The Immunology of Long COVID: Q&A Follow Up with Professor Akiko Iwasaki

February 27, 2024

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Dr. Iwasaki answers questions sent in by LISTEN participants following her presentation on November 10, 2022.

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00:32Hi, Akiko. So there were a lot
00:34of questions and we I think you
00:36have been able to answer about 10
00:38questions earlier during the talk.
00:40I will be asking you a few more
00:43questions that had been shared
00:44by many of the viewers and
00:46participants from the LISTEN study.
00:48So the first question that I
00:50have today is so not finding auto
00:54antibodies especially means that
00:56it appears as the long COVID
00:58is not an autoimmune disease.
01:01Are long haulers considered
01:03immune compromised?
01:06Yeah. So let me be clear
01:08about what we actually found.
01:10We found using the rapid Excel
01:14antigen profiling developed by
01:16Doctor Rings lab that auto antibodies
01:20against extracellular proteins
01:21or secreted proteins from humans.
01:24We're not enriched in long COVID
01:26so we haven't specifically started
01:29to look at intracellular antigens.
01:32However, as you have done Bornelli,
01:35we have also unpublished data that
01:37demonstrate that there really isn't
01:39a striking difference in Lupus
01:41related auto antibodies at the time
01:44point that we are looking at which
01:46is well over a year after infection.
01:48So this means that it it doesn't look
01:51like a typical autoimmune disease to us.
01:54It may have, for instance,
01:56of involvement of T cells which
01:58we have not examined yet.
02:00So I don't want to rule out T cell
02:03mediated autoimmunity as a possibility.
02:06However, we we are not,
02:08we don't have any concrete evidence that
02:11supports autoimmunity at this point.
02:13It is possible though,
02:15that down the road years from now,
02:17some people may have an increased
02:20risk of developing autoimmunity,
02:22just like what's been shown for
02:24a multiple sclerosis in EBV.
02:26So I don't want to rule out a
02:29link in the future,
02:30but currently we're not really seeing
02:32a very strong signal for autoimmunity.
02:36OK,
02:36I'll move on to the next question.
02:38The next question is, will those of
02:40us with PEG allergy be able to use
02:43the nasal vaccine you have developed?
02:46Oh, right. So the nasal vaccine
02:49we have developed is a booster
02:52nasal booster strategy.
02:54So how it works is we leverage the
02:59existing immune responses developed
03:01by the mRNA vaccines and by
03:04inoculating spraying the recombinant
03:07spike protein into the nose and
03:11that establishes robust antibody
03:13anti cell immunity in the nose,
03:16throat and the lung of these animals.
03:19It's it's only preclinical right now.
03:22We are trying to raise funds to be able
03:24to do this in human clinical trial.
03:26We haven't done that yet.
03:27However, when it becomes available,
03:29I don't think there is any problem with
03:32people with PEG allergy because the
03:35recombinant spike protein contains no PEG.
03:37It's just a simple purified protein,
03:40no other events, no formulations.
03:42So I think that that would be a safe
03:45thing to use for people with PEG allergy.
03:49OK.
03:49The next question is related to cortisol.
03:52So people are asking what is
03:54happening with ACTH levels then,
03:57right? So our data show that
04:00even though the cortisol level
04:02is about half of that of healthy
04:04control in the long COVID patients,
04:07the ACTH which is a hormone secreted by
04:11the pituitary gland is not elevated,
04:14meaning that normally a low level
04:17of cortisol should be countered by
04:20increasing ACTH level to elevate the
04:22cortisol level from the adrenal gland.
04:24And that is not what we're seeing.
04:26And so we suspect that there might
04:29be defect within the pituitary or the
04:31hypothalamus which kind of tells the
04:34pituitary glands to make the ACTH.
04:36Maybe these central Oxys are not working
04:39properly in the long COVID patients.
04:42So what Doctor Petrino's group is
04:45doing is to look at MRI from these
04:49Mylon COVID participants to see if
04:51there's any defect that they can pick
04:54up in the central nervous system that
04:56might explain this cortisol reduction.
05:01The next question then it's related
05:03to the study that we are doing.
05:05So it says the person asks,
05:07I have already joined and
05:09completed the initial survey,
05:10are we able to participate in a
05:12study in which they are looking
05:14for things like cytokines,
05:15cortisol, etcetera,
05:18right. So the lesson study,
05:20it is currently collecting all the
05:23surveys from all of the participants,
05:25which is really important.
05:27That's what allowed us to look
05:29at the demographics and symptoms
05:32in people with long COVID versus
05:35post vaccine long haul and so on.
05:37And in the future,
05:38in a very near future,
05:40we will be asking some of the
05:43participants to participate in
05:44research study where we are going
05:46to be looking at all the different
05:49parameters that we've studied in the My
05:51long COVID study including cytokines,
05:54antibodies and then cortisol levels
05:58and many other features that
06:00we are currently looking into.
06:02So yes, some of the listened
06:05participants will be contacted to
06:07see if they also want to provide
06:09a blood samples or saliva.
