One dose or two? This epidemiologist suggests we should follow Bugs Bunny and go for two.

Joseph Delaney writes:

I [Delaney] am starting to see the hot take of “why don’t we experiment with giving only one dose of an mRNA vaccine”. For example, see this.

We briefly brought up one such argument a couple weeks ago, but only in the context of a discussion of something else.  I hadn’t looked into the details.

Delaney continues:

So let us count the reasons that this isn’t a great idea.

  1. The vaccines were tested from phase 1 to phase 3 to find an optimal formulation. People looked at the single dose antibody titers, as compared to two doses, and it was a lot worse. This casts doubt on the durability of the immunity.
  2. Vaccine manufacturers look at these subgroups. the main Moderna trial had 30,351 participants and an efficacy of 94.5% (95% CI 86.5-97.8%). In the one dose subgroup there were 996 participants in the vaccinated group, and 1,079 in the placebo group with 7 cases vaccinated group and 39 cases placebo (80.2%; 95% CI 55.2-92.5%). So we know even short term efficacy is less.
  3. The Oxford vaccine had more participants in the low-dose/high-dose subgroup, with 3 cases in the vaccinated arm and 30 in the placebo arm (efficacy 90·0%, 95% CI: 67·4 to 97·0)
  4. In US dollars and sold in the US, the Oxford vaccine is $4 per shot versus $15/$19.50 for the mRNA vaccines. So it is a lot cheaper.
  5. The Oxford vaccine looks able to make 3 billion doses in 2021, whereas the two mRNA vaccines (combined) look to be able to produce 2 billion doses. So there is more expansion in capacity by adding Oxford than splitting the Moderna or Pfizer doses up.
  6. This ignores Sputnik V and Sinovac, which are approved in some countries already/ These vaccines claim > 90% efficacy *(Sputnik V and Sinovac). These are both based on low case counts (bad) but no worse than the one dose sub-group for Moderna.
  7. Oxford can “be stored and transported at normal refrigerated temps of 2 degrees to 8 degrees Celsius (36 degrees to 46 degrees Fahrenheit) for at least six months” whereas Pfizer must be kept at -70 degrees Celsius until six hours before use. That is a huge logistical advantage. Moderna’s vaccine is better for logistics, but it is also the vaccine with the lowest production levels.
  8. Even if the Oxford subgroup is due to the Texas Sharpshooter fallacy, the efficacy of the pooled vaccine estimate is about 70% (either you use the sib-groups or you don’t). This is likely not significantly different than one dose Moderna and will likely be more durable
So if we want to argue for an ethical imperative to move quickly, the easy way forward is to approve the Oxford vaccine. There is almost no case where the one dose of mRNA vaccine approach is going to be better than just adding in the next tier of vaccines — which have trials. Now it is possible that the FDA might decide that they are inferior and should not be given an emergency use authorization. But the one dose approach would require trials (timed to measure durability) and would take years to complete (versus actionable data now — seriously, the Oxford vaccine has a Lancet publication so the data can be scrutinized).
In a similar vein, the best thing we could do with Moderna is . . . make more of it. Solves the one versus two dose problem if there is enough for everyone. If we really wanted to make a difference — why not pay Moderna to drop the patent and make it universally free?
Or push out the Oxford vaccine faster? Hilda Bastian has some concerns with the Oxford vaccine, but at least we have the data to make an informed risk-benefit tradeoff with it (and more data is coming soon when the US trial concludes).

I don’t know anything about this myself, but I wanted to share Delaney’s post because he does seem knowledgeable. I got nothing against hot takes, but it’s also good sometimes to step back and get some perspective.

70 thoughts on “One dose or two? This epidemiologist suggests we should follow Bugs Bunny and go for two.

  1. Thanks for sharing, and (if for some reason they see this), to Joseph Delaney for writing it up!

    Numbers 3-8 aren’t arguments against doing one dose for ~2*N vs. two doses for ~N.

    But I’m glad there are 2 points to consider against one dose! First of all, they illustrate that single-dose effectiveness depends on the vaccine, which is super important to note. It’s not just mRNA vs. other types of vaccines, brand matters.

    #2 is that efficacy is lower. But not by much (for Moderna)! Per the FDA report for Moderna (Tables 15 and 17), efficacy after day 14 for a single dose was 92.1%, 95 CI: (68.8%, 99.1%) (cf., efficacy after day 14 following the second dose was 94.1%, 95% CI: (89.3%, 96.8%)). The 80% number includes those before day 14, which as you can tell in how it has been reported and in the FDA’s Figure 2, and as implied by their own primary endpoint of VE being 14 days post-second dose, is about how long they expect it to take anyway.

    #1- it’s so great to have that information now (for Pfizer/BioNTech). The FDA report for this one uses 7 days instead of 14 post-second dose, but doesn’t do this for post-first dose, so the efficacy number for one dose here is possibly more of a lower bound (with its own bounds, ha!): 52.4%. But like I said, it’s great to see titers for BNT162b2- and they are indeed a lot worse with one dose.

