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Vaccine development as a decision problem

This post by Alex Tabarrok hits all the right notes:

At current rates, the US economy is losing about $40 billion a week. Thus, if $20 billion could advance a vaccine by just one week that would be a good deal. . . . It might seem expensive to invest in capacity for a vaccine that is never approved, but it’s even more expensive to delay a vaccine that could end the pandemic.

I [Tabarrok] am also concerned that OWS is narrowing down the list of candidates too early . . . These are all good programs and one of them will probably be successful but we also want to support some long-shots because a small probability of a very big gain is still a big gain. . . .

The Accelerating Health Technologies team that I am a part of collected data on over 100 vaccine candidates and their characteristics. We then created a model to compute an optimal portfolio. We estimated that it’s necessary to have 15-20 candidates in the portfolio to get to a 80-90% chance of at least one success and that you want diverse candidates because the second candidate from the same platform probably fails if the first candidate from that platform fails. Moderna and Pfrizer are both mRNA vaccines–a platform that has never been used before–while AstraZeneca, Johnson and Johnson and Merck are using somewhat different viral vector platforms . . .

One way to diversify the portfolio is to make deals with other countries to avoid the prisoner’s dilemma of vaccine portfolios. The prisoner’s dilemma is that each country has an incentive to invest in the vaccine most likely to succeed but if every country does this the world has put all its eggs in one basket. To avoid that, you need some global coordination. . . .

I have not looked at the details here at all, but I like the general approach. I like the awareness of uncertainty, variation, costs, benefits, contingencies, and politics. We talked about how social science can used to fight coronavirus. This sort of thing is an example.

I hope this all can be done in conjunction with Bayesian inference for vaccine effects in the general population and sub-populations. I’d hate to see all this careful design and decision analysis stapled onto crude deterministic inference procedures based on statistical significance.

104 Comments

  1. LKg says:

    Tabarrok frames the problem and solution process in a highly biased manner.

    How were successful medical vaccines developed in the past?
    What do we know from past experience?

    • Phil says:

      One characteristic of successful vaccines in the past is that they took a long time to reach widespread distribution. This piece https://www.nytimes.com/interactive/2020/04/30/opinion/coronavirus-covid-vaccine.html gives some examples: Varicella 28 years, FluMist 28 years, HPV 15 years, Rotavirus 15 years, “Pediatric combination” 11 years. The piece gives a hypothetical 16-year timeline for a Covid vaccine if it were to follow a typical pattern, and offers ways to speed it up.

      The longest single item on that timeline is six years allocated to “building factories.” That seemed ridiculous at first glance but less so after I thought about it: once you have the architectural plans it takes about two years to build a large office building, and I could easily believe it would take another year or more if you’re building something specialized like a sterile medical facility. And you need to acquire the land and design the building and get permits and sign contracts and so on. A month or so ago I saw an interview with Bill Gates in which he said his foundation is already building factories, so that’s great, start building and equipping the factories before you know what vaccine you’ll be making.

      You say Tabarrok frames the problem and solution process in a “highly biased manner”, could you explain what you mean?

      • jim says:

        “Bill Gates…said his foundation is already building factories”

        What happened to all the design, permitting and land acquisition time? :)

        Development on some of those vaccines goes back to the 1960s and 1970s so I’m thinkin’ a lot of problems have been solved since then.
        With all the biotech and chip makers out there today, sterile facilities are probably not a huge problem. My guess is that if you’re willing to pay more up front and trade off some long term efficiency by using off-the-shelf building and equipment you can get things going in a pretty good hurry.

        • Luca Beltrame says:

          Many of the involved parties are already ramping up manufacturing at risk, because the demand will be massive once a vaccine is proven to work, and there’s also the risk of countries seizing up shipments.

          • Ben says:

            > Bill Gates…said his foundation is already building factories

            > What happened to all the design, permitting and land acquisition time? :)

            > Many of the involved parties are already ramping up manufacturing at risk

            I have zero manufacturing experience.

            Given that, I suspect a focus on the reality of ‘building’ would be investing in, acquiring, leasing, or searching for manufacturing capacity.

            Presumably ‘building’ is marketing speak so it sounds cooler.

      • jrkrideau says:

        it takes about two years to build a large office building, and I could easily believe it would take another year or more if you’re building something specialized like a sterile medical facility.

        This assumes a US-centric, business as usual, model. Under emergency measures one could cut this drastically. Assume good engineering and project management, adaptation of existing factory designs, and 24 hour/day, 7 days a week construction and one could cut the time drastically even if one could not just adapt existing facilities.

        While they are poor examples, China and Russia have build (more or less pre-fab?) hospitals in weeks, or at most a couple of months in the Russian case.. I assume a much lower level of complexity than a sterile manufacturing plant but it suggests a lot of the physical structure can be produced quickly.

  2. Anonymous says:

    The approach is good, I agree, but most of the $40B a week going down the tubes at the moment can be recovered with little risk. Whether or how much that changes the calculus on a $20B investment I’m not sure, but we should focus on the real cost, not the cost incurred by stupid policy that will ultimately be withdrawn without much impact.

  3. Jonathan (another one) says:

    Biased how?
    What we know about the prior experience, whatever it consists of, was that it was too slow for this case. This is about speeding up the process, so as to better equate marginal costs and benefits. So the prior experience is of little use here, no matter how well it worked (or didn’t.)

  4. Anoneuoid says:

    The elderly are among the most vulnerable to COVID-19 but immune senescence in this population poses a barrier to effective vaccination. To evaluate the effect of immune senescence on immunogenicity, we next administered 10 or 1 μg of LION/repRNA-CoV2S in 2-, 8-, and 17-month old BALB/C mice and measured anti-S IgG concentrations at 14 days after a single immunization. Significantly lower antibody titers were observed in the 17-month old mice at both doses (Fig. 4A), when compared to 2- and 8-month old mice, suggesting that higher doses and/or additional booster doses may be required in the most immune senescent populations to induce sufficient immunity.

    https://www.biorxiv.org/content/10.1101/2020.05.28.121640v1

    All these vaccine trials in young/healthy people/animals will not generalize to the population at risk. They need to be testing it in people who previously were diagnosed with covid along with the elderly and those with comorbidities (which is a huge percent of the population).

    We don’t need a vaccine for young healthy people, they can simply get the virus and have mild illness for a few days. Yet that is what this money is being wasted on.

    • Luca Beltrame says:

      The Jenner Institute in Oxford is doing that with their Phase II trial of their ChadOx1 vaccine. The candidates are people more than 65 years old or younger than 18 years old. Current target is about 6k people if I recall correctly.

      • Anoneuoid says:

        This is good. Is there any info on when the results will be out? I also heard from oxford they were worried about the rate of infection being too low now.

        • Luca Beltrame says:

          They recruited 2000 patients in Brazil to account for this problem, as well. As for results, depends. Usually it’s at least a couple of months, but you need to wait for enough people to eventually become infected. But first, they need to make sure neutralizing antibodies are produced and in “sufficient quantity” (how to tell: an idea is a comparison with hyperimmune plasma from recovered patients). This will be done on follow-up during the study.

          As far as I understand from their communication, they want to wait over the course of the summer at the very least to have satisfactory results.

    • Phil says:

      Anoneuoid,
      They should start vaccine testing with young, healthy people because they can experiment on those people without killing them.

      Even in the unlikely event that a vaccine is developed that protects younger people but provides no protection at all to older people, nor aids in the development of a vaccine that would do so, such a vaccine would still be worth a lot. (1) If nobody under 60 years old could get infected then nobody under 60 years old could pass the virus on to someone over 60 years old. Older people might have to be careful around each other, but that’s not so hard. Younger people wouldn’t need to worry about infecting their elderly parents; older people could interact with barbers and nurses and doctors and dentists and shopkeepers etc etc etc. And (2) as you surely know, the virus does cause severe symptoms in a significant fraction of young people, and “mild” but very prolonged illness in some others — they do not necessarily have “mild illness for a few days.”

