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Cold Chain (And Colder Chain) Distribution

OK, it looks like we’re finally going to be talking about a vaccine logistics issue that many people (including me) have been worried about. Specifically, how are these things going to be transported and stored? If you’re not in the biomedical field, that question might seem a bit boring and bring up mental pictures of 18-wheel trucks and forklifts of cartons, but remember, these vaccines generally aren’t dry powders. Some of them are infectious viruses themselves (the adenovirus vectors and others in that category), some of them are purified proteins (such as the Novavax candidate), and some of them are mRNAs that are packaged in very specific lipoprotein nanoparticles.

If that last category sounds like it might be the most fragile, well, you are correct-o-matic. There have been brief mentions of the stability of these candidates over the last few months, but now that things are getting very serious indeed, we’re starting to get a more detailed look at things. So let’s talk about the “cold chain”. That’s the distribution system for things (like most vaccines) that need to be kept refrigerated until they’re used in the clinic. This document from the WHO will tell you a lot more than you ever wanted to know (or thought there even was to know) about the subject. Details get down to how large the packages are (the vials in the middle will feel the effects of refrigeration last, and then warm up the slowest), the design of refrigerated trucks and their airflow, the various options for “cold pack” devices inside containers, where things are placed in chilled storage units of various sizes and how they’re retrieved, how long things need to be kept out at room temperature in order to be used and how long they must not be kept at room temperature before they have to be thrown away, and so on. There’s a lot of experience with this, and a lot of infrastructure.

But let’s qualify that last statement: there’s a lot of infrastructure in the developed world. Cold-chain distribution has always been a major challenge in places that are remote, less developed, or have generally higher ambient temperatures. You can probably think of plenty of locations that are all three of those at once. Ideally, you’d want something like a vaccine to be able to be distributed far and wide to all sorts of point-of-care locations, but in many instances people have to come to where the refrigeration is. Which is less desirable from a lot of angles.

And let’s qualify that earlier statement again: there’s a lot of infrastructure in the developed world for refrigerated cold-chain distribution. But what we’re looking at for the Moderna and Pfizer/BioNTech candidates, both of which are promising and are well into Phase II/III trials, is not just refrigeration. Moderna’s vaccine needs to be shipped and stored at -20 C (minus four Fahrenheit), while the Pfizer/BioNTech one needs to be at -70 C (-94 F). The former is enough of a challenge – freezer temperatures instead of refrigerator ones. But the latter. . .well, biology research labs all have freezers that go down that far (it’s where cell culture samples, oligonucleotide constructs, and recombinant proteins get stored), but you’re not going to find one down at the local pharmacy, which is perhaps where you were picturing lining up for a coronavirus shot.

This news sent both companies’ stock prices down late last week, because it’s definitely not what people wanted to hear. Pfizer has provided these details to the CDC about shipping and storage of their candidate: the vaccine can be shipped in “dry ice pack” boxes, but that dry ice will need to be replenished within 24 hours of receipt. The shipping carton needs to be closed within one minute of opening, and not opened more than twice per day. Vaccine vials, once removed, can be kept at refrigerator temperatures for up to 24 hours or at room temperature for no more than 2 hours after thawing. So this is going to take a very organized approach to make sure that the vaccine is handled properly without wastage. We’re looking at a lot of dry ice and a lot of orders for ultra-cold freezers if this is the candidate that gets heavy nationwide distribution. And mind you, I’m talking about organized distribution in Little Rock and Long Beach. What about La Paz and Lahore? What about Lubumbashi? Even back inside the US, what’s the nearest source of dry ice in Shiprock, New Mexico or Oceana, West Virginia?

A -70C storage regime looks like some type of centralized distribution for many areas; it just doesn’t seem practical for many point-of-care locations. It would be “thaw out a batch and get as many people through the door as you can before it goes bad”. Moderna’s candidate is surely easier to deal with, since we do at least have a lot more “standard freezer” type capacity both in distribution and local storage, but even that is going to require plenty of thought (and plenty of discipline on the receiving end). And there’s talk that a Moderna Emergency Use Authorization might include the lower temperatures anyway. Let’s keep an eye on this story, and on the requirements for the other vaccines in testing. You would have to expect the recombinant-protein candidates (Novavax and others) to need less stringent storage conditions, but I don’t know about the adenovirus vector ones (and very much look forward to more details). This could be a big factor.

Update: see the comments for thoughts from some cold-chain specialists. Some are saying that this is more doable than it looks (given sufficient spending!), but the end-user problem remains. . .

112 comments on “Cold Chain (And Colder Chain) Distribution”

  1. Gary Cornell says:

    I did a back of envelope calculation about what will be needed to distribute the Pfizer vaccine, which it seems requires the most refrigeration (-70c), that may interest you, It’s actually quite doable if we get started now at building out the infrastructure:

    https://garycornell.com/2020/08/30/back-of-envelope-calculation-the-number-and-the-costs-of-freezers-needed-for-the-pfizer-vaccine/

    1. MagickChicken says:

      I like how you say the freezers need to be ultra-reliable, then use a Thermo Scientific freezer as an example. We’re so boned.