    That prompted me to go looking for titer info for Moderna (https://www.nejm.org/doi/full/10.1056/NEJMc2032195)- pretty good after one dose.

    But to their point, “if we want to argue for an ethical imperative to move quickly, the easy way forward is to approve the Oxford/AZ vaccine” (yes!) since “we have the data to make an informed risk-benefit tradeoff.” It appears we can also learn from the data above to make informed tradeoffs (or not) on the mRNA vaccines, too. But perhaps this is also a moot point since in the US the administered:distributed ratio is way less than 1:2 anyway!

    Caveat: I think I am able to accurately interpret the numbers and graphs but am by no means a subject matter expert.

  2. I think Delaney is not quite representing the one-dose perspective correctly. The version of it that I’ve seen (e.g. [by Zeynep Tufekci and Michael Mina](https://www.nytimes.com/2020/12/18/opinion/coronavirus-vaccine-doses.html) and at [Marginal Revolution](https://marginalrevolution.com/marginalrevolution/2020/12/double-the-inoculated-population-with-one-dose.html)) is not exactly just one dose and that’s it. It’s use all the doses we have now and not save any for the second dose – but eventually everyone will get the second dose, just maybe not at the recommended timeline. So the argument is more about the timing of the second dose (and there probably is also a lot of debate among one-does proponents on when people should start getting second doses). This is only a slight distinction and maybe doesn’t change Delaney’s response, but I think it’s worth mentioning.

    Also, I’m not sure if I completely agree with Delaney’s #2 of “So we know even short term efficacy is less”. It’s probably true but the confidence intervals overlap and the subgroup analysis – I’m guessing – did not adjust for differences in group composition.

    Finally, I don’t think Delaney’s proposal to push out the Oxford vaccine faster contradicts the one-dose proposal. Why not do both? To be clear, I personally have no idea if either proposal is the right thing to do or not but this doesn’t seem like a one-or-the-other thing. Same with the proposal to produce more of the mRNA vaccines.

    • So the question of do just one dose (for a potentially long period) did show up in the Twitter thread and it was what I was replying to. I absolutely agree with not storing a second dose (which some Canadian provinces are doing) but with using new deliveries to provide the second dose.

      I’ll admit to not testing for significance, but the confidence interval in the one dose group also includes much lower efficacy estimates. Obviously more data would be better. That said, Daniel (above) has a decent argument that I am not using the right contrast and the short term immunity for Moderna might be similar for one dose versus two. Pfizer’s own estimates for their vaccine are very low (52.5%!!) but that matches big differences in immune response so it might just be different for the two vaccines.

      The more I argue this, the more “make more Moderna” seems like a no-lose strategy as they have the best one dose evidence and their cold chain requirements are a much smaller logistical challenge. Ironically, it is the vaccine that we are planning on the smallest production of.

      • I think what’s missing from this discussion is a cost-benefit analysis. The benchmark we should be comparing these plans against is total infections and total deaths. Even if one dose is less effective, do less people die in total if more people are inoculated in Jan/Feb/March?

      • “Pfizer’s own estimates for their vaccine are very low (52.5%!!)”

        That is for the period of time from the Day 1 after the first shot to Day 21 when the second shot was given.

        For the period of time from Day 1 to Day 11 there is essentially no difference in efficacy between the vaccinated group and the placebo group. From Day 12 through Day 21 efficacy was essentially identical to the post-second shot efficacy.

        The problem is durability of the immune response that’s triggered.

        The UK’s decision to employ a modified two-shot regimen (second shot given up to 12 weeks after the first rather than Pfizer’s recommended three weeks or AZ’s recommended four weeks) is a gamble. Will Pfizer’s good efficacy from a first shot that starts on Day 12 hold up for 12 weeks, and will the booster effect on the immune system be as effective (or close to as effective) as when it is given as recommended after 21 days?

        The UK is desperate because of the rapid dominance of the new, more contagious form and I personally doubt that they would’ve made this decision if this had not happened.

        • I’m sure we will have observational data on people who either return for the second dose late or don’t return at all. Also some will mix and match Pfizer and Moderna or even Pfizer and AZ. I hope they do titers on some sample of the late returning people.

  3. Thanks, Daniel.

    There is definitely some difference between products. One of the big take-aways from the Twitter thread that started this thinking is that there is a lot of consensus that we should make more Moderna vaccine. The dose is also quite different than the Pfizer vaccine, which could make a big difference between one versus two doses. It is a pity that we never had a single dose arm for Moderna, although the 2000 participants with only one dose are likely to give some ability to do inference here. Durability is the biggest unknown, in my opinion, although this group might be able to answer that question. The NEJM paper was cool but the participants all had the booster so we don’t know long term trends. That said, there might might be rational plans like pushing the booster out to 3 months that might end up doing better. It is a hard problem.

