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Coronavirus Vaccine Prospects

Time for another look at the coronavirus vaccine front, since we have several recent news items. Word has come from GSK and Sanofi that they are going to collaborate on vaccine development, which brings together two of the more experienced large organizations in the field. It looks like Sanofi is bringing the spike protein and GSK is bringing the adjuvant (more on what that means below). Their press release says that they plan to go into human patients late this year and to have everything ready for regulatory filing in the second half of 2021. For its part, Pfizer has announced that they’re pushing up their schedule with BioNTech and possibly starting human trials in August, which probably puts them on a similar timeline for eventual filing.

“But that’s next year!” will be the reaction of many who are hoping for a vaccine ASAP, and I can understand why. The thing is, that would be absolutely unprecedented speed, way past the current record set by the Ebola vaccine, which took about five years. More typical development times are ten years or more. But hold that thought while you peruse another news item today from J&J. They have an even more aggressive timeline proposed for their own vaccine work: they have already announced that they have a candidate, and they say that they plan first-in-human trials in September. Data will be available from those in December, and in January 2021 they say that they will have the first batches of vaccine ready for an FDA Emergency Use Authorization. Now that is shooting for the world record on both the scientific and regulatory fronts.

So let’s talk vaccine development, because everything is going to have to work perfectly for any such timetable to be realized. Here’s a good overview of the coronavirus vaccine world in Nature Reviews Drug Discovery. The official WHO list is here, and at BioCentury they have constantly updated open-access summaries of the vaccines and other therapies that are in the clinic and the ones that are still preclinical. They have also just published this excellent overview of the vaccine issues; I recommend reading that one after you’ve picked up some background from this post.

NRDD counts 115 (!) vaccine programs, of which 37 are unconfirmed (no further information available on them) and 78 are definitely real. Of those 78, five of them are in the clinic, although that number will be climbing rapidly. You have Moderna’s mRNA1273, which as the name tells you is an mRNA candidate, and  Inovio’s INO4800, which is a DNA plasmid, There are two cellular candidates from Shenzhen Geno-Immune Medical Institute: LV-SMENP-DC, a dendritic cell vaccine  that’s been modified with lentivirus vectors to express viral proteins, and an artificial antigen-presenting cell (aAPC) vaccine along the same lines. And finally there’s a more traditional protein-fragment vaccine, Ad5-nCoV from CanSino.

Let’s go into what all those mean. You will note the diversity of approaches in that list, and that’s not even the whole spread. When you go back into the preclinical candidates, you have in addition “virus-like particles”, viral vectors, both replicating and non-replicating, live attenuated viruses, inactivated viruses, and more. From this you may deduce correctly that there are a lot of ways to set off the immune response. What are the differences between them?

Types of Vaccines

For starters, “Live attenuated virus” is just what it sounds like, although as always there’s room to argue about whether the word “live” should ever be used when talking about viruses at all. At any rate, this would be a real infectious virus that just doesn’t give you much of a disease but does give you immunity to the wild-type virus. The smallpox, chickenpox, rotavirus, and MMR vaccines are all of this type, and they can be very effective – in fact the most effective vaccines are mostly of this type. The protection comes on more quickly and completely, with less need for booster shots and with longer-lasting effects. The tricky part is developing one of those attenuated viruses in the range where it produces effective immunity on infection but is definitely not effective at putting people in the hospital. There is a process of getting milder with time that happens with many viruses in general as they co-exist with their hosts, and the idea here is to speed that up in the lab by passaging the virus through human cells again and again and letting it mutate. Ideally, you want a strain that has ended up with a very long path to mutating back to virulence, of course!

The next class are the inactivated virus types. In that case, even if you think virii are alive (I don’t), these are dead, having run down the curtain and joined the bleedin’ choir invisible. This was originally done by exposing pathogen preparations to high temperatures, but now is often done by through nasty denaturing disinfectants like formalin or beta-propiolactone, things that alter the proteins enough to keep the virus from working, but perhaps not so much that they don’t set off the right immune response. That’s a bit of an art form, of course, and this generally has to be tried a number of times in order to get a reproducible immune response and a reproducible way to manufacture the inactive virus. As you would imagine administering a pile of disabled protein pieces in this manner is often not as effective as the live-virus approach above, which makes the human cells crank out viral proteins on their own. You’re into big ol’ injection plus booster shot territory for the most part. The hepatitis A vaccine and the seasonal flu vaccine are of this type.

Update: the relative efficacy of all these types are broad categories that can overlap – see for example the polio vaccines, where the best inactivated ones can offer more immunity in some ways than the attenuated ones. But the latter can be dosed orally, which is a big help in a planetwide vaccination campaign, which tells you that there are several factors to consider in a real-world deployment. . .

