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Serious Adverse Event Time

Lots of uncertainty in the vaccine world today: as many will have heard, the Oxford/AstraZeneca trial in the UK, the US, and Brazil has been paused due to a serious adverse event. The New York Times, citing a source with knowledge of the event, reported last night that this was transverse myelitis. And Nature has noted that the volunteer information sheet mentions such a case as having happened in July – it’s unclear if we’re seeing a second case, or more details on that earlier one, or what. Update: as mentioned in the comments, a later version of the information sheet says that this person was later diagnosed with an unrelated neurological problem, so that might be good news – we’ll see!)

Second update: CNN has obtained an internal AZ report on this incident, and it indeed appears to have been transverse myelitis. There needs to be more openness about all of this.

Transverse myelitis is a rare disorder, an inflammation in the spinal cord that runs right across it (thus the “transverse”) The worrying part is that it (like Guillain-Barré, discussed here) is known to be associated with an autoimmune response that can be a sequel of viral infection. Indeed, it has been associated with SARS-CoV-2 infection itself. It has also been thought to be a rare event after vaccination, but there’s disagreement about that. Here’s a 2009 review of the literature that suggests that it is such, but it’s also worth noting that the Institute of Medicine concluded in 2012 that the evidence for causality was weak. Nonetheless, the association with the immune response to viral infection itself seems solid – there are surely other causes of transverse myelitis, but that’s one of them. And mimicking an immune response to a viral infection is just what a vaccine is supposed to accomplish, and keep in mind that the Oxford vaccine (like the other viral-vector candidates) is in fact a virus, a re-engineered chimpanzee adenovirus in this case, whose entire mode of action is to infect cells in the body. So I think this is indeed an event to be taken seriously, and I think pausing the trial to take stock of what’s going on is entirely appropriate.

Unfortunately, it might end up being very difficult to come to a conclusion, especially if this is a single case. (Edit: if this is a second case, though, that will be very bad news indeed) Welcome to vaccine safety trials and the difficulty of working with such data! As mentioned before, since vaccines are designed to be given exclusively to people who are not sick (a very unusual situation in drug development work!), the safety standards have to be very high. But the adverse events themselves (especially the serious ones) can be extremely rare, and the only way to get a statistical foothold on them is to have a very large controlled patient population under study. The Oxford/AstraZeneca trial is enrolling nearly 30,000 people, and the problem is that that may still not be enough for a definite answer on something like this. We’ll all await more information and I’ll revisit this as it becomes available.

89 comments on “Serious Adverse Event Time”

  1. Peter Kenny says:

    I seem to recall a connection between Guillain-Barré Syndrome and Zika Virus infection and have linked notes from CDC on this topic as the URL for this comment.

  2. SteveM says:

    The developer of the Gamaleya vaccine comments on the relative risk of their product after the AZ report:

    COVID-19: RDIF Points to Absence of Long-Term Studies on Vaccines Based on Monkey Adenoviral Vectors

    https://sputniknews.com/russia/202009091080405657-rdif-highlights-safety-of-russias-sputnik-v-after-oxford-covid-19-vaccine-trials-paused/

    That’s out of my wheel house. Perhaps others could comment on if his observations are legitimate.

    1. E_Ray says:

      Really? You’re talking about the Russian vaccine that was tested in maybe 100 people? And if there was a serious case in those people, do you really think anyone would ever hear about it?

    2. kultakutri says:

      Sputnik news? Really? The pro-Russian source of disinformation?

  3. Dash says:

    Surprisingly the Phase II trial of Oxford/AstraZeneca vaccine conducted by SII in India hasn’t been paused and will be continued as planned. Is that normal?

  4. Ug says:

    Question: do we already know for sure whether the person with the adverse event was in the vaccine or the placebo arm of the trial?

    1. Patrick says:

      Presumably the trial halt was called by the supervisory/monitoring group (whatever it’s called here) and at least part of that apparatus is unblinded, so they can evaluate results.

      And so, presumably yes, they know it’s in the experimental arm and NOT the control arm. Anything else resulting in a halt would be kinda insane.

      1. Adam Hallett says:

        The control group received the meningococcal vaccine. It might not be so insane to halt the trial in this case?

        1. Nicholas Weininger says:

          Yeah, this was what I came here to ask. In order to evaluate the seriousness of this we’d probably need to know

          (a) how common this is in the general population, i.e. if you took N people (where N is however many they enrolled in the trial) and watched them for a couple of months how likely is it that you’d see one of them get this?

          (b) how common it is as a side effect of the placebo vaccine.

          Anyone know either of those numbers?

