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Vaccine Possibilities

Now that we’re seeing that coronavirus vaccines are indeed possible (and are on their way), let’s talk about the remaining unanswered questions and the things that we will be getting more data on. Here are some of the big issues – it’ll be good to see this stuff coming into focus. I’ll put these into the form of questions (think of it as a tribute to the late Alex Trebek, whom I was glad to help remember in this article, and more here). Each one will have a summary answer at the end of the section, if you just want to skip to that part.

How long will the vaccine protection last?

This one can’t be answered with total confidence by any other way than just waiting and watching. But we will be able to give a meaningful answer well before that, fortunately. Here, just out in the last couple of days, is the most long-term and comprehensive look at the duration of immunity in recovered coronavirus patients. In fact, it appears to be the largest and most detailed study of post-viral-infection immunity in the entire medical literature (!) It’s from a multi-center team at the La Jolla Institute for Immunology, UCSD, and Mt. Sinai, and it looks at 185 patients who had a range of infection experiences, from asymptomatic to severe. 38 of the subjects provided longitudinal blood samples across six months.

We’ve already seen from the convalescent plasma comparison samples in the various vaccine Phase I trials that the antibody response to coronavirus infection can be quite variable, and that was the case in this study as well. That gives you wide error bars when you try to calculate half-lives, and it’s not even clear what kind of decay curve the antibody levels will best fit to (it might well be different in different patients). But one figure to take home is that 90% of the subjects were still seropositive for neutralizing antibodies at the 6 to 8 month time points. The authors point out that in primate studies, even low titers (>1:20) of such neutralizing antibodies were still largely protective, so if humans work similarly, that’s a good sign. An even better sign, though, are the numbers for memory B cells, which are the long-term antibody producers that help to provide immunological memory. B-cells specific to the Spike and to the nucleocapsid coronavirus proteins actually increased over a five-month period post-symptom-onset, thus with no apparent half-life at all. These had interesting variations in antibody type (by the end of the period, they were strongly IgG, the others having dropped off), but as the paper notes, we really don’t have many viral infection profiles in humans to compare these results to. B-cell memory overall, though, looks to be long-lasting, and is expected by these results to stretch into years. For what it’s worth, there are patients who survived the 1918 influenza pandemic who had B cells that still responded with fresh neutralizing antibodies after over 90 years, so they can be rather hardy.

What about the other immune (and immune memory) component, T cells? The news there is good as well. CD4+ and CD8+ memory T cells appear to have half-lives of at least five or six months in these patients, and helper T cells (crucial for those memory B cells to respond later on) were completely stable over the entire period studied. Again, there are very few viral infection studies to compare this one to, but these numbers look consistent with long-term protection via reactivated immune memory.

Looking over the whole set of patients, it was clear that the immune system’s famously individual character was on full display here. That heterogeneity could well be the reason that there are real cases of re-infection, although it still seems to be rare. Different components of the immune response (both in antibodies and T cells) varied widely among patients, and these differences only became more pronounced over time. Nevertheless, at the five-month time point in a measure of five components of immune response and memory, 96% of patients were still positive on at least three of them (the categories were IgG antibodies against the Spike receptor-binding domain (RBD), IgA antibodies against the same Spike RBD, memory B cells aimed at the RBD, total SARS-CoV-2-specific CD8+ T cells, and total SARS-CoV-2-specific CD4+ T cells).

Bottom line: Taken together, this study, several others over the past few months, and this recent work all paint a consistent picture of a strong, normal, lasting immune response in the great majority of patients. Add in the results we’re seeing from the two vaccines that have reported interim data so far, and I think that the prospects for lasting immunity from vaccination are also very good. Remember, the early vaccine data suggested antibody responses at least as strong as those found in naturally infected cases. There seems (so far) every reason to think that vaccine-based immunity will be as good or better than that conferred by actual coronavirus infection. I very much look forward to more data to shore up this conclusion, but that’s how it looks to me at the moment.

How effective are these vaccines? Will they provide total protection or not?

We’re just starting to get numbers on this, and we are definitely going to know more as the various trials read out interim data and then reach their conclusions. So far, though, the efficacies we’re seeing have been more than I had really hoped for. I thought that they would work, and I didn’t think that meant just the FDA’s floor of 50% efficacy, but I sure didn’t have the nerve to predict that the first two readouts would be 95% (Pfizer just reported their final readout this morning). I can’t overemphasize how good that news is, especially when you compare it to some earlier worries that a useful coronavirus vaccine might not even be possible at all. Cross that one off the list!

Those efficacy numbers, though, are measured for symptomatic coronavirus cases. The vaccine trial participants are not being pulled in at regular intervals for testing to see if they’ve gone positive-though-asymptomatic. We may get controlled data of that sort eventually, but for now, we know from the Moderna trial that the few people who came down with symptoms at all had very mild cases. The antibody levels that we’re seeing would argue for a low probability of having a significant number of vaccinated people walking around asymptomatically shedding coronavirus, and for anyone who does to be shedding a lot less of it for a shorter period of time.

From a public health standpoint, that’s what you need. Epidemics are a matter of probabilities, and you can lower the chances of spread for a virus like this in any number of ways. They surely vary in efficacy, but include keeping distant from other people and avoiding any crowding in general, wearing masks, avoiding indoor situations with people that you haven’t been exposed to (such as going to the grocery store when it’s not so crowded), minimizing the time you spend in any higher-risk situation in general (getting those groceries in an organized fashion and getting back outside), and more. The fewer people there are around shedding infectious particles, the better (obviously), but the worst case for a weakly effective vaccine might be that it could actually raise that number for a while by creating more asymptomatic cases rather than having the infection make people aware that they need to stay the hell inside. But I don’t think we’re going to see that. I think that the efficacy levels we’re seeing are indeed going to be epidemic-breaking if we can get sufficient numbers of people vaccinated. Right now we’re up around the efficacy of the measles vaccine, which is very effective against a virus that is far more infectious than SARS-Cov-2. . .if enough people take it. (Believe it, if the current coronavirus were as infectious as measles is, we would be hosed).

Bottom line: the results we have so far indicate that these vaccines will indeed provide strong protection in the great majority of patients. The number of asymptomatic cases among the vaccinated population will be a harder number to pin down, but I believe that we should be in good enough shape there as well, based on antibody levels in the primate studies and what we’re seeing in humans.

What about coronavirus mutations? Will the virus move out from under the vaccine’s targeting?