    Items 3 to 8 were a question of whether we could implement an alternate plan to cover people until we know more about one versus two doses of the mRNA vaccines, as the Zeynep Tufekci piece (that I did not realize started the discussion) was based on doing trials to find out the answer: https://www.nytimes.com/2020/12/18/opinion/coronavirus-vaccine-doses.html

    I have wondered if we could accelerate coverage in the interim by speeding up a second tier of vaccines. This, of course, presumes that the problem is vaccine production and not distribution. I am currently now worrying that distribution is the main barrier.

      • Thanks for the link, Chris. I’m interested in Tufekci’s response.

        Andrew: do you have any previous blog posts that address this issue of weaponization of scientific communication in the popular press? I know you have many posts that discuss science communication and you are a strong advocate of transparent post-publication review, but off the top of my head I don’t recall a post that discusses your thoughts on discourse in formal academic venues versus popular media. If not, may I suggest you make a post about the above article? I’m interested to hear your and this community’s thoughts.

        I think I generally disagree with the article. I do agree with the notion that communicators bare some responsibility for how their messages are interpreted but I don’t agree with the idea that we should give so much power to bad actors as to let them frame public discourse. There is definitely a balance to be had but I don’t think the article gets the balance point exactly right. In fact, I think more scientific nuance in popular media may be a solution to polarization. It’s better that the NYTimes piece exists alongside with the Twitter stuff rather than having only the Twitter stuff (which would exist even if the debate centralized in academic journals imo). Also, I think more openness is just a better way to do science in general. We’ve discussed on this blog before how errors within an academic sub-group can be correlated so it makes sense to me that including more diverse members in the discussion would be helpful. If the discussion started in NEJM some useful commentators could easily have missed it.

        • Thanks too to Chris for the link. A problem with popular press and science reporting is the inclusion of opposing viewpoints with little context. Advocates and cranks are good at cherrypicking and weaponising information. When they are included for ‘balance’ their views are considered equally valid to the consensus science view. There is some interesting work being done on the idea of ‘evidentiary balance’ to avoid this problem.
          “Journalists communicating risk-related uncertainty must accurately convey scientific evidence supporting particular conclusions. Scholars have explored how “balanced” coverage of opposing risk claims shapes uncertainty judgments. In situations where a preponderance of evidence points to a particular conclusion, balanced coverage reduces confidence in such a consensus and heightens uncertainty about whether a risk exists. Using the autism-vaccine controversy as a case study, we describe how journalists can cover multiple sides of an issue and provide insight into where the strength of evidence lies by focusing on “evidentiary balance.”” – https://pubmed.ncbi.nlm.nih.gov/25010352/ Including “evidentiary balance” in news media coverage of vaccine risk

        • Not sure if Andrew’s written about this but I’d also be interested in hearing his take on it. I’ve spent some time thinking about questions like this as they relate to uncertainty communication in public-facing predictions/data, and my stance has generally aligned with your suggestion in that I think we should be reporting more nuance and uncertainty, not less. Also because this is hard and often not done well, I think a good journalist should also see it as their responsibility to help their readers become better critics of what they consume elsewhere. But public health crises like pandemics where the externalities are significant are perhaps the most challenging test case for this view.

          This case is also interesting in that it’s less about presenting data or claims but ignoring uncertainty, and more about not publicly suggesting something because it would be acknowledging uncertainty. Maybe for that reason it seems like an extreme stance. Holding a view like this also implies a level of confidence about how to weigh the risks of the message against the possible benefits, which seems hard like a hard a priori judgment to make. This reminds me a little of the sentiment after the 2016 and then 2020 election, that we shouldn’t be providing election forecasts because people aren’t capable of understanding the probability (I wrote a few posts on this back in November).

        • Several good points. To comment specifically on “I think we should be reporting more nuance and uncertainty, not less. Also because this is hard and often not done well, I think a good journalist should also see it as their responsibility to help their readers become better critics of what they consume elsewhere.”:

          I think we (as a culture) need more/better education about uncertainty, and that this needs to start in elementary school and continue in high school, undergraduate, and graduate education. The common human desire for certainty (or aversion to uncertainty) needs a lot of education to counterbalance it.

        • Thanks, Jessica. I definitely agree that the setting of an urgent public health crisis warrants consideration. It’s definitely plausible to me that the best thing to do in normal times is different than during a pandemic.

          It’s also worth noting that the article is not entirely about science. It’s also political. The decision of two-doses vs. one-dose depends not only on ascertaining and estimating the costs, benefits, and risks, but also on your objective function and risk tolerance. So perhaps there’s an argument that the public has the right to know or should be informed on this debate. But also maybe not as we don’t want to move too much to populism. I don’t know!

        • Michael

          > but I don’t agree with the idea that we should give so much power to bad actors as to let them frame public discourse.