          Also, the NIH article says that they’ll throw away all the already-manufactured doses if they find that this case was in fact vaccine-related, which seems crazy to just do without running some more numbers. There surely is some finite number X such that if every time you vaccinate X people one of them gets this, it’s still a net good, because the amount of COVID morbidity and mortality you prevent by vaccinating X people exceeds the damage done to that one person.

          1. confused says:

            >>There surely is some finite number X such that if every time you vaccinate X people one of them gets this, it’s still a net good, because the amount of COVID morbidity and mortality you prevent by vaccinating X people exceeds the damage done to that one person.

            Yeah, this concerns me too. I think the amount of harm caused by COVID is large enough that the bar for safety for a COVID vaccine, *assuming it is effective* could be set a lot lower than ‘usual’.

            But even if that makes sense in straight cost/benefit terms, such a vaccine might not see enough uptake to actually help.

          2. Marjorie says:

            From a utilitarian point of view, you’re right, but we’re not just going to vaccinate statisticians. The majority of people will refuse to be vaccinated if there is an established risk of serious side effects, even if the risk is minimal.

          3. Dark Day says:

            . . . and also, at risk of committing physical violence against a deceased equine, we live in an era of scientific illiteracy and innumeracy, fueled by social media-driven conspiracy theories and anti-science bias; this is not the same era as the 1950s and early ’60s, when public confidence in science was such that the polio vaccine, despite some pretty serious setbacks along the way, could be accepted on good faith by the vast majority of Americans. The cold, hard fact is that to garner sufficient uptake in this day and age, a vaccine will have to be held to standards higher than any we’ve seen before — higher, perhaps, than “mere” science and statistical probability are capable of attaining.

          4. confused says:

            @Dark Day: But what is “sufficient uptake”?

            It might not actually be that high.

            Even after approval, it will take time to vaccinate everyone in the US who wants to be vaccinated. We could easily see 20% of the total population infected before a vaccine is available.

            Also, most of the deaths are in a relatively small (elderly) proportion of the population… who might be more willing to take a vaccine with somewhat higher risk, since their risk from COVID is so much higher. If the vaccine is relatively effective then vaccinating most of the elderly population might prevent most COVID deaths.

            I would think a vaccine should be approved first for people over a certain age, then for younger adults, and last for the entire population (since the risk from COVID under age 20 or so is *really* low).

          5. Dark Day says:

            @Confused —

            Unless my math is off, I don’t see where you’re getting that 20% figure. Right now we have had 6.41 million cases documented in the U.S.; that’s just about 2% of the total population. What kind of disastrous spike in new cases are you predicting? Or are you suggesting that it will take the better part of another decade simply to distribute and administer vaccines?

          6. Marko says:

            Dark Days , surely you don’t believe the documented cases represent more than a small fraction of the total who’ve been infected , do you ?

            This is one of the best-performing models out there , and they have the total infected at 15.2%. Nobody with half a brain thinks it’s less than 10% :

            https://covid19-projections.com/

          7. Dark Day says:

            Marko — You may well be right. If so, this is another example of that horrible irony where more cases might actually be GOOD news — the question now, of course, will be the extent to which any kind of lasting immunity results from having been infected. The Iceland antibody study seems to indicate that it might, although the cases of reinfection we’ve seen (esp. the one in which the “second” infection was more seriously symptomatic than the first one) remain troubling. I don’t doubt that immunity brought about by a vaccine could be stronger than “natural” immunity, especially if the vaccine stimulates a robust T-Cell response (e.g., Pfizer, AZ, and — if I’m not mistaken — Novavax), but that would still mean that the vaccine would be “rushing against nature,” so to speak, to develop enough overall immunity before those 10 – 15% of the people who’ve already been infected become at risk to get infected again.

          8. Dark Day says:

            . . . and again, at risk of redundancy, I’m hardly the only one concerned about uptake in the currenet politicized enivornment —

            https://www.newsweek.com/covid-19-vaccine-can-shot-arm-americans-trump-opinion-1531166

          9. Michael says:

            Dark Day, while of course we don’t know duration of immunity, one of two things have to be true (so far) based on everything we have observed at a population level: either reinfection is very rare, or reinfection is abundant but overwhelmingly asymptomatic/mild.

            The “Reno Case” you talk about is very scary, but two separate infections within 45 days, with the second one worse, must be among a small group of outliers (again, so far) or else health care systems would be utterly swamped by now. Humans and their immune systems are highly heterogeneous.

          10. Dark Day says:

            We probably don’t have any data on this yet — but are there any projections in terms of whether mildly symptomatic or asymptomatic re-infected people are less contagious than “first-timers”?

        2. David E. Young, MD says:

          Curious. The 30,000 trial in the US of the AZD1222 vaccine has a saline placebo arm. It is 2:1 for the actually vaccine. No Meningiococcus vaccine as the control. Strange… I am having a difficult time finding the non-US Oxford vaccine trial on clinicaltrials.gov. It may be there, but it is not obvious to me. It doesn’t come up using the most sensible search words. Are you able to provide a link?