The SARS-Cov-2 virus has indeed been throwing off mutations, but all viruses do. They replicate quickly, and errors pile up. Fortunately, though, none of these have proven to be a problem so far. There’s been a lot of talk about the D614G mutation being more infectious, but the difficulty of proving that shows that it’s certainly not way more infectious, if it is at all. And it doesn’t seem to have a noticeable effect on disease severity – so far, no mutation has.

The recent news from Denmark about a multi-residue mutant (“Cluster 5”) that might be less susceptible to the antibodies raised by the current vaccines is a real concern, but the news there, thus far, is also reassuring. The vaccine efficacy warning might be true, but it was also based on a small amount of preliminary data. And the Cluster-5 variant has not been detected since September, which suggests that (if anything) this combination of mutations actually might make the virus less likely to spread. From what we’ve been seeing with the Spike protein, evading the current antibodies looks like it’s going to be difficult to do while retaining infectiousness at the same time. We already know from a Pfizer analysis that many of the common mutations are just as susceptible to neutralizing antibodies raised by their vaccine. Update: here’s an effort to monitor the developing mutations to keep an eye out for just these issues.

I know that many people are wondering about the similarity to influenza, and to the yearly (and not always incredibly effective) flu vaccines. Flu viruses, though, change their proteins far more easily and thoroughly than the coronavirus does, which is why we need a new vaccine every year to start with. SARS-Cov-2 doesn’t have anything like that mix-and-match mechanism, and it’s a damn good thing.

Bottom line: the coronavirus can’t undergo the wholesale changes that we see with the influenza viruses. And the mutations we’re seeing so far appear to still be under the umbrella of the antibody protection we’ll be raising with vaccination, which argues that it’s difficult to escape it.

What about efficacy in different groups of people? Where will the vaccines work the best, and where might there be gaps?

This is another area that is definitely going to come into better focus as the current trials go on. For the moment, we know that the results we have seen so far come from participants in a range of ages and ethnic backgrounds. There’s not much expectation that things will vary much (if any at all) across the latter, although it’s always good to know that for sure, and not least so you can point to hard evidence that it’s so. Age, though, can definitely be a factor. Older people are quite likely more susceptible to coronavirus infection in the first place, and are absolutely, positively at higher risk of severe disease or death if they do get infected. The immune response changes with aging, and it is very reasonable to wonder if the response to vaccination changes in a meaningful way, too.

But as mentioned above, we have more data from the Pfizer vaccine effort just this morning. The overall efficacy was 95%, and the efficacy in patients 65 and older was all the way down to 94%. This is excellent news. No numbers yet for people with pre-exisiting conditions and risk factors, but I’m definitely encouraged by what we’re seeing so far.

Bottom line: our first look at efficacy in older patients is very good indeed, and that’s the most significant high-risk patient subgroup taken care of right off the top.

How safe are these vaccines? What do we know about side effects?

As mentioned in the Moderna write-up here the other day, that team saw around 10% of their vaccinated cohort come down with noticeable side effects such as muscle and joint pain, fatigue, pain at the injection site, etc. These were Grade 3 events – basically, enough to send you to bed, but definitely not enough to send you to the hospital – but they were short-lived. For reference, those numbers seem to be very close to those for the current Shingrix vaccine against shingles, from GSK (thanks to their butt-kicking adjuvant mixture of a Salmonella lipopolysaccharide and a natural product from a South American tree). It’s a reasonable trade for coronavirus protection, as far as I’m concerned. And my reading of the Pfizer announcement today makes me think that their side effect profile is even a bit milder. They have fatigue in 3.8% of their patients, and all the other side effects come in lower.

What about lower-incidence side effects? Well, 30,000 patients is a pretty big sample, but on the other hand, the immune system is as idiosyncratic as it can be. There may well be people out there who will have much worse reactions to these vaccines. If you have a literal one in a million, you’re simply not going to see that in a trial this size, or actually in any trial at all. These are about as big as clinical trial numbers ever get. At that point, you’d be looking at such a hypothetical bad outcome in about two or three hundred people if we gave the shot to every single person in the US. And the public health calculation that’s made every time a vaccine is approved is that this is a worthwhile tradeoff. Let’s be honest: if we could instantly vaccinate every person in the country and in doing so killed 200 people on the spot, that is an excellent trade against a disease that has killed off far more Americans than that every single day since the last week of March. Yesterday’s death toll was over 1500 people, and the numbers are climbing.

How about long-term problems, then? These are possible with vaccines, but rare. And unfortunately, there is truly no way to know about them without actually experiencing that long term. We simply don’t know enough immunology to do it any other way. Given the track record over the last century of vaccination, though, this seems to be another deal worth making.

Bottom line: immediate safety looks good so far. Rare side effects and long-term ones are still possible, but based on what we’ve seen with other vaccines, they do not look to be anywhere at all significant compared to the pandemic we have in front of us.

OK, what about the rollout? Who’s getting these things first? When does everyone else get a chance to line up?

Harder questions to answer – there are a lot of variables. Pfizer and Moderna both say that they can make in the range of 20 million doses by the end of the year, but what we don’t know is (1) when the FDA will grant Emergency Use Authorization, (2) how many of these doses can be distributed and how that’s going to happen, (3) what the number of doses available right now might be, (4) how the ramp-up of both production and distribution are going to be coupled in the coming months, (5) what’s going to show up with the other vaccine candidates in testing, and so on.

The person in charge of the “Operation Warp Speed” logistics is Gen. Gustave Perna, who has been in charge of the Army’s Materiel Command (just the sort of background you’d want for an effort this size, I think). We know that manufacturing has already been underway on an “at risk” basis, and it looks like those bets are paying off, given the clinical results. Here’s the rollout strategy that has been announced so far, and it certainly seems sound from what I know about these things. It does leave some questions open, such as what groups are in the initial queue. You would have to think that health care workers would be at the top of the list – these people are risking their health and their lives as they deal with a constant stream of infectious patients, and losing them to illness or death has a severe impact on our ability to deal with the situation.

That situation, it has to be said, is going to be getting worse. It’s been getting worse for weeks, and it looks like it’s going to keep doing that for several weeks more even if we do everything right. And let’s be honest: as a country, as a population, we’re not doing everything right. There are a lot of people taking sensible precautions, but others are letting their guard down when they shouldn’t, and there are of course other people who never put their guards up in the first place and seem to have little intention of doing so. The map says “uncontrolled spread” across most of the US, and they ain’t lying. These vaccines are coming at extraordinary, record-breaking speed, but not fast enough for us to avoid what looks sure to be a 2,000-deaths-a-day situation. Take the worst air crashes in aviation history, and imagine three, four, five, six of them a day. All day Monday. All day Tuesday. No letup. Every single day of the week and all weekend long, a hideous no-survivors crash every few hours. That’s what we’re experiencing right now in terms of the sheer number of deaths.

