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  1. #1
    Join Date
    Feb 2007
    Hot'Lanta... home of the Falcons!

    Important information on COVID-19

    Here at the DBR we are quite fortunate to have a community that contains more than a few experts on various topics. At times, those experts can provide invaluable information to the entire community.

    Toward that end, the DBR moderator community want to highlight a pair of recent posts from the Coronavirus Plaguewatch thread. We recognize the thread is long and not everyone is able to keep up with it, which is why these two posts are being pulled out to ensure they can be read by the entire community.

    It is possible that we will periodically add new, informative posts to this thread, but if you want to reply to any of these posts, we ask that you do so in the Coronavirus thread itself. Replies to this thread will be locked, though it will be stickied to the top of the Off-Topic forum.

    Thanks and prepare to be educated...

    -Jason "we are truly lucky to have experienced medical professionals answering our questions at a time like this" Evans
    I don't know what you are doing right now, but if you aren't listening to the DBR Podcast, you're doing it wrong.

  2. #2
    Join Date
    Feb 2007
    Hot'Lanta... home of the Falcons!
    This post came in response to a discussion about an article in The Atlantic that cast some doubts about how America would react to a vaccine. If you want to read the entire conversation, try dropping in on the Covid thread here.

    Quote Originally Posted by tbyers11 View Post
    Hi - I have a PhD in viral immunology and worked in the field for 20 years, the last 10 with a large company that makes vaccines and I currently work in R&D for flu vaccine development. There are a lot of questions on many posts in response to the Atlantic article. Since freshmanjs listed many of them here I'll give responses to the best of my knowledge here

    A vaccine is likely to limit serious disease rather than all disease. - Yes, the COVID-19 vaccine as with many vaccine is not likely to provide sterilizing immunity but will hopefully reduce death, hospitalizations and severe cases greatly. If the "death rate" could drop from say 1% to 0.1% and the hospitalization rate from 15% to 1.5% that would be great. SARS-CoV-2 is not going to disappear a few months after a vaccine is available but if we can manage it like the other respiratory viruses that circulate (flu, RSV, parainfluenza, common corona, rhino) would be the goal

    A lot of doses will be required and that is logistically complicated - It seems very likely that the first COVID vaccine approaches in the pipeline will require 2 doses with the second one occurring about 3-4 weeks after the first. And then subjects would likely have their peak Ab response about 2 weeks after the second dose. So vaccine Ab immunity will peak about 6 weeks after first dose. Anytime that a vaccine requires 2 dose it is logistically much more difficult but it is not a failing of these first COVID vaccine approaches it is common that vaccine to naive (unencountered) viruses require 2 doses

    The 2009 flu vaccine only ended up being used in 20% of the population because demand was low, as the disease had become much less prevalent - Not as much of the 2009 "swine" flu H1N1 vaccine was used as was produced is true, but it wasn't due to that strain of flu becoming less prevalent. The H1N1 pdm/A/California strain that appeared in 2009 was the exact H1N1 strain in the seasonal flu vaccine for 7 years (meaning it was most prevalent circulating strain). The swine flu vaccine process began in April (after it was discovered) in March and large amounts of doses were made by Oct/Nov which is impressive. However, that specific vaccine was not needed as much as was thought because pre-existing T cell immunity from previous (but different H1N1) seemed to lessen the severity of the disease in most people

    Flu mist is scary because it's alive. - FluMist is live but it attenuated through cold temperature adaptation. It only replicates at around 33C when the human body is 37C. So while there is risk with any live vaccine, FluMist was quite safe. I do have issue with the NYT article about how live, intranasal vaccines would be preferable for coronavirus. While it is a true statement that intranasal administration of a live vaccine would theoretically be preferred because it is more likely to induce IgA Abs (the type associated with mucosal response in the lungs), the reality is that has no one has effectively proved that in dozens of years in human flu vaccine research. FluMist did show better response in kids (we gave it to our son when he younger) it was largely thought that improvement was due to enhanced T cell responses to FluMist and not to IgA Abs. VaxArt (mentioned in the NYT article) has been trying an oral flu vaccine approach for awhile but AFAIK have not gotten to a phase 3 efficacy trial yet. IgG Abs induced by intramuscular administration seem likely to work well enough for COVID-19 (early results are promising but not yet definitive