          1. David,

            UK study (MenA vaccine control arm) is NCT04400838, Phase II/III sponsored by University of Oxford (https://clinicaltrials.gov/ct2/show/NCT04400838)

            Brazilian study, which also has a MenA vaccine control arm ISRCTN89951424
            (http://www.isrctn.com/ISRCTN89951424), Phase III, sponsored by University of Oxford

    2. Marko says:

      “…The board tasked with overseeing the data and safety components of the AstraZeneca clinical trials confirmed that the participant was injected with the company’s Covid-19 vaccine and not a placebo, Soriot said on the conference call, which was set up by the investment bank J.P. Morgan.”

      https://www.statnews.com/2020/09/09/astrazeneca-covid19-vaccine-trial-hold-patient-report/

  5. FoodScientist says:

    I don’t think they would pause the trial if they were in the placebo arm. They probably checked first.

  6. Matthew says:

    Bound to happen sooner or later, by chance, coincidence or otherwise.

    Let’s just hope the media doesn’t over exaggerate the issue.

    1. SteveM says:

      TM occurrence is said to be rare, (1,400 cases annually in the U.S.) What is probability of at least one occurrence in the healthy population that was inoculated with the AZ vaccine? Given the numbers, I suppose that could be estimated. I hope someone does.

      Here is the NIH write-up on TM:

      https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Transverse-Myelitis-Fact-Sheet

      1. Patrick says:

        Someone already has, and various someones are crunching *very hard* on those and related numbers *right now*, to try to sort this out. That’s exactly what’s going on during the halt.

      2. David K says:

        I back of the envelope calculated around .3% on the low end. However, what is the percentage of any rare event by random happening in the trial itself? Very high.

      3. Tom Maguire says:

        While we wait for the experts, a Quick and Dirty calculation is pretty straightforward.

        US has a population of 280MM (for our purposes,an under-estimate is more conservative.)

        1,400 cases per year is 350 per quarter (assumes no seasonality with, eg, colds and flu). Trial has only been underway a few months.

        So in a population of 280MM we’d expect 350 cases in a quarter. That is 1.25E-06. Tiny!

        But small probability with high frequency eventually becomes inevitability. With, eg, 5,000 already enrolled in the vaccine arm, we would need all 5,000 to dodge a very low probability event. One person has a (1 minus 1.25E-06) chance of avoiding infection. Raise that to the 5,000th power and we get a 99.4% chance the entire group will NOT get TM.

        The US trial proposed enrolling 20,000 for the vaccine. IF the UK trial is similar AND full, then
        (1 minus 1.25E-06)^20,000 = 97.5% chance no one gets TM.

        So, one might say this is either hard luck or caused by the vaccine. BUT!

        We are looking at TM because that is what resulted. Lots of other stray diseases might have occurred, but didn’t. So are we suffering from hindsight bias here?

        TM is just one of a number of auto-immune inflammatory diseases. Suppose ALL such diseased present 14,000 per year, not just 1,400 from TM. Then with 5,000 enrolled we would have a 93.9% chance of avoiding a serious adverse event. An event happening looks more plausible, as long as we aren’t limited to just TM.

        Well. I’m out of ammo, and thank heaven for experts. Based on the background on TM, the patient’s case history will be a key part of the evaluation.

        1. David E. Young, MD says:

          Merkel cell carcinoma of the skin is a very rare cancer. If someone on a vaccine trial gets MCC, I would presume it is a coincidence. Same with a prolapsed bladder, or bacterial endocarditis, achilles tendon rupture, or angiodysplasia of the colonic wall. But transverse myelitis has already been said to occur after some vaccines. That makes it more difficult to dismiss

          1. Another Kevin says:

            You mention that you’d dismiss Achilles tendon rupture as an unrelated event.

            Didn’t we make that mistake with fluoroquinolone antibiotics?

    2. Dark Day says:

      OF COURSE they will, and what the “mainstream” media doesn’t over-exaggerate, social media will. This is raw meat thrown to the anti-vaxxers.

      In a rational world, the public reaction to this might be, “Good. Science works. We’ll see whether this case is an outlier; we’ll use research to cut the wheat from the chaff, and we’ll be more confident that vaccines which complete Phase III without adverse events like this are likely to be safe.”

      But we don’t live in a rational world. We live in a scientifically illiterate, innumerate society. This could well put the kibosh on any hope of attaining sufficient uptake of any vaccine that does eventually get approved. We may be stumbling through COVID Purgatory for a long, long time,

  7. cynical1 says:

    So the scientific community is more than happy to link a rare autoimmune demyelinating disease (Gillan-Barre or transverse myelitis) to viral infections but, despite overwhelming epidemiology linking Epstein-Barr virus to multiple sclerosis and lupus, absolutely no effort has been put towards therapeutics targeting that virus with either disease. Wonder why that is…….

