OT: COVID Science - Pfizer/Moderna vaccines >90% effective; Regeneron antibody cocktail looks very promising in phase II/III trial and more
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Small numbers in select group of well subjects progressing to mild disease. Not so fast my friend. You are potentially looking at yearly vax and boosters. The subpopulations who need it the most may also reject it.
We need a durable response that keeps vulnerable from progressing to icu. Also what immunity looks like in this disease is not well defined and the ability of a vaccine to halt the vector state, the ability to stop infectivity
Possibly yearly, which I can live with to not possibly die - sure, we don't know yet how seriously ill the people woh get vaccinated and still get the virus will get (in theory less ill than if they hadn't been vaccinated) and we don't know how long immunity will last, although the vast majority of recovered patients look to have 6+ months of good levels of neutralizing antibodies. But, given those questions and the supercold supply chain and needing two shots and not having enough doses for 3-6 months, at least, is why we need more vaccines and probably better ones. Also, recall that "success" was considered 50% efficacy, so 90% is a gamechanger, IMO.
My problem with the promotion of this headline is people letting their guard down in terms of the other more effective measures of masking and social distancing. I already have patients thinking they're going to get a shot and ride the subway to Yankee stadium.
So right now I think this is good news especially when we have not much else and it's reasonable to think that severe disease may be prevented...maybe... but it's too little, too late in my opinion and it's not going to be a Magic bullet and you are looking at the winter of my discontent coming full steam ahead.
So right now I think this is good news especially when we have not much else and it's reasonable to think that severe disease may be prevented...maybe... but it's too little, too late in my opinion and it's not going to be a Magic bullet and you are looking at the winter of my discontent coming full steam ahead.
Agreed, especially with hospitalization rates poised to skyrocket to maybe 1.5-2X what they were in April and July, meaning there's a very serious risk of overwhelming health care systems in some locations (we're already there in some) - and hospitalizations are a far better indicator of the pandemic's seriousness than cases. Also, deaths are likely to go back up to close to April levels again, since we don't yet have the widespread better treatments yet (antibodies look good, but we don't have nearly enough for all patients yet) and vaccines won't help for a couple of months, at least.
Until then, I absolutely agree our best hope is distancing and 100% masking, when distancing isn't possible, and especially avoiding indoor contact with people (particularly those one doesn't have confidence in with regard to behaviors). Also, we've been trying to keep this thread to science without getting political and while masks are science to me, they're not to everybody, so I've avoided talking about them.
Cases in NY/NJ are also up, but keep in mind that they're still well below levels seen in April (as are hospitalizations - see the graphics below), since the case levels were likely 2-3X what were reported back then, since we had very little testing going on compared to now. Still, not a good trend in our area.
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Even if you get it shot you still have to not be a dumb ass. Just like the flu shot.
Also we will not even get a chance at this until spring or summer 2021.
Also we will not even get a chance at this until spring or summer 2021.
Not enrolling enough elderly people or minorities. From recent BMJ
A vaccine that has been proved to reduce the risk of symptomatic disease by a certain proportion should, you might think, reduce serious outcomes such as hospital admissions and deaths in equal proportion.
Peter Marks, an FDA official with responsibility over vaccine approvals, recently stated as much about influenza vaccination, which “only prevents flu in about half the people who get it. And yet that’s very important because that means that it leads to half as many deaths related to influenza each year.”24
But when vaccines are not equally effective in all populations the theory breaks down.
If frail elderly people, who are understood to die in disproportionate numbers from both influenza25 and covid-19, are not enrolled into vaccine trials in sufficient numbers to determine whether case numbers are reduced in this group, there can be little basis for assuming any benefit in terms of hospital admissions or mortality. Whatever reduction in cases is seen in the overall study population (most of which may be among healthy adults), this benefit may not apply to the frail elderly subpopulation, and few lives may be saved.