      Thermo Fisher Scientific: The Walmart of the Science World (R)

      1. Ian Krase says:

        Wait, really? I was not aware of that.

      2. Timothy D Cummins says:

        We have had 2 defective freezers coming from them in the last 4 months!

  2. Barry says:

    For areas of high population density–where contagion is most likely–it will be possible to line up thousands and shoot them like military inductees. That doesn’t require individual vials, and the cold (or very cold) chain is a solved problem. Remote villages are a whole ‘nuther problem

    1. Sc says:

      I wonder how many people will be infected in line to get the vavcine.

    2. sort_of_knowledgeable says:

      So you have a big crowd of people gathered to receive the first dose of vaccine that is 80% only when 2 doses are given. This may end end up spreading the virus.

    3. Bobby says:

      Inovio Pharmaceuticals solve the problem with cold chain. INO-4800

  3. Canuck says:

    Well, we should be just fine shipping the Moderna vaccine most of the winter on a flat-bed as -20C is easily within reach up here. And if it has to be exactly -20C, then some amount of heat might be required in beard-freezing-to-face weather. This might buy us late Nov – late March or even early April.

    Although I’ll grant that -70C is a stretch even on the cold days :-).

  4. Tom A says:

    Familiar with TATS (time and temperature sensitive) materials for aerospace. Consistent process conformance by the humans involved in the total supply chain is a challenge. Freezers infrastructure is a lesser concern. My take is a product requiring -70C is DOA. As soon as an easier to handle solid performing competing vaccine comes along Pfizer/Biontech will be history.

    Also there may be practical limits to the amount of dry ice you can include in a package if it’s being shipped air freight. Department of Transportation and FAA regulations, together with International Air Transport Association rules would prevail.

    1. Patrick says:

      I’m pretty sure those rules could be relaxed in these sort of instances, since the dry ice danger is presumably asphyxiation for the handlers, which shouldn’t be much of a problem if you know what you’re handling.

      Frankly, no transport regulation will stand in the way of this *by itself*, anything in the way will get interrogated and examined to confirm it is both applicable and of sufficient concern given the situation. As they should be.

      1. Morgrim says:

        Yeah, this is the sort of thing that is of sufficient value and urgency that it could get dedicated flights, priority runway clearance, and for the long haul steps possibly the unusual military transport haulers that DON’T pressurise the cargo hold, which will certainly cover the “keep it cold for 12 hours” angle (but the ground crew better be lined up waiting to pounce).

        Which is a logistical NIGHTMARE but in theory one that can be solved.

  5. wilhelm Cody says:

    Nearest supplier of dry ice to Shiprock, NM is Four Corners Ice in Farmington, NM (about 28 miles and 32 minutes, population around 45,000.) After that you might need to go all the way to Cortez, CO (Arigas Dry Ice, about 42 miles and 43 minutes, population about 8,500). Most likely, people would travel to the Farmington metropolis to get their shots at a local clinic.

    The internet is your friend.

    1. Phil says:

      Ha, you beat me to it! Farmington is a 1/2 hour from Shiprock and has a ton of industry, there’s no doubt dry ice is plentiful there.

    2. Davey says:

      It appears then that the logistics of immunizing the Hopi and Navajo people are going to be… complicated.

    3. Rich says:

      Yep, the liquified/bottled gas companies have outlets all over the place (to serve the welding and foodservice industries, as well as medical and more exotic uses) and they generally do dry ice, even here in NZ.

  6. bruce1966 says:

    I know I shouldn’t complain, this isn’t much in the big scheme of things, but the small pharma company I work for uses dry ice for a lot of things, and if the Pfizer vaccine takes off there isn’t going to be any dry ice for us.

    The vendors are already saying there’s a shortage; the stuff gets made from byproduct CO2 at ethanol plants, and ethanol production is down because people aren’t driving so much these days.

    1. Barry says:

      Seriously, there is no shortage of CO2 and there won’t be.

      1. Patrick says:

        Shortage of CO2 in appropriate form and location for dry ice production, though?

      2. khoadley says:

        “No shortage of CO2 and there won’t be” … Errm:

        There was a CO2 shortage in Europe during the summer of 2018, which lead to a shortage of beer and carbonated drinks during the World Cup: https://www.bbc.co.uk/news/business-44628993

        And as Bruce said, there’s been a CO2 shortage this summer – again threatening beer supplies – during to the indirect effects of the pandemic: https://news.sky.com/story/coronavirus-how-the-pandemic-could-cause-a-shortage-of-beer-and-fizzy-drinks-11975329

        Beer or vaccines ?

        1. Walter Sobchak says:

          If you need to add industrial CO2 to your beer, you are doing it wrong.

        2. loupgarous says:

          Vacationing with family, Peltier coolers solved much of the need to chill fizzy drinks and perishable meats en route to our vacation destination. I’ve also used the same coolers (“Koolatron”) to keep food the right temperature while evacuating during hurricanes.

          1. Defenestrator says:

            Peltiers are cheap and portable, but way less efficient than compressor-based coolers. They also have pretty diminishing returns in terms of the temperature delta they can maintain. You’d need a fair bit of space and power to keep much at even -20C, much less lower temperatures. Maybe useful to augment a commodity compressor to drop the last 30C or so.