    1. Patrick says:

      What’s *your* theory, then? It would be interesting to hear. I kind of assume it’s some version of “they stand to profit by not treating”, etc.

      So: For every company that stands to benefit by retaining a market by *not* treating something so they can keep selling something, there are half a dozen startups desperate to eat their lunch by treating it better. Oh, and patent clocks ticking before generics eat their lunch too.

      1. cynical1 says:

        My theory on what? Some great conspiracy? Sorry, can’t help you out there. No great conspiracy just intellectual laziness in the scientific community. I have neither the time nor interest in going through all of the mechanistic theories of viral links to autoimmunity on a blog post for your benefit. What you said doesn’t even make sense, there is a market for both Lupus and MS and the industry is using various drugs to treat them. Money is being made. However, no company has or is looking at antiviral mechanisms in autoimmune diseases yet we readily admit and take for granted that viruses play a role in demyelinating diseases of which MS is also one. My one and only point.

        1. Reader 2 says:

          There are some trials that have/are testing the therapeutic link between viruses and MS: GNbAC1 and redemsivir for HERV, and valacylovir/acyclovir for herpes a while back. There is still a lot of basic research to be done first.

  8. Tom Maguire says:

    Unanswered Questions: The protocol (at least in the US, I assume elsewhere) calls for two shots four weeks apart. Presumably, those awaiting their second shot are now caught in the pause.

    https://clinicaltrials.gov/ct2/show/study/NCT04516746

    How long is a typical pause and how disruptive to the results might it be if some patients are vaccinated two-three months apart?

  9. Anon says:

    Hypothetical: Even with the polio vaccine, there was a risk of a “few” vaccinated individuals contracting the actual disease. If I recall correctly, based on a risk/benefit analysis, the decision was made to proceed. Vaccine manufacturers were granted legal immunity, a practice I believe carries on to this day. Given the enormous economic impact of Covid, would society reach a decision to “accept collateral losses” and perhaps price in a compensation fund for the vaccine to take care of the highly unfortunate few that end up suffering from unavoidable very low probability bodily harm? (If this has happened in 2 patients in a Phase III trial, the probability looks a lot higher). What are folks thoughts on this eventuality?

    1. SteveM says:

      How the benefit/risk trade space should be examined question is a very good one.

      An interesting politically related uncertainty would be the U.S. response if a vaccine originating in China or Russia is proven to be clinically superior and available at a competitive price.

      Would the current hyperbolic anti-China/anti-Russia animus coupled with the usual Big Pharma political machinations prevent a superior vaccine from being marketed in the U.S.?

    2. Dark Day says:

      The polio vaccine rolled out during a very different era – most Americans trusted science and scientists; even the Cutter Lab incident, as tragic as it was, wasn’t enough to derail the overall vaccination effort. It’s a different word today. “GOTCHA!” has replaced responsible journalism, and social media-driven conspiracy theories have replaced serious reporting and investigative research. Unfortunately, there’s very little comparison between “now” and “then”.

    3. ghyu says:

      Lower safety standards are acceptable if there is a significant risk from the actual disease to the person taking the vaccine. This was the case for children who got the polio vaccine, but covid is different. If autoimmune events come up with a frequency of 1 in 20,000 then the vaccine might be as dangerous as the virus to children. Such a virus should only be recommended to the elderly.

    4. Charles H. says:

      IIUC, this is the second case of the same disease, but the first case was decided to be unrelated to the vaccine. I don’t know how uncertain that decision was. This case they haven’t decided yet, and I don’t know on what grounds they would decide.

      So my current feeling is …. maybe. I can’t even estimate probabilities. Basing them on population frequencies probably doesn’t work, because there are probably factors that bias things one way or another. A pause to figure things out if probably the correct action.

      As for compensation…yes, there should be compensation given to those who suffer adverse effects. Don’t expect to make them whole, but it should cover medical expenses and economic support. How much support should depend on the severity of the effects, but it shouldn’t be punitive to either party. And it shouldn’t involve lawyers.

  10. Chris Phillips says:

    “The New York Times, citing a source with knowledge of the event, reported last night that this was transverse myelitis. And Nature has noted that the volunteer information sheet mentions such a case as having happened in July – it’s unclear if we’re seeing a second case, or more details on that earlier one, or what.”

    Perhaps it’s worth mentioning that that volunteer information sheet is dated 12 July and says that the case “has not required medical treatment and is being investigated”. And that a later version of the information sheet (5 August) refers only to neurological symptoms and says “The volunteer was later diagnosed with an unrelated neurological illness.”