          Problem is, IMO, no one actually gets to choose whether or how bad actors get to frame the discourse except the bad actors.

          > There is definitely a balance to be had but I don’t think the article gets the balance point exactly right. In fact, I think more scientific nuance in popular media may be a solution to polarization. It’s better that the NYTimes piece exists alongside with the Twitter stuff rather than having only the Twitter stuff (which would exist even if the debate centralized in academic journals imo).

          I”m not sure that there’s evidence of this. On the other hand there does seem to be evidence that efforts at “debunking” or even more neutrally framed, communicating more scientific nuance, if anything creates a blowback effect where people only double-down on their previous beliefs – particularly if the more nuanced information being presented challenges their ideologically-oriented preferences. Seems to me that you’re suggesting a kind of “information deficit” model, the effectiveness of which is heavily debated within the climate change domain, at least.

          > Also, I think more openness is just a better way to do science in general.

          Sure – but (1) this isn’t really a question of how science is done, but a question regarding how it’s best communicated and (2) the question, it seems to me, is how is it best communicated not in some hypothetical framework of what we’d like it to be, but on the ground given what we see happening.

          Just to be clear, I”m not saying that I think there’s an obvious answer here.

        • Thanks, Joshua.

          Regarding the first point, to expand on my point further, I think I agree that no one can control how bad actors act but people can frame discourse by creating a kind of anchor point. For example, I think the NYT editorial was a good and nuanced argument – and to my knowledge was the first in major popular media, so many subsequent conversations (both academic and otherwise) were in response to that argument. A different scenario might be that the first big-time popular press editorial on this debate is less focused and talks about “the failure of public health”, leaves out some nuance like starting clinical trials immediately and timing, and maybe even says some wrong things about epidemiology. Then, there’s a lot of temptation in the popular discourse to throw away the baby with the bathwater so to speak.

          Another way to think about this is in a “nature abhors a vacuum” kind of way. This sort of thing will appear in the popular press anyway whether you like it or not so might as well make it quality.

          I don’t have any evidence for these things. Just spit-balling some possibilities and my (weak) beliefs. Interested in other perspectives!

          After more reflection I think I agree with your other two points.

        • Michael –

          Yes, that’s a good point. It seems logical to me that there could be a somewhat different calculus in play early on in a public debate as opposed to when people have started aligning up in camps. And yes, public discussion early on might help to influence how people line themselves up.

  4. Would anyone have more in-depth sources of the bio-chemistry and bio-physics of any of the processes involved? What is it exactly that necessitates two doses in the first place?

    Let’s please remember that in all the studies so far (and they are all about 40K participants) the outcome was left to chance, due to ethical concerns. We cannot even begin to assume that covid is uniformly spread throughout air, similar to PM2.5 particle pollution.

    Nobody really knows the true effectiveness for any of the competing vaccines. I find that finding of a subgroup in a half-dose trial hilarious (Brazil, I believe). It clearly is a fluke, unless someone could explain the mechanism by which half a dose, followed by a full one, offers better protection.

    Too many unknowns still. Not to mention that everybody is clueless if sterilization occurs.

    Thanks

    • “What is it exactly that necessitates two doses in the first place? ”

      My understanding is that the immune system is primed by the first dose, and really amped up by the second dose. One BIG dose is possible but probably would cause many more severe adverse reactions.

      “unless someone could explain the mechanism by which half a dose, followed by a full one, offers better protection.”

      The mechanism again is that the immune system is primed by the first dose to cause a reaction to the second dose. A small dose initially could conceivably prime the immune system lightly, then it doesn’t attack the second dose as rapidly and so the second dose does more good, whereas an initial large prime followed by a second dose causes the second dose to be eliminated rapidly before much antigen presenting cell activity.

      It’s entirely plausible that the smaller first followed by normal second dose would do better.

      • Thank you, Daniel, but those are the basics of how vaccines work. I meant really in-depth, at the cellular biochemistry/biophysics level. There are 1001, quite complicated processes that are taken into account.
        Perhaps someone who works in that area is on this blog and can chime in.

  5. My take on this is:

    1) With the difficulty of distribution, and the inevitable lower take-up than originally assumed, it’s insane to keep doses in the freezer for later if there are people willing to take the doses now.
    2) I agree with Michael J above, the 1 dose vs 2 dose is really about “when to give the 2nd dose”?
    3) We will discover that it makes more sense to give everyone a booster every year for $15 for the next 5 years at least than to let the immunity wane.

    All this suggests roll out the vaccine as fast as possible, one dose to as many as possible, and then start rolling out second doses when the observed demand for first doses begins to wane, which will be a lot faster than public health people think.

    I’ve already seen some UCLA research employees get the vaccine “because the number of healthcare providers who actually show up for their appointment was much less than anticipated and the doses would have been wasted” (not a direct quote, but something like that).