06:13So this is another question
06:15from an interested participant.
06:17Very much agree with the urgency
06:19for vaccine complications.
06:20So much information coming out
06:22from everywhere on long COVID.
06:24But Yale Listen is the only major
06:27institution even mentioning vaccine effects.
06:30Can you increase profile of
06:32vaccine complication research
06:33since you are the only one doing?
06:36It's hard to maintain pro
06:38vaccine stance in the absence
06:40of etiology or therapeutics.
06:42Very hesitantly got the booster,
06:44but I'm quite worried that I'm an
06:46idiot to continue to get boosters.
06:51Well this is yeah,
06:53I'm sorry that you're suffering
06:55from this and I hope you did not
06:58suffer any post booster effect.
07:00So the currently it's frustrating
07:03that we don't even understand what
07:06to recommend to people who have a
07:09long COVID or post vaccine issues
07:12whether they the the boosters are
07:14going to be safe and what percentage
07:16of the people are going to have
07:19a similar kind of symptoms that
07:21they experience with other shots.
07:23So without having the the data
07:26to support one way or the other,
07:30boosters are obviously very important
07:33for providing protection from
07:35severe disease from the current
07:38Omicron pandemic that's going on.
07:41And so you're not at all idiot
07:43to to get the booster and I I
07:47really hope you didn't suffer any
07:50consequences that are more than
07:52just regular React reactogenicities.
07:56So yeah,
07:57this is a very important
07:59question and and as I mentioned
08:02earlier in my other responses,
08:05you know the vaccine post vaccine
08:07syndrome that that we are seeing
08:10here in the lesson study and and
08:12elsewhere in the world hasn't
08:14been studied rigorously.
08:16And that's what we're trying to do with
08:20the lesson and to elevate the profile.
08:23I think the best way to elevate
08:25the profile is actually doing the
08:28study and demonstrating biological
08:30factors that correlate with vaccine
08:33related adverse events.
08:35That way we can understand the
08:38underlying etiology of that disease
08:40and whether that's related to long
08:43COVID and ultimately the driver
08:45of of those diseases.
08:48So we are hoping that through doing
08:51rigorous studies that we will be
08:53able to highlight and elevate the
08:55importance of doing such a study.
08:58And that's why at Yale lesson we
09:01are dedicated to figuring out both
09:04kinds of diseases at the same time.
09:08So here's a question about the viral genome.
09:12Do we know if there has been a study
09:14that analyzed full genome of virus
09:17indicating replicating competent virus?
09:21OK. So I think this question pertains
09:25to the viral reservoir or OK.
09:29So yeah, I I don't know of any
09:33studies that have test looked at
09:36the sequences of the viral genome
09:39that's within these tissues.
09:41That's a very important question and
09:44very important research endeavor
09:46to actually do because right now
09:48we don't know whether the bits of
09:50RNA that people are detecting from
09:52intestinal biopsies for example,
09:54whether they represent fully replication
09:57competent virus or some defective,
10:01you know, particle or just segments
10:03of the genome that remains somehow in
10:06different compartments within the cell.
10:08So this is a very important question
10:11that needs to be addressed.
10:13I I haven't seen much studies on that yet.
10:18Here is a question about
10:20mitochondrial damage.
10:21So the participant is asking
10:22how much focus is being placed
10:25on mitochondrial damage related
10:26to vaccine injury and viral
10:29induced long haul or long COVID,
10:32Right. So one of the the key physiological
10:36defects that are have been reported
10:39for at least long COVID is that oxygen
10:43utilization by tissue is quite impaired,
10:47meaning that even though they're
10:49circulating oxygen levels in the blood,
10:51that blood blood oxygen isn't being
10:54properly utilized by the tissue like the
10:56muscles and other areas that we all need.
10:59Every cell in the body needs oxygen,
11:02whether that stems from mitochondrial defect,
11:06mitochondrial damage,
11:07or whether it stems from vascular
11:11defect or microcloths or some other
11:14issues we don't quite understand yet.
11:17There is plenty of evidence for platelet
11:21activation and micro clot formation and
11:26vascular damage in long COVID patients and
11:31and and that could certainly results in
11:34the reduced use of oxygen by the tissue.
11:37So whether the defect is
11:39upstream of mitochondria,
11:41or within the mitochondria or
11:43downstream of mitochondria,
11:44we don't quite understand well.
11:48Our team is also looking into this by
11:51looking at morphology of the mitochondria.
11:54We are collaborating with an expert
11:57Doctor Thomas Horvath at Yale
11:59University who looks at this using
12:02electron microscopy and we're also
12:04measuring the function of mitochondria
12:07from the people with long COVID.
12:10And obviously once the listen study
12:13launches we would love to do the
12:16same for vaccine related adverse
12:18event people with with that as well.
12:21Thank you. Here is a participant
12:24who wants to know a little more
12:27about post vaccination syndromes.
12:29This participant first congratulates
12:30you for your amazing work and then the
12:34question is post vaccination syndromes
12:35have never formally been studied even
12:37though we have seen them for HPV vaccines.