    1. Derek Lowe says:

      Good point – I’ll make a note of that in the post itself.

      1. Michael says:

        Derek, STAT is reporting (based on an AZ conference call with investors) that the earlier volunteer had multiple sclerosis not related to the trial, and that the present volunteer will thankfully be released from the hospital soon, although of course more investigation is required.

      2. A Nonny Mouse says:

        The first case is reported as being undiagnosed MS,which is why things were up and running shortly after.

    2. Marko says:

      Some further clarification :

      ” #COVID19 So $AZN/Oxford vaccine trial both clinical holds appear due to concerns of transverse myelitis

      1st case in July had symptoms of TM, later diagnosed w multiple sclerosis per STAT, deemed unrelated

      2nd case this wk had symptoms of TM, diagnosis not been confirmed yet”

      https://twitter.com/AndyBiotech/status/1303730191936761860

      1. Dark Day says:

        The different versions of this event being reported are very confusing.

        The Twitter link cited above says that this particular patient “has not required medical treatment.” It also suggests that the AZ trials “could resume early next week,” which is much sooner than other estimates that have already been given.

        Meanwhile according to the website Axios, AZ’s CEO, Pascal Soriot, reported that the patient “had serious neurological symptoms consistent with a rare spinal disorder . . . [t]he participant was a woman from the United Kingdom who will likely be able to leave the hospital by Wednesday.” According to this article, Soriot also confirmed that the patient had received a coronavirus vaccine and not a placebo.

        1. charlotte ferguson says:

          I believe the patient that did ‘not require medical treatment’ (as per the patient medical sheet) was the first patient no? And the hospitalised patient Soriot is discussing is the second? Perhaps I am confused also..

          1. Dark Day says:

            Ms. Ferguson — that might be true. The wording was a little unclear, and I apologize if I misread it.

            Actually, thinking about this a little more, if it’s reported and interpreted correctly [fat chance?!] this cou;d actually be advantageous for eventual vaccine acceptance among the population. People could see this as evidence of integrity on AZ’s part, and whether or not it might make them leery of AZ’s vaccine when/it does finally get approved, it could make them more confident in a different vaccine that completed all three phases without this kind of glitch. And Novavax, which remains my personal focus of interest (I still cling to the hope that the adjuvant will increase the efficacy of their vaccine, especialy for “older” people like myself), won’t have anything ready for review until sometime later — which, given what’s happening right now, can only be good for them.

  11. Dark Day says:

    Sorry — the “early next week” was from a Reuters report on the same incident, not the Twitter link provided by Marko above. I was juggling several reports at once.

    1. charlotte ferguson says:

      Thanks for the reply dark day- apologies I can’t reply on the other thread. I am in the UK and my parents are from Australia who both have significant deals with AZ so this is a setback for me. But you’re completely right there are so many in the pipeline and this is overall a good thing. I will do some research into norovax- thanks

  12. JeffC says:

    To be honest the most likely outcome here is that the AZ-Oxford vaccine is a bust. The SAE is too serious and seeing 2 cases (even if one was felt to just be a co-incidence) when so few patients have been enrolled (compared to how many does are going to be given globally) to ignore as an acceptable side effect. The assumption has to be that it’s drug related and so AZ have to show they understand the side effect and can somehow mitigate it. And that is going to take a bit of time. Unless, they really are lucky and can prove it’s not drug related. But getting off clinical hold is not something that is typically done in days or weeks. By then they will have been overtaken by a number of other vaccines who presumably don’t have this side effect (let’s hope).

    1. Hopeful Layman says:

      Well — isn’t it the case that roughly 40% of vaccines that make to Phase III usually complete the process and get approved? If that’s the case, then we have seven condenders right now (incl. Novavax, which is just beginning Phase III, if I’m not mistaken). That means that four are likely to fail. If this ends up being “one down, three to go,” it’s not the end of the world. In fact, if three vaccines actually do emerge as successful, that would be a remarkable accomplishment.

  13. Roy Badami says:

    There also seems to be a report of one clinical trial participant having a fever of 39.4C after receiving the vaccine. I’m guessing that might be high enough to start to be a bit of a cause for concern?

    https://www.theguardian.com/world/2020/sep/09/oxford-covid-19-vaccine-trial-participant-undeterred-by-pause

    1. Not-an-epidemiologist says:

      You’re assuming that this participant is genuine (there is no indication in the article that the Guardian confirmed this) and was actually receiving the vaccine and not the placebo …

      1. Roy Badami says:

        Sure, lots we don’t know and none of this has been corroborated yet, that I’ve seen. But the article goes on to say “He was also told he was one of a handful of participants who had experienced a similar reaction”.