Yet another common sort of vaccine uses just a particular protein, protein fragment or subunit piece of a pathogen. (For some bacterial diseases, you can also try to raise antibodies to some protein toxin that the bacteria produce, rather than to the bacteria themselves). The key is to pick one that provokes a strong immune response, and since there are a lot of possibilities, working through them can be a process all its own. The good part is that you can then produce the protein recombinantly and in quantity, once you’ve narrowed down. There are other possibilities, of course – this could be a glycoprotein, or even just a piece of polysaccharide from an organism’s outer coating, since those can be quite distinctive. The tricky part here is getting enough response – the immune system can be very sensitive to pathogen attack, but these pathogen pieces can be less effective in triggering antibody production, and generally need adjuvants to work well (see below!) Vaccines of this class include ones for shingles, hepatitis B, HPV, meningococcus, and more.

Update: there’s a sort of intermediate step between protein subunits and inactivated or attenuated viruses, the “virus-like particle” (VLP) vaccines. That’s an assembly of several recombinant protein units into something that has the broad size, shape and organization of the real virus, but is not infectious. You can mix and alter the subunits however you like to get the best effect, with the complicating factor that there are a lot of potential choices. The HPV cervical-cancer vaccine (Gardasil) is a well-known example, and there’s a hepatitis B vaccine in this class as well.

A more recent approach is a DNA vaccine. This uses a circular DNA plasmid, coding for some antigen protein, which has been engineered with strong promoter signals and stop signals at both ends of the sequence. The plan is that this will be taken up by cells, where the DNA may well then be transcribed into RNA and that then translated into protein, which sets off the immune response. A nice feature, as with the attenuated-virus technique, is that you’re taking advantage of all the cellular machinery to make your antigen proteins for you, so they come out folded correctly and with the necessary post-translational modifications already done for you. There is no human vaccine yet that uses any DNA technique, although there is a Zika DNA vaccine for horses. Some candidates have been tried, but haven’t elicited enough of a response. Another tricky part is stability of the DNA plasmid, both on storage and on injection, but these problems have had a lot of money poured into them from the gene therapy end, and the situation has improved over the years. Overall, though, I would say that a DNA vaccine for SARS-CoV2 would be a real come-from-behind story.

Similary, the mRNA vaccine idea has had a great deal of work put into it in recent years. That’s conceptually similar to the DNA vaccine idea, only you’re jumping in at the messenger RNA stage. I wrote a bit about it in the CureVac post – basically, the immunogenicity was noticed as an unexpected side effect in experiments giving mRNA to animals, and people have gradually taken it from there. As with the DNA vaccines, you can actually get two kinds of immune response – the innate immune system can recognize foreign nucleic acid sequences floating around as a sign of infection, and the adaptive immune system can generate antibodies to the resulting proteins. One of the challenges has been getting a bit less of the innate response and a bit more of the adaptive one (which is what counts for the long-term immunity that you want from a vaccine). The mention the other day of younger recovering Covid-19 patient who don’t seem to have developed antibodies is an example of that very problem: a really robust innate response could clear the virus in an infected person, but leave them without much long-term immunity.

mRNA has some potential advantages over DNA, and (perhaps) over all the virus and protein techniques laid out above. It’s pretty much the most stripped-down vector that you can imagine, so you don’t run into so much immune-response-to-the-vector trouble, which can be a problem on repeat dosing with other vaccine technologies, and it can’t possibly be inserted into the genome. A big problem over the years has been getting the mRNA species to last long enough on dosing, to be taken up into the cells efficiently, and to be well translated into protein once that happened. The first link in the preceding paragraph has a great deal of information on this, with links to yet more reviews, and I won’t even try to summarize it all. But there have been extensive modifications made to the RNA sequences themselves and to the formulations that they’re dosed in (a lot of this by pretty brutal trial-and-error work), and the technique might be ready for prime time. We don’t quite know that yet, though. The DNA vaccines have been around longer and (as mentioned) haven’t produced a human therapy yet. Are the mRNA ones better, or is it that we just don’t know about the disappointments to come? We’re going to find out more quickly than we had planned.

There’s another related technique that has been used successfully in humans, though. If you want to really stack the deck for protein production, you can take a known virus (which doesn’t have to be related to the pathogen you’re vaccinating against) and re-engineer its nucleic acid payload (DNA or RNA) to deliver just the piece you want. In that case, you’re back into the “live attenuated virus” technique, but by sort of cobbling one together from different parts. This may sound pretty similar to gene therapy, which also generally uses viral vectors, and if so your intuition is right on target – the two fields have had a lot to teach each other. The Ebola vaccine uses this method, with a livestock virus as the vector, and there are many other virus types under investigation for this sort of delivery. Update: broke this into a separate category for clarity.

Adjuvants

There’s another key vaccination technique that I haven’t mentioned, and it applies to all of the techniques above: adjuvants. Obviously, the big thing you want from a vaccination is a robust, long-lasting immune response, and it turns out that various additives can provoke just that. These are all about that balance between the innate and adaptive immune response mentioned above; the idea is to get the best carryover from the immediate innate mechanisms to drive the antibody-centric adaptive ones. See this post for a quick immune-system primer, and there are of course many other places to learn about this – the key here is the handoff to the antigen-presenting cells and the helper T cells.