      3. Not a Doctor says:

        No shortage of water in the world, either. Non-salt, clean water is a completely different story.

      4. tlp says:

        Two years ago we actually experienced temporary shortage of dry ice in Bay Area due to sudden high demand from Cannabis industry. We had delivery delayed by a week.

      5. CM says:

        Literally just had a lab facilities update where the current significant dry ice shortage was discussed, this was in the Bay Area.

      6. HTSguy says:

        There is also a (filled) CO2 cylinder shortage at the moment in the Bay Area. Some combination of cylinder themselves being hoarded by larger Biotechs and the CO2 shortage.

    2. John Hasler says:

      It should be possible to crank up dry ice production at those ethanol plants specifically for this use. The important point is that the equipment exists.

    3. SteveM says:

      I am prepared to do my patriotic duty and drink more beer

      1. Sean Fhearsalach says:

        It will have to be real ale

  7. Daniel Barkalow says:

    I was kind of picturing the biotech company next door to my work holding a vaccine clinic for the neighborhood. I figure they’d have the -70C storage and cold chain logistics, and Biogen might be looking to pay off a karmic debt.

    This might be a reason that we’d get approval for a mRNA vaccine and then approval for another vaccine that takes more time to develop but less time to set up logistics for outside of cities.

  8. Eric Nuxoll says:

    The vials have to be thawed for use, and can be used for 24 hours afterwards, so I assume the issue just gradual degradation, not some sort of critical temperature event (e.g. phase change). If the degradation products aren’t toxic, wouldn’t the answer be to just dose more, especially since this product is (as I understand it) much cheaper and faster to manufacture than most other vaccines? More work needs to be done to figure out how to either stabilize it or factor the degradation into the dosing, but that should all be solvable. It takes time, though, which Pfizer isn’t going to spend in a race like this, since places that don’t have access to (very) cold storage also don’t have (lots of) money. But maybe by the time they’ve cashed the checks from the rich, developed cities and competitors begin appearing (assuming those trials aren’t squashed by the first vaccine), Pfizer will have come up with a version that doesn’t require -70.

    1. Pedwards says:

      The problem is that we don’t know if the degradation products are toxic or not, and even if they aren’t toxic by themselves we won’t know whether or not they affect how the body reacts to the vaccine. Combine that with the fact that increased doses can start giving more severe side effects, and it’s better to try to keep them cold instead of trying to untangle what’s going on with a vial that’s been warm for too long. Especially seeing as everyone’s trying to get these vaccines out as quickly (and safely) as possible.

      1. Some idiot says:

        One thing I’ll hang my hat on is that the people in the Stability area will be working off their nether regions to get that data in place before it is launched. Put another way, I don’t really see a drug being approved without that info.

        1. Pedwards says:

          I have no doubt that the Stability folks are working hard on that. But there’s still no guarantee that the degradation products are going to be pharmacologically inert, and it’s already been showed that higher doses lead to more side effects. From a standpoint of vaccine uptake, I’d rather deal with making sure everything’s kept cold vs. having more people than usual start claiming on twitter and facebook that the vaccine gave them COVID because they felt extra crappy after the jab.

          1. Some idiot says:

            There is no doubt whatsoever that many of the degradation products are going to have biological effects (and, going by Sod’s law, not good ones). And I agree 100% that the last thing we need is ammunition for anti-vaxxers to say that the stuff is out to injure us.

            But… My point is that this is precisely what the Stability folk do (I have been involved with part of that in the filing for completely unrelated biological formulated drugs). They stress samples at different temperatures for different times, determine breakdown patterns, identify the breakdown products (over a certain level, and that level may needed to be adjusted a bit down depending what is found), and the breakdown products screened for biological activity.

            From statistics from such studies (run on quite a number of different batches of product) calculation are performed in order to determine acceptable hold times at different temperatures (vibration is also an issue, although probably less so with a frozen solid than a solution), and so _when_ (not if…) a deviation comes in due to (eg) loss of cooling in a transport, from the temperature curves they can calculate how much hold time the samples “have left” at given temperatures.

            All of this needs to be done in detail prior to filing, and no authority worth its salt would approve something without this work being done. It’s damn hard time-consuming work, and although the people in question have relatively little time to work with, I am sure that they will be hard at it… (Btw, disclaimer: I am in no way involved in _any_ vaccine work whatsoever).

            In addition, it would also be a condition of approval that these studies continue even after approval, with every single batch being subjected to both stability and accelerated stability studies, the latter so that potential problems with a new batch can be picked up _before_ it can cause a problem…

  9. Steve Scott says:

    I did a lot of web searching on this topic over the weekend and here’s what I found:

    Novavax’s vaccine “ …”can be stored at between 4 C to 8 C — refrigerator temperature.”

    https://www.statnews.com/2020/07/07/novavax-maker-of-a-covid-19-vaccine-is-backed-by-operation-warp-speed/

    And this is apparently true of the protein based vaccines in general.

    Adenovirus vaccines: From Wall Street Journal:
    “AstraZeneca PLC said it expects the vaccine it is developing with University of Oxford researchers to require refrigeration, but declined to give details.”