    • > it’s insane to keep doses in the freezer for later if there are people willing to take the doses now.
      > I’ve already seen some UCLA research employees get the vaccine “because the number of healthcare providers

      It sounds like this is already a solved problem.

      > We will discover that it makes more sense to give everyone a booster every year

      That wasn’t the question?

      > I agree with Michael J above, the 1 dose vs 2 dose is really about “when to give the 2nd dose”?

      I don’t think you can really simplify it down like that considering all the points raised at the top of this post.

      This sounds more like a question of logistics than one of arguing over how much we can change vaccine schedules (especially considering the UCLA anecdote). Conceivably you could get away from the vaccine-in-reserve problem by trying to do better logistics (figuring out who the customers are and delivering vaccines there).

      Sure you could do more if you assume the timing of the second dose doesn’t matter, but unless you have a way to estimate the extra benefit of that, I don’t think this argument is very good at all (cause we’re weighing that unknown extra benefit against ignoring the vaccine dose scheduling, which seems like it could be a pretty serious thing to give up).

      Reminds me of the bufferbloat thing on your website (which was a neat read, thanks! I installed SQM on my router).

      • The history of vaccines as I understand it suggests that timing is more about politics and less about biology. It’s like the “expiration dates” on pills. The US Military did research showing that pills decades past their expiration date still have essentially all of their efficacy. Now, if you took one dose, and then waited 12 months to get the second I’d be concerned about efficacy, but if you take the first dose and wait 10 weeks instead of 3 to get the second. I’d be willing to take odds on it being pretty close to fully effective. This is the kind of thing I’m personally thinking about in all this.

        I don’t think the logistics are a “solved problem” at all. The US wanted to vaccinate 20M people a week for the last 2 weeks, they reached 10% of that rate.

        • > I don’t think the logistics are a “solved problem” at all

          Fair, I didn’t mean to imply that (in fact I meant the opposite of that overall). There I was pointing out the contradiction in the UCLA anecdote as compared to the statement about vaccines being kept in freezers and not distributed, which I guess isn’t that big of an issue.

        • An organization like UCLA can go a lot farther withautonomous decision making compared to many public health organizations ridden with politics and people worried about losing their livelihoods I really worry about large percentages of vaccines going in trash cans more than an extra week or four between doses

        • >>The US Military did research showing that pills decades past their expiration date still have essentially all of their efficacy

          Huh, really? I’d be very interested to see that…

        • >>I don’t think the logistics are a “solved problem” at all. The US wanted to vaccinate 20M people a week for the last 2 weeks, they reached 10% of that rate.

          Is there a good source where one can follow the progress of this? Honestly, even 4M people vaccinated so far (even just first dose) is significantly better than what I would have expected by now (of course, this year has significantly lowered my opinion of public health bureaucracies, and not just US ones either…)

      • > Reminds me of the bufferbloat thing on your website (which was a neat read, thanks! I installed SQM on my router).

        Also, thanks for this comment! It’s great to hear from people who enjoy the stuff I write. and Bufferbloat is kind of a major 2020 thing… with realtime communications exploding. Glad if I could help.

        • I think I improved my bufferbloat situation quite a bit, but didn’t quite get the whole thing working (bah humbug). I was trying to play BO4 with my buddy on Xbox via a shared 4G connection and we never were able to join the same game (unhelpful errors in the game about lobby not being joinable). I tried a bunch of port forwarding but just gave up — dunno how to debug such things.

          Either way it was pretty amusing to find tips and tricks for playing CoD via the stats blarg.

      • I think we won’t know about the need for a booster for those who get the initial two doses for a long time. Look at how it works with Tetanus and other vaccines for which you have to get boosters for your whole life but not that often.

        It’s a mistake to call the Pfizer and Moderna second doses boosters I think. They are the real vaccines and the first doses are primers. A single vaccine, like for measles, would be closer to to the second
        vaccine.

        We know so little about open experiences at this point. One thing that worries me is if the reactions to the second dose are stronger we will see reduced compliance and more resistance to vaccinating. That’s why it’s pretty irresponsible to be essentially messaging to people that they are greedy for getting the whole vaccine.

  6. What you do not want is levels of anti-S1 binding antibodies that are not neutralizing. This is the recipe for ADE.

    The second boosting dose avoids this for a time. This entire discussion is ridiculous because it ignores the primary risks. Do not start messing with what was done during the trials based on speculations that ignore the primary risk!

      • And this:

        The consequences of people skipping a second vaccine dose could be significant. Although the coronavirus is unlikely to become vaccine-resistant, that could change if millions of individuals only get one dose of a vaccine that requires two treatments, said biologist David Kennedy, who studies viruses at Penn State University and co-authored a recent paper urging drug makers to look for signs of mutation in the coronavirus.

        The problem, according to Kennedy: If someone who has had only a single dose is exposed to the virus, their immune system might not be able to kill it off. That could allow the virus to develop a response to the limited immunity provided by that one dose.