The adjuvant field started out, frankly, as about the closest thing to voodoo that you’ll find in infectious disease treatment. Antibodies were generated by injecting horses and extracting their plasma, and a veterinarian (Gaston Ramon) noticed in the 1920s that the yields were higher from animals that had developed a strong reaction at the original injection site. He started experimenting with additives to induce such reactions, including things like tapioca starch. In the same era, Alexander Glenny was formulating various diphtheria vaccines and noticed that the ones that included aluminum salts were much more effective. No one really knew the details of how these things did what they did, but aluminum salts are still very common in vaccines nearly a century later. We’ve learned more about what’s going on – in the 1990s, the first new adjuvants in decades began to show up, and more have been added. For example, the GSK shingles vaccine (Shingrix) has lipoproteins from Salmonella bacteria added to it along with terpene glycosides from the Chilean soap-bark tree, which seems to be an especially powerful combination. I can tell you that the reaction at the site of injection for that one is very impressive, especially on the second shot! GSK’s expertise in this field is in fact what they’re bringing to the collaboration with Sanofi mentioned in the first paragraph, and they’re collaborated with many others as well.

Developing a Covid-19 Vaccine: Efficacy

OK, back to the broad picture of developing a coronavirus vaccine: the question is, which of all these possible techniques is the most effective and safe? That we are only going to find out, in the end, by dosing people. Lots of people. With therapies targeting the immune system, there is in the end no other way to know, because of the complexities of the human immune response and its wide variation in the human population. Rushing the process is going to take a vast amount of effort, and some of the steps are going to have to be done on a scale never before attempted. There’s another point that can’t be ignored, either: if we want this done as quickly as we would like, there are going to have to be some shortcuts.

To that point, one reason that the Moderna vaccine got off the mark so quickly is that the mRNA route can be intrinsically faster, but a bigger reason is the step of seeing how well it works in animals was entirely skipped, a very unusual step indeed. That’s partly because it’s still unclear which animal model will be the most informative. We have a bit of a head start thanks to the work that’s been done on the earlier human coronavirus pathogens for SARS and MERS, but you may recall Monday’s post talking about how SARS and the nCoV-19 virus do show real differences in various tests (there are many lines of evidence for that). We can expect those differences to carry over to the animal models as well. One approach that I know that people are taking is to breed animals that have been engineered with the human form of the ACE2 protein which seems crucial for viral entry – one way or another, we should be able to find a small animal (mouse, hamster, etc.) that can be useful, but will it be found in time to actually be useful? My guess is that several other clinical vaccine candidates will end up going the same route as Moderna’s, and skip past animal efficacy entirely. Believe me, that’s a shortcut, and there will be others.

Fortunately, testing for vaccine efficacy can be (fairly) straightforward, and it involves many of the same issues that are being frantically beaten on for antibody testing: does a vaccinated patient develop antibodies? How many? Are they the right kinds to neutralize the virus? And how long do they last? Those first three are the subject of a huge amount of work right now, and although it’s nerve-wracking at the moment I have no doubt that these are questions that can be and will be resolved. We’re going to have a lot to think about with what endpoints we’ll be measuring for efficacy, to be sure – surrogate ones will be faster, but will regulatory agencies want to see more patient-focused clinical endpoints as well?

Here is a review from the dear, long-gone days of 2016 of the standard development process for a new preventative vaccine. Take a look at the lengthy, detailed, overlapping, interlocking system of trials that such vaccines have undergone in the past, and reflect that we’re not going to be able to do all of that if we want a vaccine on the timelines stated at the beginning of this post. Ideally, you want to study these efficacy questions in Phase II trials in different populations (age, gender, pre-existing health conditions and range of medications being taken), all with different dosing schedules, and carefully tune things up for bigger Phase III runs. We’ll be able to deal with some of that by running a lot of simultaneous trials instead of doing things more sequentially, but that’s not going to cover every issue. Not by a long shot. Remember, there are at least 78 of these things under development right now – there will be fierce attrition, and only a few (low single digits) will make it deep into the process, but it’s still a fearsome process to get all this organized.

And some things cannot be accelerated by any means known to humanity. The last point above, how long immunity lasts, is a big question for both people naturally infected by SARS-Cov2 and for those given a vaccine, and unfortunately there is no way to answer that one other than time, which is in short supply these days. The field provides many examples of vaccines whose protection has not held up as well as expected as the years went on. My guess is that we may end up with a first-round vaccine that doesn’t last as long as it might, but will provide enough immunity to do the job and provide cover for us to collect more data on an optimized candidate.