    I was unable to find any information on cold storage for adenovirus vaccines in general. Curious.

    Moderna: According to two different reports, its vaccine could be held in a refrigerator at the point of administration for one day, or ten days. Quite a difference. They are exploring this and expect to know more in a month or two.
    And they are pursuing “stability data” to show that it can be stored at minus 4 degrees F, apparently not proven yet.

    Pfizer: could be stored in a refrigerator for either one day, or two days, according to different articles. Pfizer also hoping to ship frozen vials directly to the point of vaccination, and working on a version that could be distributed at warmer temperatures, but that won’t be ready until late 2021.

    1. Steve Scott says:

      And here is some more information that I just gleaned. Apparently, the Oxford/Astrazeneca vaccine only needs to be refrigerated, not frozen- no doubt true of other adenovirus vaccines in general. And Moderna expects its vaccine can be stored in a refrigerator at the point of administration for seven days (between the one and ten day quotes above).

      https://www.biopharmadive.com/news/moderna-pfizer-biontech-coronavirus-vaccine-stability/584209/

      1. Interesting, Cliff; What would be a typical additive cost per vial of the KT400D-60 cold chain packaging solution from Serum Institute in Pune, India to a developing world tier-3 town (say Kakamega, Kenya as the prototypical example)?

  10. FoodScientist says:

    You can easily make dry ice from cylinders of CO2(a liquid at pressure/ RT). They might have to remove them from the cafeteria soda fountains. The little dry ice block makers are like $200. You can also get dry ice from many grocery stores supplied by penguin.

    They will probably line so many people up, make them wait until it’s ready, then vaccinate them all.

  11. FoodScientist says:

    The real issue is what are they going to do when a dry ice cooled truck breaks down somewhere inconvenient or gets can opened on a low bridge.

  12. MTK says:

    All of these logistical issues such as fill-finish, medical grade glass vial supply, syringe and needle supply, cold storage and shipment, etc. are solvable. It’s more an issue of how much time, money, and effort it will take to have everything in place.

    The whole we’ll “have” a vaccine by X date is meaningless. “Have” depends on whether you mean an approval and what type of approval, one that’s been through sufficient clinical trials, a widely available safe and effective vaccine, or maybe even one that people will actually be confident in getting.

    About a month ago the left-leaning Center for American Progress issued a plan for vaccine manufacture and distribution. Agree or disagree with its recommendations but it did point out many of the potential issues facing widespread COVID-19 vaccination.

  13. Marko says:

    Ain’t we an exceptional country ? YEE HAW !!

    But , dang , I wished I knew how to get these raw oysters out to my cousin Billy Bob over in Texas without them spoilin’ and stinkin’ up the place. I got the same dang problem with these vaccine vials. How in the world do you keep crap cold? I bet the Chinese , or even the Russians , have a solution to this. But they ain’t talkin’ to me anymore.

    Well , shit , let’s just wing it , shall we ? Let freedom ring , and so forth…..

    1. eyesoars says:

      Ah, the joys of vibrio.

      /s

  14. ColdChain says:

    Interesting read–thank you for posting.

    From a pharma cold chain specialist perspective, I think both the -20 and -80C regimes will be easier (relatively) to accomplish than your readers might expect–at least in the US. Even globally, there’s nothing new here in terms of technical requirements, it’s just the scale and affordability.

    To hear that one company has made a decision that dry ice must be replenished within 24 hours means they’ve already made one such affordability decision: there are plenty of packaging types available that could extend this time out beyond 72 hours, but they get expensive quick.

    Back to domestic US distribution: the -80C drug might actually be the easier shipment to qualify and build out swiftly, as dry ice tends to be more available, with less lead time, than -20C end to end methods. A dry ice-cooled distribution model is already in place at several pharma companies, and there’s plenty of US distribution partners with the resources already in place to handle high volumes of shipments. -20C freezer trucks (“Ice cream trucks” in the trucking world) break down–a truck carrying a 200kg dry ice container though, can break down, and that dry ice is still keeping things frozen, unlike the freezer truck which loses it’s refrigerant compressor on breakdown. We get into sublimation rates, of course, but still: there’s nowhere in the US currently which can’t be reached in 3 days time, absolute max, by air/road that isn’t already receiving some goods on dry ice. We currently ship 1000s of vials at a go in such large dry ice containers, to any number of areas (both rural and metro) in the US.

    A reader above mentioned IATA and DOT regs–thankfully, most of the packaging available on the market has already been designed with IATA and DOT in mind. US air carriers will have ultimate say on how much dry ice is allowed on a flight, but they already ship pharmaceuticals on dry ice daily–I can see it being very reasonable for air carriers to block out groups of flights from the nearest airport to manufacturing facility that will be ‘pre-cleared’ to carry lots of vials in dry ice.

    The hardest part of this, as always, will be at the end-use facility: we already have packaging that allow for less-than-minute openings with trays that pop right out of the dry ice, ready to administer X # of vials. Getting clinic staff to follow that opening regime, and then seal the box back up quickly, is usually the hardest part.

