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A Look at Novavax

Lots of work going on today, so let me just send the readership to this excellent article about Novavax, by Jason Mast at Endpoints. That vaccine has moved into even more prominence lately with the recent adenovirus vaccine events, and it seems clear that it could be a big part of getting the world vaccinated. But it’s been hard to get all the parts moving at the same time, and Mast’s piece goes into great detail about it all.

It’s also a look at the “How come we can’t just get all the companies to make all the vaccines” question, not to mention the “If we’d just abolish the patents everything would be so much better” idea. The logistics and technology-transfer issues are (sadly) more complicated than that. Abolishing patents will not provide more shaker bags or more Chilean tree bark, nor provide more of the key filtration materials needed for production. These processes have a lot of potential choke points and rate-limiting steps in them, and there is no wand that will wave that complexity away.

But I do hope that Novavax lifts off soon, in both the regulatory and production senses. Here in the US, people are starting to get used to the idea that the end of the pandemic is in sight, but a look at India shows that the global view isn’t so rosy. We can still mess this up, even with vaccines in hand, and we’d better not.

44 comments on “A Look at Novavax”

  1. anon the II says:

    Hmm! I think I just detected a ripple effect. After 10 years, I’ve almost exhausted our lab’s Costco size supply of Celite. So I went to Buy@Duke and ordered some more from VWR. I got my confirmation email with a delivery date some time in May. OK. The next day, I got another email with a revised shipping date: 11/19/2021. What’s up with Celite? I think I just discovered one of those ‘key filtration materials” you’re talking about.

  2. John F says:

    Dumbass question. Have you (or the purchasing department) tried other vendors, like Sigma-Aldrich? They show several variants – several in stock. (I had no idea that there were so many different kinds – obviously optimized for different filtration purposes…

    1. Eric K says:

      Not a dumbass question at all. We are feeling ripple effects of supply chain breakdown, and will continue to do so for several months. I know for myself 500ml centrifuge bottles, as well as T175 plates, both used for production of gene therapies at research scale have been difficult to source over the past few months. Corning shut down production for a while, which lead us to seek other sources, but even then it has been difficult. I don’t think it’s exclusively the concentration of goods going to vaccine manufacturing, but also the major issues COVID itself threw into manufacturing such as loss of personnel, shift work, and even suez canal blockage (haha). I don’t think you should be so confident. Beyond that, the estimated delivery dates and ‘stock’ listings online have been extremely inconsistent. We’ve had delivery dates fluctuating quite a bit.

      1. Ben says:

        I work for a large biotech company (industrial and ag, not pharma) and quite early on in the pandemic the first thing we ran out of were tips for our robotic liquid handlers. As you might guess, they were all swooped up by the clinical testing outfits for covid testing. Even today, they’re still hard to come by though we can usually find off-brands that work well enough.

  3. Marko says:

    “Abolishing patents will not provide more shaker bags or more Chilean tree bark, nor provide more of the key filtration materials needed for production. These processes have a lot of potential choke points and rate-limiting steps in them, and there is no wand that will wave that complexity away.”

    Suppliers are always operating on a “just in time” basis for purely economic reasons, which is why there are often shortages in times of unanticipated high demand. However, if there is a demand that can be anticipated – such as that created by a global sharing of the vaccine technology – suppliers would have the incentive to gear up to meet that coming demand. That increase in capacity would not happen immediately , of course, but it would happen. And without any hand-waving required.

    As it is, suppliers see that much of the world won’t have access to vaccines for years, due to artificial limits on production capacity even if supplies were plentiful, so why invest?

    Not surprised that you would take the pro-max-profit stance on this.

    1. Shazbot says:

      JIT isn’t just intended to increase profits, there are in some circumstances serious issues related to basic things like “where do you store all this stuff”, and “how do we stock parts for the 42,000 different kinds of electrical motors, if we need to actually store six of each individual models?”

      This year I’ve been hit personally with being unable to source more mundane stuff such as pallets of salt.

      What happened with the salt is that the city didn’t run out of salt, it was that a huge amount is both brought in and consumed every month, enough to fill a good-sized warehouse, and after an interruption in shipping you fulfill the first orders first, instead of the most recent ones.. which also means that since everyone’s waiting on the stuff to be shipped, you can’t jump the queue with another supplier because every other supplier is also waiting on the same thing, and naturally they’re going to fulfill their oldest orders first, too.