      • jim says:

        Excellent, well said Phil.

      • Anoneuoid says:

        Even in the unlikely event that a vaccine is developed that protects younger people but provides no protection at all to older people, nor aids in the development of a vaccine that would do so, such a vaccine would still be worth a lot.

        It is not unlikely at all, it is what we should expect to happen based on what has been published on SARS. If it is similar to SARS, weak antibodies are going to be worse than no antibodies at all.

        To evaluate the efficacy of existing vaccines against infection with SHC014-MA15, we vaccinated aged mice with double-inactivated whole SARS-CoV (DIV). Previous work showed that DIV could neutralize and protect young mice from challenge with a homologous virus14; however, the vaccine failed to protect aged animals in which augmented immune pathology was also observed, indicating the possibility of the animals being harmed because of the vaccination15. Here we found that DIV did not provide protection from challenge with SHC014-MA15 with regards to weight loss or viral titer (Supplementary Fig. 5a,b). Consistent with a previous report with other heterologous group 2b CoVs15, serum from DIV-vaccinated, aged mice also failed to neutralize SHC014-MA15 (Supplementary Fig. 5c). Notably, DIV vaccination resulted in robust immune pathology (Supplementary Table 4) and eosinophilia (Supplementary Fig. 5d–f). Together, these results confirm that the DIV vaccine would not be protective against infection with SHC014 and could possibly augment disease in the aged vaccinated group.

        https://www.nature.com/articles/nm.3985

        (1) If nobody under 60 years old could get infected then nobody under 60 years old could pass the virus on to someone over 60 years old.

        Young healthy people can just get sick for a few days, self isolate and emerge with much more robust immunity than they will get from a vaccine with little excess risk. Also, the number of people over 60 and/or having some health issue like diabetes, heart disease, obesity, etc is very large. I’d guess that less than half the US population would qualify for these vaccine trials.

        And (2) as you surely know, the virus does cause severe symptoms in a significant fraction of young people, and “mild” but very prolonged illness in some others — they do not necessarily have “mild illness for a few days.”

        The vast majority of young people don’t even notice it.

        • Brent Hutto says:

          Anoneuoid said:

          (1) If nobody under 60 years old could get infected then nobody under 60 years old could pass the virus on to someone over 60 years old.

          Young healthy people can just get sick for a few days, self isolate and emerge with much more robust immunity than they will get from a vaccine with little excess risk. Also, the number of people over 60 and/or having some health issue like diabetes, heart disease, obesity, etc is very large. I’d guess that less than half the US population would qualify for these vaccine trials.

          And (2) as you surely know, the virus does cause severe symptoms in a significant fraction of young people, and “mild” but very prolonged illness in some others — they do not necessarily have “mild illness for a few days.”

          The vast majority of young people don’t even notice it.

          Don’t you know we’re All In This Together ™? Haven’t you been paying attention to WHO and CDC messaging?

          • Anoneuoid says:

            Haven’t you been paying attention to WHO and CDC messaging?

            The WHO has definitely been a source of misinformation throughout, the CDC has at least provided the all cause mortality data I scrape but honestly not much more.

        • > The vast majority of young people don’t even notice it.

          I don’t think this is a well established fact. The fact is we have almost no information about things like what fraction of younger people have had this disease. Antibody testing has been fairly problematic because most places are still in the single digit percentages range, and the false positive rate is also in the single digit percentages range, and so the probability that you’ve even had the disease if you antibody-test positive is actually pretty low. Lots of people are probably getting positive tests, saying “gee I don’t remember even feeling sick” and assuming that the virus is super mild among their agegroup or something… When in fact they didn’t ever have it.

          • back of the envelope: suppose 3% of people have had this disease in a region, and there’s a 5% false positive rate in antibody testing… suppose p(test pos | had disease) = .97

            P(had disease | tested positive) = p(tested pos | had disease) * p(had disease) / (p(tested pos | had disease) p(had disease) + p(tested pos | not had disease) p(not had disease) )
            = .97*.03 / (.97 * .03 + .05 * .97) = 37%

            so about 2/3 of people who are testing positive never had the disease… no wonder they hardly noticed it.

            • Anoneuoid says:

              Well, I’ve been saying for awhile I suspect the PCR tests are something like 70% false positives and 70% false negatives and have yet to see anyone actually compare the whole process including the swabbing procedure to a gold standard. But the same ~80% asymptomatic is typical for a viral infection (maybe the tests for all viruses are just as inaccurate):
              https://www.thelancet.com/journals/lanres/article/PIIS2213-2600%2814%2970053-0/fulltext?rss=yes

              Then there is the problem of so few younger people even getting diagnosed, surely they were exposed at some point… The first hint towards the large number of mild/asymptomatics was the 70k patient study out of China in Feb that had a huge underrepresentation of younger patients.

              Also, I still haven’t seen the rate of positive antibody tests in people who previously tested positive on PCR or were otherwise diagnosed (for asymptomatic, mild, or severe illness). Wouldn’t surprise me that you don’t get a strong antibody response if you dont get very sick and t-cell immunity was reported to last much longer than detectable antibodies for SARS: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115611/

            • Chris Wilson says:

              Yea, I think Daniels in right track here. I heard Osterholm – who did important work correcting flawed serology for the initial influenza vaccines, for which he was raked over the coals rather than thanked – say recently that our serology here is a giant mess. We’re flying blind in terms of understanding true prevalence or transmission dynamics.

              • Anoneuoid says:

                The high rate of asymptomatic infection wasn’t even based on the antibody tests though. It goes back to Feb, before such tests existed (that we know about, maybe China already had that data).

            • Anoneuoid says:

              Here we go:

              > Our data have important implications for the use of conventional IgG serology as a tool
              to address the COVID-19 pandemic. Population-based IgG seroprevalence may underestimate
              the occurrence of mild infections, with the degree of underestimation dependent on the
              sensitivity of the screening method. Rapid tests with reported sensitivity of 90% in hospitalized
              patients may have substantially lower sensitivity in sera from mild or asymptomatic infections.
              High sensitivity assays like the one we employed, with robust high to low dynamic range, can
              provide a more complete picture of cumulative incidence.
              https://old.reddit.com/r/COVID19/comments/gzmsud/magnitude_and_kinetics_of_antisarscov2_antibody/

              And these were all still people who sought treatment…

              • confused says:

                I was just wondering about this yesterday, because…

                New York State has a bit over 30,000 reported COVID deaths; Texas has about 1850.

                The New York state government reported statewide seroprevalence of ~14% (~20-25% for NYC); the population of New York State is about 20 million, so ~14% means something like 2.75 million people infected.

                This implies an IFR about 1.1%, which sounds plausible.

                But… if the IFR is ~1.1%, that means Texas’ deaths would convert to something like 170,000 true infections. But TX has over 75,000 *confirmed cases*. If TX has detected nearly half of all infections, our testing would have been way better than anyone else’s in the US, and I don’t think the testing data really bears that out.

                So how can this be reconciled?

                – deaths could be significantly under-reported in Texas. But from looking at CDC excess deaths data, this doesn’t seem to be possible at a level that would make a significant difference.

                – the IFR could be far lower in Texas than in NY. Some difference might be expected, since the TX population skews younger (median age ~35 vs. ~39). But I wouldn’t expect *that* much of a difference. Maybe viral dose effects? Or vitamin D effects? Or something?

                – the NY serology results could be far too low.

              • Anoneuoid says:

                Compare NY state all cause mortality to NYC for this year: http://xayadata.com/mortstates.pdf

                Usually by now there would be ~40k deaths in NY and 20k of them from NYC, which makes sense since NYC is about half the pop of NY state. This year its like 50k in NY and 45k in NYC. So way fewer deaths than expected in NY outside of NYC?

                Somethings up with the data from NY.