Developing a Covid-19 Vaccine: Safety

But that takes us to the second question for any new therapy: safety, and its balance with efficacy. This is an especially fraught question with any therapy that’s targeting the immune response, because the downsides are gigantic: a runaway immune reaction can disable someone for life or even kill them within minutes where they stand. Guillain-Barré syndrome is an example: your body reacts to an antigen (a viral infection or a vaccination) by deciding that the myelin sheaths around your nerves are also the enemy, and starts destroying them. Very bad news, and although most people recover, a few die. Roughly estimated, even a seasonal flu vaccine might kill about one out of every ten million recipients though such a reaction – we give it to everyone possible, though, because far more people will die if we don’t. The 1976 swine flu debacle shows what can happen, both in perception and in reality, when you get this balance wrong. But you can’t avoid the problem: the huge person-to-person variation in everyone’s immune system means that these severe events can never be ruled out at some low level if you’re dosing enough people.

Now you see the exact bind that vaccine development has always been in, because the whole point is to treat millions, even billions of people who are not currently sick, to protect them against disease while not doing more harm along the way by setting off the body’s fiercest and most alarming biological responses. I have no doubt that the companies and regulatory agencies involved will be doing everything they can to address safety issues, but if you’re looking at a vaccine getting an EUA early next year, well. . .

Developing a Covid-19 Vaccine: Logistics

Another big problem is going to be manufacturing and distribution. Many readers will have heard about the difficulties that sometimes occur during the flu-vaccine production process, leading to shortages. Depending on what vaccine technology comes out on top, manufacturing enough doses in a reproducible fashion could be quite challenging – space and finger fatigue don’t permit going into all the details, but they are many and complex. Keep in mind as well that many vaccines need “cold chain” distribution and storage, which is always a layer of complexity. What if an eventual vaccine needs more than one round of administration, as many of the adjuvant-formulated ones do? Keeping track of that and following up on it is yet another issue.

My guess is that scale-up and manufacturing could well be the biggest chance for the timelines mentioned earlier to blow up, so there is going to be a massive effort to front-load the work on these problems  – this is why, for example, Bill Gates has already indicated willingness to fund factories for up to seven vaccines up front. The live-attenuated virus, inactivated virus, recombinant protein, and nucleic acid vaccines will all involve completely different production methods and formulations, and since we don’t know which way we’ll be going, this would seem the only way to address the issue. Pfizer and others have already said that they’re going to be working on production even before the efficacy data come in, which needless to say is not the usual business practice. I think we’ll get vaccine efficacy, one way or another, although it sure won’t be characterized as thoroughly as it normally would. And I think we’re already agreeing to cut corners on safety, whether anyone says so in as many words or not. But producing the vaccine on scale could be a bigger issue yet, and as the process goes on, that’s where I would keep an eye out for trouble.

It is a tightrope, folks, and we’re going to be trying to run across it. Watch closely; with any luck we will never see anything quite like this again.

 

 

162 comments on “Coronavirus Vaccine Prospects”

  1. Aleksei Besogonov says:

    “virii”?

    The correct Latin plural would be “vira”, although it was not actually seen in any Latin texts. Can we just stick with “viruses”?

    1. Derek Lowe says:

      Since I went full Monty Python later in the sentence, I figured hey, why not. . .

    2. Natural chemist says:

      If “virus” was a Latin noun, why wouldn’t it be a 2nd declension masculine noun and so be “viri” in the plural? Wouldn’t “vira” be appropriate for a neuter noun?

      1. CIP says:

        In Latin the word is actually singular only.
        But modern biologists use a plural form and as it’s a neuter form of the 2nd declination, the plural is “vira”

        1. JP Leonard says:

          I guess it would be singular only because it meant poisonous sap, so it was a mass noun rather than a counting noun.

    3. John Eppstein says:

      Nope. In the Latin second (masculine) declension the suffixes are -us -i -o -um -o. The second suffix is the genitive ending, which is also shared with the nominative plural. So “virus”, “virii.(The other forms aren’t used in English.)

      There is a second declension neuter form in which the nominative singular is -um and the plural is in fact -a, which is probably what’s confusing you.

      Hence 2nd declension masculine “virus, virii”; 2nd declension neuter “datum, data”

      The suffix -a is first (feminine) declension nominative, genitive is -ae, again shared with the nominative plural. (the suffixes for the full singular declension are -a -ae -ae -am -a

      My dad made me study Latin from 5th grade through 7th. I hated it but it is occasionally useful.

      1. loupgarous says:

        Learning Latin, while young, helps with picking up the modern romance languages (French, Italian, Spanish, et cetera) later. But it’s complicated to study Latin after having grown up speaking a romance language (in my case, French). False cognates lurk everywhere.

      2. eub says:

        There is really no excuse for “virii” — that would come from a second-declension noise whose nominative is “virius”. Like “gladius” -> “gladii”. “Virus” if it were a second-declension “-us” would have the plural “viri”.

        But “virus” is neuter. So second-declension rules don’t apply (or it would be “virum” -> “vira”).

        The Latin word appears to have been a mass noun that just didn’t have a plural.

        1. Patavinus says:

          Virus is indeed neuter, it is an ecception. Its plural, only attested in modern scientific Latin is “vira”. You cannot always deduce the gender of a Latin noun by its ending, e.g. “incola” (inhabitant) is masculine, “quercus” (oak) is feminine.

