the T cells and T cells are the
• 46:38central command of the immune system.
• 46:40If you don't have T cells,
• 46:42B cells don't know what to do another.
• 46:45You know innate immune cells
• 46:46don't know what to do,
• 46:48so the T cells are this.
• 46:50This command center is being degraded
• 46:52or you know diminished by the virus and
• 46:55so all the subsequent immune responses
• 46:57that occur are misdirected or not very well.
• 47:00You know conducted,
• 47:01whereas in the case of vaccines we have
• 47:04absolutely no impact on the T cell I mean.
• 47:06They're not going to touch the T cells
• 47:09with respect to numbers or their function,
• 47:12but rather the stimulate them so
• 47:14that the antibody secreting cells
• 47:16the B cells can be engaged,
• 47:18and so the vaccine is really designed only
• 47:21to provide the best kind of immune response,
• 47:24whereas the infection does a whole bunch
• 47:27of other things that interfere with our
• 47:29ability to fight the viral infection.
• 47:32And that's really with all viruses,
• 47:34right?
• 47:34They have so many evasion mechanisms.
• 47:37That that they without them they
• 47:39cannot be a successful pathogen.
• 47:41So there's a huge difference between
• 47:43the immune response that happened to
• 47:46live infectious virus versus those
• 47:47that happened during a vaccination,
• 47:49and that may be why we're seeing
• 47:52such an amazing effect of the vaccine
• 47:54in inducing super physiological
• 47:56levels of antibody.
• 47:57Meaning most people don't develop that
• 48:00kind of anybody with a natural infection.
• 48:03But with the two dose of vaccine,
• 48:05we're seeing like incredible titers of
• 48:08anybody that's going to hopefully give
• 48:10us protection for at least a year or so.
• 48:13So that's really the difference.
• 48:16Thank you, I think we might have
• 48:18time for one or two more questions,
• 48:21so the topic of children hasn't really
• 48:24been discussed much in this area.
• 48:26So could you talk to us about long COVID and
• 48:30do children get it right?
• 48:32So I have heard you know the children.
• 48:35The data are still coming out because you
• 48:38know they just became eligible recently,
• 48:40so we don't know what the impact
• 48:43of the vaccines are for the
• 48:45long COVID in children yet.
• 48:47However, we know that Long
• 48:49Cove it does happen in children
• 48:52even in very young children,
• 48:54so I think that you know that this
• 48:57unfortunate doesn't spare people over
• 49:00younger age and unlike the infection itself,
• 49:03most people who are younger
• 49:05are having very mild or some
• 49:07asymptomatic infection was alone.
• 49:09COVID can happen in this group,
• 49:12so I think that's really more
• 49:14reason why we need to accelerate.
• 49:17Vaccination in the younger
• 49:19people because you know,
• 49:20even though they might recover with
• 49:23a mild infection with the kovid,
• 49:25they may suffer from long term symptoms.
• 49:28An I think the vaccines done.
• 49:32And the last question of the morning is.
• 49:37Add Seed's answer suggests that
• 49:39vaccines will provide better long
• 49:41term immunity than natural infection.
• 49:44Yes, I believe it does because of
• 49:47what I just said that the the vaccines
• 49:50are inducing incredible levels of
• 49:52neutralizing anybody as well as just
• 49:55a high tide or anybody and they're
• 49:57seeming to be pretty well maintained.
• 50:00Over time there was a study that
• 50:03examined them at six months point an
• 50:05the titers are still staying very high,
• 50:08so that kind of very slow regression
• 50:11of the antibody levels suggests that.
• 50:14The longevity as well as potency
• 50:16of antibody may be better after
• 50:18vaccination than unnatural infection,
• 50:20and so hopefully I mean this
• 50:23is really our way out of this.
• 50:25Pandemic is to get vaccinated and to be
• 50:28protected from acute and long cobin.
• 50:32Wonderful well keep going keep
• 50:34going just have to say thank you
• 50:36so much for spending your Saturday
• 50:37morning with this wonderful group
• 50:39of Yale School of Medicine alumni.
• 50:41It was a fascinating talk.
• 50:42I everyones questions were
• 50:43answered so thank you so much
• 50:45and enjoy the rest of your day.
• 50:48Thank you so much
• 50:49Aaron. OK thanks everybody and I will
• 50:52share that Dean stun Bermond is talking
• 50:55at 11:00 o'clock if anyone's interested.
• 50:58He's the School of Public Health teen
• 51:01and he's also talking about COVID.
• 51:05In the public health setting,
• 51:06so you can switch over for an 11:00 o'clock
• 51:09presentation if you're interested and
• 51:11enjoy the rest of your alumni weekend.