This is hard to evaluate in the current trials because there are large gaps in the types of people being enrolled in the phase III trials (table 1). Despite recruiting tens of thousands, only two trials are enrolling children less than 18 years old. All exclude immunocompromised people and pregnant or breastfeeding women, and though the trials are enrolling elderly people, few or perhaps none of the studies would seem to be designed to conclusively answer whether there is a benefit in this population, despite their obvious vulnerability to covid-19.
“Adults over 65 will be an important subgroup that we will be looking at,” Moderna’s Zaks told The BMJ. “That said . . . any given study is powered for its primary endpoint—in our case covid-19 disease irrespective of age.”
Al Sommer, dean emeritus of the Johns Hopkins School of Public Health, told The BMJ, “If they have not powered for evidence of benefit in the elderly, I would find that a significant, unfortunate shortcoming.” He emphasised the need for “innovative follow-up studies that will enable us to better determine the direct level of protection immunisation has on the young and, separately, the elderly, in addition to those at the highest risk of severe disease and hospitalisation.”
One view is that trial data should be there for all target populations. “If we don’t have adequate data in the greater than 65 year old group, then the greater than 65 year old person shouldn’t get this vaccine, which would be a shame because they’re the ones who are most likely to die from this infection,” said vaccinologist Paul Offit.8 “We have to generate those data,” he said. “I can’t see how anybody—the Data and Safety Monitoring Board or the FDA Vaccine Advisory Committee, or FDA decision-makers—would ever allow a vaccine to be recommended for that group without having adequate data.”
“I feel the same way about minorities,” Offit added. “You can’t convince minority populations to get this vaccine unless they are represented in these trials. Otherwise, they’re going to feel like they’re guinea pigs, and understandably so.”
A vaccine that has been proved to reduce the risk of symptomatic disease by a certain proportion should, you might think, reduce serious outcomes such as hospital admissions and deaths in equal proportion.
Peter Marks, an FDA official with responsibility over vaccine approvals, recently stated as much about influenza vaccination, which “only prevents flu in about half the people who get it. And yet that’s very important because that means that it leads to half as many deaths related to influenza each year.”24
But when vaccines are not equally effective in all populations the theory breaks down.
If frail elderly people, who are understood to die in disproportionate numbers from both influenza25 and covid-19, are not enrolled into vaccine trials in sufficient numbers to determine whether case numbers are reduced in this group, there can be little basis for assuming any benefit in terms of hospital admissions or mortality. Whatever reduction in cases is seen in the overall study population (most of which may be among healthy adults), this benefit may not apply to the frail elderly subpopulation, and few lives may be saved.
This is hard to evaluate in the current trials because there are large gaps in the types of people being enrolled in the phase III trials (table 1). Despite recruiting tens of thousands, only two trials are enrolling children less than 18 years old. All exclude immunocompromised people and pregnant or breastfeeding women, and though the trials are enrolling elderly people, few or perhaps none of the studies would seem to be designed to conclusively answer whether there is a benefit in this population, despite their obvious vulnerability to covid-19.
“Adults over 65 will be an important subgroup that we will be looking at,” Moderna’s Zaks told The BMJ. “That said . . . any given study is powered for its primary endpoint—in our case covid-19 disease irrespective of age.”
Al Sommer, dean emeritus of the Johns Hopkins School of Public Health, told The BMJ, “If they have not powered for evidence of benefit in the elderly, I would find that a significant, unfortunate shortcoming.” He emphasised the need for “innovative follow-up studies that will enable us to better determine the direct level of protection immunisation has on the young and, separately, the elderly, in addition to those at the highest risk of severe disease and hospitalisation.”
One view is that trial data should be there for all target populations. “If we don’t have adequate data in the greater than 65 year old group, then the greater than 65 year old person shouldn’t get this vaccine, which would be a shame because they’re the ones who are most likely to die from this infection,” said vaccinologist Paul Offit.8 “We have to generate those data,” he said. “I can’t see how anybody—the Data and Safety Monitoring Board or the FDA Vaccine Advisory Committee, or FDA decision-makers—would ever allow a vaccine to be recommended for that group without having adequate data.”