          1. Steve Gombosi says:

            2nd declension neuters in “-us” are really rare. “Virus” does seem to be one of them, but there aren’t enough of them to really be able to establish a paradigm for plural formation. The hypothetical plural *might* be either “viri” or “vira”. It’s definitely *not* “virii”. That last one is the sort of thing the OED quaintly refers to as an “illiterate back formation”. Since pluralizing “virus” is a purely modern notion, perhaps the English “viruses” will suffice? It seems to work well enough for “campus”, after all.

          2. Derek Lowe says:

            I have no expectations that anyone will believe me, but I once heard a faculty member break out “campii” to refer to the East and West campuses at Duke. Although I will say that he grinned as he did so.

          3. loupgarous says:

            It’s probably correct to apply the encyclopedic rule, and use English endings for foreign words which are widely used and understood as English words – like “virus”. This debate came up in the 1980s for “virus” when used to describe computer malware – in that usage, it’s an English word, and the plural’s “viruses”.

            But that opens the can of worms of what’s correct Latin usage in medicolegal terms. That often varies from classical Latin.

      3. Steve Gombosi says:

        Uh, no. Dusting off my decades-old Classics major (I double-majored in Classics and Chemistry):

        The ending for the nominative plural for a masculine second declension noun is “-i”. One “i”, not two. The correct Latin plural should be “viri”. As others have noted, there are no extant texts that use the word in the plural – only the nominative singular and the genitive singular (which is also “viri”).

        1. John Sposato says:

          A debate like this is one of the many reasons why academics are so thoroughly ridiculed by the hoi polloi, of which I am a proud member. You are all very much smarter than I am, but you waste that vast intelligence by arguing minutia…uh, minutiae…minutii…Damn!
          (I hope I was correct on that little math problem that shows I’m not a bot.)

        2. Sleuthus says:

          Wait, “viri”=men, doesn’t it?

    4. Jon Wallis says:

      +1 for viruses.

      Yes, the word has a Latin origin, but it’s being used as part of English now, so whatever the rule might be in Latin is irrelevant – much like the nonsense about not splitting infinitives (not actually possible in Latin; possible, acceptable and sometimes essential for clarity in English).

      1. Richard Martin says:

        Splitting infinitives is hideous. it’s like consecutive fifths or octaves in music. Most people haven’t the faintest idea what I’m talking about but these dumbing-down characteristics are all part-and-parcel of the collapse and slow death of society, leading inexorably to the annihilation of the planet through a third world war.
        Not a day too soon, I say.

        1. Andrew Hinton says:

          I totally disagree about split infinitives. It is a rule that lacks justification in any practical sense. Forcing the separatation of the descriptive term from the described verb is inefficient and awkward. And I agree with Jon that doing so at times reduces clarity. I only do it at work because I am required to, but whenever I do I can’t refrain from mumbling about what a silly rule this is.

  2. Alyssa Vance says:

    Moderna says they could have limited availability this fall. That’s assuming it works, of course….

    https://www.fiercebiotech.com/biotech/moderna-s-covid-19-vaccine-could-reach-healthcare-workers-fall

  3. Robert R. Fenichel says:

    In the list of vaccine targets that starts with shingles and hepatitis B, you list “meningitis” as a vaccine target, but this is not right. Lots of different organisms can cause inflammation of the meninges, and there are non-infectious meningitides too. “Meningitis” in that list should be changed to “meningococcus.”.

    1. Derek Lowe says:

      Good point! Just fixed it, thanks.

      1. DR says:

        One small typo: “Ideally, you want want to study…”

        Great post, excellent summary for the different classes of vaccines!

  4. charlie says:

    Why not just a dose of the virus?

    If you’re under 50, very little risk.

    Public health aside, another 2 months of lockdown and the food supply chain will be completely disrupted. Lots of stored pork and grains, but we can give up on fresh produce and chicken.

    1. loupgarous says:

      Subsisting on stored pork and grains… air freshener will be the next thing people binge-buy. The local Wal-Mart sold out of regular-size packages of toilet paper last week, leaving us late shoppers with no alternative to buying the handy 20-roll size and getting squint-eyed glances at check-out.

    2. Cole says:

      There has been a lot of talk about just using live virus as if it’s some radical idea that disrupters have come up with that Big Pharma is too set in its ways to consider. People talk about it being an easy way to circumvent clinical trials and manufacturing issues. I suppose it’s appealing at its face, but the reason vaccines are made using all the methods mentioned above is that they are far safer than using the wild type virus. A live virus vaccine or even ‘controlled’ deliberate exposure would both be much more likely to generate adverse events while still requiring massive institutional infrastructure to implement. Manufacturing would still take time to scale up while also having the extra hurdle of having to keep all the manufactured virus well contained to risk actually spreading the virus further.

      1. Paul says:

        My grandmother told me that when she was a child (early 1900s), if a kid in the neighborhood got chicken pox, measles, mumps, or rubella, neighbors would bring their children to be deliberately exposed so that they would get the disease over with and develop immunity. A crude sort of wild virus “vaccination”.