        Of course, we expect fever as a possible vaccine side effect, and we don’t know that the 39.4C measurement is accurate anyway (the article reads to me that he took his own temperature at home). I was really more curious about how high a fever is too high to be tolerated as a vaccine side effect? At what point do you have to say, “we’re going to have to reduce the dose”, even if that means restarting the phase 3 trial from scratch?

  14. Roy Badami says:

    Apparently the previous incident was multiple sclerosis, and “deemed to be unrelated to the Covid-19 vaccine treatment”.

    https://www.statnews.com/2020/09/09/astrazeneca-covid19-vaccine-trial-hold-patient-report/

    1. MTK says:

      Gotta think that they’re going to take an another hard look at that first case and really make sure it was due to MS, and not just “deemed” to be.

      1. cynical1 says:

        I think you just stated the most important point yet. Multiple sclerosis is in the differential diagnosis for transverse myelitis. I’d really like to see the workup on the first patient who was supposedly diagnosed with MS. There are a lot of things that cause demyelination in the CNS. I also remember Natalizumab being approved and on the market for MS only to be withdrawn later because of PML showing up. Turns out there were deaths in the clinical trials from PML as well. They were just misdiagnosed.

        1. FoodScientist says:

          They probably sequenced their genome asap for the MS

  15. Rudolf says:

    And how rigorously do you think the Russians and Chinese are monitoring those who have received their vaccines. Both seem to be employing widespread usage within priority groups as a substitute for or at least paralleling formal P111 trials.
    At least AZ are responsibly playing it by the book and hopefully will be able to confirm this is an unrelated event.
    However it any event it is grist to the mill of the anti-vaxers and of the eyeball hungry media.

  16. atp says:

    If this pushes back vaccine development it makes synthetic antibodies a more important. How are they progressing?

  17. Squarebird says:

    I got diagnosed with Transverse Myelitis back in November 2019. A month before the TM incident, I was feeling very sick and thought I had some sort of parasite/bacteria/virus from something I had eaten here in LA. I even went to China that same month to see a stomach doctor while visiting my parents in Hong Kong. The neurologists still don’t know the cause of my TM, but this news today about the vaccine freaked me out.
    TM is a very rare disease, and even I have to explain it to some doctors who don’t know about it.
    I’ve read that there’s been around 10 cases of people getting TM a month after Covid.
    Trust me when i say this: The Corona “new normal” is nothing like the “new normal” I experience with TM. You definitely don’t want to get this, and maybe it’s just safer getting the actual virus than the vaccine.
    Getting TM from a vaccine is probably one of the worse things that could happen to you.
    I’m lucky to still be able to walk, but most ppl with TM are in a wheelchair.
    All I know is that the world is crazy right now…

  18. Mr Bill - Oh NO! says:

    Hey Derek – Thank you for posting this information! When I saw this on the news the other night, I had a Paul Harvey moment, wondering what was ‘the rest of the story.’ Appreciate you ferreting out the facts and sharing it!

    Adverse Event! Adverse Event! Guess this means. this vaccine is essentially dead on arrival. Will any amount of hand wringing and after the fact justification going to satisfy the anti-vaxers! I can see it now —> Don’t take the AZ vaccine unless one wants to wear Depends for the rest of their lives. Sigh

    Way I see it in any diverse population, there are going to be enough anomalies or heterogeneity that AE’s are inevitable. I just hope, rather than tossing the baby out with the bathwater, scientist figure out what preexisting conditions are contraindicated, or who is the “safe” population to get this vaccine and limit its distribution on that basis, if it can still do some good, even though it’s not for everyone, it should get approved. After all don’t clinicians have to make decisions on which medicine to prescribe, based on a host of factors?

    Now the real work of communication, in understandable language, begins and will be critical going forward, especially in this cancel culture we find ourselves in.

  19. Barry says:

    The adenovirus vector itself is not beyond suspicions:
    “Adenoviruses are best known as causes of respiratory, diarrheal, and other simple febrile illnesses, but species B adenoviruses can be associated with more severe disease, including severe pneumonia, aseptic meningitis, encephalitis, and transverse myelitis”
    https://academic.oup.com/cid/article/36/5/550/451768

    The subject will inevitably mount immune response both to the Spike protein payload and to the adenovirus vector. If a vector antigen resembles a self-antigen on the myelin, you could sometimes elicit such a cross-reactivity.

  20. Silverlakebodhisattva says:

    Query, (based on my late mom’s history of (relatively indolent) history of MS, back the day (1963-1990) when there was NO real treatment): any possibility that SAE #1’s MS was activated/exacerbated by immune response to the vaccine?