“I feel the same way about minorities,” Offit added. “You can’t convince minority populations to get this vaccine unless they are represented in these trials. Otherwise, they’re going to feel like they’re guinea pigs, and understandably so.”
The FDA granted Eli Lilly an Emergency Use Authorization for pre-approval use of their single monoclonal antibody for treatment of mild to moderately ill (not yet hospitalized) COVID patients, based on the data shared in the above post. It's a bit surprising, though that they approved the 700 mg dose, which did not actually show efficacy for the main endpoint (the 2800 mg dose did). Perhaps they want to be able to treat 4X as many patients and have some additional data that wasn't shared, but many were questioning this dose (as per links in the post above). Wonder if we'll see an EUA for the Regeneron two-antibody cocktail soon (which has much better clinical results).
https://www.cnbc.com/2020/11/09/us-allows-emergency-use-of-eli-lillys-covid-antibody-therapy.html
https://investor.lilly.com/news-rel...-antibody-bamlanivimab-ly-cov555-receives-fda
In a perfect world more elderly patients would be in the vaccine trials, but many experts and ethicists question the desire of people most at risk of enrolling, as well as the ethics of doing so. Some think just doing the phase I/II dosing to evaluate immune response in the elderly is the way to go and to then ensure that the elderly get enough of a dose in the real world to elicit the desired response. Some, though, think they should've been more included. Tough call, as I'm "almost" elderly and am not sure I would've wanted to participate vs. remaining quarantined until a vaccine was available.
Question for @numbers or other scientists. If 2 or 3 vaccines are released, all with different mechanisms of action, it would seem that the virus is less likely to mutate or develop an ability to defend itself. Is this a valid assumption?
I think what you mean to ask that if other vaccines are made differently can they protect more with given viral mutation and drift. That's actually a good question and the answer is sometimes. for instance, the flu shot known as flu- blok is known to give more extensive coverage against the phenomena that you're talking about. It's how the vaccine is made and in this case it's genetic engineering versus for instance egg-based.
But with mRNA vaccines you will be targeting the attachment sites of the virus and mutation in theory should not matter very much because - whether a mutation has more virulence and infectivity -it still needs to attach to the same site as a less virulent strain. But if a viral mutation starts to affect the attachment sites or sub attachment sites in a significant way, then we're in some poop. With more time we will get better vaccines because we will understand more the complex immune mechanism behind this virus and you can get multiple better immune responses against mutation etc when you have whole virus vaccines for instance. Who knows maybe in a couple years we will have an inactivated whole virus vaccine squirted up your nose that's 100 percent against the entire spectrum of this disease.
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Took this morning off so I play devil's advocate.
I see this as the other way around. It may be unethical not to have enrolled enough of those "non mainstream groups" especially in this charged atmosphere - shaped by the Tuskegee experiment shadow and in times where some think and I'll quote a patient of mine. " You ain't injectin me with that poison.''
Which test would you recommend and how soon after traveling home would you recommend? I read the Harvard Health site, and while antigen testing is quicker, it seems it has more false positives. We are not particularly worried about our flight, as we are double masked and in first class, not sitting next to strangers. I understand the incubation period. I am supposed to get a test upon return regardless of if I have symptoms, but it seems we should wait at least 2-3 days?
If you are a nonsymptomatic vital worker then you need to get your butt back to work with a negative rapid test antigen or pcr (I have seen some employers who demand that it's PCR) just before return to work. Otherwise most people will get ill between 3 to 5 days upon return from risky area if you are exposed at the gate let's say. but that's why the quarantine goes out to 14 days (if you're not considered vital because that's the incubation period.)
Thank you. I'm a first responder. I may just quarantine. We usually stay at least one gate away from our gate, and board last.