    1. MTK says:

      It’s not a technical issue, it’s a scale and time issue.

      It’s one thing to make, inventory, ship, store, and distribute millions of vaccine doses over a year, but now we’re talking 100’s of millions in half the time.

      I also worry that we might actually address all of that then end up with massive excess inventory if vaccine uptake is slow due to public mistrust. If that happens where and how are all those doses going to be stored and how many are going to end having to be destroyed due to stability questions?

      This isn’t just a matter of turning the crank faster. It will end up being the largest and most condensed public health initiative ever. There’s a lot that of challenges.

  15. Roy Badami says:

    A bit of Googling found a previous Chadox1 vaccine trial (not COVID) that was using -80C storage.

    So I think the requirement for a cold chain at dry ice temperatures is a reasonable working assumption for the early vaccines, no matter which wins the race.

  16. PS says:

    The DOD is the lead, in distributing the Vaccines with four star general heading it at least in this country. Department of Defence with its expertise and vast resources in Logistics is well suited for such a task at least in the beginning till all things are in place.

    1. ColdChain says:

      PS–very true! The DOD vaccine supply chain has a foundational underpinning supported by some cold chain folks in private industry (the big mfg that makes the vaccines for DOD)–between DOD logistics and the manufacturer’s staff (who in turn rely on a distribution partner courier), the -80C requirement is really just a matter of integrating the COVID vaccine into that existing supply chain. I think people would really be quite surprised at what already exists in the US, on cargo bellies of domestic passenger flights, in plain white transport vans, etc. The only thing required here, assuming a 2mil vial on dry ice, is the allocation of resources for immediate need. The capability to ship at temp and on time has already been deployed many times over.

    2. Political skeptic says:

      How do you think this will affect trust and uptake in minority communities, and communities with a lot of immigrants, where many people do not trust the U.S. miiltary?

      1. PS says:

        In US at least, when the choice is between being on a ventilator for two weeks and dying alone, OR taking a vaccine trust and choice is easy to comeby.

        1. Arjun says:

          If you are implying that the choice (between being on a ventilator and taking a vaccine that one mistrusts) will lead one to easily chose the vaccine, just look at how many people simply will not wear a mask. That simply is not how the human mind works.

          1. Arjun says:

            …and if everybody used a mask correctly, washed their hands, used sanitezers and maintained social distancing, like the virologists have been recommending from the very beginning, we may not actually have been having such urgent conversations in the first place!

    3. Nanobodaddy says:

      Have the extra logistical complications of needing a two-dose vaccine been figured into these calculations? We will need well over 640 million doses to vaccinate each American two times, and the two doses have to be available a month apart for each person vaccinated. This means that they’ll probably have to be shipped concurrently, won’t they?

  17. John Hasler says:

    Can the Pfizer vaccine be stored at the temperature of liquid nitrogen? It’s widely available for industrial use and dewars are thick on the ground anywhere cattle are bred for transporting semen.. Even if it has to be at -70 C it would not be hard to build small LN2 powered freezers to maintain that.

  18. JRD says:

    Even if there is a functional, reliable cold chain infrastructure, do you trust our leaders to even bother to use it?

    I’m thinking of the Vanity Fair article where it’s reported that the presidential son-in-law bypassed all the systems in place and simply placed a call to his friends in high places. Then a million test kits suddenly showed up in Washington straight from the United Arab Emirates. But due to their ignorance, they were all ruined: “The tests may have been rendered ineffective because of how they were stored when they were shipped from the Middle East. ‘The reagents should be kept cold,’ the spokesperson said.” (And nobody wanted to pay for them, either.)

    https://www.vanityfair.com/news/2020/07/how-jared-kushners-secret-testing-plan-went-poof-into-thin-air

  19. Zambo says:

    What exactly is the reason for the Moderna vaccine requiring such a less low temperature than the Pfizer?

  20. David in Kent says:

    There are lots of clinical trial samples currently shipped around the world to central labs for testing using dry ice in special certified containers. The system works pretty reliably but costs serious money. Presumably the cost per item would be much less where there is a bulk shipment but with many destinations to be served, many of them in inaccessible locations the cost for global distribution is going to be significant.

  21. cliff findlay says:

    To everyone concerned: The solution to this problem already exists. The product is the KT400D-60 produced by TOWER cold chain solutions. It is passive, maintains -80 to -60 for over 120 hours and loads in less than 60 secs. If you are interested please click here. https://towercoldchain.com/kt400d-60/ thought this may be of interest to you all? If you need any further information please don’t hesitate to get in contact.

    1. (reposting because of misplaced ‘reply’ press)
      Interesting, Cliff; What would be a typical additive cost per vial of the KT400D-60 cold chain packaging solution from Serum Institute in Pune, India to a developing world tier-3 town (say Kakamega, Kenya as a prototypical example)?

  22. Hopeful Layman says:

    I’m not sure where this belongs, so please forgive me if this is the inappropriate place. But it occurs to me that if these adenovirus-vectored vaccines prove effective, they might make the problem of storage and shipping virutally moot. There are many other potential benefits to them, of course — perhaps this research deserves an entire discussion of its own? — but they are certainly relevant to the discussion at hand, as well.