  21. JW says:

    Quote
    “since vaccines are designed to be given exclusively to people who are not sick (a very unusual situation in drug development work!), the safety standards have to be very high”

    If the US continue their home run in cases, it’s not about people who are not sick, but people who will be sick unless vaccinated.

    For high-risk groups the vaccination date is driven more by the date of approval, not so much by production limits. Can they be protected now, or is it still certain death for them if prevalence is high enough?

    Cheap and mandatory mass antigen testing or a miracle cure could change that, however.

  22. li zhi says:

    I’m by no means well-informed about vaccine clinical trials. But. I am dubious that “…vaccines are designed to be given exclusively to people who are not sick…” It seems to me that since there are a lot (~14,000? (plus combinations)) of ways to BE sick, and (arguably) only one (or a few) way to be “not sick”, that designing a preventative for the latter isn’t economically viable. Did you perhaps mean “…are only tested on…” rather than “…designed to be given exclusively to…”? or perhaps “targeted”? Anyway, I’m sure that if a vaccine had a 90% probability of a serious adverse event if given to someone with a mild cold*, that it wouldn’t be approved, even if the AE rate, overall was 0.0001% . Am I wrong? *Or diabetes? Or …

    1. Barry says:

      Before getting any vaccination in the U.S. (exception for rabies?) one is asked about fever, etc.
      Testing is done in healthy individuals and approval is for healthy individuals. Beyond that, it would be off-label.

    2. Derek Lowe says:

      The idea is that they’re designed to be given to people who don’t have any disease serious enough to forestall getting a vaccine – as opposed to normal drug development, where the only patient population are people who have the exact disease under investigation.

  23. Nit says:

    Sorry, but “sequel of viral infection” would be another viral infection. You mistyped “sequela”.

  24. Rudolf says:

    Note that the UK Regulatory Authorities having reviewed the evidence have cleared AZ to continue with the trial.
    This sort of thing happens regularly, but normally would attract no public attention. In this case with the Oxford vaccine probably the most advanced in testing world wide and everyone’s eyes therefore on it, publicity was unavoidable.
    It is unfortunate that the responsible precautionary approach adopted by AZ and the UK regulators will add grist to the mill of the anti- vax brigade.
    Is Covid a game to them?

    1. Chris Phillips says:

      I thought this article from Bloomberg, published 10 days ago, was interesting. It includes a timeline with estimated dates (from an analytics company called Airfinity) for interim and final results from the main Phase III trials. They expect interim results from one of the AstraZeneca trials any time now, and in October four more sets of interim results from AstraZeneca, Pfizer, Moderna and Sinovac and final results from one of the AstraZeneca trials, with interim results from Johnson and Johnson early in November:
      https://www.bloomberg.com/news/articles/2020-09-03/frontrunning-covid-vaccines-will-soon-see-their-moment-of-truth

      I was also interested to see this paper with statistics on success rates for clinical trials. If I’m interpreting it correctly, for vaccines in general 85% of those that get as far as Phase III have been approved. While I appreciate that COVID-19 will be a far from typical situation, that is higher than I had expected:
      https://www.researchgate.net/publication/322917762_Estimation_of_clinical_trial_success_rates_and_related_parameters

    2. Dark Day says:

      No, it’s not a game to them — but I do think that the “glitch” in the AZ trials will cast a dark shadow on their vaccine, even when/if it does complete Phase III and win approval. Under the best of circumstances, many/most laypeople don’t really understand the scientific process, and in our era of social-media-driven disinformation and ignorance, we’re far from the “best” of circumstances.

      One of two possible scenarios may result: (1) If another vaccine also completes Phase III successfully and wins approval (which will certainy happen at some point, even if not at “warp speed”), people who were too leery to accept AZ’s vaccine will rush to take the new one; or (2) as you suggest, the AZ “glitch” will entrench and expand the anti-vax beliefs so thoroughly that NO vaccine will be trusted enough to allow for sufficient uptake. And remember, even before the current situation arose, confidence in a vaccine among people of color in the U.S. was hovering somewhere around, or just below, 50% — some of our most at-risk individuals are among the least likely to get vaccinated.

      Which brings me to another question: Just as it’s possible for a candidate to win the popular vote but lose an election due to Electoral College math (i.e., winning most states, but not the “right” states), is it possible for overall vaccine uptake to reach — let’s say — 75 – 80%, but the rate of uptake among high-risk communities to remain too low for mass immunity to really take hold? COVID “hot spots” don’t stay isolated forever, so unless an acceptable rate of uptake is seen across AND within all communtiies, not just as an aggregate total among the population as a whole, I could see this as being a very serious hindrance.

      1. confused says:

        If the US overall had herd immunity due to vaccination but specific hotspots did not, wouldn’t that mean local outbreaks, but not further spread?