        “In imperfect vaccines, that’s where we see resistance pop-up,” Kennedy said. “The more individuals who have one dose of these vaccines, the more concerned I would be.”

        https://www.cbsnews.com/news/covid-vaccine-two-shots-undermine-efforts/

    • This critique makes sense if you buy the labor theory of value. I’m kinda fine with companies earning massive profits for life-saving treatments and diagnostics. I’d rather companies get paid based on the value their products create rather than the cost it takes to make the product.

      Moderna basically created the vaccine over a weekend after the SARS-COV-2 genome was published (well before any funding was available via Operation Warp Speed), so saying the US government paid the full cost of research is patently false. The US requires trials of a certain kind, and many companies go through the whole rigmarole. Might it have been better to have wide early release after an initial safety phase and efficacy being determined in a human challenge trial? If the government requires expensive trials to be carried out in an emergency (note the Astra Zeneca is having to perform another trial to try to get an EUA from the FDA even though the UK has already approved it), perhaps the government should bear some of the cost burden it is imposing.

      There are certainly things wrong with the intellectual property system in the US, but patenting for the Moderna and Pfizer vaccines is probably not what is keeping the world from getting those vaccines. As mentioned in the linked article, the production process for the mRNA vaccines is incredibly complex, and other vaccine facilities would take a while to be retooled (if possible) for mRNA vaccine production. And once those facilities are retooled, who’s going to manufacture the vaccines that still need to be given, like TDAP, MMR, Polio, etc., etc.? Who also would manufacture the non-mRNA vaccines that are probably much more crucial to vaccinating to the majority of the world’s population. And as mentioned in the article, Pfizer and Moderna could license their technology as they hit their own manufacturing capacity constraints.

      The article also notes that China has several vaccine candidates (with one already approved in the UAE), noting that western vaccine manufacturers aren’t that far ahead of vaccine manufacturers in other locales, yet the authors can’t see the tension between that fact and their belief that patents for Moderna and Pfizer are keeping vaccines from the rest of the world.

      • JFA –

        > yet the authors can’t see the tension between that fact and their belief that patents for Moderna and Pfizer are keeping vaccines from the rest of the world.

        That seems suggestive of an unnecessarily binary framing. India and South Africa lobbied for lifting restrictions for a reason. Keeping vaccines from the rest of the world could mean making it more difficult for some parts of the rest of the world to get vaccines, resulting in unnecessary deaths. Such a development isn’t mutually exclusive with China making vaccines.

        • Maybe… but the authors are so sure that Moderna and Pfizer wanting to protect their intellectual property (which includes methods of manufacturing not just the particular vaccine) is what is keeping the world from being vaccinated. Not only are the manufacturing methods complex (suggesting that retooling factories (and ensuring a good level of quality control) would take a while) but so are the cold chains for those vaccines to get from factory to injection. Presumably any vaccine that requires less than 20 degrees C will be less effective at vaccinating the world. But you have the Chinese vaccine and the Astra Zeneca vaccine (which has only been approved in the UK) that could much more feasibly be used for broader vaccination. Should they just give it away? I dunno… but if you think so, then you should lay more blame on the Chinese government for not making their vaccine open source. It also doesn’t seem that India is just sitting this one out as the Serum Institute of India (which has received $150 million from the Gates Foundation to increase production of the AstraZeneca and Novavax vaccines) is working with Astra Zeneca and a few other biotech firms. And if you’re concerned that developing country governments can’t afford to pay for the vaccines, India’s own billionaires could certainly pay for any manufacturing licenses they might need. South Africa also has a few billionaires who could also be so generous.

          The analysis that Moderna’s and Pfizer’s patents are keeping the world from being vaccinated seems more of an expression of disdain for profit than an actual analysis of the situation as it is. Other vaccines are ready to go, have gotten approval from some governments, don’t require extreme cold storage, don’t require factories to retool with uncertain outcomes on quality control, already have expanded manufacturing capacity in India. Given all this, I’m not sure how Moderna and Pfizer are preventing vaccination of poorer countries.

          I will also point out that almost no discussion of Covid vaccination manufacturing has included much analysis on what other vaccines won’t be produced if current factories are used for Covid vaccine production.

        • JFA –

          So I”m thinking what’s going on here is that you think the article reflects a lefty bias against profits, and you want to present a less biased take. I thin it’s an interesting question – and obviously the question of whether drug companies being protected by patents is a net benefit, particularly for vaccines, is going to interact with political viewpoints.

          However…

          > but the authors are so sure that Moderna and Pfizer wanting to protect their intellectual property (which includes methods of manufacturing not just the particular vaccine) is what is keeping the world from being vaccinated.