                Data downloaded from here: https://gis.cdc.gov/grasp/fluview/mortality.html

              • Anoneuoid says:

                Also see page 2 here for data incompleteness for each week at a national level: xayadata.com/covidstates.pdf

                Those thin lines are the reported mortality as it came out each week this year. So you can see the last 3-4 weeks on the plot will usually get a substantial increase later but it shouldnt add up to as much as we see in NY. If anyone can find those historical releases at the state level let me know.

              • confused says:

                This CDC page still shows excess deaths in New York excluding New York City:

                https://www.cdc.gov/nchs/nvss/vsrr/covid19/excess_deaths.htm

                (The option for “New York” in the dropdown menu is actually NY minus NYC; it has fewer deaths than NYC.)

                So I don’t think the problem is extreme under-reporting of deaths in NY minus NYC.

                I ought to be clearer about what I was saying about under-reporting: it’s not that Texas has no under-reporting (no excess deaths not explained by COVID deaths), it’s that NY and especially NYC has a lot of under-reporting and Texas’s doesn’t look worse. (Week of May 16 looks relatively bad, but this is probably due to lags in reporting of COVID deaths; and even so, not nearly as bad as NYC in early April, when there were more excess-deaths-not-explained-by-COVID than the normal *total* weekly deaths!)

              • confused: I think there is probably a seasonal effect, and NYC got hit *early* during a period where there was still snow on the ground etc…

                I don’t know if the seasonal effect comes from vit D, from air temperature, from humidity, from sunlight, from indoor heating, or whatever, but if there’s a seasonal effect, and TX infections happened later, and also in a more southern location, it could be a major cause of reduced deaths.

                Of course, this just suggests potentially a very dangerous fall/winter coming up.

              • Anoneuoid says:

                Estimates of excess deaths can be calculated in a variety of ways, and will vary depending on the methodology and assumptions about how many deaths are expected to occur. Estimates of excess deaths presented in this webpage were calculated using Farrington surveillance algorithms (1). A range of values for the number of excess deaths was calculated as the difference between the observed count and one of two thresholds (either the average expected count or the upper bound of the 95% CI), by week and jurisdiction.

                Provisional death counts are weighted to account for incomplete data. However, data for the most recent week(s) are still likely to be incomplete. Weights are based on completeness of provisional data in prior years, but the timeliness of data may have changed in 2020 relative to prior years, so the resulting weighted estimates may be too high in some jurisdictions and too low in others. As more information about the accuracy of the weighted estimates is obtained, further refinements to the weights may be made, which will impact the estimates.

                This is why Im not looking at excess deaths. I dont like it when models and assumptions get mixed with data.

                Good catch on the NYC excluding NY state though. So, if thats the same as the data download, which would make some sense, about 1/3 of the deaths in NY state historically come from NYC.

                For NYC I see pop of 8.3 million and NY state 19.4 Million

                https://en.m.wikipedia.org/wiki/New_York_City

                https://en.m.wikipedia.org/wiki/New_York_(state)

                So 42% of the pop but only 1/3 of the deaths. Is NYC younger than the rest of the state?

                As to the comparison of NYC to Texas IFR, I would look into the nursing home deaths: https://www.health.ny.gov/statistics/diseases/covid-19/fatalities_nursing_home_acf.pdf

                Im on mobile so cant easily add them up at the moment. Also they were also following the inappropriate early intubation policy still recommended by the WHO early on (Cameron-Sidell started raising the alarm March 31st) and travel nurses who went there from elsewhere were saying they were killing patients by having inexperienced people run dialysis machines instead of reassigning someone who knew how to work it, etc.

                https://m.youtube.com/watch?v=k9GYTc53r2o
                https://m.youtube.com/watch?v=3YAzZ6deWro

                Then also that the seroprevelance is going to be an underestimate of the number of infections, like you say. And as time passes it will be a worse underestimate.

              • Andrew says:

                Anon:

                According to a zero-effort google search and no data checking, yes, the median age in NYC is 2 1/2 years lower than the median age in NY State.

              • Anoneuoid says:

                Thanks.

              • confused says:

                @Daniel Lakeland: yeah, seasonality may make a difference in IFR as well as chance of being infected … especially if vitamin D is a driving factor of respiratory infection seasonality, or if viral dose has a major effect on severity of infection.

                I’m not surprised by Texas’s IFR being lower than NY / NYC’s… I’d expect that, even without seasonality, since TX’s demographics skew younger, and maybe viral dose makes a difference. It’s just that unless Texas has *many* fewer undetected infections than the US average*, the effect would be a lot larger than I would have expected.

                *The US has ~110,000 deaths. If IFR is ~1%, comparable to New York, there should be over 11 million infections (“over” because deaths lag infections significantly); if the overall US average IFR is lower, it would be more. The US has ~2 million detected cases, so even conservatively, that’s less than 1/5 of all infection — possibly much less.

              • Joshua says:

                confused –

                I’ve become convinced, that with the track record of seroprevalence testing and the absolutely terrible seroprevalence estimating, we should prolly go with case fatality rates and then adjust that number by estimates of % of asymptomatic cases to estimate fatality rates. Of course estimating asymptomatic % also looks to be all over the map.

                And then there’s the lack of standardization and validation of estimated #s of deaths.

                But al of that said, seems to me you should be adjusting Your numbers for consideration of asymptomatic cases if you’re going to be calculating with case numbers as an input.

              • Anoneuoid says:

                Here’s another nurse saying that in NYC people were coming in with anxiety attacks, getting immediately put on ventilators, and repeatedly testing negative for covid. Yet they were still labeled as confirmed covid: https://m.youtube.com/watch?v=UIDsKdeFOmQ&feature=youtu.be

              • Joshua says:

                Anoneuoid –

                That video is making the rounds on the rightwing blogosphere. I wouldn’t be surprised if it becomes another “censorship” rallying cry after being taken down off of YouTube.

                I’m curious if you more or less take what she says at face value – in particular the part at the end where she asks if “they” killed her patient, who was doing fine, 20 minutes after they ordered her out of the room?

                Do you find her portrayal of the situation to be highly credible? Do you think it is at least somewhat suspect?

              • Anoneuoid says:

                Do you find her portrayal of the situation to be highly credible?

                Yes, it is exactly the type of stuff I would expect to be going on to explain the high death rates.

                People do not get how dangerous most of these medical interventions are. It is like letting someone with no experience try to fix your car by swapping in and out random parts and fluids.

                And just wait for this vaccine if they continue on the way they are.

              • Anoneuoid says:

                And just wait for this vaccine if they continue on the way they are.

                Because there doesn’t seem to be too much expertise here on the way ADE works, I should clarify. It wont be like you get injected with the vaccine and immediately get sick. It will be that your immune system is primed to have a bad response later.

                There are other risks too, as for any vaccine, but that is the main one to address first.

              • Joshua says:

                Anoneuoid –

                I’m curious about a few more things, if you don’t mind.

                What do you make of her accusations that this was about the money to be made by deliberately mis-classifying patients, and/or indifference to patients’ welfare, as opposed to the idea that there was a lot of chaos in a very difficult circumstance with a novel disease? Do you believe her offered causal explanation is accurate?

                What about her view that not giving high vitamin C dosages to very ill patients was basically malpractice? (Her view on HCQ is a bit incoherent as she seems to think it should have been used with very ill patients but also says that she doesn’t think it’s effective with very ill patients). Do you think that view of her is well-grounded medically?

                How to you integrate her testimonial with the testimonials of other nurses and other frontline workers who have a difffeent take on what went on?

              • Anoneuoid says:

                I dont think you need a specific reason for “healthcare” to harm people, like I said our knowledge of the body is very rudimentary and its easier to break things you dont understand than fix it. We dont even know why the flu goes away in the summer, which would seem like a useful piece of info to know…

                But if one place is much worse than another it is probably for a multitude of reasons including perverse incentives.

                And I dont know if not giving vitamin c is malpractice but not checking the levels to see if the patient is deficient definately is at this point. And I havent seen the levels of a single covid patient reported.