Bottom line: the very first people to get these new vaccines will almost surely be health care workers, and starting some time on in December. The rollout after that has too many variables to usefully predict, but it’s going to be the biggest thing of its type ever attempted, in people-per-unit-time. And yes, I think it’s going to work, and not a minute too soon.

93 comments on “Vaccine Possibilities”

  1. Andy K says:

    The issue about asymptomatic transmission will only be answered by post-marketing surveillance and real world results I think, combined with viral kinetics and maybe challenge trials. I think most tests have a 1-2% false positive rate – if you think about the challenge of using that in a trial, every time you tested the 44k patients on the Pfizer study you’d have as many as 800 asymptomatic “cases” diagnosed based on the false positive rate alone right? The signal-to-noise would be awful. Just a thought – I may be wrong…

    1. Todd says:

      Those people aren’t getting tested once, and that’s it. Any positives are likely getting reflexed, and they’re probably confirming them using different methodologies. While each test does have a non zero false positive rage, stacking the tests allows you to confirm those positives. Also, these people are likely getting tested for COVID-19 more than once during the trial. It’s safe to assume that these positives are legit, though we can’t prove it until a paper comes out.

    2. Nick says:

      Those tests are only that insensitive in a vacuum; once repeated or confirmed your confidence goes up substantially. Take a look at Dr. Daniel Griffin’s testing calculator (https://calculator.unitedinresearch.com/complex_dashboard) is a pretty good way to look at probabilities based on sequential testing.

      1. Patrick says:

        I don’t *think* I see a discussion of sequential testing there? I see confirmatory testing with respect to test pools, but that’s obviously different.

        With any form of sequential testing, you have to ask: why did the test give an incorrect result before? Is that error independent or correlated? Independent would be “someone messed up the machine that run”, so if that’s your source, you can just multiply error rates for two tests and you’re good.

        Or is the error “I have a burn/break inside my nose where they stick the swab and so I don’t have 100% normal mucus membranes, so this sampling method doesn’t work” (to give an extreme example), or “the particular test antigen doesn’t match up well with the strain inside me”. Or, much more prosaically, the level in my is below the detection sensitivity of this specific test.

        These errors will persist in repeated testing.

        I don’t know that I’ve seen numbers on the error sources/types for positive and negative errors for the common types of tests. Does anyone here have a sense of it?

        (Different methods for confirmation are, therefore, the way to go.)

        1. x says:

          “Does anyone here have a sense of it?”

          Sure. I’m a medical laboratory technologist – in other words, I have a BS in medical laboratory science and I run the tests.

          The people who design assays and come up with best practices for collection are generally aware of potential sources of interference like the ones you suggested, and while we do see tests that are just garbage from time to time, the majority of false results are due to ordinary imprecision or known interference, not bad methodology or biological variation.

          A test that was unable to detect clinically-significant levels of some analyte because some positives fall below linearity (i.e. the test isn’t sensitive enough) would be a pretty useless test and hopefully wouldn’t make it out of R&D.

    3. MARK A VOTAPEK says:

      You’re not MSU Andy K, are you? If so, i’m laughing. Always pictured you as the epidemiologist type…

    4. Julie Crudele says:

      Pfizer and Moderna only tested people with symptoms. They aren’t testing the whole cohort periodically.

    5. Pam says:

      The false positive rate on PCR tests are significantly lower than 1%. I’m in Australia and in my state we are averaging roughly 15,000 test a day. It has been 10 days since we had ANY positive test. I think about 2 weeks ago there were news reports that a previous positive test had been found to be a false positive.

  2. Andrew Richards says:

    Dr. Lowe,
    One either very important or very stupid question I haven’t seen addressed yet —
    how much of this changes for the mass of people out there who have already been infected, especially if they don’t know for sure. Let’s say they had COVID-like symptoms in Feb/Mar/Apr but were never able to get tested.
    Are there any additional concerns for this sizable population regarding the safety and/or efficacy of any of these vaccines?

    1. John Wayne says:

      That is a pretty good question. With the caveat that I am not a clinician, I would expect that people with previous immune responses to COVID will tend to have more significant side effects upon the first dose. If this happens to you, talk to your doctor about the options (do you get the second dose or not, based on severity of response to the first)

      The complication is that they will want to get you the second dose in the event that your immune system isn’t cooperating, rather than you already have protection. This is the challenge clinicians have; they have to make a call without the data.

      1. Ian Malone says:

        Somewhat relevant, it looks like Pfizer have this data, though I haven’t looked at their trial protocol:
        “Analysis of the data indicates a vaccine efficacy rate of 95% (p<0.0001) in participants without prior SARS-CoV-2 infection (first primary objective) and also in participants with and without prior SARS-CoV-2 infection (second primary objective), in each case measured from 7 days after the second dose."
        https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-conclude-phase-3-study-covid-19-vaccine

    2. Valdis Andersons says:

      Have a look at any of the phase 1/2 data from any of the 3-4 front running vaccine candidates. They all have a few people already nAB positive at baseline and the data shows that the vaccines for them act like some superpowered booster shots (that one person from the Oxford phase 1/2 trial with an IC 1:1000 titer at baseline jumping to 1:8000 after the first dose comes to mind, but there were more and in all trials).

    3. Not-an-epidemiologist says:

      Did you ever worry about having already had one of the particular flu variants the yearly vaccine is against when you got your flu shot? Or, even better — did you ever need a tetanus booster after an injury and think, “Oh, gee, it’s only been a year since my last shot, I’d better not get one?”

      If you’ve already had covid-19, getting vaccinated should improve and strengthen your immune response against the virus.

      1. Bunsen Honeydew says:

        True, but we humans have been living alongside the flu and tetanus for millennia. SARS-CoV2 is a NOVEL virus and is prompting some people to have dangerous hyperimmune responses. I, myself, had a full-blown cytokine storm that would have killed a great many people. A strong immune response is excellent, but there are real and dangerous limits to that idea. I am 100% in favor of vaccines, but for myself, in this one particular circumstance, I would like to see some fulsome data on the issue of immune response and side effects in Covid-19 survivors.

        1. Julie Crudele says:

          SARS-CoV2 is a novel strain of coronavirus, which we have been living with for millennia. It’s not like it’s some class of virus we haven’t all had.