Apologies to anyone I might have offended in describing facetiously- to make a point -how scientists can target/attract one particular group (ie younger, healthier, body conscious caucasian males)
to the unfortunate exclusion of others who are as or more important to research. Was being deliberately facetious in my sarcastic description of said males to make a point and not meant to insult, well, anyone except for maybe the industrial, scientific community.
I was once a young caucasian kid myself playing CYO basketball.
to the unfortunate exclusion of others who are as or more important to research. Was being deliberately facetious in my sarcastic description of said males to make a point and not meant to insult, well, anyone except for maybe the industrial, scientific community.
I was once a young caucasian kid myself playing CYO basketball.
Must have missed it. But nothing offends me about covid. You are a great poster, and thank you for sharing information here. It is much appreciated.
No excuses for what was said even if it was alleged sarcasm. For months people on this board were chastised, banned, suspended and publicly ridiculed for similar. Now it’s ok and we should all have our kumbaya moment. Let’s all make nice and forget what has occurred looking forward to a new chapter in American History. Be careful admitting you played CYO BB that could upset some of our posters.
Many agree with you on this and I see the point - I was just trying to highlight why some might not have taken that approach. The good news is that with >90% efficacy, which is way better than the FDA's 50% success criterion, I think we're going to see a much higher percentage of people getting the vaccine than originally thought - especially with cases (and more importantly, hospitalizations and soon deaths) going through the roof, as most of us expected in the colder months.
KS - I haven't researched requirements for returning to work, but the one thing I would say is I would think employers/groups would insist on a PCR test, since it's far more sensitive than any antigen test and from their perspective, the biggest risk to them is someone returning with a false negative, while actually being positive, which is far, far more likely via an antigen test.
Two good articles in the Times on antibodies and T-cells. The first one provides further evidence (from cited papers) that waning antibody responses in infected/recovered patients are not a major concern as this kind of reduction is seen for many infectious/viral diseases, as the body has no need to keep a large "standing army" of antibodies, when it can simply make more if threatened again by a virus that it has fought off before.
The second one is about some major advances in the US and UK on developing faster, more useful blood tests to check for T-cells, the types of white blood cells that can recognize and attack/kill viruses with specific antigens/proteins, like the coronavirus and its spike protein epitopes. These tests are now becoming more sensitive than the antibody tests we've been hearing a lot about for months, which are used to identify if someone has been exposed to the virus and recovered, plus in recovered patients, T-cell levels don't seem to drop off as much as antibody levels, so it could be a better test to reveal if one had been infected and fought it off (even if asymptomatic).
There are also some people who have T-cells which confer some "cross-immunity" from previous common cold coronaviruses to SARS-CoV-2, probably lessening the impact (but not preventing the infection) on people who have never been infected by SARS-CoV-2 before, although there is still much to figure out on that count. Have talked about both of these a ton in the old COVID threads, but these updates are both good news.
https://www.nytimes.com/2020/10/27/...tion=click&module=RelatedLinks&pgtype=Article
https://www.nytimes.com/2020/11/10/...s-immunity.html#click=https://t.co/rGeGE2FE0t
The second one is about some major advances in the US and UK on developing faster, more useful blood tests to check for T-cells, the types of white blood cells that can recognize and attack/kill viruses with specific antigens/proteins, like the coronavirus and its spike protein epitopes. These tests are now becoming more sensitive than the antibody tests we've been hearing a lot about for months, which are used to identify if someone has been exposed to the virus and recovered, plus in recovered patients, T-cell levels don't seem to drop off as much as antibody levels, so it could be a better test to reveal if one had been infected and fought it off (even if asymptomatic).