              • Anoneuoid says:

                As to HCQ + zinc, why are there dozens of studies giving HCQ to people already hospitalized without zinc but not a single one checking giving the supposedly effective treatment when its said to work?

                Once again, theres “no evidence” because no one did the study.

              • Anoneuoid says:

                Another thing I havent seen as a breakdown of male vs female smokers and nonsmokers. They obviously have this data, why has no one published it?

              • confused says:

                @Joshua:
                “I’ve become convinced, that with the track record of seroprevalence testing and the absolutely terrible seroprevalence estimating, we should prolly go with case fatality rates and then adjust that number by estimates of % of asymptomatic cases to estimate fatality rates.”

                I think that would be even more error-prone than seroprevalence, since cases don’t divide into “asymptomatic” and “confirmed”. In TX, in April probably only a tiny proportion of symptomatic mild cases were actually detected, TX testing was not very good in April.

                Going forward we might be detecting half of all infections or something, since TX is getting good at finding hotspots. But surely not half of all infections (or even all symptomatic infections) since COVID arrived in Texas (nominally March – but if Louisiana and Georgia had it in February, it’s hard to believe we didn’t.)

                >>seems to me you should be adjusting Your numbers for consideration of asymptomatic cases if you’re going to be calculating with case numbers as an input.

                Yeah, that’s exactly the problem. If say a third to a half of cases are asymptomatic, 180,000 infections would convert to something like 90,000 – 120,000 symptomatic cases. Texas has a bit over 80,000 confirmed cases… given number of tests per capita, especially before mid-May, I simply can’t believe that 2/3 or more of all (even mildly) symptomatic cases were detected.

              • Joshua says:

                Confused –

                I’m the one who’s confused. For Texas let’s assume a 50% asymptomatic rate. So you’ve got 160,000 cases (#confirmed X 2) and 1,900 deaths = 1.2 IFR.

                The CDC is getting the 35% asymptomatic number from somewhere. I don’t have a ton of confidence in that number but I’m no expert for sure. Thwre was a meta-analysis that used that technique and they are experts.

                My non-exoert guess is that it should be easier to accurately estimate asymptomatic vs. symptomatic using a better test than estimating with the unreliable seroprevalence tests, especially with such a high false positive rate becsuee of the low base rate. Sure, it ain’t perfect. The asymptomatic vs. symptomatic designation might be more a gradient than a binary condition…but I don’t see how anyone could have any faith in the seroprevalence estimates.

              • Joshua says:

                Anoneuoid –

                > I dont think you need a specific reason for “healthcare” to harm people…

                She effectively accused people of murder for hire. I’m not exaggerating.

                So the question is whether you find that a credible accusation. If you don’t, then the question I have is why would you find the other things she says to be credible?

              • confused says:

                >>I’m the one who’s confused. For Texas let’s assume a 50% asymptomatic rate. So you’ve got 160,000 cases (#confirmed X 2) and 1,900 deaths = 1.2 IFR.

                No – cases aren’t either “asymptomatic” or “confirmed”. To be “confirmed” you have to actually be tested, and for quite a while tests were not that available, so only the more serious / high-risk cases were actually tested.

                Back then the advice was often to stay at home & not go to the doctor if your symptoms were mild. And there are a lot more mild cases than serious ones…

                Also, at least early on, the PCR tests may have had a pretty significant false negative rate (due to bad sampling procedure, not PCR itself).

                Plus, there is (at least anecdotally) a reluctance to seek medical care for mild symptoms (of anything) among a certain subset of at least younger male Americans.

                So even if there were *zero* asymptomatic cases I wouldn’t expect anywhere *near* 1/2 of cases to be detected! (Total up to now, that is, counting March and April when testing was poorly available; we might well be catching 1/2 of new infections.)

              • Joshua says:

                confused –

                > To be “confirmed” you have to actually be tested, and for quite a while tests were not that available, so only the more serious / high-risk cases were actually tested.

                Ah. OK. I get your point now, and fair enough. Yes, there is good reason to think that the true case number is considerably higher than the confirmed case number. Seems to me it’s pretty hard to have any good idea of the difference. Right now the positive test rate in Texas is @7.5% so I guess there’s good reason to think that there’s a lot more people who think they are infected than who actually are – but sure, for quite a while even symptomatic people weren’t being tested and just told to go home and isolate.

                It would be interesting to see someone tackle the question of what the ratio of true cases to confirmed cases might be. Essentially, the seroprevalence studies should be just that. But they seem totally unreliable to me.

                If we were to trust the seroprevalence study in Spain, the supposed true case number is about 10 x the number of confirmed cases (which would put the infection fatality rate at about 1%).

              • confused says:

                Yes, for Spain the serology-estimated IFR would be near 1%. Which is why I said that the serology-estimated IFR also near 1% for NY seemed plausible.

                But if TX real infections were 10x confirmed cases, we would have ~800,000 real infections and thus a “naive” IFR of under 0.25%. Sure, this would go up since deaths lag infections and reporting of deaths may lag further, but TX has over 55,000 *recovered* confirmed cases, so 10x that would be 550,000 and thus an IFR under 0.35% even accounting for that.

                I would expect TX to have a somewhat lower IFR than NY or Spain since the population is younger and quality of care may also be better (due to healthcare workers in NYC/Madrid being overworked, and perhaps because Texas got COVID later and knowledge of supportive care has improved). But a factor of 2.5x to 4x seems pretty large.

                But I am wondering if in some of these populations serology may give too low numbers (maybe not actually “false negatives”, but people defeating the infection without producing detectable levels of antibodies due to innate immune system, T-cell immunity, or something).

                It also seems hard to believe that NYC caught even 1/10 of its infections given that they were specifically telling people with mild/moderate symptoms not to seek testing until pretty recently!!! (And nearly all the infections occurred quite a while ago, NYC has few new cases.)

              • Anoneuoid says:

                She effectively accused people of murder for hire. I’m not exaggerating.

                I didnt hear that, the doctor said theres no evidence to use vitamin c because hes ignorant about vitamin c.

                That noone has measured the vitamin c levels in some of these patients at different stages of the illness is malpractice though.

                I guarantee the sicker they are the more depleted the blood levels. Then you have to administer some oral/IV and see how much and how long you need to do it for until the pharmacokinetics returns back to normal.

              • Joshua says:

                Anoneuid –

                First of all, she’s not just some random Florence Nightingale, but a member of the Plandemic conspiracy believers. Buds with Judy Mikovits. Has a book coming out.

                She has an agenda.

                Here you can get some context for her accusations of murder for hire:

                https://zdoggmd.com/elmhurst-hospital/

                Secondly, she said they were misclasifying people as COVID-19 positive for the money, then putting them in rooms with positive people and engaging in malpractice in treatment. No discussion of the pressures of the situation. That would be murder for hire. Read what people who worked with her say.

                My radar first got set off when she acted like no one could be obviously positive even though testing negative. Then, what she said about HCQ was contradictory and incoherent. She clearly had a political agenda. Then she clearly was way ahead of the evidence on massive dosing with vitamin C.

                Consider her agenda. Then get back to me w/r/t her credibility.

                Do you realty want to be a fellow traveler on the Plandemic bandwagon?

              • Anoneuoid says:

                Then she clearly was way ahead of the evidence on massive dosing with vitamin C.

                No shes not. Given what we know about vitamin c it would be extremely surprising if especially the severe patients were not deficient and giving enough to correct the deficiency (and keep it corrected until they are healthy, dont stop after 4 days or something) was not beneficial.

              • Anoneuoid says:

                Also, the only thing that may be less toxic than sodium ascorbate is water. And more people have gotten sick or died from too much water, so I even question that. And it is very cheap too.

                So cost-benefit analysis -> find out how much vitamin c they need to have healthy levels (which, granted, requires very careful handling of the samples and hplc so is expensive), and give them enough to correct it.