        2. Dan says:

          I could be very wrong on this, but in general I’d expect that the immune over-response doesn’t happen in the early stages of the infection, but after it’s already well established and the immune system goes into panic mode. Since the vaccine doesn’t put replicating virus in you, I would be surprised if it were capable of getting to the stage that provokes such a response, even in someone who already got sick.

          Something worth keeping an eye on, but I wouldn’t expect it to be a problem.

    4. Kevin H says:

      The seroprevalence rate in the U.S. population was somewhere in the (very broad) neighborhood of 5% around the end of summer.

      In a 30,000-participant trial (where half of them are getting the non-placebo intervention), you would expect at least several hundred participants who receive the vaccine to have had an asymptomatic or undiagnosed previous infection.

      5% of 15,000 is 750 individuals–not a huge impromptu trial, but not a tiny one either. The fact that we didn’t see any really devastating adverse events at least puts a ceiling on the likelihood that this subgroup of the population would have a dangerous sensitivity to the vaccines.

  3. M says:

    I really wonder what the true infection rate is. I think we may be at a point where it’s almost impossible to know who is and is not a carrier, despite testing. The rapid rise in spread (which has started to come back down in parts of the EU, thankfully) worldwide points to many asymptomatic/mild carriers who are spreading it to others because everyone in those situations is largely unaware of the true risk.

    Avoiding indoor gatherings is really a good idea right now, but given the northern hemisphere is entering winter, that won’t be easy for everyone to do. It’s a difficult situation, to be sure. Vaccine uptake will be critical in 2021.

  4. Lynne says:

    Each state should have a plan for phased vaccination based on risk. I know Indiana and Ohio have each released their preliminary plans. This allows states to prioritize the greatest needs in their states. The plans from these states have broken out plans into phases based on when quantities are expected to be more limited vs when they are expected to be higher. Having the ability to put Moderna’s into standard refrigeration adds more flexibility for setting up vaccination clinics in high risk communities or rural areas. For example, in phase 1 when quantities are limited, health care workers with potential direct or indirect contact w patient or infectious materials are top priority in Indiana followed closely by all essential workers and other high risk populations. This enables states to prioritize populations that have shown to be the highest risk for severe illness or death. Over 65 have the highest mortality, but in many states, blacks and hispanics have higher rates of severe illness, especially w comorbidities. In others, it might be indigenous populations.

  5. Hawkeye says:

    Interesting that the figure on the bottom of page 5 of “From the Factory to the Frontlines” contains:

    “Doses available per month (baseline as of 07/16)”.

    …smells like it was lifted from an earlier hypothetical….

    1. John says:

      Nothing strange there: those are the numbers from July 16, 2020.

  6. John Morey says:

    You write an amazing blog in a concise fashion. I am a layperson but I have a brain and can follow what you say, no problem. Just wanted to say thank you.

    1. Sarah says:

      Seconding this. I’m an academic, but a social scientist, so most of this is way outside my wheelhouse. I’m so thankful I found your blog early on in the pandemic. It’s been a source of so much information and reassurance. I’ve shared many of your posts widely. Keep up the great work and thank you for providing this public service!

      1. Ann says:

        As a computer programmer working in physics, I also appreciate such detailed write-ups in language that I can understand. This blog is my go-to source of reliable information every time I hear new rumors about COVID.

        1. Jason P says:

          Perhaps others aren’t aware but this blog is not the first time Derek has utilized that skill. He has a book out that teaches chemistry in layman’s terms.

          https://tinyurl.com/yyfxh8xf

          Thought I recall some more “teaching” books in the works?

          At some point, early in the pandemic Derek switched his blog from scientific jargon to more attainable prose and we all are much wiser and richer for that effort!

          1. Derek Lowe says:

            The wider audience for the coronavirus posts has led to a bit less geeking-out in the posts, it’s true. Geekery is likely to make a comeback in 2021, along with lots of other stuff. . .

    2. David says:

      Another cheer, Derek. I’m a physician (though not a specialist in infectious disease), working in clinical trials, so I join the blog readership with some relevant background. Your work is accurate, reasonably complete, and as devoid of bias as any popular science writing on the subject anywhere.

      Thank you.

    3. John B says:

      Couldn’t agree more. And couldn’t be more appreciative of Dr. Lowe’s work. I never read about this issues before the pandemic and this blog has become my first go-to whenever there is vaccine news. There’s no other resource like it.

    4. Kai Lowell says:

      Yes, absolutely this. I’m a layperson (with a somewhat unusual interest in science, especially chemistry, to be fair) and I very much appreciate how approachably all this is written.

    5. Johno the Teacher says:

      Science teacher here, and yes indeed!

  7. Eric Miller says:

    It’ll be interesting to look at retrospective data for vaccinated folks to assess whether the vaccines do offer near-complete protection. If being vaccinated means that patients can still contract mild/asymptomatic cases, presumably that could be picked up via an anti-nucleocapsid protein serological test, which the vaccine doesn’t contain, and which would indicate that they’d encountered the virus itself in a meaningful way. Thankfully it doesn’t seem that the ACA is at risk, but if pre-existing condition protections had been thrown out, you would have seen a lot of insurance companies very interested in learning about true infection status – would have been a mess.

  8. HAJ says:

    Dr. Lowe,
    These blog posts are very helpful. Can you speak to the “next round” of trials coming from the vaccine leaders, such as the new J&J 2-dose, and Pfizer’s next trial(s)?

  9. Matthew says:

    For those interested in immune response durability in people with Covid19 (not vaccine but probably quite related) see the most recent paper by Shane Crotty, et al.

  10. Gary Cornell says:

    It will be interesting to see the actual numbers for seniors. Given the prevalence in this group is roughly 1/3 of what it is in people 18-55, while happily they still are claiming they got a statistically significant result, the P value for that group has to be significantly less good than in people under 55. I’m just glad it was significant as I was worried they wouldn’t have enough cases in the group! Note I wouldn’t be surprised if it was only significant for people over 55 taken as a whole and not say for people over 75 as a cohort as I am willing to bet they simply didn’t have enough cases in people over 75 – because the prevalence (1/15 compared to the 18-55 group) is so much lower in that age group (thankfully).

    1. Ian Malone says:

      I’ve tried reverse engineering this, however the numbers aren’t really available. They say ~94% in over 65s, but the demographic breakdown numbers available lump that into 56-85 age range (41% across all study). If we make some really big assumptions, same proportion of infections in older subjects as whole study, ~20% in 65+, then you’d have 34 infections and 2 of those in treatment, which would still be highly significant (one in a million order), but with a greater uncertainty about the range (~75-98%).