    Other thoughts on timing and manufacturing supply chain: This is an issue not be given enough attention in the rightfully optimistic articles about Ph 1 success. Moderna is supposed to start their Phase 3 efficacy trial next week. If everything works perfectly it will take 3 months to know if the trial was successful. Not all 30,000 people can get the vaccine on Day 1. Normally it would take 2 months to enroll this many people. Assume they streamline it to 1 month. As I said above it will take about 6 weeks to reach peak Ab response with a 2 dose regimen. So in an efficacy trial that would be the bare minimum time to determine if the vaccine is better at preventing/reducing disease than the placebo. So that's 10 weeks. Need some time to compile the data and present to FDA. This would normally take months but even if it fast tracked that's 2 weeks and about 3 months total.

    However, as the Atlantic article pointed out we have to manufacture 100 million doses, which is a huge undertaking. For my company it takes normally 5-6 months of highly entwined processes to make, fill vials, package, and distribute 100 million doses of flu vaccine. The filling, packaging, and distribution requires a lot of expertise but that expertise can be bought. The tricky part is upscaling your manufacturing processes from say thousands of research grade doses to millions of manufacture grade doses. This process can theoretically go quicker with mRNA but can be fraught with lots of pitfalls. Moderna has contracted with Lonza to do this but who knows. In addition to the technical and logistical difficulties, normally you don't start manufacturing a vaccine at risk (before FDA licensure). Not a sound financial strategy. Now Operation Warp Speed is likely to help provide $$$ to start these processes at risk but I'd say we have 1-2 months minimum from licensure to having say 10 million doses available.

    Deciding who gets these doses and how to distribute these doses should be underway by the federal government right now. But I have seen no efforts on this front. NIH/FDA have experience in the running trial and regulatory approval but not in distribution. That is generally left to the individual companies. That doesn't seem like a good idea for COVID.

    So in summary. I am more optimistic than the tone of the Atlantic article that we will have effective vaccines. I agree with Jesse Goodman (former FDA official quoted in the Atlantic article) that we are probably 5 months from say 10 million doses of a vaccine. This won't be wrapped up by Christmas. Not even close. However, I think that with the second wave of companies (that are a few months behind Moderna/Pfizer) we will have hundreds of millions of vaccine available by late spring early summer 2021. Enough to vaccine all in US that want it. If enough people get the vaccine, I think we could have a situation where COVID-19 is a bit more like a normal respiratory virus public health situation by fall 2021. However, sadly we won't really know if that is the case until we get through the 2021 flu season. So, in my opinion there is a likely path at the end of the tunnel I just don't think it is quite as close as some articles make it seem.
    I don't know what you are doing right now, but if you aren't listening to the DBR Podcast, you're doing it wrong.

  3. #3
    Join Date
    Feb 2007
    Hot'Lanta... home of the Falcons!
    And if you have not been reading all of RSVMan's posts in the COVID thread, you are missing out on some serious knowledge. Like tbeyers, RSV is a immunology professional.

    Quote Originally Posted by rsvman View Post
    I read through the article. I didn't think it was that bad, actually. The person they quoted about potential for misted live-virus vaccine is a friend of mine I used to work with at Vanderbilt many years ago. She is an influenza expert. Many of the trials that allowed FluMist to go to market were carried out at Vanderbilt by a team that included her, Bill Gruber, Peter Wright, and others.

    FluMist was never dangerous. At all. Period.

    When thinking about live attenuated vaccines, there are a few things of importance; perhaps the most crucial point was not mentioned in the article (Dr. Neuzil probably thought it was too complex for a lay article) and that is this: How stable is the attenuation?