There are also some people who have T-cells which confer some "cross-immunity" from previous common cold coronaviruses to SARS-CoV-2, probably lessening the impact (but not preventing the infection) on people who have never been infected by SARS-CoV-2 before, although there is still much to figure out on that count. Have talked about both of these a ton in the old COVID threads, but these updates are both good news.
https://www.nytimes.com/2020/10/27/...tion=click&module=RelatedLinks&pgtype=Article
https://www.nytimes.com/2020/11/10/...s-immunity.html#click=https://t.co/rGeGE2FE0t
Update on the mink-COVID issue. Most experts seem to think that the risks from the slightly mutated coronavirus finding a home in minks and infections going between minks and humans don't pose any more of a threat than the major strains that have been in humans since the start of the pandemic and likely should not affect the efficacy of any vaccines. In fact, Denmark has put their culling of mink herds on hold for now.
However, the risk many are concerned with is that the animals become a "reservoir" of the virus, such that even if we eradicate the virus in humans via vaccines and other controls, it's possible that as immunity wears off, animals could be a source of reintroduction of the virus back into the population. That's why a COVID vaccine could end up being something everyone gets every few years.
Having said all that, we still need more data on the mutation sequences in minks (and other animals) and on whether these would behave differently in humans.
https://www.scientificamerican.com/article/the-real-danger-posed-by-coronavirus-infected-mink/
Should have data on the Moderna mRNA vaccine (very similar to the Pfizer/BioNTech one) within days to a week, which is excellent news. No reason to believe efficacy and safety will be much different, given fairly similar responses seen in phase I/II trials, but then again, that's why we run the trials - to be sure. Dr. Fauci is very bullish on this and other vaccines, now that we've seen great results from Pfizer (I share his optimism, fwiw). We just have to get through the next 2-3 months - which are almost certainly going to be the worst we've seen...
https://www.reuters.com/article/reutersComService_2_MOLT/idUSKBN27R1SO?utm_source=reddit.com
https://www.reuters.com/article/reutersComService_2_MOLT/idUSKBN27R1SO?utm_source=reddit.com
A cytopathologist pointed this review out to me today and told me the reasons she will be sitting this round out is contained herein:
Warning heavy science contained; nice illustrations
www.ncbi.nlm.nih.gov
Warning heavy science contained; nice illustrations
Progress and Pitfalls in the Quest for Effective SARS-CoV-2 (COVID-19) Vaccines
There are currently around 200 SARS-CoV-2 candidate vaccines in preclinical and clinical trials throughout the world. The various candidates employ a range of vaccine strategies including some novel approaches. Currently, the goal is to prove that they ...
www.ncbi.nlm.nih.gov
I'm already psyched for the 2021 basketball season at the RAC.
A cytopathologist pointed this review out to me today and told me the reasons she will be sitting this round out is contained herein:
Warning heavy science contained; nice illustrations
Progress and Pitfalls in the Quest for Effective SARS-CoV-2 (COVID-19) Vaccines
There are currently around 200 SARS-CoV-2 candidate vaccines in preclinical and clinical trials throughout the world. The various candidates employ a range of vaccine strategies including some novel approaches. Currently, the goal is to prove that they ...
Great paper, with truly excellent detail, analysis and graphics, including an excellent discussion of the pros and cons of each type of vaccine candidate. However, in reading through it, I didn't get any sense that sitting this out was being implied.
I completely get wanting to see the full clinical data set from each vaccine and for those of us not first in line, we should also get to see a ton of post-approval data on the Pfizer and other vaccines as they roll out, so hopefully by the time it's time for "non-priority" people like me and most others to get the vaccine, we'll have a much better handle on true efficacy and safety.
Can you elaborate on what, specifically in the paper, has this colleague so concerned? I have a fairly well known virologist friend where I used to work (Merck), who is ready to get vaccinated today, despite our imperfect knowledge.
The second article is about the company, Adaptive Biotechnologies. They have used this approach for many years to ask if people have T cells that have the right TCR to kill tumors. Now they think it will work to find to ask if people have the T cells with the right TCR to attack the virus. The TCR (T cell receptor) is the key that makes T cells work with a specific lock. I'm attending a Shane Crotty seminar at 11AM today - if there is a chance I will ask him if he thinks this will work.