    1. Hopeful Layman says:

      I apologize. Here’s a link I should have included in my previous post. It’s one of several that are available.
      http://www.sci-news.com/medicine/nasal-vaccine-sars-cov-2-08786.html

  23. Chuck G says:

    Inovio – “INO-4800, as it is the only nucleic-acid based vaccine that is stable at room temperature for more than a year and does not require to be frozen in transport or for years of storage, which are important factors when implementing mass immunizations to battle the current pandemic.”

  24. Hopeful Layman says:

    Everyone please accept my apologies for the multiple posts. I have never posted here, so I guess I don’t understand exactly how it works. I waited for things to get posted and they didn’t, so I assumed the spam filter rejected them because of the multiple links in them. Again, I apologize. I’m not trying to troll.

  25. debinski says:

    “The U.S. has already manufactured and stockpiled “hundreds of thousands of doses” of coronavirus vaccines in the hopes that one will be effective in combating the virus, a senior administration official said Tuesday.”
    https://www.foxbusiness.com/healthcare/us-stockpiling-three-different-types-of-coronavirus-vaccines-through-operation-warp-speed

    Moderna, Pfizer and Astrazeneca? Looks like they will be predisposed to approve these vaccines quickly and possibly prematurely….

    1. PS says:

      Vaccine ready for patients by Nov 1, just before the elections.No politics!

      1. dark day says:

        We’re hosed.

        1. Dark Day says:

          Okay, let me emend that. MAYBE we’re hosed. Certainly, distribution will be immensely complex, logistically — if the CDC’s intent is simply to try to ensure that states have a good distribution infrastructure in place, well in advance, to facilitate things when a vaccine does get approved, this might not be as ominous as it looks; in fact, it could be a good thing. We can’t necessarily trust headline writers and non-scientific/non-medical journalists to fully understand or convey things like context and nuances. But, especially given the recent plasma fiasco, it certainly does not inspire confidence.

  26. TallDave says:

    have more and more concerns about demand

    kills me (hopefully not literally) that Lilly and Regeneron developed what is likely a high-efficacy treatment but can’t get enough people to volunteer for the trial… sigh

    eventually, years from now, it will occur to some staffer on a hopelessly partisan Congressional subcommittee that had the gov’t simply offered $1000 to every sick person taking the trial, they could have saved trillions of dollars in additional lost GDP (not to mention thousands of lives) over the extra months of delay for an outlay of mere millions

    1. Sarah says:

      Do we know when we might get any info on the MAbs? Are the trials dead in the water or just slowed down? Are they still hoping for data in Oct?

  27. debinski says:

    This interview with Fauci makes me feel a little better about vaccine(s) potentially be available this fall: https://www.medscape.com/viewarticle/936750?src=mkm_covid_update_200902_mscpedit_&uac=87334SZ&impID=2544043&faf=1#vp_1
    But can anyone explain how so few infections would prove efficacy according to Dr Redfield “In trials of this size, researchers will know if a vaccine is effective after as few as 150 to 175 infections, said Dr. Robert Redfield” ?

    1. Marko says:

      With equally-sized vaccine and placebo arms , 150 infections would demonstrate statistical significance if the effect size is 50% or greater. So you’d see , let’s say , 100 infections in the placebo group but only 50 infections in the vaccine group at the same time point. That’s enough to tell you the vaccine works in the broad group in preventing infection.

      The problem with such low numbers is that you wouldn’t be able to say much about sub-groups, like the over-65 age group , because you likely wouldn’t have sufficient numbers to show significance there.

      1. debinski says:

        OK, thanks. So taking that a step further…the current daily US infection rate is about 6000/350M = 0.000017142. Pfizer said they were half enrolled (and that was a while ago) so there are at least 15,000 volunteers who will have received both shots my mid to late Sept. At the current infection rate, (15000 x 0.000017142) .25713 study subjects will be infected each day. So in less than 10 days from mid Sept (by late Sept) we should have 250 study subjects infected, more than enough to detect a statistically significant difference if there is a 50% effect size?

        1. debinski says:

          Sorry, that 100 days, not 10. But still with enrollment continuing, I can see getting there this fall.

          1. Marko says:

            I like to keep it simple.

            Consider that most estimates of total infected so far in the US run at ~10-15% of the population. Given that the outbreak has been running for 6-7 months so far , that means that roughly 1-2% of the US pop is infected each month. Thus , among 15k placebo trial participants , you’d expect ~150-300 infections one month after trial initiation , and similar new infection numbers per month thereafter. This assumes that infection rates don’t drop drastically for some reason , but since this is the US , I don’t think we have to worry about that.

        2. Peter Cirona says:

          remember that approximately 1/3 of the 15,000 volunteers will have received the placebo.

          1. Marko says:

            True , but it doesn’t change much. Let’s say you only get 75 infections in the 5000 placebo group, and 75 in the 10000 vaccine group , you still have your 50% reduction , and it would still be significant.

        3. confused says:

          6000 infections in the whole US population per day?

          I don’t think it can possibly be that low, we have way more confirmed cases/day than that.

          I think even 100,000 infections/day (which would mean we are detecting more than 1/3 of all infections) is pretty low-end.