            • Joshua says:

              BTW, I should add of course we have no particular reason to trust anything those people write at that link – or even the claims that they worked with her.

              Or even that the photo with Judy is real.

              It could all be fake. Just like it could be that she has an agenda and put together deliberately misleading video to push an agenda. Truth told, I think that is more likely. But who really knows?

        • Phil says:

          Anoneuoid,
          You’re reading a lot into two studies, on mice, of a specific type of vaccine for a different disease.

          But as I discussed earlier, even if you’re right that a vaccine will help younger people but not older people it would still be extremely valuable.

          When you say “the vast majority of young people don’t even notice it”, are you dividing the world into “old” and “young”? If so, I think you’re just wrong if you’re saying the ‘vast majority’ of non-old people don’t even notice it. If, instead, you’re saying something like most people under 25 don’t even notice it…well, first I’m not sure that’s true, but even if it were, there are plenty of people older than 25 but younger than, say, 70, who are at low risk of dying but at high risk of an extremely unpleasant experience.

          I’m not sure about the numbers now, but as of mid-March about 50% of US coronavirus who were in intensive care were under age 65; in France the fraction was lower, but still over 35%. Plenty of non-old people get very sick.

          • Joshua says:

            Not to mention, a vaccine that is effective for younger people could be beneficial in another aspect; even if it would mostly be protecting ounger people who won’t likely die from COVID-19 (although as you point out it would protect many people from getting ill), it would prevent them from being infectious – which would have carry-on benefits to older people (or more generally, vulnerable people).

          • Anoneuoid says:

            There are more studies on ADE and the role of age in response to vaccines in general and SARS in particular, but afaik there is only the one that reported on covid in aged animals. When I post a source to a blog usually just take it as a “starting point”. I can post more if you want.

            Point is though, it is *very likely* that the vaccine will be much less effective or even dangerous to the entire population at risk of severe illness (the elderly and/or sick). I’m guessing you think it is unlikely only because you are unfamiliar with the topic.

            And you can talk about “plenty of young people” getting very sick but plenty of people get very sick no matter what. From what I’ve seen I’m personally not scared at all of this virus (not in an at risk group). I think I already had it anyway but wouldn’t mind getting exposed to get immunity for sure, it could act as a booster anyway. There is no need to spend billions on a vaccine for people like me.

            I

            • Luca Beltrame says:

              Early results from CanSino’s vaccine (inactivated SARS-CoV-2) point to no ADE at least in animals, same for Oxford’s ChadOx.

              • Anoneuoid says:

                Was this in young animals whose antibodies had not yet waned?

              • Anoneuoid says:

                It is like people keep running random studies with no theoretical understanding. The danger from the vaccine is when the animal has weak antibodies. Strong or no antibodies are better than weak. This can happen three ways:

                1) You are old/sick or otherwise have a weak immune system
                2) You are exposed to a similar but not identical virus so the antibody binding is weaker
                3) You are exposed to the same (or at least immunologically identical) virus after the antibodies from the first exposure/vaccine have waned

                Those are the scenarios they should be assessing in the safety trials. As far as I know, the study I cited above that tested 5 mice is the entirety of the publicly available data attempting to address the actual safety issues: https://www.biorxiv.org/content/10.1101/2020.05.28.121640v1

              • Anoneuoid says:

                Here is one out today. Some children who were mild/asymptomatic and presumably exposed weeks/months ago are testing positive for antibodies. These children who have some kind of inflammatory syndrome had a weaker antibody response than adults who ended up in intensive care: https://www.medrxiv.org/content/10.1101/2020.06.05.20123117v1

                It is this weak response (low quantity, low affinity, whatever) we should be concerned about when it comes to a vaccine. I’d love to see the same kind of data in adults who tested positive that had asymptomatic/mild illness.

              • confused says:

                Well, yes, that’s because (in my limited understanding) they don’t do phase I trials in high-risk groups, and that’s what we’ve seen results from so far.

                If the vaccine gives bad results in young healthy people, you really don’t want to give it to vulnerable people! It’s a screening step, not proof that it works.

                The trials done so far don’t show that the vaccines are either safe or effective. They do show that the vaccines are worth continuing into further trials.

                If antibody-dependent enhancement was going to be a big problem, wouldn’t we have seen it by now in “natural” disease (rather than vaccines?) Elderly people who were infected and produced only weak antibodies (due to age/poor state of their immune system), then were reinfected (since their antibodies were weak) and had worse outcomes? With how many people have been infected, there must have been a bunch with relatively poor immune responses. But we’re really not seeing reinfections with COVID.

                I’m not arguing it’s not possible with this virus, but if it was particularly common/likely…

              • Anoneuoid says:

                If antibody-dependent enhancement was going to be a big problem, wouldn’t we have seen it by now in “natural” disease (rather than vaccines?) Elderly people who were infected and produced only weak antibodies (due to age/poor state of their immune system), then were reinfected (since their antibodies were weak) and had worse outcomes?

                It is quite possible that is another reason why it is so much more deadly in the elderly, especially in population dense areas. They got sick, got put in a hospital with other covid patients, then the virus went around causing ADE.

                Especially because usually it takes a bit for the immune system to learn the right antibody to make, the initial ones usually have less affinity or not be as selective towards the virus: https://en.wikipedia.org/wiki/Affinity_maturation

              • confused says:

                I guess it’s possible, but then why do we see so few reports of reinfection, and the ones we have seen look to be actually “false positives” on the later tests? (They’re not really “false positives” from the perspective of PCR – there really is viral RNA present – but they’re “false positives” from the perspective of infection – what’s being detected in e.g. the South Korea “reinfections” was ‘old’ viral fragments no longer capable of infectiousness, not complete active viruses.)

              • Anoneuoid says:

                I guess it’s possible, but then why do we see so few reports of reinfection

                Can you clarify why you would expect to see this? I would not expect to see this, so you are making some kind of different assumption.

                1) You are old/immunocompromised and get exposed.
                – Then you probably didnt survive, or if you did the severe illness triggered a strong antibody response

                2) You are young healthy and had mild illness
                – Then you were probably never diagnosed to begin with

                What leads you to think we would see many reinfections?

                And anyway, relying on this type of speculation when the animal studies could be cheaply and easily done is ridiculous.

              • confused says:

                I would expect to see severe reinfections if ADE was likely/common (not just possible) from natural infection for two reasons.

                – While elderly people are at far higher risk from COVID, most do survive, and not all have severe illness. There are asymptomatic cases even among fairly elderly people.

                – With 2 million confirmed infections in the US alone, and lots more in other countries with relatively decent reporting, there will be hundreds of thousands of people who are neither very young nor extremely old, who had infections bad enough to be detected, but not *that* bad.

                I think reinfections probably are possible once in a while; viruses that are generally thought of as providing immunity against reinfection aren’t 100%. I had chickenpox twice (and I have a pretty strong immune system, the last time I went to the doctor for anything infectious was 2009 H1N1). But the reinfections are probably very rare and maybe milder, or we’d see them.

              • Anoneuoid says:

                There are asymptomatic cases even among fairly elderly people.

                What is the antibody profile in such cases?

                there will be hundreds of thousands of people who are neither very young nor extremely old, who had infections bad enough to be detected, but not *that* bad.

                The people expected to have a weak antibody repsonse where they wane after only few weeks/months had something more like the sniffles. You don’t need to almost die for your body to build up a robust antibody response, if you did then vaccines wouldnt work at all.

                So, unless there is data out there that antibodies have waned already in a substantial subset of those previously diagnosed I would not expect to see reinfections. And also, t-cell mediated immunity will modify the illness the second time around so it might not get noticed for that reason.

              • Martha (Smith) says:

                Confused said, “I had chickenpox twice”.

                Can you be sure of this? Or might it have been something like having chicken pox once and cowpox another time?

              • confused says:

                I was thinking more about people who only developed weak antibodies to start with, not waning over time (it probably hasn’t been long enough to see that).