        Hotspots wouldn’t stay *isolated* but wouldn’t herd immunity elsewhere prevent expansion?

        Isn’t that essentially what’s happened as vaccination rates in particular communities fall below herd immunity for things like measles/whooping cough – relatively local outbreaks, but not regional or nationwide ones?

        Or am I missing something?

        1. Dark Day says:

          Yes, that’s my question. Not being an epidemiologist, I honestly don’t know the answer.

          More importantly, though, those “hotspots” would be vectors of ongoing illness and death, often in communities already segregated from — and shunned by — the “mainstream” majority. At worst, they could become “COVID ghettos” where this infection, along with all the other medical and social pathologies that threaten life and safety in poor communities and communities of color, would remain a constant, toxic threat. We cannot afford to become complacent, assuming that because only “those people” were at risk, it would no longer be an important national priority. I know that’s not what you’re saying, but I think we have to admit that attitudes like that are all too common in the U.S. (e.g., gun violence, narcotics addiction, underfunded school systems, inadequate housing, etc.etc.etc.) We can’t afford to slip into this kind of thinking in this case.

  25. Hopeful Layman says:

    Not sure how to respond to this news — earlier reports I read seemed to indicate that a nasal vaccine might be feasilbe, but would take quite a bit of time to develop. Now these reports seem to be suggesting that already-existing vaccines could simply be spritzed into patients’ noses or mouths, and inhaled that way. Is this a meaningful development, or are the journalists misunderstanding what’s going on?

    1. Barry says:

      Formulation of a vaccine would be different for a nasal delivery. But the same antigen (Spike protein or RBD of the Spike protein for most of the candidates) might be delivered either by injection or as a nasal gavage, or as an aerosol to the nose. But it would require whole new Clinical trials.
      So it depends on what one means by “same vaccine”

  26. DataWatcher says:

    This looks disturbingly as if AstraZeneca did some serious fudging in their initial press releases. I’ll stop short of accusing them of blatantly unethical behavior, but I’m wondering what other people here think of this.

  27. Jean-françois Guéganton says:

    Bonjour,
    Mon petit fils a été vacciné à 9 mois avec le ROR (MMR en anglais). Alors qu’il était en pleine forme avant la vaccination, quelques jours après il était paralysé. Il a eu une myélite transverse. Il a aujourd’hui 10 ans et reste fortement handicapé, marchant difficilement avec un déambulateur. Les médecins qui l’ont soigné à Marseille (France) nous ont affirmé qu’ils ne savaient pas ce qui avait déclenché cette maladie mais qu’ils étaient certains que ce n’était pas la vaccination. Aucun signalement n’a été fait aux autorités de santé. La notice du ROR indique maintenant la myélite comme effet secondaire, ce qui n’était pas le cas quand mon petit fils a été vacciné. Avant cela j’étais favorable aux vaccination, aujourd’hui après m’être beaucoup renseigné je suis beaucoup plus critique. Je pense que les laboratoires et les autorités de santé exagèrent beaucoup les risques de ne pas être vacciné et minimisent énormément les risques des effets secondaires.

  28. Chris Phillips says:

    Perhaps it’s worth noting another adverse event in the Brazilian trial of the AstraZeneca/Oxford University vaccine, namely the death of a participant. But according to unofficial sources, the person who died had received the placebo, and the trial has continued without a pause:
    https://www.washingtonpost.com/world/the_americas/coronavirus-oxford-astrazeneca-vaccine-trial-death/2020/10/21/3f5bedac-13c0-11eb-ad6f-36c93e6e94fb_story.html

  29. Chris Phillips says:

    According to Bloomberg, Moncef Slaoui says he understands the restarting of the AstraZeneca trial is “imminent” and hopes that the Johnson and Johnson trial will also restart this week:
    https://www.bloomberg.com/news/articles/2020-10-21/warp-speed-chief-says-j-j-astra-trials-could-restart-this-week

    1. Chris Phillips says:

      The AstraZeneca vaccine trial has now resumed (after nearly seven weeks) and the Johnson and Johnson trial is expected to resume next Monday or Tuesday:
      https://www.reuters.com/article/us-health-coronavirus-astrazeneca-usa/astrazeneca-resumes-us-covid-19-vaccine-trial-and-jj-prepares-to-do-same-idUSKBN2782KF

      1. confused says:

        I wonder what will happen for those people who got the 1st shot before the halt, but not the 2nd. Does the longer time in between impact the trial?

        (Or does this vaccine candidate not require 2 shots?)

        1. DataWatcher says:

          AZ requires two — J&J just one (which is one reason a lot of people are really hoping for it).

          1. confused says:

            OK, thanks – so what would increased time between 1st and 2nd shot mean for the AZ vaccine?

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