      The amount of storage and warehousing required for this one product would take up a good sized warehouse, and that’s for the relatively small city I live in. There are tens of thousands of items like this, ranging from specific ten cent fuses to pallet sized ones, and the amount of storage necessary would make it impossible to supply a large variety of products.

      You could keep more in storage if you drastically reduced the number of options available, but that wouldn’t be a better solution.

      1. Marko says:

        I have to admit, I now agree with Derek that hand-waving will be an issue here, just not in the way he suggested.

  4. mjs says:

    A question regarding the Endpoints article “As fears mount over J&J and AstraZeneca…”

    Is the blood clot problem a vaccine-killer or something manageable? Allergic reactions to vaccines seem to be a serious, rare, and manageable problem. Most importantly, the problem is known. Some pre-screening is possible — “Have you ever had a reaction…?” Those giving the vaccinations are presumably trained to recognize the symptoms of an allergic reaction, and the treatment is immediately available. (When I had the flu shot, the tray with the flu vaccine also had an epi-pen.)

    Is the hold on the JNJ vaccine primarily to work out a system to identify people with the blood clot problem and treat the clotting without heparin?

    1. Epidemograf says:

      It might be simply a problem of improving the purification process. The authors who described the first 11 German CSVT cases in NEJM just released a preprint in which they described which components of the AZ vaccine were involved in triggering the blood clots. What they found was that each vaccine contained about 35-40 micrograms of human cell residue (including DNA fragments) that was involved in platelet activation:
      “ChAdOx1 nCov-19 vaccine activates platelet by multiple mechanisms including platelet interaction with adenovirus, cell-culture derived proteins (currently, it is unknown which of the > 1,000 proteins identified in the vaccine are involved in platelet activation), and EDTA.”
      https://www.researchsquare.com/article/rs-440461/v1

      1. steve says:

        Interesting but doesn’t explain why it affects only 0.00001 of the population.

        1. Mariner says:

          Could be a luck of the draw with some people more susceptible to developing a problem than others.

          Regardless of how commonplace the issue is, it might explain how the proportion of cases in some EU countries are so different to those reported in the UK. Different factories, slightly different processed and QA standards? Of course, there is also the consideration that some of the doses given in the UK come from SSI (I think I saw a report about 5 million coming from India?) so that might muddy the waters one way or the other.

          The Russians made a statement the other week that their vaccines were heavily filtered so they were perhaps correct that the Sputnik V shouldn’t show such a problem?

          1. Thomas says:

            “Heavily filtered” is not exactly a scientific standard, is it?

      2. Joe says:

        Why on Earth is there any human DNA in the AZ vaccine?! That in itself is a concern.

        1. Epidemograf says:

          The DNA is from the HEK-293 T-Rex cell line used for virus propagation. It seems that AZ did not used enough nuclease to remove host DNA. Four lots were examined and human proteins comprised 43% to 60% of the total protein content per vaccine lot.

    2. Christian Weisgerber says:

      The clotting events are very rare, so they are not a vaccine-killer anyway.

      The condition is diagnosable and treatable, and now that the medical community has been made aware, fatalities should become even rarer. The problem is that the standard treatment for thrombosis (give heparin) and thrombocytopenia (transfuse platelets) is the opposite of what you want to do in the vaccine-induced cases. See for instance the “For Clinicians” section in this CDC health alert:
      https://emergency.cdc.gov/han/2021/han00442.asp

      And no, there is no way to identify susceptible patients in advance.

      1. Mariner says:

        Latest data from the UK is that there have now been 168 of these severe clotting cases following use of the AZ vaccine, all but one of which came after the first dose. 32 deaths. 21.2 million first doses given so far. We’ve been giving a lot more second doses than first doses for a few weeks now so it will be important to see just how many more cases arise after the second dose. I say that as somebody with an interest in the matter as I’m due to have my second dose in June! And I had a mild, persistent headache for a few weeks after my first dose so I’m hoping that’s nothing to be too concerned about.

        Ignoring the case after the second dose, it works out as about 1 case per 126,000 doses given. Not good, but not a terrible number considering the circumstances we currently face. I wonder how the number of cases following the J&J will compare once updated numbers are released?

        If it’s a filtering issue, you’d hope that something could be done about it and quickly. Would still be worth using the doses already produced, however.