                Chickenpox twice: I mean, I was pretty young then, could have been misdiagnosed I guess… but not cowpox, I think. Apparently a lab-acquired case in 2010 was the first ever human case in the US, so I don’t think it’s “around”.

              • confused says:

                Anoneuoid: I guess, let me ask the question this way.

                Unless I’m misunderstanding, you seem to be saying not only that antibody-dependent enhancement is a *potential* problem for COVID vaccine development, but that *multiple* vaccine candidates being currently developed *probably* will cause ADE at a high enough rate to make them useless/harmful – at least in elderly at-risk populations.

                Is that a correct restatement of what you’re saying?

                If so, why are you confident that ADE will a) be seen at all in COVID-19, and b) be common enough to prove a serious problem for the vaccine (as opposed to a 1 in 100,000 fluke event)?

                I know ADE turned up in SARS, but while this virus is genetically similar, it’s clinically pretty different.

              • Anoneuoid says:

                I know ADE turned up in SARS, but while this virus is genetically similar, it’s clinically pretty different.

                It showed up when they tested aged animals…

                https://statmodeling.stat.columbia.edu/2020/06/06/vaccine-development-as-a-decision-problem/#comment-1353742

                They have to test scenarios likely to lead to ADE, not young healthy animals against the same virus whose antibodies havent waned and say “no evidence of ADE”.

                Honestly this is insane that people dont want them to check this.

              • Anoneuoid says:

                We found that higher concentrations of anti-sera against SARS-CoV neutralized SARS-CoV infection, while highly diluted anti-sera significantly increased SARS-CoV infection and induced higher levels of apoptosis. Results from infectivity assays indicate that SARS-CoV ADE is primarily mediated by diluted antibodies against envelope spike proteins rather than nucleocapsid proteins. We also generated monoclonal antibodies against SARS-CoV spike proteins and observed that most of them promoted SARS-CoV infection. Combined, our results suggest that antibodies against SARS-CoV spike proteins may trigger ADE effects. The data raise new questions regarding a potential SARS-CoV vaccine, while shedding light on mechanisms involved in SARS pathogenesis.

                https://www.sciencedirect.com/science/article/pii/S0006291X14013321

                What possible reason do people have to not want to see these experiments replicated for SARS2?

              • Martha (Smith) says:

                confused said
                “Chickenpox twice: I mean, I was pretty young then, could have been misdiagnosed I guess… but not cowpox, I think. Apparently a lab-acquired case in 2010 was the first ever human case in the US, so I don’t think it’s “around”.”

                What you write does seem consistent with what I can find on the web. But it is inconsistent with what my father told me — namely, that he had never gotten vaccinated against smallpox, because he had had cowpox as a boy (while working on an uncle’s farm — would have been sometime between around 1915 – 1921). Either he was misguided, or there was indeed cowpox around (at least in Michigan) then, but there were no official records of the disease from that era (which does seem plausible).

              • Anoneuoid, I don’t think people “don’t want them to check this”. I think it’s just that most people here know that this is a topic that is being discussed and have some confidence that it will be investigated in time. I do think it’s a little early to expect widespread testing of this sort of thing across all these vaccine candidates. You’re not necessarily likely to test this in aged mice until you have some idea that it’s worth testing the vaccine at all… Many of these vaccine projects were started around March 1.

                I agree with you that I’d want to see these tests. I do believe that they will be done. The people who actually design vaccines do have *some* idea what they’re doing.

              • Anoneuoid says:

                It should have been done already, instead in paper after paper I see the researchers saying “no evidence for ADE, its just theoretical, we need to be aggressive”, when they havent checked the situations where it is likely.

                “The theoretical possibility [of ADE] is there,” says Rafi Ahmed, director of the Emory Vaccine Center. “The more difficult question becomes, how do you balance this concern with moving forward? There’s not an easy answer.”

                https://www.nature.com/articles/d41587-020-00016-w

                You balance it by checking for ADE under the same circumstances it showed up for SARS and elsewhere. Ie, few or low affinity antibodies towards SARS2 or viruses with similar epitopes.

              • Joshua says:

                My partner claims that her son had chickenpox twice, mildly once when he was very young and then again more severely when he was somerhat older.

                And I am totally convinced that my partner is never wrong about anything.

              • Martha (Smith) says:

                Joshua said,
                “My partner claims that her son had chickenpox twice, mildly once when he was very young and then again more severely when he was somewhat older.”

                I didn’t have it until I was 13 — and can attest that it was more severe than it seemed to be in younger kids. I remember that my lip was all swollen up from a blister on it (although perhaps the worst part was my brother’s reaction: He caught it from me and was 14 , in high school, so it was really an indignity for him to have to stay out of school with chicken pox — and, of course, he blamed it all on me.)

              • Joshua says:

                The first time her kid got it, it was from a pox party – the thinking was to get it over with when they were younger because then it would be less severe.

              • confused says:

                I see what you are saying about what to test for… but that doesn’t quite answer my question.

                It seems entirely reasonable to say, “at this point, some or all of these vaccine candidates *could* be worse than useless because of ADE”.

                The part I am questioning is where you use phrases like “will not generalize to the population at risk” and “what we should expect to happen”. I’d say “may not generalize” and “could possibly happen”. I really don’t see why we should expect ADE to be ‘more likely than not’ rather than ‘a possible concern’.

                Other than by direct comparison to SARS-1, and I am not convinced that that is as relevant as all that, since the clinical picture of this virus is very different.

                And yes — I think Daniel Lakeland is right. I am pretty confident that the tests that need to be done, will be done. The vaccines are being “rushed” – from the perspective of drug development, an industry and regulatory structure that is incredibly slow and hyper-cautious. I don’t think they are being “rushed” from an outside perspective. (That would be, for example, offering it to everyone who wants it after just Phase I trials are completed — which isn’t being done).

                cowpox in Michigan: I really don’t know. Dairy workers in England got cowpox from cows, that’s how vaccination was discovered in the first place. So it’s possible, maybe the “first case” really means something like “first lab-confirmed case” or something…

              • Anoneuoid says:

                Other than by direct comparison to SARS-1, and I am not convinced that that is as relevant as all that, since the clinical picture of this virus is very different.

                Why do you say the clinical picture is very different? I mean the clinical picture from what was reported out of China looks totally different from today because people stopped putting them on ventilators early like for SARS. Why didn’t we hear about the loss of smell, etc until recently?

                So first, I don’t think we have a good clinical picture of either of these viruses but especially not SARS. Second what differences? They look very similar to me.

                And yes — I think Daniel Lakeland is right. I am pretty confident that the tests that need to be done, will be done. The vaccines are being “rushed” – from the perspective of drug development, an industry and regulatory structure that is incredibly slow and hyper-cautious. I don’t think they are being “rushed” from an outside perspective. (That would be, for example, offering it to everyone who wants it after just Phase I trials are completed — which isn’t being done).

                If you fund a study on 10 young healthy mice there is zero reason to not have also included a set of aged mice given what we know. It requires negligible extra funding to do this and is a common sense measure. Same for vaccinated for SARS2 and challenging with SARS1.

                Setting up a situation where waning can be studied in a decent time period would require more effort but to get basic info on the other two scenarios there’s no excuse. Everyone knew about this back in February.

              • confused says:

                Why do I say the clinical picture is very different? Because SARS fatality rate was ~10%; COVID seems to be ~1% in hard-hit populations (NY/Italy/Spain) and may be somewhat lower elsewhere. COVID seems to have a lot of asymptomatics too.

              • confused says:

                Why didn’t we hear about loss of smell until recently? I’d imagine, though based on no real evidence, because it’s not that scary – it’s not going to be the first symptom people worry about – so it was probably poorly and intermittently reported so it took time to find a trend.

                (Also a lot of respiratory things can mess up the sense of smell by just blocking up the nose/congestion. My seasonal allergies definitely interfere with my sense of smell. So it might not have been considered that notable at the beginning.)