12:40Have you looked into G protein coupled
12:43receptor antibodies which have been
12:46identified in patients with POTS or DIS,
12:48Autonomia, long COVID and MECFS?
12:53Right. So because we have the
12:55fortune of collaborating with
12:57Doctor Aaron Ring's lab who has
13:01multiple GPCRS included in the REAP,
13:04we are able to detect if there are
13:07any of auto antibodies against GPCRS.
13:10And you know we are seeing,
13:12I mean so even healthy people have
13:16have multiple auto antibodies that
13:18that don't really cause any diseases.
13:20So it's very important to understand
13:23how different are these anti GPCR
13:25antibodies in a disease group
13:27compared to the healthy control.
13:30And so far studies that the the
13:33questioner is referring to hasn't
13:36done that hasn't really compared Potts
13:38versus healthy controls and so on.
13:41And there is a study that that has
13:43compared on the GPCR antibody levels
13:45in Potts versus healthy control and
13:47they haven't found any differences
13:49in the level or the intensity.
13:51So we have to be cautious like every
13:55study needs to be looked at with this
13:58with the eye of whether there has
14:01been a proper control group included.
14:03And if not,
14:04we need to be able to do that in the future.
14:07Otherwise we may be you know
14:10focusing on antibody auto antibodies
14:13that are not at all pathologic.
14:16As I mentioned,
14:17all of us carry lots of auto
14:19antibodies that don't do anything.
14:21So let's just be cautious about that
14:23to to do a proper study with the right
14:27controls and then see if there are
14:29specific auto antibodies that are coming up.
14:32So far with our Mylon COVID,
14:35we are not seeing specific
14:38anti GPCR antibodies that are
14:40enriched in long COVID patients.
14:44Thank you, Akiko.
14:45So the next question is
14:47from a participant who says,
14:49so we are still identifying
14:52characteristics of long COVID and
14:54there is no focus on pathology.
14:57So that's the question.
14:58Oh, I'm sorry. Can you
15:00repeat the question? Yeah,
15:01sure. So the participant is a little
15:03upset that we are still identifying
15:06characteristics of long COVID without
15:08focusing on the pathology so far. Oh,
15:12I see. Well, that's what we're trying
15:14to focus on with our own studies.
15:17It's to look at the what is the
15:20pathology and more specifically what
15:22is the pathogenesis of this disease,
15:25which means what are the molecular
15:28triggers that ultimately results in
15:31the defects that are being detected
15:34in the patients with one COVID or
15:37vaccine related adverse events.
15:39So for instance the vascular
15:40damage and things like that are
15:43downstream of something that happens
15:44as a result of the infection.
15:47We want to connect the dots between the
15:49infection all the way to the pathology
15:52that's being detected in these patients.
15:54So without that line,
15:56it's very difficult to intervene
15:58with this process, right.
15:59So if what if we want to give the
16:02most promising therapy for people who
16:05are suffering from these diseases,
16:07we really need to know the driver.
16:10And in order to understand the driver,
16:12you need to just deeply profile these people.
16:15And and that's what the whole purpose of.
16:17Yeah, listen study is.
16:20Thank
16:20you, Kiko. So this brings me to the
16:23last question that I have on my list.
16:25So the last question is about EBV
16:28reactivation. The question is,
16:30could the EBV or other latent viruses,
16:33reactivation of which be mainly due
16:35to the overall TH1 to TH2 shift?
16:40Yeah, I mean, I'd love to know
16:43why EBV reactivation is occurring
16:46in a subset of long haulers.
16:50There are many theories.
16:51We don't have a a real answer yet,
16:53but many sort of triggers can cause
16:57reactivation of these latent viruses,
17:01one of which is defect in T
17:05cell surveillance of these viral
17:08latent viruses and that may be
17:10what's happening in these people.
17:12So Jim Heath's group has shown
17:15nicely looking at the longitudinal
17:18study from the time of COVID
17:21infection to three months post
17:24COVID infection that there is this,
17:29the viremia that occurs as a
17:31result of EBB reactivation happens
17:33in a subset of people who who
17:35then go on to develop long COVID.
17:38So it's one of the four risk factors
17:40for developing long COVID that you
17:42can look at during the acute phase.
17:45So that to me suggests that this ebb
17:48latency is somehow broken or or like
17:52allowing to become reactivated as a
17:54result of the acute infection phase.
17:57And that could be because of the
18:00source code V2 viruses impact on
18:03T cells or surveillance by the T
18:06cells that is enabling these like
18:09latent viruses to become activated.
18:12There could be other reasons.
18:14And one of my graduate students is
18:17actually looking at why this might
18:19happen using a variety of different models.
18:23Right now,
18:23we don't know how the ebb reactivated
18:26and what the consequences of that is.
18:29So it's a very important question,
18:31but we have very little data on that.
18:34OK, go.
18:35These were the questions that
18:36I had on my list. Thank you
18:38for your time. Thank you so much, Bernali.