I've seen lots of Adaptive Biotechnologies data for cancer - very impressive. I knew they were working on this Sars-CoV-2 assay. I can't believe I never checked to see if they were a publically traded company - I would have bought the stock!
Yes, interesting story. Cool that you get to be involved in this stuff - Crotty is one of the folks I check on Twitter occasionally. Him and Florian Krammer from a virology perspective.
Crotty is an outstanding scientist. I don't know much about Krammer.
BTW, if you are interested in the Adaptive Biotechnologies work, they are having a free webinar today: From Bench to Biomarker: Applications of the immunoSEQ Assay Across the Clinical Development Pipeline
Agree with you and I will get it as well soon I expect.
Lol. She's a bit wacky but very bright and began rambling when I called to discuss a melanoma case. So, Iike you i went through paper she referenced and pondered your exact question. assumed she was referring to t cell responses in older and vulnerable since humoral immunity in older farts greatly wanes and concern about enhancement and cross reactive responses, and geographic and phenotype concerns - virus causes varied pathological and sometimes contradictory immune responses in different individuals.
but, think she's more concerned about the rush and sceptical about the industrial complex.
here is her abridged email response in that regard:
"Informed consent disclosure to vaccine trial subjects of risk of covid-19 vaccines worsening clinical disease:
https://onlinelibrary.wiley.com/doi/10.1111/ijcp.13795
"Nowhere near ready to be given to our most important people. Nottaking it as a cytologist, especially at this early stage, and after having followed all the research and studies from the beginning, plus having written and illustrated about viruses and other pathogens found in this cytopathology lab.
good summary of why:
ICAN, a vaccine safety watchdog group, wrote to CDC threatening to sue if they did not agree to a totally benign placebo instead of another vaccine, meningococcal vaccine. They agreed but Astra-Zenica's trial using the vaccine as a placebo was not changed.
Rushing too fast too quickly. By allowing this to skip animal trials and the failed SARS vaccine trials of 2005, there is valid concern about this vaccine. A member of a colleagues state pharmacy board noted two deaths from Astra-Zeneca vaccine early on raised their concern. Risk of death from this disease in health care workers is low, and more maximum isolation post-symptom occurrence should help decrease the need to rush this.
long term studies on animals should be first no matter what."
Not a good look when trying to get public buy-in. Already hearing people claim (whether right or wrong) the whole release is just to goose corporate profits. Leads to skepticism of the vaccine.
I asked him - he thinks the approach would be very powerful, but he is not convinced it will work largely because MHC differences among people will result in too broad TCR usage. I would agree - yet I have seen the cancer data and I know people doing this type of bioinformatics. I think he is underestimating what can be done these days.
Crotty also had a slide showing Fauci testifying to congress holding his Cell paper. He said the best tweet in response to posting the picture was "I suggest printing it out onto a custom blanket and cradle yourself into sweet validation every night" 😆
That's a priceless tweet, lol.Crotty also had a slide showing Fauci testifying to congress holding his Cell paper. He said the best tweet in response to posting the picture was "I suggest printing it out onto a custom blanket and cradle yourself into sweet validation every night" 😆
When you say the "approach" are you talking about the application to cancer/tumors and, if so, can you explain how it works? Are you saying this is a diagnostic approach to finding which people have the right T-cell-receptors to direct the T-cells to destroy cancer cells? And could it go beyond that to trying to figure out how to either supply or turn on such receptors (via pharmaceuticals presumably) as part of a cancer therapy? Almost sounds like the opposite of the PD-1/PD-L1 inhibitors, which allow the immune system to kill cancer cells, i.e., the approach would be more like a way to activate ordinarily inactive TCRs to attack cancer cells. Is that even close? Sorry, my immunology knowledge is weak.
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