              • Anoneuoid says:

                Why do I say the clinical picture is very different? Because SARS fatality rate was ~10%; COVID seems to be ~1% in hard-hit populations (NY/Italy/Spain) and may be somewhat lower elsewhere. COVID seems to have a lot of asymptomatics too.

                If everyone with covid got immediately put on ventilators like the WHO recommends the death rate would be 10-100x higher too.

                Plus I don’t think we have any idea how many people actually had SARS.

              • confused says:

                Yeah but if SARS had had a COVID-like IFR, 10 to 20 times lower (assuming a 0.5%-1% range for COVID), that would have meant 10-20x undetected cases, so why was it contained?

                And the “inherent” difference between SARS and COVID might be even larger since SARS had few patients overall. Hotspots like NYC and Northern Italy might have seen an increased IFR due to worse care (hospitals in NYC were not overwhelmed in the sense of “turning patients away”, but quality of care may have dropped because of overwork among the healthcare workers).

              • Anoneuoid says:

                Yeah but if SARS had had a COVID-like IFR, 10 to 20 times lower (assuming a 0.5%-1% range for COVID), that would have meant 10-20x undetected cases, so why was it contained?

                You dont need more cases to explain it, just be quick to put those diagnosed on ventilators, in negative pressure rooms with other SARS patients that concentrates the virus, etc.

                But I also dont see how the surveillance back then would have detected a similar number of mild/asymptomatic cases as for covid.

                10-100x difference in IFR seems plausible to me.

                And anyway, why do we need to speculate based on crappy data when there have been months to just do a few experiments in mice and cell lines to check if ADE risk is similar to SARS?

                Instead we know 5 old mice had a weaker antibody response to one vaccine than younger mice. Thats it.

              • confused says:

                >>But I also dont see how the surveillance back then would have detected a similar number of mild/asymptomatic cases as for covid.

                I’m not saying it would have… I’m saying that if those cases had existed, and not been detected (as I agree would have been likely), SARS would probably have continued to spread worldwide rather than being contained & dying out.

                So they probably did not exist, and SARS is probably a very different *disease* (in terms of effects-on-infected-humans) than COVID-19, even if the *viruses themselves* are very genetically similar.

                I’ve seen it argued (though in a ‘popular/general’ media article, not a scientific one) that COVID-19 is essentially more contagious/easily spread *because* it is less deadly… because most cases are more-mild-but-more-easily-spreading upper-respiratory infections, rather than the more dangerous lower-respiratory-progressing-to-systemic ones.

                Though there are also media reports of ‘COVID toes’ being associated specifically with *mild* cases, and that’s “systemic” I guess, so who knows…

                Still, there does seem to be some validity to the ease-of-spread being associated with the disease being ‘less dramatic’ overall… for the same reason that Ebola has failed to spread in the US, despite being introduced more than once. (Because Ebola patients are really obviously sick, you obviously want to avoid them, and they get a high level of caution applied quickly.)

              • Anoneuoid says:

                > I’m not saying it would have… I’m saying that if those cases had existed, and not been detected (as I agree would have been likely), SARS would probably have continued to spread worldwide rather than being contained & dying out.

                Maybe it did, and I don’t think SARS2 is very infectious either. There are just a relatively few super spreaders and idiotic policies like a touchscreen robot giving covid advice, encouraging people to hug those from a region of outbreak, etc.

                But I don’t know what this has to so with not needing to check if the risk of ADE is the same as seen for SARS.

              • confused says:

                I really don’t think SARS could still be around and not be noticed (if it mutated enough to not be noticed, it would have to be different enough that still calling it SARS would be pointless).

                I’m not saying that we shouldn’t check for ADE – we absolutely should! I am just questioning your characterization of it as something highly probable / almost certain to happen in COVID, vs. a potentially very serious concern that might or might not actually exist for this disease.

            • Phil says:

              Anon,
              You’ve moved the goalposts a long way on your claim: initially you said it’s likely that it would provide no benefit at all to old people, now you’re saying it’s very likely it will be “much less effective.” That’s a huge difference. If it’s 99% effective at preventing infection in young people and 50% effective in old people, that would be much less effective in old people than in young people but I would definitely want all of the old people I know to get the vaccine unless the risk of severe side effects was very high.

              As for your statement that “there is no need to spend billions on a vaccine for people like me,” sure, if all we cared about was people like you we could do lots of things differently.

              But I do care about people who aren’t like you. I don’t want you getting infected and passing the illness along to my mom.

              Different people have different values, and those values lead to different rational decisions. It’s fine with me if you don’t care whether you pass the virus on to other people — I think it says something bad about you, but that’s your problem, not mine — but I think you go too far when you say that because a decision doesn’t make sense under your value system, it therefore doesn’t make sense.

              • Anoneuoid says:

                You’ve moved the goalposts a long way on your claim: initially you said it’s likely that it would provide no benefit at all to old people, now you’re saying it’s very likely it will be “much less effective.”

                Sorry, that was your initial claim of “not effective at all” I responded to. Nothing has zero effectiveness, I actually expect it will be actively harmful.

                But I do care about people who aren’t like you.

                Yes, those are the people a vaccine needs to be developed for! If you care about them, you should want a vaccine developed that is safe for them to take. Why do you not want this?

              • Anoneuoid says:

                I should also say I now know two people having serious health issues as a result of this lockdown and fear of the virus. One started having seizures (probably due to anxiety/depression meds that lower the seizure threshold) and the other was so sedentary for months they blew out their back just standing up. Both are people terrified to leave the home over a virus that was little threat to them.

                This needs to end, quickest way is all the people who are at little risk go expose themselves then self quarantine for a week.

              • Phil says:

                Anon,

                To answer your phony question: of _course_ I, like everyone else, want a vaccine that is effective for the population that is most at risk. But
                one of the early stages in vaccine development is to make sure the proposed vaccine isn’t dangerous. The first tests are done on healthy young people because they have the most margin for recovery if something does indeed go bad. (Here is an example https://www.statnews.com/2020/05/26/moderna-vaccine-candidate-trial-participant-severe-reaction/) It would be practically criminal, and maybe literally criminal, to do the initial testing on morbidly obese elderly diabetics, as you are promoting. You want to find something that works for the most vulnerable people, if you can, but you can’t start there.

                Hitting a few minor points too:
                1. Even if you are right that it is highly likely that any vaccine that is effective for younger people will be harmful to older ones, “highly likely” is not “absolutely certain”. Even if you are right, there is a chance of an effective vaccine for the at-risk population, so let’s pursue that.

                2. I don’t agree that any vaccine that helps the young isis “highly likely” to harm older people. Here https://www.cdc.gov/vaccines/schedules/downloads/adult/adult-combined-schedule.pdf is the CDC’s chart of recommended vaccinations by group, including age group. I see only three that are not recommended for people over 65, and I think on only one of those cases (live influenza) that’s because of the likelihood of harm.

                3. You say “This needs to end, quickest way is all the people who are at little risk go expose themselves then self quarantine for a week.” That would not end this because this would not be enough people to reach herd immunity and there would still be a large fraction of the population with no immunity. The details depend on how you define ‘little risk.’ We could draw the line at healthy people under 30 and hardly kill anyone, but that’s much less than half the population and will certainly not stop the pandemic. Do it with healthy people under 40 and you still don’t have half the population but you will kill a substantial number of people and many others will suffer lasting ill effects. Draw it at 50 and you’re finally getting a decent percentage of the population (though not enough to attain herd immunity) but now you’re killing quite a few people and doing severe harm to many others.

                For what it’s worth, although I am old enough for my age to be a factor (I’m 54) I am in pretty good physical condition and I think I’d be very unlikely to die if I become infected. I am not worried for myself and I understand the frustration of people who are not worried for themselves and who are suffering profound hardship from the economic shutdown. But we need to be clear-eyed about the consequences of the courses of action we are considering. Saying that if only everyone under (say) 40 went ahead and got infected and then quarantined for a week the whole thing would be over, that’s just not right. It puts me in mind of HL Mencken’s quote “there is always a solution to every human problem; neat, plausible, and wrong.”