      A lot of unknowns there, maybe there’s a higher rate of symptomatic infections in the older group (because older infected people are more likely to be symptomatic), maybe it’s lower (because they might be more careful about avoiding it, or it hasn’t got to them yet, in the UK we can see lags in infection across demographics). Maybe my wild 20% guess is wrong (I’ve basically just divided the 56+ number by two to account for age structure, which looks about right vs https://www.indexmundi.com/united_states/age_structure.html). The lowest numbers you can hit a 94% estimate with are 1:16 – 1:18 or 2:31 – 2:36, the 1:16 – 1:18 group would still be significant (at a much less impressive level), but with wider confidence intervals, scraping 50% at the low end. (However that would mean only 10% of infections in participants over 65 years old.)

      Actually, I’ve had a look at the protocol, https://clinicaltrials.gov/ct2/show/NCT04368728, “In 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3: ≥12 years of age [stratified as 12-15, 16-55 or >55 years of age]).” So, barring people aged 55 at recruitment who have since turned 56 (and I’m not certain they’d take that into account for the participant diversity figure), the 40% 56+ figure is probably actually entirely 65+. Caveats about assuming infection rate still apply.

      1. Ian Malone says:

        Got carried away writing my reply and missed you’d commented on prevelance (I guess that’s symptomatic prevalence?). At 60:40 age split and 3:1 infection rate, we get 180:40 infection split, which puts us into the 30ish infections in this age group ballpark. (Sort of assuming the efficacy is the same in age groups, but if it’s lower that would land us in more infections in the 65+ group again, which would increase the confidence for the estimate, and the estimate is a similar efficacy rate.)

    2. sort_of_knowledgeable says:

      I went to a binomial statistical website and you still will get a robust result with 10000 trial subset of 30000. If you estimate that 30 people in a 5000 person control group implies a 0.006 percent chance of becoming ill then chance of the vaccinated group of 5000 having 6 or less people becoming ill by chance is < 0.000001. If you get down to say a trial with 1000 people 75 or older then your statistical significance drops.

      But what are you going to do after a big trial specific for 75+ year olds and find that effectiveness drops to 60%? Research the possibility of giving them a third shot? Assuming transmission is greatly reduced by the introduction of the vaccine to the majority of people under 70 we could be waiting years to determine the results of such a trial.

      1. OtherMichael says:

        If efficacy were drastically lower in people age 60+, you’d want to carefully analyze and model what results in the fewest deaths: prioritizing giving the vaccine to the oldest/most vulnerable, or those with the densest contact networks (school age children, essential infrastructure workers, etc).

    3. Ian Malone says:

      I’ve got a post on this seemingly still in moderation, but the short version is the diversity figures they publish say about 40% participants in the 56+ years old group, and the trial protocol has 18-55 and 65-85 year old groups with nothing in between.

      So we can guess 40% actually 65+ and using your 1/3 infection rate gives younger:older 180:40 expected rate of infections, with 170 overall that implies about 31 in the 65+ group, for 94% effectiveness that means either 1:30 (97%) or 2:29 (93%), which are both highly significant (one in a million order) and have 95% confidence intervals going down to 71 or 75%. Purely to get close to 94% I think 2:31 or 2:32 is a bit more likely, doesn’t really change the picture much.

      This assumes the infection rate is the same across the age groups despite the vaccine, but if it was higher in the 65+ group we’d have more infections and more certainty about the 94% figure. (Purely numerically to get 94% as your nearest estimate you need either about 1 treatment vs 17 placebo or 2 treatment vs 31 placebo, there’s a small range around 17 and 31, but you can’t for example have 1 treatment 20 placebo, as then 95% is closer. 1 vs 17 would still hit statistical significance for most trials, but confidence intervals are then around 60% efficacy at the low end.)

      1. Derek Lowe says:

        Your earlier comment should be published now.

        1. Ian Malone says:

          Thank you, and to echo other comments, thank you for this blog in general. As a non-chemist (or possibly near-miss) I was originally hooked via “Things I Wont Work With”, but I’ve found your views on the AD landscape really helpful and the effort to summarise what’s going on with Covid has been heroic.

  11. Anon says:

    Thanks for another great distillation on this topic! Minor typo – “And the public health calculation ***that’ss*** made every time a vaccine is approved is that this is a worthwhile tradeoff.

  12. Julia says:

    Thank you for your concise and very helpful explanations. A significant logistic issue seems to be that two doses of these vaccines are needed. Is it known whether one dose provides at least some degree of protection?

    1. paperclip says:

      The BioNTech CEO has said that the first dose offers a high degree of protection. I don’t believe there’s right now many specifics beyond that.

      1. MTK says:

        Hhmmm.

        Depending on the numbers, meaning what is the efficacy rate for one dose vs two, might we not be better off administering one dose to more people as opposed to two doses for less people?

        Since doses will be limited early on this would seem to be an important question to answer.

        1. Some idiot says:

          Good question (and one I would like to know the answer to), but unfortunately in practical terms it is likely to be irrelevant. Since (the the best of my knowledge) the Phase 3 trials were done using the two doses, (a) I would be very surprised if a company tried to get marketing authorisation with a single dose, and (b) I would be absolutely astonished if the authorities approved it.

          Starting up a phase 3 trial to see whether or not it is sufficiently effective to make a difference with only one shot would be, to put it mildly, problematic on ethical grounds. I’m a bit too tired at the moment to consider that particular minefield in detail, but I am pretty sure that the companies would have filed it under “let’s not go there”, particularly considering they bet the house (wisely, in my opinion) on the double dose (excluding J&J, of course, for obvious reasons).

          1. wubbles says:

            Literally millions more people could get the vaccine. I’d happily volunteer for such a challenge trial.

          2. JS says:

            Many ethical minefields here.

            I agree that doing a trial with something you expect to work less well than the current best approach presents a ethical problem that you would need to consider carefully before proceeding. Very carefully. Same for trying a lower dose twice.

            But suppose that the data already available (from infections in the time between the doses) shows that one dose gives 90% protection with a large error bar, while two doses give 95% with a smaller error bar. Is it then ethical to give 2 doses to 10 million people instead of 1 dose to 20 million?

            Apart from being able to vaccinate more people, there could also be a benefit from the point of side effects. This could be quite relevant at the lower risk end of the population and is why some vaccines have changed over time.