        1. Marko says:

          I find it odd that similar attention wasn’t paid to PVT, also a serious side effect, and the fact that the incidence of PVT was >25x lower among AZ vaccine recipients compared to the mRNA vaccines:

          “….A similar pattern was seen in portal vein thrombosis (PVT) blood clots, which occurred in 436.4 per million people who had COVID. That compared to 44.9 per million for the Pfizer-Moderna vaccine group, and 1.6 per million for those receiving the AstraZeneca vaccine.”

          https://www.webmd.com/vaccines/covid-19-vaccine/news/20210416/study-blood-clots-more-likely-from-covid-than-vaccines

          One obvious explanation for this lack of attention is that the “expert” agenda has been to bash adenovirus-based vaccines, while holding up mRNA vaccines as being pristine. If so, it’s working.

          1. Joe says:

            How dangerous is PVT in comparison?

          2. Marko says:

            Wikipedia says mortality is ~10%, but I think you’d need a study to confirm the vaccine-associated PVT mortality rate.

          3. Dr. B says:

            Most PVT that I see is in cirrhotics, so not healthy people (do of course see some in other conditions). No idea what the mortality is in a healthy person who gets PVT as a result of vaccination, but I feel fairly confident it’s a better situation than cerebral vein thrombosis, which often presents as a hemorrhagic stroke at which point serious permanent damage has often already been done.

            While I’m very pro-vaccine (and happily vaccinated), I do think this is a difficult issue for some people. If you’re a healthy 20-something who has a job where you can work from home, have groceries delivered, etc, and you’re willing to do that quite rigorously to minimize your risk of getting covid, not clear that the best risk for you on an individual basis isn’t to keep isolating and skip the vaccine, at least for now. Were I a 20-something healthy young woman I think I might want to do that until I felt like we understood the safety profile of each vaccine better, and hold out for the one that has the best profile for my age/sex/etc.

            Of course if I couldn’t/wouldn’t isolate, different story.

          4. Micha Elyi says:

            “I find it odd that similar attention wasn’t paid to PVT…”–Marko

            I don’t. PVT affected mostly men. In contrast, the clotting events of concern with the Johnson & Johnson/Janssen and Oxford/AstraZeneca DNA adenovirus vector vaccines, thrombosis with thrombocytopenia syndrome (TTS), were initially seen in females. Females are rescued. Men’s lives are tossed aside.

  5. Klagenfurt says:

    Chilean tree bark? Here’s a job for synthetic chemists: Five-step total synthesis of saponin in 80% yield. Impress me.

  6. Norman says:

    Can anyone point me to an overview of the science behind the Novavax vaccine? I understand that it’s a Spike protein itself bundled in a delivery vehicle. How common is this technology? What are the immunological or technical hurdles to this kind of vaccines? That kind of thing. I haven’t been able to find anything in Derek’s earlier posts, but may have missed it.

    1. Yuri Kudinov says:

      Novavax vaccine resembles a virus: 50 nm lipid nanoparticles decorated with Spike proteins. Virus-like particles (VLP’s). https://science.sciencemag.org/content/sci/370/6517/649.full.pdf
      If you would like to learn more about VLP-based vaccines, Martin Bachmann wrote an excellent review recently [pubmed_32472710]. According to Dr. Bachmann, there is much room for improvement.
      First, making a slow-release vaccine depot is critical. Antigen persistence promotes antibody affinity maturation, reduces dominance of unwanted epitopes, and makes a single shot vaccine possible [pubmed_31080066]. To make a depot, Novavax vaccine nanoparticles can be absorbed on mesoporous silica rods [pubmed_29507416], or tyrosine crystals. Dr. Bachmann likes tyrosine crystals because they are nontoxic, degrade after 3 days invivo, and are approved by the FDA. Tyrosine crystals loaded with VLP particles generate potent immune responses even against weak cancer antigens [pubmed_33324411; pubmed_31027511].
      Second, high epitope density is another thing to consider. Spike proteins should be arranged in a 5×5 nm matrix on the surface of vaccine particles (see Figure 2 here https://www.nature.com/articles/s41541-020-00264-6 ).
      Third, vaccine particles must be larger than 25 nm. Smaller particles pass through lymph nodes too quickly: no antigen persistence = weak immunity.
      Fourth, there are better adjuvants than Chilean tree bark, or aluminum hydroxide.