              • Anoneuoid says:

                You say “This needs to end, quickest way is all the people who are at little risk go expose themselves then self quarantine for a week.” That would not end this because this would not be enough people to reach herd immunity and there would still be a large fraction of the population with no immunity

                So then you must agree that a vaccine that is only safe in young healthy people wont accomplish this either…

                That is why we need a vaccine that is safe for the at risk population to be useful. Like i said above, so far I have only seen a vaccine tested in 5 old rats and they didn’t report anything about what happened to them upon later challenge, only weak antibody response.

                I am trying to stop a giant catastrophe by making people aware of this and you are calling me “bad” because of that.

              • Anoneuoid says:

                And lets not forget the last thing I warned against, “early intubation”. Which has now been widely accepted to have been a very bad idea: https://old.reddit.com/r/COVID19/comments/fc8f7z/what_the_role_of_mechanical_ventilation_on_the/

                If people listen to these common sense things I am saying less people die.

              • Phil says:

                Anon,
                I said “This needs to end, quickest way is all the people who are at little risk go expose themselves then self quarantine for a week.” That would not end this because this would not be enough people to reach herd immunity and there would still be a large fraction of the population with no immunity”

                You replied: “So then you must agree that a vaccine that is only safe in young healthy people wont accomplish this either…”

                Well of course I agree with that, wtf.

                I’m struggling a bit here because you seem to implicitly, or in a few cases explicitly, try to turn everything into either/or: everyone is either young at no risk or at high risk; a vaccine is either useful and ends the pandemic or useless and doesn’t. I know you don’t normally think this way so I wonder what’s going on with this particular topic.

                A vaccine can save a lot of lives and allow resumption of much economic activity even if it is not perfect. Indeed it can do those things even if it provides no immunity at all to the most vulnerable 20% or 30% of the population, as you are convinced will be the case for reasons that escape me. If the vaccine is that imperfect then we will still have an immense public health challenge and economic challenge to deal with, but the situation will be vastly better than the one we are in right now. I very much doubt you disagree with anything in this paragraph. To the extent that we disagree, I think it’s your belief that we could achieve the same effect without a vaccine, just by letting everyone except the most vulnerable get infected.

                It seems possible that we will not have a reasonably effective vaccine for years. If that’s the case then we may get desperate enough to just let a lot of people get infected and take the hit in terms of deaths and severe health effects among many people, so it’s possible that we will go your desired route. But that be much, much worse than having even a very imperfect vaccine.

              • Anoneuoid says:

                Here is the first thing what I want: These vaccines to be tested in old/sick animals before distributed to the general population.

                There is more that should be done you can gather from this post: https://statmodeling.stat.columbia.edu/2020/06/06/vaccine-development-as-a-decision-problem/#comment-1354168

                But start there. So far we have the limited report about 5 mice and those results point to the catastrophe I expect if this vaccine is rushed.

              • confused says:

                From what I’ve seen, the prospects for COVID vaccines look pretty good, and people working on them are very *very* aware of the concerns about antibody-dependent enhancement.

                But I don’t think we can confidently make broad statements about what ‘herd immunity’ without a vaccine would mean.

                – We don’t really know what the herd immunity threshold would be (a classic R0 based calculation may be a poor fit for this disease, where transmission seems to be largely driven by super-spreaders; if potential super-spreaders who have more social contacts get infected first, the herd immunity threshold may be lower), and it may be very variable between places with different contact patterns (population density, mobility, etc.)

                – Are the serology tests good enough to know what the seroprevalence really is?

                If we don’t know what the herd immunity threshold is, and we may not know what the current seroprevalence is either, we can’t know how far we are from ‘herd immunity’.

                And I think the problem with letting all the younger people (say under 40 or 45) get infected is more that it wouldn’t actually work – not that it would lead to tons of deaths. Young people live with older people, work in nursing homes, in healthcare (and thus with older patients).

                However, a “protect the elderly and those who live/work with them” strategy might well have led to better outcomes than a society-wide one, with less “second-order” health harm (psychological consequences of isolation; missed/delayed cancer screenings, surgeries, etc.) and less economic damage. About 40% of US COVID deaths were in nursing homes, and in some states it’s up to 80%.

              • Anoneuoid says:

                From what I’ve seen, the prospects for COVID vaccines look pretty good, and people working on them are very *very* aware of the concerns about antibody-dependent enhancement.

                They may be aware but so far the entirety of testing at risk groups Ive seen published are those 5 old mice. And even there no later challenge with virus was done. I expect all these vaccines to fail if those tests are eventually done.

                Except maybe this one: https://www.cambridge.org/core/journals/qrb-discovery/article/biovacc19-a-candidate-vaccine-for-covid19-sarscov2-developed-from-analysis-of-its-general-method-of-action-for-infectivity/DBBC0FA6E3763B0067CAAD8F3363E527#

          • confused says:

            I am not sure these statements are mutually exclusive.

            Given that something like a third to a half of *all* infections are asymptomatic, maybe more in some populations, it doesn’t seem implausible that a majority of infections among the young and healthy are asymptomatic. And if by “notice it” one means, “notice the symptoms as qualitatively different than the average cough or cold and become concerned/seek medical care” rather than “notice any symptoms at all”, that majority could plausibly become a “vast majority”.

            I.E. – if you are tested for COVID as part of a mass occupational testing program of, say, meatpacking plant workers or healthcare workers, test positive, and have a cough, you’re not “asymptomatic”. But that doesn’t mean everyone who has a cough seeks medical care or even thinks of themselves as being “sick”.

            But that doesn’t mean that the burden of disease among the smaller fraction who *do* experience serious symptoms is insignificant.

            Imagine a hypothetical disease that is 90% asymptomatic, sends 1% of people to the hospital, and kills 0.1%. It would certainly be true that the vast majority of people who catch the disease never notice. But if 50 million people catch it, that’s still 500,000 hospitalizations and 50,000 deaths.

  5. Dwyer says:

    ” We estimated that it’s necessary to have 15-20 candidates in the portfolio to get to a 80-90% chance of at least one success… “

    … how could such an estimate be rationally determined ?

    There is no evidence that an effective COVID-19 vaccine recipe is just out there somewhere waiting to be discovered. It might never be found or even exist.

    Existing seasonal-Flu vaccines are only partially effective in practice.
    Vaccine against the Common-Cold viruses (same general family as COVID-19) have somehow eluded many decades of worldwide research.

    And if this vaccine approach is so good — why risk under funding it — allocate at least a Trillion Dollars to it (the US Government had no difficulty instantly coming up with 3 Trillion Dollars in COVID-19 fiscal stimulus, with more to come)

    • Luca Beltrame says:

      Common cold is generally not coronavirus related, but rhinovirus. As for influenza, the reason vaccines are so unreliable is due to the structure of the viral RNA in the influenza virus, which causes a very high number of recombination events during the replication in the host cell, and thus chances for the virus to elude the immune system.

      Also, coronaviruses have proof-reading in their RNA replication enzyme, so their rate of mutation is far lower than influenza: a vaccine that works might keep its potency for quite a while.

  6. Ignazio says:

    Alright, we should never listen to Tabarrok and his buddies at GMU econ and the Mercatus center at GMU (Tyler Cowen, Robin Hanson, Bryan Caplan, etc.). They have been directly appointed by the Koch foundation, with the objective of pushing the far-right political and ideological objectives of the Koch family (i.e., destroying unions, eliminating environmental regulations, and eliminating antitrust law).

    https://www.insidehighered.com/news/2018/05/01/koch-agreements-george-mason-gave-foundation-role-faculty-hiring-and-oversight

    Whatever they say, it’s either factually wrong, disproven, or despicable.

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