  13. Mike Owens says:

    Is there a general rule of thumb or guesstimate for how long vaccine mRNA translates once inside a cell?

    1. sgcox says:

      Assuming it translates at the same rate as normal mRNA, the Spike protein molecule, 1273 aa, will be produced in 3 minutes. No idea how many copies single mRNA will make before get degraded. Vaccine mRNA has ben optimised for stability so should be on the upper range but would be great to know numbers. Even more important parameter is how many copies of mRNA get into cells. Translation rate itself is probably not very important factor when estimating the amount of antigen produced after immunization.

  14. Mark Andrew says:

    Thanks for this update Derek–great stuff! One thing I almost forgot about in reading all the good vaccine news is that they both require two doses. Does each does consist of exactly the same amount of vaccine? How do we keep track of who has gotten a dose and verify that? Is it just up to the individual? Could we see something like a vaccine “punch card” where you take it to your first and then second appointments? Does the general public that isn’t reading this blog realize that they’ll have to get two doses and in between them act as if they can still get sick?

    1. Phil says:

      Hopefully they’ll get important information from their healthcare provider, and not be expected to pick it up somewhere on the Internet…

  15. partial agonist says:

    Has Pfizer or Moderna announced a trial in the under-21 that would permit bridge approval for non-adults in a reasonable timeframe? I am hoping that happens in time to get them coverage not too far after we old folks can get it.

    1. Phong Nguyen says:

      Pfizer started testing kids 12 and up in October.

  16. Michael says:

    Derek, how did you do on “Jeopardy”?

    1. Derek Lowe says:

      Just added a link in the post to a full description!

  17. Iain Flynn says:

    Can we say anything beyond the banal about what the Pfizer/Moderna results means for the Oxford/AstraZeneca vaccine? I understand that they all target the same spike protein, but is there any reason at all why the latter would not work given that we now know the others do?

    1. Julie Crudele says:

      Since Pfizer first announced their data, I took this to mean the majority of these vaccines would make it across the finish line. It’s definitely proof-of-concept.

  18. pete says:

    A final Jeopardy question:
    To my limited knowledge these RNA-based approaches to making vaccines have been tried before for other viruses: RSV, maybe Ebola, etc, etc (disclaimer: I’m not a up to date on this field)

    If so, why is it that Moderna & Pfizer/BioNtech are (apparently) hitting a HOME RUN here with SARS-COV2 when the results with other RNA-based antiviral efforts have not made headline news ??

    Like, is it simply down to target epitope choice? That is, is the Spike protein of SARS-COV2 so vastly much more immunogenic that chosen targets on other targeted viruses?

    1. pete says:

      *than* chosen targets

    2. J N says:

      Have other mRNA vaccines made it to Phase 3? I just saw that a flu vaccine made it through Phase 1 – successfully – mostly as a proof of concept a few years back.

    3. FrankN says:

      mRNA vaccines are a new technology. AFAIK, CoViD19 is the first disease mRNA vaccines have ever been tried on through the full clinical cycle.

      The Ebola etc. stuff has been adressed by vector vaccines, with rather mediocre success. J&J, e.g. has this summer been granted provisional market authorisation by the EMA for its AD26-based Ebola vaccine, in spite of only 50% efficacy in clinical trials. That is the same platform they are now using for their CoViD19 vaccine.

      Other developers, among them the Oxford (AZ) team, have been trying vector vaccines on MERS. Since the MERS outbreak was short-lived, those vaccines never made it into clinical trial, even though pre-clinical results were quite encouraging.

  19. Kory says:

    Any thoughts about the N439K variant with respect to vaccine efficacy?

  20. Philip Roberts says:

    Do we know if the vaccines also keep recipients from being an asymptomatic carrier?

    1. Barry says:

      Both Pfizer and Moderna tallied symptomatic infections. If they even looked for asymptomatic infections, they haven’t reported that.

  21. J N says:

    Derek: Do you have any comments on the maturity and safety of the mRNA platform in general?

    What advantages does it have over other more established methodologies?

    Aside from instability, what disadvantages does it have?

  22. Erik Dienemann says:

    Derek – I posted about the Crotty et al paper last night on the usual social media sites I post (FB/message boards) on and I’m sure it was fine, but I have to say, your blog article today on that and so many key questions we have as we move forward, could be your best one ever and that’s saying something as you have the best science blog out there. It’s simply fantastic and I’ve posted it on all those same places, with many compliments. Thank you.

  23. ScientistSailor says:

    With efficacy of 94-95%, how many people do we have to vaccinate to break the transmission?

  24. Dan says:

    Re: side-effects.
    30k is okayish for the safety of the vaccine itself, but for something like ADE we only have 300ish mRNA-vaccinated people encountering the virus. So, chances of that are <~0.33%?

    Probably good enough to give to the elderly, but nowhere near enough to force the vaccine onto college students.

    1. sort_of_knowledgeable says:

      My understanding is that 5 severe cases are needed for the EUA so the chances of getting a severe case when unvaccinated can be compared with getting a severe case from ADE.

    2. RHB says:

      Having retired from all blog commenting a while ago (thinking myself too jaded, too glib, too wordy, and even sometimes all three at once), I’d like to take liberty of a one off comeback to post comment on:

      “Let’s be honest: if we could instantly vaccinate every person in the country and in doing so killed 200 people on the spot, that is an excellent trade against a disease that has killed off far more Americans than that every single day since the last week of March. Yesterday’s death toll was over 1500 people, and the numbers are climbing.”

      …Here goes. First a conflict of interest disclaimer, in that my family and I have had all the usual vaccinations over the years, latest being my own annual flu jab – a drive through event at the village hall car park on a very wet Saturday morning with around 20 volunteers in rain gear and face masks marshalling traffic flow while simultaneously holding umbrellas aloft, the surgery being out of bounds since late March to help, “stop the spread.”

      Took some organising, this stunt – thank you very much to all involved. Good to be reminded of how a long ago War won on a long ago Home Front. In and out of the village hall car park in under five minutes, barely felt a thing thanks to the wondrous annual ministrations of the wondrous Sister O’C (ah… cue annual swoon, swoon…) and arm didn’t even ache the next day.

      And another disclaimer: poster is chemist by training not well versed in immunology, virology and epidemiology, preferring to ‘ologies’ intricacies the simpler and more direct, yet strangely fluid, world of charge flow, atoms and small molecules, that somehow perform physiological miracles without us even now fully understanding how or why.