        1. Matt says:

          Chicken pox parties were still very common in many parts of the US into the 90s (before nearly all children were vaccinated).

          1. Chris Phoenix says:

            Chicken pox parties are still a thing in France, and the vaccine is not used AFAIK. This isn’t from anti-vax stupidity – they prefer the stronger immunity you get from actual chicken pox infection, and think the disease is mild enough in young kids.

            As a very pro-vax parent (and not an MD), I can see both sides on this one (shingles might tip the balance toward vaccine).

        2. Philip says:

          Not that long ago the former Kentucky governor took his nine kids to a chickenpox party.

          https://www.washingtonpost.com/politics/2019/03/21/gop-governor-doesnt-believe-chickenpox-vaccines-he-took-his-nine-kids-pox-party-instead/

          I am very happy he is the former governor.

        3. eyesoars says:

          Yes they did. Because when there wasn’t a vaccine, you wanted to get the ‘childhood diseases’ while young: better odds on a good outcome. Partially leftover childhood immunities from Mom, partly more responsive immune system. Getting mumps, german measles, and other such diseases as a teen or adult was a much riskier proposition.

        4. Cathima says:

          Sounds safer than the vaccine

          1. Elliott says:

            Cathima–really?
            Then (this from the CDC)–in the good ol’ days before the measles vaccine, you would have expected the following:
            Estimated 3 to 4 million people in the United States were infected each year. Also each year, among reported cases, an estimated 400 to 500 people died, 48,000 were hospitalized, and 1,000 suffered encephalitis (swelling of the brain) from measles.

            Measles used the be the leading cause of brain damage in children. Now, we have no deaths from the disease and problems from the vaccine are so miniscule that they can’t be distinguished from background. If you believe otherwise, then you are seriously delusional. Or–possibly just a Russian bot. In which case, go away.

          2. Derek Lowe says:

            Hear, hear. People have forgotten what measles was really like and imagine that it’s just a cute childhood infection.

    3. Ian says:

      I would like to know a professional/knowledgeable persons opinion on this? The “self” inoculate narrative appears quite often in political forums and in my opinion requires a nuanced response. i.e. It’s not only people over 50 that have a severe response to the virus … we don’t know enough?

      Unfortunately, many folk will want a binary response to charlie’s question.

      1. charlie says:

        There is enough data. If you’re under 50, not obese, and don’t have kidney problems the risk is very low.

        The issue I see is there is no way to know how much virus is needed to trigger an immune response, and figuring that out is as hard as making a vaccine.

        1. Vaudaux says:

          Define “low” in “the risk is very low”, considering reports of serious illness and deaths among doctors, nurses, bus drivers, grocery store clerks and workers in meat packing plants.

          1. eub says:

            It’s also not at all clear that a mild case of this coronavirus can be expected to confer immunity. Its common-cold relatives infect people repeatedly lifelong, same strains, without needing much genetic drift either.

        2. SirWired says:

          There’s been more-than-enough hale-and-hearty healthcare workers hospitalized or killed by the virus that your confidence that the young and healthy have little to fear is not quite so certain. (Especially given how death appears to, at least sometimes, be driven by a robust immune response.)

          Not to mention the number of people that wouldn’t get killed by deliberate infection, but would require scarce hospital resources to keep that from happening.

          1. charlie says:

            At least according to the CDC, there have been 319 deaths for people under 44.

            That’s out of 9681 total deaths.

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

            So about 3% of deaths. Widespread agreement that heath care workers are being exposed to much larger viral loads. We don’t know anything about the conditions of the 319 under 44 who died. (obesity). The point of doing a low viral dose is to avoid the problem like healthcare workers, and screening for obesity is very easy.

            Nothing about hospitalizations, although we know the the under 50 rate is also lowers.

            Again none of this is news — this has been the case in almost every country since January.

          2. Jay says:

            I personally know one of the victims younger than 40. He was healthy, no known medical issues, ran marathons. 34 years old, had just moved to New York. You don’t need to be highly compromised to die from this.

      2. Science Mechanic says:

        Inoculation with the live virus renders the recipient infectious for some amount of time. Are you prepared to house said recipients for 2-3 weeks each after inoculation to prevent community spread?

        The difference with a vaccine is it ideally renders the recipient immune without making them infectious (or suffering the personal risks of infection).

        1. dwh says:

          While obviously being in the midst of a global pandemic can have us revisit our cost benefit assumptions, the reasons that we do not give the virus to people include at least the following:
          1. Safety. If we give the virus to a large swath of the population under 50 (~200 M people in the US) we are likely to have somewhere in the range of 10,000-100,000 deaths attributable to the “vaccine”. We do not currently understand enough about the virus to avoid this. It is also not clear what the long term consequences of infection might be. Measles related subacute sclerosing panencephalitis is an example of a low frequency, high consequence (i.e., death) long term effect of infection with that virus. We currently cannot rule out longer term morbidity associated with SARS-CoV-2 infection, so that poses a significant safety concern when thinking about intentionally exposing large populations.