  28. Barry says:

    @Marko
    A linear assumption that we got to ~10%-15% by the accumulation of 1%-2% new infections/month is wholly inappropriate for a geometric process like viral propagation.

    1. confused says:

      US overall growth hasn’t really been exponential for a while, it’s been a combination of slow exponential growth (R a bit above 1, but not much) in some states and slow exponential decay (R a bit below 1, but not much) since probably May.

      The big difference between now and 2 months ago is that then large-population states like TX/CA/FL were growing, now it’s small states like IA/ND/SD while the large ones decline.

    2. Marko says:

      It’s plenty close enough for this exercise. In other , more sane countries , where the first wave was suppressed and maintained at a low level , you might have a point , but in the US where we’ve had – and will continue to have – a relatively steady burn, these estimates will prove to be in the ballpark when the trial results come out.

      If you have different estimates , why don’t you show us your work ?

      1. confused says:

        “will continue to have” for the next month or so at least. It might drop sharply after that unless there is a true fall wave (and COVID may not be that seasonal); the states that are seeing growth now are mostly very low-population ones, and the US so far hasn’t really seen the same place get hit twice (even in Louisiana, the areas seeing a lot of cases in July were not the same ones as in March).

  29. debinski says:

    Sorry 6000/day was incorrect (but so were my calculations so they cancelled out) – the graph I was looking at had new cases and deaths together on the same axis and it was unclear. It’s more like 40,000 new cases/day. And the trials are targeting hot spots so the rate should be even higher.

  30. debinski says:

    Third times a charm. I recalculated this assuming 40,000 cases/350M people per day (according to Johns Hopkins), which should be low balling it if trials are conducted in hot spots. Pfizer reports 23,000 patients enrolled as of today. They have 11,500 placebo pts (the trial has a 1:1 ratio PLB:active) that can be infected. The rate of infection would be 0.0001143 X 11,500 = 1.314/day which means they need 76 days to get 100 placebo pts infected (and 50 active pts infected). So hopefully they beat this by concentrating on areas with higher infection rates but even 76 days is not bad. Also they continue to add more patients and since there is constant surveillance for symptoms, they will catch more cases than the overall US rates reflect.

    1. Dark Day says:

      Is anyone else besides me struck by the appalling irony that all of a sudden, massive spikes in cases are GOOD news (for successful vaccine trials)?

      1. FrankN says:

        Yep. This concerns especially Argentina, where the case count is sky-rocketing. Could help BioNTech/ Pfizer, the only ones conducting Phase 3 there, to demonstrate vaccine effectiveness much earlier than envisaged, i.e. possibly by mid-October.

        1. DataWatcher says:

          If for no other reason than to avoid the further politicization of this entire situation if a vaccine appears “rushed” (hence exacerbating the distrust of vaccines that threatens to minimize the effectiveness of even a very good one, when/if it’s rolled out in the U.S.), I deeply hope that neither of these Phase III trials results in useable data before the end of the year.

    2. Bill says:

      “40,000 per day” per test confirmation

      Didn’t CDC population studies find actual cases to be 6X to 24X the test results? And suggested a generic 10X for typical populations?

      If I’ve got that right we should assume US is seeing 400,000 new cases per day. If not, please straighten me out.

      1. Dark Day says:

        If anything even remotely close to that were the case, and assuming that having had the virus confers at least some immunity, might that mean that a vaccine could coneivably be more efficient, and that mass immunity (if not technically “herd immunity”) might be easier to achieve than originaly thought? (Related to this is a more ominous question — if, in fact, it turns out that reinfection after recovery is a legitimate fear — possibly due to the introduction of new mutant strains — is this the “final” word that herd immunity will never be possible?)

  31. bruce 1966 says:

    WBUR now has an article about the dry ice shortage in the Boston area and beyond.

    https://www.wbur.org/commonhealth/2020/09/04/covid-vaccine-dry-ice-shortage

  32. Tony Phan says:

    Solving cold chain issue is a good engineering exercise however, in practice, it would be much better to select a more effective vaccine that develops neutralizing antibodies four times higher than human convalescent sera, can be stored at 2°C to 8°C and can be produced 1 to 2 billion doses a year. That’s Novavax NVX-CoV2373.

    1. Hopeful Layman says:

      I also have high hopes for Novavax because of the adjuvant. Especially for higher-risk people (including over-65ers like me!), that could be a significant advantage. It might actually be a blessing that Novavax is lagging a little behind some of the others in their timeline; maybe their final results won’t be public, and hence a rollout wouldn’t begin, until this election is over and this toxic politicization of the entire vaccine issue MIGHT (we hope!) subside into a more rational discusson.

      1. Hopeful Layman says:

        That being said, though, I am a little concerned about Novavax reporting that they’re aiming to file for regulatory approval by December. They’re just now into ther Phase II trials; do they really expect to complete both Phase II AND Phase III in three months? That sounds very problematic to me.

  33. Seth says:

    I get the second dose in the Pfizer trial this week (9/9/2020) at the PMG Research Clinic in Charlotte. Is it safe to assume the research samples have been transported and stored properly? I would think Pfizer has been very careful about this.