      Now let’s suppose 200 million Americans are vaccinated, the rest being virulent ant-vaxxers, sluggish apothetikers, and a largely silent, but still numerically significant, minority, privately quietly narked and alienated to the end of the earth by the virulence of state sponsored, media promoted, public health hysteria and generalised nannyism that’s infected nations, continents and hemispheres since the start of the 2020 Killer Virus Show. Movie Contagion II played out for real to empty cinemas and full living rooms throughout said nations, continents, hemispheres and, for all we know, broadcast out to the Entire Universe…

      The 200 people “killed on the spot” that are such “an excellent trade” equate to one in a million of the 200 million hypothetically injected with the Pfizer or Moderna mRNA vaccines, that’s 0.0001% of the vaccinated US population. On the face of it, does indeed sound a fair price to pay for a viral disease with at best an Infection-Fatality-Ratio (IFR) of 0.1%, which in principle could correspond to 200,000 American deaths if virus left to do its worst unchecked. Or put the other way round, 199,800 lives hypothetically saved.

      But let’s suppose the 200 “killed on the spot” are largely from a subset of the vaccinated population, and by a quirk of immunology that’s not understood beforehand, and doesn’t start to show up in earnest until millions are vaccinated, that subset is taken from young, fit and healthy under 25 year olds…

      …’Cos who knows, maybe an mRNA vaccine with a Mechanism Of Action never before released en masse, could in rare cases induce a hyper immune response in young men and women in the prime of health who’ve standard issue of the primest B cells, T cells, antibodies, or whatever combination thereof that enables a young god or goddess to dismiss an invader with ease of Babe Ruth swatting a home run, or for Limeys on the wrong end and Aussies on the right end, The 20 year old Don pulversing 334 in a single day at Headingley, Leeds, England, on 11 July 1930 – summarised 83 years later in the (Manchester) Guardian as, “a ferocious, sustained assault such as cricket had never experienced…”

      Starts to look a bit hypothetically different, eh? Near 200 under 25 year olds in their prime, primed by nature to see off the virus with supreme ease, killed outright in an act of supreme sacrifice to save 199, 800 lives, predominantly, by the way, elderly wrinklies and sub-wrinklies like me (although with all due respect, I primely like to think not…). Is it just my hyper allergenicity, or anyone else picked up that faint hoot of whistles blowing down the ages at 07.00 hours on 1 July 1916 (The Somme, France)?

      ‘Cos also at back of mind is that CD28 superagonist clinical trial looked up again just now, which back in 2006 blew over 6 fit and healthy volunteers in a morning. Summarised openly and honestly by the implicated company’s founder (“The storm has cleared: lessons from the CD28 superagonist TGN1412 trial,” Nat Rev Immunol, 2012). Bit over my head, but all seems well understood in hindsight, yet would have needed divine foresight to see what was coming. Something to do with T cells…

      So frankly fit young lads and laddesses, I’d have a good think about this one, lest you could turn out to be on the wrong end of a quirk. Annoying things, quirks. Most of the time in life you put up with ‘em, but once in a while you have to stand up for yourself and say enough’s enough…

      …Be gone, though blasted quirk. Bish, bash, bosh. And if the government Health Secretary keeps on saying vaccination could become compulsory, ignore him, and if pushed, bish bash bosh. Pretty sure compulsion illegal anyway, never mind downright immoral and unethical. Human Rights and all that, 1984 and All That.

      Conversely, wrinklies and sub-wrinklies, vaccination odds much more in your favour, so in all probability go for it. Get down to the village hall car park ASAP and form an orderly queue for your minute in the sun with Sister O’C. Hold Infinity in the palm of your hand and Eternity in an hour…

      1. Michael says:

        I’d say it would still be worth it on utilitarian grounds for those people to be vaccinated in general: several times that many people would be dying anyway, so to argue against this conclusion you’d have to say either that younger people’s lives matter more (which might make sense if you calculate value from quality of life and remaining years of life, but I doubt governments would want to set that precedent) or that it’s wrong to let someone die even if it saves more people’s lives. Perhaps it would make sense for most younger people to wait and see if these sorts of side effects are more likely to affect them, but that’s going to happen anyway if the vaccine is distributed based on need (since then, aside from doctors &c., older people would get it first).
        As far as human rights are concerned, in the US there’s already a precedent (Jacobson v. Massachusetts, 1905, regarding compulsory vaccination for smallpox during a smallpox outbreak) stating that compulsory vaccination, when actually necessary to save people’s lives, is part of the government’s police power to stop citizens from injuring each other (Jacobson v. Massachusetts has already been used to justify current public health measures like lockdown orders, mask mandates, and suspensions of nonessential medical procedures), and most states do currently require vaccinations for children attending public schools (with exemptions for people with health conditions that would make this dangerous and usually for religious objections), so states can legally require people to get a coronavirus vaccine (although I wouldn’t be surprised if anti-vaxxers or libertarians stop some of them from actually doing this). I’m not sure about the UK: this article states that current laws don’t allow the government to make vaccination mandatory through executive action, but I can’t tell whether the Parliament would legally be able to pass a law requiring vaccination.
        (I’m submitting this again because it didn’t appear the first time.)

        1. RHB says:

          Thank you for interesting perspectives. The utilitarian perspective that matters most to me is could a fit and healthy 18 year old and a ditto 20 year old be more at risk from a new vaccine released at warp speed than from SARS 2 itself, a disease which, unlike Spanish flu, seems to date mercifully benign for fit and healthy young people? The other perspective is that these two 18 and 20 year old lives do matter more than their late 60something father’s does. End of.

          As for the Jacobson vs Mass precedent, first off SARS 2 ain’t smallpox for fit and healthy 18 and 20 year olds. Second off, laws vary across states and countries, so arguably all’s relative not absolute (what’s new). Third off, using smallpox legal precedent to justify disproportionate state action based on dodgy “Science” and “Scientific Evidence” can only reasonably be seen as… dodgy. Dodgy dossiers, anyone?

          Thank you also for the BBC link confirming vaccination not compulsory in the UK, which of course means non-mandatory for school attendance. Pity 14 days school non-attendance nowadays mandatory for British Year 13s tracked and traced back to a desk within 2 metres of a positive tester pinged by a dodgy test. Yet as far as I’m aware, barely a blown nose, cough or sneeze anywhere to be heard. Latest score 29-17 for the Year 13 I know best, but will only take a ping or two more to overturn the gap before this term’s final whistle blown.

          This happening, remember, in the British Isles, font of modern European democracy, where, from Magna Carta and Habeas Corpus forward, respect for individual rights, liberties and freedoms evolved over centuries, culminating in the annus mirabilis of 1967 – capital punishment abolished, abortion and homosexuality de-criminalised.