          2. Ethics. Our approach to medical interventions is to make sure the cost benefit of the patient is considered. The primary intent of a vaccine is to protect the individual and herd immunity is a secondary benefit. Giving the virus to individuals would not be of any direct medical benefit to the individual (i.e., they would get the disease) and would instead be solely intended to benefit society as a whole. Given that there is little doubt that there would still be significant disease and death in the population intentionally administered the virus (when you multiply even low rates by large populations the absolute numbers get big), this is not something that would be compatible with our current consensus approach to medicine. While one can certainly attempt to argue the contrary, we as a society are tend to be oriented away from medical interventions which actively cause harm to some individuals in an attempt to help broader society.

          3. Logistics. As pointed out above, administering the virus will make the individuals infectious for several weeks and at risk for transmitting the disease. We would be at high risk for losing control beyond the intended population.

          1. Chris Phoenix says:

            If outcome depends on viral dose, then getting inoculated with a calculated low dose of the virus could indeed benefit the individual vs. the chance of a higher exposure later.

            I’m 49 with borderline high blood pressure. Rather than take a ~1% risk of death and unknown (but likely greater) risk of permanent lung damage, my whole family (including children) is probably going to stay home 100% for a year.

            If I knew we could become immune at low risk by inoculating the whole family simultaneously with a careful dose of wild-type virus, I’d be very tempted to do it. But of course we don’t know that yet.

    4. DanielT says:

      There is of course my proposal that we use epidemiology and genomics to go and look for an attenuated strain that has already been run through a Phase III trial for us by nature. Nobody seems to think it is even worth looking into.

      1. SirWired says:

        “Epidemology and Genomics” to find a less-dangerous strain would be unlikely to be a short process. Not to mention the further (time-consuming) work that would have to be done to ensure that it was stable enough to not mutate right back into something that killed people, but similar enough to the strains that do to be useful.

        And it would be a resource-intensive process; full-sequencing of viruses from a [bleep!]-ton of patients, and then figuring out who they passed it onto, and doing a full analysis of how that population did, would be difficult, at best. (And there ain’t no “at best” going on right now.) Absent something like “10,000 people got sick after attending [event that doesn’t exist anywhere in the world right now] and every single one got better after a week of a nasty cough.” I’m not sure there’s a feasible way to even find candidates that way.

        1. DanielT says:

          Ah the “it might be hard so let’s not even bother” response. If you are serious about wanting to know, I do address all this. You can read the proposal in detail in the link in my name in my first post.

    5. Daniel says:

      I would also be interested in reading more about options that involve a live virus, ranging from things like pox parties to things like the current chickenpox vaccine. For example, how much would it speed up vaccine development if we were just seeking something that put at most 1 out of every 1000 recipients in the hospital (or 1 in 10000, or 1 in 100)?

      I’ve seen a couple things on the topic from generalists who seem to be taking inspiration from things like pox parties and early efforts against smallpox, and would love to read an overview which has the level of technical detail of Derek’s post.

    6. Sam Pope PhD, JD says:

      If someone gave you a bowl of skittles and one was cyanide instead of a skittles but looked the same. Would it matter significantly to you if there were 100 or 1000 in the bowl to begin with?
      Before you say yes, be honest with yourself. Anyway that single number of sick and dead individuals does not begin to reflect the cost of that choice. It has deep economic cost, making the 2 trillion dollar US stimulus package look like chump change, as well as social and psychological cost on the entire population.

    7. Susan says:

      It’s ludicrous to give the “virus” to people under 50 and say there’s very little risk. Given the fact, that a lot of the population don’t even know whether or not they’re running around with a defunct immune system or perhaps a gene that perhaps causes thrombophilia or something of the like , and then having that patient become critically ill or even dying. .

  5. Thanks for mentioning logistics, a very overlooked component of getting anything to market. Reminds me of a great book by Paul Offit, The Cutter Incident. https://amzn.to/2Vv2OIn

  6. gcc says:

    I’m curious whether the mRNA- and DNA-based vaccines being tested encode intracellular or secreted antigens. I know antibodies can develop against intracellular proteins (as happens in some autoimmune diseases), but I wouldn’t think that expressing viral antigens in the cytoplasm would be a very efficient way to generate neutralizing antibodies against the virus.

    I’m also curious how the mRNA-based vaccines are produced and how easily those processes would scale up. Are they chemically synthesized or made by in vitro transcription?

    1. Derek Lowe says:

      The latter, for sure, especially on scale.

    2. dwh says:

      The primary DNA and RNA vaccine candidates are encoding variants of the SARS-CoV-2 spike protein. Inovio’s is a consensus sequence based on the design of a MERS candidate they had in clinical testing adapted for SARS-CoV-2 using the 4 sets of viral sequence data that had available at the time. I am not sure of the specifics of the Moderna candidate. In the case of DNA and RNA vaccines, the signal sequence promoting the desired processing is included with the antigenic sequence. I would say that secretion signals such as the leader sequence from proteins such as human tissue plasminogen activator are most commonly utilized, but depending on the target antigen and the desired immunological response, other signal sequences for transmembrane or endogenous processing may be used.