      1. Norman says:

        Thanks!

    2. sgcox says:

      here is one recent review.
      https://www.sciencedirect.com/science/article/pii/S0169409X21000016
      Not sure how accurate and comprehensive it is but looks ok to me.
      The main hurdle is, as I understand, a proper adjuvant. Without it immune system will not mount adaptive immune response and in best case your protein will be chewed up into nutritious mixture of amino acids and in worst case produce anaphylactic shock.
      Sanofi teamed up with GSK and used their proven adjuvant which worked very well in other vaccines but not in this case. Go figure.

      1. Norman says:

        Thanks!

      2. Norman says:

        That ScienceDirect article was exactly what I was looking for. Lots of details, very well explained. Thanks again.

  7. Richard W. says:

    Is NVAX a buy?

  8. A Nonny Mouse says:

    And they are involved with the malaria vaccine, results just published

    https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3830681

  9. Carmen says:

    A look at Jenssen, please

  10. Marko says:

    Biden, the World Needs Your Help to End the Pandemic

    https://www.nytimes.com/2021/04/23/opinion/global-vaccine-patents.html

    “Last year, India and South Africa requested a waiver from World Trade Organization rules governing intellectual property for technology dealing with the pandemic. Dozens of mostly developing countries have since joined them. A handful of rich nations, including the United States, oppose the waiver, but there’s a widespread belief that if America changes its position, other countries will follow. Much of the world is waiting to see what Biden does.

    There’s an enormous consensus in favor of a waiver. It includes dozens of Nobel laureates and the former leaders of Britain, Canada, Costa Rica, France, Malawi, New Zealand and many other countries….”

    1. theasdgamer says:

      Let’s do it for _all_ intellectual property, including any patents you own.

      One of the reasons why science took off was that English law protected intellectual property.

      1. Marko says:

        If you don’t see the difference between protecting the IP on a better mousetrap vs. protecting the IP on a vaccine capable of saving hundreds of thousands of lives globally in the immediate future, then you’re even dumber than I thought, which I wouldn’t have considered possible.

        1. Thomas says:

          Pharma is not bad at licensing to poor countries. For example remdesivir, that is made in Egypt for use in less developed countries.
          I suppose that’s similar for many HiV medicines. And the AZ vaccine made in India. And likely many more.
          But in case of global supply chain issues, that doesn’t help.

          1. FHJ says:

            That more like dumping toxic waste. And try to look at exactly that patent, there are more than “1000” related compunds I think no one is screaming for access to remdesivir. It’s written by top IP lawyers to be maximum opaque. I think the parent compunds is the oral Hepatitis C compund. So no real generosity with that drug. Ok they tried and failed, again, also with Ebola first. No need to keep this drug around for now seems ineffective and probably a bit toxic.

  11. Casandra says:

    There would be no Moderna, Bioentech, or Novavax without the protection of intellectual property. Even if you seize their IP, the whole point is you could not produce one for extra jab because global supply chains are too tight to increase production. It doesn’t matter what the sociology majors at the NYT or Nobel Laureates think. It would be vandalism without a point……..

  12. J says:

    ” Why waiving patents might not boost global access to coronavirus vaccines

    A controversial proposal for a waiver on intellectual property has pitted countries against one another.”

    https://www.politico.eu/article/waiving-patents-coronavirus-vaccine/

  13. Marko says:

    Bolsonaro celebrates rapid elimination of useless eaters as a result of his pursuit of “natural” herd immunity:

    https://twitter.com/dogarrett/status/1386353540851974146

    No comment from the GBD proponents, but they all have their thumbs up, if that tells you anything.

  14. Fred Flint says:

    The author conveniently forgot to mention one of the main benefits of waving a patent. It would get a lot more manufacturing capacity online. There are lots of factories that could be making the vaccine but are not because it’s not worth their while if they have to pay patent license fees. I think there are at least a thousand of these factories just in India that are sitting idle.

    1. Derek Lowe says:

      No Fred, there are not a thousand factories of this sort sitting idle in India. You do not appreciate what it takes to manufacture these vaccines.

  15. stewart says:

    A potentially interesting perspective and report on the SARS-COV-2 S protein

    https://science.sciencemag.org/content/372/6541/466
    https://science.sciencemag.org/content/372/6541/525

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