    1. debinski says:

      I am also in Pfizer’s trial and get the second dose this week. When I got the first dose and had completed all the preliminary procedures, I remember them saying I would be getting the vaccine in a few minutes “after it was warmed up” or something to that effect. Pfizer must have provided them with freezers. I’m sure they would not take any chances on the study vaccine degrading.

  34. loupgarous says:

    Reflections:

    “the US so far hasn’t really seen the same place get hit twice (even in Louisiana, the areas seeing a lot of cases in July were not the same ones as in March).”

    . Hurricane Laura last month was a case in point – we haven’t had a named storm that deadly or destructive fall in that area since 1957. The US Army Office of Civil Defense made a case study of Audrey’s death toll and destructiveness (I used to have a bound copy) in which the point was repeateatedly made that it was an excellent simulation of a nuclear detonation, not necessarily as a valuable point target but for sheer destruction over a large area.

    Other observations – What about electrical Peltier cooling devices to keep vaccines cool at points of care? You wouldn’t need 120 VAC power, just 12 VDC.
    Or NH4NO3(s) + water =NH4+(aq) + NO3–(aq)?
    Neither of these are definitive solutions, but either could (along with other partial solutions) help cool vaccines in remote areas.

  35. loupgarous says:

    Peltier thermoelectric coolers are inexpensive enough that it might be possible for Big Pharma to provide them (for vaccines that don’t require MUCH cooling, anyway) as part of a promotional package to assure patient/point of care compliance. I’ve seen more expensive things bundled that way.

  36. DataWatcher says:

    Meanwhile, both the Administration and the pharmaceutical companies REALLY need to think about the effect on uptake of a perceived “rushed” vaccine. Publc perception matters, especially in our social-media-glutted age. If wating another month or two might mean more public trust, i.e., more actual vaccinations upon rollout, this is an essential consideration; it could mean the difference between success and failure.

  37. Crestlinger says:

    The cold, hard, truth of things. Thanks for the read!

    1. Dark Day says:

      We’ll see how the new revelations that Trump basically lied from the beginning about the severity of COVID-19 will affect people’s trust in any vaccine that might be approved under his watch — I’m guessing that the already-dire uptake predictions will now tank.

      I don’t think we’ll see any kind of approval before Election Day, but I honestly hope nothing gets approved until after Inauguration Day in January (assuming that Biden/Harris win the election). It’s our ONLY chance, even if it’s a long shot under the best of circumstances, to have enough uptake (especially among African-Americans and other high-risk populations) to begin to approximate anything approaching mass immunity.

      1. confused says:

        I actually don’t think this will change much. People who are pro-Trump won’t believe it, and will anyone else be surprised? It certainly wasn’t a surprise to me.

  38. Hopeful Layman says:

    Interesting to speculate about how much “freedom of choice” we’ll really have, if multiple vaccines end up being available. Dr. Fauci addressed this in a recent online discussion, and his prediction was — probably not much.

    Transcribing directly from the interview, he said: “The companies are going to be advertising, as to the specifics, the specifications of their product; I think it’s going to be more or less something that’s less sophiticated than ‘This is what happens to be available in the supply place where you’re getting your vaccines,’ as opposed to ‘You pick the one you want.’ And maybe if a certain pharmacy chain buys out and they become the ones that distributen it, fine, or if there’s another mechanism of distribution that the government is more deeply involved with, then that’s the one you’re going to get. I don’t think you’re going to be able to pick and choose, like you would in a candy store.”

    Ideas? Opinions? Personally, as someone over 65, I was hoping that I might be able to opt for a vaccine that had been shown to be especially effective on older people, but maybe this won’t be the case. On the other hand, will physicians have more leeway to prescribe vaccine in accordance with a patient’s specific needs?

  39. Rick says:

    Why use trucks to transport vaccines to clinic in developed countries?

    Air transportation systems are currently underutilized and have available capacity. Airports are configured to flow large numbers of vehicles and people through them. Arrival and departure ramps could be reconfigured as drive-up vaccination stations for those scheduled for vaccinations on a given day.

    On the other hand the frozen food industry figured out -20C distribution some time ago.

  40. FrankN says:

    Derek – as you have been wondering about vaccine supply to Shiprock NM…
    I guess that question can be considered solved, since the John Hopkins University will be conducting Phase 3 trials for the BioNTech/Pfizer vaccine among the Navajo Nation out of Shiplock.
    https://www.nhonews.com/news/2020/sep/15/navajo-nation-participate-pfizer-biontech-covid-19/

  41. Scott Koblack says:

    If I could ask, why do we need cold storage any more? There’s a company called Soligenix that says they have a method to freeze-dry vaccines so that cold storage isn’t necessary. Wouldn’t that solve the problem?

    1. Marko says:

      It might in the longer term. In the short term , however , you’ll have the problem of proving to the FDA that the reconstituted freeze-dried product is identical to the original. Freeze-drying/reconstitution isn’t always an entirely benign procedure.

      I’d think that the vaccine manufacturers would have already looked at this early in the development process , especially for those vaccine candidates with troublesome cold chain requirements.

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