    Once you put a live, replication competent vaccine virus into a human body, it replicates. Virus can make many, many copies of themselves. In some past vaccines, with multiple rounds of replication the attenuation would go away, yielding a wild-type virus. This was case, for example, with oral polio vaccine. Oral polio vaccine attenuation was actually highly unstable. It reverted to wild type virus with alarming frequency. It was also spread very easily in the community, which actually helped contribute to herd immunity (even "unvaccinated" people were getting vaccinated!). The good news was that even wild type polio infection was benign in the vast majority of people who contracted it. Thus, we were able to get away with using an unstable vaccine for many years, and achieving herd immunity by having the vaccine spread all over the community. Babies and children vaccinated with oral polio vaccine would shed it in their stools for weeks to months. Because of this, for many years we had small numbers of children getting what was known as "VAPP" (vaccine-associated paralytic poliomyelitis), generally between 3 and perhaps 10 or 11 kids per year in the U.S., averaging about 5 or 6 per year. I actually took care of one of these kids when I was at Vandy. This is the reason that we moved away from oral polio vaccine and now exclusively use the injectable vaccine (which is not live).

    On the other hand, we have been using live measles, mumps, rubella, and varicella vaccines for long periods of time without any real problems.

    Back to FluMist. There is a lingering belief that the vaccine could be spread to others, but there have been no reliable case reports of this. The original studies looking at the potential for spread were done in daycare centers, to maximize the chances that spread would occur. They gave half the toddlers in the daycare the vaccine. They did nasal samples for vaccine virus every day in every kid, looking to see how long it was shed and whether it would spread. The official report of the research says that there was one child who did not receive vaccine who developed infection with the vaccine virus, but in truth it was probably a labeling error. Kid A, who got the vaccine, tested, on consecutive days, positive, positive, positive, negative, positive, positive. Kid B, who did not receive vaccine, tested, on consecutive days, negative, negative, negative, positive, negative negative. So on that one day, the vaccinated child suddenly stopped shedding for one day, but started up again the next? And the unvaccinated kid, supposedly infected with the vaccine virus, shed it for only one day and then cleared it? And that day just happened to coincide with the day the vaccinated kid cleared it transiently? Yeah, right. The samples were labelled incorrectly (in my opinion). So, bottom line, even toddlers in a daycare couldn't figure out how to share it with others. And, the attenuation was incredibly stable.

    The reason FluMist fell out of favor was not because it was dangerous but because there was a problem that led to inefficient protection from H1N1 for one season. The problem was solved by the company by the next year, but by then the horse was out of the barn.

    It is not at all clear to me that a live attenuated vaccine misted up the nose would be superior to other forms of vaccines for SARS-CoV-2, although the argument could be made that allowing a replication-competent vaccine virus to replicate generally produces a broader response, usually including some T-cell responses to internal proteins, which could be helpful as most viral mutations take place in the outer proteins.

    What was I talking about? Oh yeah, live attenuated viral vaccines. So, the next concern is will the vaccine produce immunity without making the recipient ill? That's a fine line to walk; attenuate the virus too much and it will be tolerated fine but not produce significant immunity. Attenuate it not enough and it will make people sick.

    Finally, will it be spread to others? The general public would see spread as bad, and it probably mostly is, because if we had a live virus vaccine we would not give it to people who are severely immune suppressed. If it spread around readily we could not control who would get "vaccinated," and that could lead to disastrous consequences.

    Sorry if this was too long. Talk about walking a fine line...if I gloss over stuff too much it won't have any meaning but if I go too deeply into it, nobody will want to read it and/or it will be really difficult to understand. I hope this was on that line, providing information that is understandable and helpful without being overly technical and ridiculously boring.
    I don't know what you are doing right now, but if you aren't listening to the DBR Podcast, you're doing it wrong.

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