          Yet now, serving in a government led by a self-professedly libertarian Prime Minister, is a GOV.UK Health Secretary who blithely proclaims from the press conference podium that SARS 2 vaccination might need to be made compulsory, a measure that would of course need passing in a House of Commons with 10% occupancy and 90% zooming in and out, conveniently turning the notorious bear pit into a bit of a teddy bear’s picnic.

          In other words, vaccine compulsion could conceivably pass, backed by a GOV.UK majority of 80 sheep. Minus the occasional differentially coloured sheep here and there. A millenium of stumbling and striving toward the light reduced to baa baaa baaaa in the twilight.

          So, in the Theatre of the Absurd that from afar passes for current British governmental life, all that’s left for a late 60something to do is take the bit part of the blind white haired soothsayer, calling out to Caesar, “Beware the Ides of March,” and hearing in reply, “Let him pass, he is a dreamer…”

          https://www.youtube.com/watch?v=ZVA5Ru1bqeA

    3. Don says:

      College students are going to be about as low priority as you can get, so there will probably be at least a few hundred million people worldwide vaccinated over the course of months before the choice is anything but hypothetical. By that point we should know a lot more.

      1. RHB says:

        Fair point, although when my son went back to college month before last to my surprise he was offered a flu jab organised by the college. Given within 2 days, there being a big push on in the UK to extend the population spectrum vaccinated against flu to avoid the double whammy of flu and SARS 2.2 this winter season.

        So given the UK may well have ordered more SARS 2.2 shots than head of population, and given GOV.UK’s managerial mindedness, and given the history as one f****** school after another that some of us incline to think more often than not prevails, you can never know for sure what future mishaps to allow yourself to think about avoiding stumbling across.

      2. Irene says:

        Once students are back doing in-person college, they should be fairly high priority. Many live in dorms, and they mingle a lot in many different inadequately ventilated buildings. They also travel a lot, and use public transportation, and work at crummy jobs, and just flat out are around more people more of the time than other folks.

  25. steve says:

    So first, in terms of T cell responses, Pfizer’s vaccine induces both T and B but Moderna’s only antibody. So that’s a big differential. Second, having surrogate markers of immunity doesn’t really tell you how long protection lasts. We’ll only know that by infection rates. There are four seasonal coronavirus that infect us every year causing 20-30% of colds and we NEVER develop herd immunity to them. Whether we’ll develop it to SARS-CoV-2 after vaccination and for how long remains to be seen. Finally, with regard to ADE the spike proteins were engineered to avoid it and there is absolutely no evidence for it.

    1. DataWatcher says:

      So . . . is the Moderna vaccine being over-hyped?

  26. Tom A says:

    Another advantage of the mRNA based Pfizer and Moderna vaccines is they have zero connection to fetal cells. Any candidate with the remotest fetal cell provenance is likely to have a more difficult acceptance even if highly effective.

  27. Andy says:

    Is it plausible to speculate that the failure rate (5% for the Pfizer and Moderna vaccines) may approximately equal the reinfection rate for those who caught the virus itself? In other words, could there be a common mechanism here that causes 5% of individuals exposed to either the virus or the vaccine to not have long-lasting immunity? If so, it would portend good news in controlling the pandemic in areas that have been ravaged.

    Am I way off base here?

  28. Chris Phillips says:

    Publication of results from Phase II trials of the Oxford vaccine, showing similar immunogenicity across all age groups after the booster dose:
    https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32466-1/fulltext

  29. Marcus Theory says:

    “Let’s be honest: if we could instantly vaccinate every person in the country and in doing so killed 200 people on the spot, that is an excellent trade…”

    I take your point, but this strikes me as the kind of thing scientists shouldn’t say to a lay audience. There’s going to be a lot of skittishness around the vaccine as it is, and statements that make it sound like researchers are willing to sacrifice people’s lives do not boost confidence. Even when the second clause is inarguable:

    “…against a disease that has killed off far more Americans than that every single day since the last week of March.”

    It’s important to be honest when discussing side effects, and I’m not saying we should be euphemistic or have blinkers on; it just seems worth being more careful with phrasing.

    1. Barry says:

      This is why our federal government (or an earlier version of it) indemnifies vaccine makers.
      https://www.hrsa.gov/vaccine-compensation/index.html

    2. Derek Lowe says:

      I thought about this for a while, for just the reasons you mention. But I came down on the side of “better to lay it out there”, rather than be accused of trying to tap-dance around the subject. But you definitely have a case.

    3. DanielT says:

      Marcus while this is a worry, the solution I think it to make an analogy with something less abstract. I like airbags – people are killed regularly in car crashes by their airbag, but they are a tiny fraction of those saved by their airbag in similar crashes.

  30. Konstantinos Spingos says:

    One very important question: how are we going to evidence-based-answer what should be done with those already affected and supposed to be immune? It is not a trivial number, nor the possible outcome is trivial either.

  31. Rajesh Krishnan says:

    Small point on side effects, such as headache. Devil will be in details. I’m in the Pfizer trial and got my first shot in a town close to the smoke hotspots due to the NorCal wildfires this year. Sure as heck had a headache coincident with the shot. Due to shot? Due to smoke? Who knows.

  32. Alan says:

    Can someone tell me if the plan is to vaccinate everyone including all those who have had the disease?
    If so what will the vaccine induce in our immune systems that the actual disease doesn’t

  33. Lluis says:

    There is a though that has been nagging me for a while: Latest evidence seems to indicate that the IFR (Infection Fatality Rate) is about 0.6% across all the age groups. In some areas in Spain, e.g. Madrid, the excess mortality has been 15000, what after applying the IFR means that around 2.5M have been infected already. This means that >40% of the population might have some form of immunity (re-infection still a rare event). This is close to the thresholds that have been estimated for herd immunity to kick in – and maybe explaining why the infection is slowing down despite all the bars being still open !. If things carry on at a similar rate, after Xmas, we might see much reduces rates of infection. If this scenario turns out to materialize (is speculation, I know) what would you advocate as a vaccination policy ?

    1. RHB says:

      Very good question.

  34. Britt says:

    “How about long-term problems, then? These are possible with vaccines, but rare.”

    How real is this possibility? What is the history of (non-live) vaccines causing long-term problems that would not show up in the first couple of months?

  35. R Mello says:

    When planners and strategists talk about “health care workers” do they include in that population janitorial and custodial staff in the hospitals, clinics, and nursing homes?

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