          Once again, I’m not sure that’s a fair reading. I don’t think they’re saying that’s what’s keeping the world from getting vaccinated, but that more people would get vaccinated more quickly if the patent protections weren’t in place. Specifically, that “these rights are slowing the diffusion of life-saving medicines in a crisis.” I would highly doubt that they’d argue that there aren’t logistical manufacturing and distribution obstacles that also contribute to slow the diffusion.

          I’m not sure how to get to the meat of the question if I see a distinction there whereas you don’t.

          > I dunno… but if you think so, then you should lay more blame on the Chinese government for not making their vaccine open source.

          Saying that they should “give it away” (after being funded to develop it, mind you) isn’t mutually exclusive of arguing that China should make their vaccine open source. But that said, arguing for China to do something is arguably even less likely to bring it about than arguing that Western drug companies should do something.

          > It also doesn’t seem that India is just sitting this one out

          They mention in the article, specifically, that India has some of the resources need to manufacture vaccines.

          > And if you’re concerned that developing country governments can’t afford to pay for the vaccines, India’s own billionaires could certainly pay for any manufacturing licenses they might need. South Africa also has a few billionaires who could also be so generous.

          I’d imagine the authors would agree with you about that, and that they’d likely advocate for Indian and South African billionaires to contribute to the cause.

          > The analysis that Moderna’s and Pfizer’s patents are keeping the world from being vaccinated seems more of an expression of disdain for profit than an actual analysis of the situation as it is.

          So I’d imagine that their disdain for the profit motive in vaccine manufacture and distribution affects their viewpoint – but again how do you uncover that if your reaction is a mischaracterization of their viewpoint?

          > Given all this, I’m not sure how Moderna and Pfizer are preventing vaccination of poorer countries.

          Yet again, I think that’s not an accurate characterization of what they argued.

    • The reason patents exists is to encourage people to spend their own money to create new things. The alternative is to pay people to create new things. It is odd (to say the least) to both pay people to create a new thing and also give them a patent for the new thing.

      Another problem with medical patents is that it means the items are being sold for far above what they cost to produce. So, there is a strong incentive for the patent holders to mislead or lie to encourage sales, e.g., the opioid crisis.

  7. Daniel Lakeland– “What is it exactly that necessitates two doses in the first place? ”

    … it’s an arbitrary decision to reduce serious side effects from the vaccine — 2 weaker doses rather than 1 full-strength dose are judged to be safer for mass inoculations (allergic reactions are the big worry)

      • The first dose trains the system for the second.
        Did you see safety studies about the issue of side effects based on dosage? What’s the basis for the “mega” label?
        For measles young children get two steps for this reason while unvaccinated adults get one. But I have not seen this claim for adults. For flu the elderly actually get a special stronger version.

  8. As a general follow-up, I have never seen a fun discussion overtaken so quickly by events. 

    In Ontario, Rick Hillier has actually requested Health Canada to approve single dose Moderna, see: https://www.ctvnews.ca/health/coronavirus/hillier-asks-health-canada-to-consider-single-dose-moderna-vaccine-doctors-skeptical-1.5247750

    We’ll have the answer from population level data to a high enough precision for public health decisions, as we can limit the bias to low enough for public health decisions by comparing Canadian provinces.

    Meanwhile, the UK said “why not both” [did they read the comments here?]. They approved the Oxford vaccine and allowed a 3 month gap for the Pfizer vaccine (https://www.gov.uk/government/news/oxford-universityastrazeneca-vaccine-authorised-by-uk-medicines-regulator) which is basically pushing on both pathways at once (increasing supply via the fast to make vaccine and stretching out the high-efficacy Pfizer one).

    So I suspect we’ll know the answer from observational administrative data in about the same time frame as we would from a clinical trial.

    • n Ontario, Rick Hillier has actually requested Health Canada to approve single dose Moderna

      Ah yes, I’ve always wanted a retired Canadian Forces General suggesting medical treatments. So much better than an expert on vaccinations or an epidemiologist.

      As dhogaza points out below Pfizer is not impressed.

      Still I am sure Hillier and BoJo are far better qualified to make the call than those silly scientists that developed the vaccine.

    • Joseph:

      Have you worked with Canada data?

      Are you sure that vaccinations will be tracked _along_ with health care data?

      > We’ll have the answer from population level data to a high enough precision for public health decisions, as we can limit the bias to low enough for public health decisions by comparing Canadian provinces.
      I know that was not possible about 5 years ago – what has changed?

      Maybe OHDSI in countries with comprehensive coverage of health care provision to all citizens (e.g. Spain). None of that will be in Canada.

      • Yes, I work in Canada (ironically part of a grant to look at covid-19 in admin data on one of the provinces). I would be shocked if one of the provinces managed to mess this up, but I suppose anything is possible. Universal care means central medical claims so you can track a person (unless they get care internationally and do not apply for reimbursement)

  9. Pfizer is not thrilled about the decision taken in the UK:

    ‘Pfizer/BioNTech said categorically that their vaccine was not designed to be used in two shots 12 weeks apart, which the JCVI has now authorised in the UK. In a statement, the firms said there was no evidence the first shot continued to work beyond three weeks.

    “Data from the phase 3 study demonstrated that, although partial protection from the vaccine appears to begin as early as 12 days after the first dose, two doses of the vaccine are required to provide the maximum protection against the disease, a vaccine efficacy of 95%. There are no data to demonstrate that protection after the first dose is sustained after 21 days,” they said.’

    • “there is no data” is not the same thing as “there is no protection” but it is the same thing as “Pfizer will make a lot less money a lot less quickly”

      I guess maybe we’ll find out after there is data once they start doing 12 week intervals. My prediction: two doses 12 weeks apart will provide substantial protection, probably above the efficacy of the Oxford vaccine which is only in the 70-80% range.

      • ‘“there is no data” is not the same thing as “there is no protection” but it is the same thing as “Pfizer will make a lot less money a lot less quickly”’

        Sure. Also if protection drops off significantly over that 10 week period between first-shot protection kicking in big time you’ll get more cases and deaths and Pfizer will take a hit on that, as well, despite this not following their regimen. So that costs them money, too. So this could be all about money and nothing else. I’m doubtful, though.

        I think it is about the UK panicking because cases are skyrocketing and the more infectious strain is causing their Rt values to rapidly increase to the point where they’re frightened they’ll remain above one even in the face of increasing lockdown and other mitigation measures. (I say “values” because of regional differences due to population density and the like and the pattern of spread of the new strain).

        “My prediction: two doses 12 weeks apart will provide substantial protection, probably above the efficacy of the Oxford vaccine which is only in the 70-80% range.”

        I think the approval of the AZ (Oxford) vaccine based on limited data is driven by “an abundance of concern” (for those who don’t approve of my use of “panic” above).

        Combined with its being home-grown, and a large number of doses available.

        Also the comparison isn’t two doses of Pfizer given 12 weeks apart compared to the AZ (Oxford) vaccine being given on schedule. The comparison is with both being given 12 weeks apart. But I agree with you that two doses of Pfizer’s vaccine given 12 weeks apart is likely to be more effective than the AZ (Oxford) vaccine.

        A nuance here is that this extended schedule is meant to make first shots available to those who are vulnerable and the second shot schedule is “no more than 12 weeks”. I’ll guess that they’ll try to get second shots out there for the most vulnerable closer to the manufacturer’s recommended time frame.

        • Having seen so much bullshit this year regarding COVID I think it’s critical to avoid legalistic rule-making. I’m afraid of things like “I’ll get fired if I give you this vaccine because it’s 3 days after the appt you were supposed to be at” so go home and I’m going to throw this dose in the trash. a lot more than I am the biological consequences of those 3 days, or even 3 weeks.

        • From the CDC guidelines for the Pfizer vaccine:

          “Second doses administered within a grace period of ≤4 days from the recommended date for the second dose are considered valid; however, doses administered earlier do not need to be repeated. The second dose should be administered as close to the recommended interval as possible. However, there is no maximum interval between the first and second dose for either vaccine.”

          So your fantasy situation is simply that, fantasy. You’re not going to get screwed over and refused a second shot because you’re outside the four day window, nor is someone going to get fired if they give you that second shot outside the four day window, nor will you be refused and the dose tossed into the trash if you ask for that second shot outside the four day window.

          Well, there might be individual caregivers who screw up, but it certainly won’t be due to policy.

        • If you wait to long they may do a titer and then have you start at step 1 again. That’s basically what Fauci said on TV the other night.

          We don’t know how quickly the impact of dose 1 fades.

          For sure there will be tons of observational data soon as people miss appointments or go to two different clinics and get two different vaccines.

          Also it will be interesting to see what happens in the control arms of the original trials as those people start getting vaccinated.

          One issue no one has mentioned in this is that now what we have emerging is a standard of care. As we move eventually, in maybe a year, out of emergency mode, any change in recommendation will be compared to that. What’s happening now is that people are saying that because it is a pandemic we should us less efficacious care for more people.

        • “For sure there will be tons of observational data soon as people miss appointments or go to two different clinics and get two different vaccines.”

          Yes, there was discussion of this at the vaccine review board meetings.

  10. Even if a single dose provides only 50% of the takers protection for a few months, it buys time by reducing caseloads in an overburdened health care system which many places is moments from collapse. Moreover, even without total protection the first doses appear to reduce disease severity for some time

    • Exactly. No one would suggest we should just stop doing two doses at all.. but vaccinating 100M people with one dose over several months followed by a second dose over several more months might easily be better than vaccinating 50M people twice over that timeframe and having 50M totally unprotected. I think it’s worth analyzing and certainly worth collecting data on how things happen for those who inevitably wind up not getting the second dose on time anyway, which will just happen naturally undoubtedly.

Leave a Reply to Navigator Cancel reply

Your email address will not be published. Required fields are marked *