  7. Clifford Berg says:

    “they plan first-in-human trials in September”

    That doesn’t sound like a fast track to me.
    A fast track is when NIH, FDA, or whoever needs to approve the trial gets on a plane or skype session and meets the same day, and says, “What do you need to start next week?” and gets the researchers what they need, and the team is assembled over the weekend, patients are identified through cooperating clinical sources, and the trial starts Monday.

    A year to test a vaccine, for a condition that runs its course in two weeks? It should be possible to run three trials – phases 1, 2, and 3 – in six weeks. But what it takes is the will, and the cooperation of those who have the power to make things happen.

    1. Derek Lowe says:

      I’m afraid that’s more of a movie-script version of what it takes to run a clinical trial. I’ll be writing a post soon on why this isn’t done this way, and in fact *can’t* be done this way.

      1. Fully agree. The setting up of the trials, particularly if multi-center, multi-continent and many patients will be very complex. There will be big discussions on safety issues and inclusion/exclusion criteria. What safety parameters would be examined? What is success? Presence of anti-bodies? Hospitalizations? Morbidity? Death? And, of course, liability and lawsuits are always an issue. All doable but incredibly costly and time consuming. As they say in business in these situations: you can have any two of the following but not all three- high quality, cheap, fast.

    2. Druid says:

      You do need to know how long the immunity lasts in people. That takes as long as it lasts. I should think the minimum would be 70% effective after 6 months. Immunizing more often than once a year is challenging.

    3. loupgarous says:

      Nature sometimes doesn’t cooperate the way we’d like. Derek mentioned Guillain-Barré syndrome, and about 8.8 cases per million of us who got the vaccinated after the 1976 swine flu outbreak wound up with GBS in various degrees of severity (of course, some research shows influenza itself can induce GBS). Safety trials can’t be rushed and still pick up every adverse side effect. Rushing through safety trials to save time under government orders is how the Federal government wound up picking up the tab for childhood immunization-related injuries.

      Ccoronaviruses, like strains of influenza, mutate, so this year’s vaccine may not protect you against next year’s new menu item at the Wuhan wet market. Pushing through design on the early stages of development or rushing efficacy studies in the late stages could give you a vaccine that kinda, sorta works. That’s why those decisions don’t get made in conference calls from business class.

    4. DrSAR says:

      I think Clifford Berg is on to something and should maybe be put in charge of pregnancies which take way too long at 9 months. If he can organize properly motivated teams of 9 women we’ll be cranking them babies out in one month tops.

    5. Richard Jefferys says:

      Paul Stoffels from J&J has explained the reason for that:

      https://www.sciencemag.org/news/2020/03/1-billion-bet-pharma-giant-and-us-government-team-all-out-coronavirus-vaccine-push

      Q: Why will it take until September to launch a phase I clinical trial when others have aggressively moved to the clinic more quickly?

      A: With vectors like Ad26, you need to get the seeds [copies of the engineered virus] to do biological manufacturing. That takes time to make sure we select the right clones and that we have a stable selection so we can grow the right ones. We grow them up so that we have the seeds for the next years to come to produce thousands of hundreds of batches.

  8. loupgarous says:

    Guillain-Barré syndrome is spelled like that.

    Easy mistake to make, we’ve been trying for centuries to wrest spelling rules back from the Normans after 1066.

  9. Some idiot says:

    Probably a stupid question, but here goes…

    You mention that with bacteria, it is often the bacterial toxins (or parts thereof) which are used to generate antibodies. In these cases, with the antibodies “just” target the toxins (ok, I understand that the toxins can a really, really serious problem in their own right…!), or do they also have some effect on the bacteria themselves?

    1. Derek Lowe says:

      Not a stupid question at all! To the best of my knowledge, these “toxoid” vaccinations only raise immunity to the toxins themselves, but the effects of those are the real problem with such pathogens (tetanus, diphtheria), so that’s enough. If you can get past the problems presented by the toxin, the immune system can generally deal with the bacteria.

      1. SirWired says:

        I’d been wondering that *for years*, so thank you!

  10. Mark says:

    Thanks for another informative and informed posting.

  11. Frank M says:

    As hospital capacity becomes available, would it make sense for young, healthy adults to volunteer to get the virus and self-isolate. States could determine a safe number of the population to have the virus spread to them and monitor the results. Obviously on a volunteer basis…

    Stupid idea?

    1. James Millar says:

      Couple weeks ago it might have sounded interesting, but there’s been some anecdotal stuff about young patients not doing as well as expected, I’m sure the data’s out there to find. Also, there was mention here of some patients not really developing a proper immunity (due, it seems, to the innate immune system getting on the job too fast to share, basically)

  12. Cb says:

    Since RNA viruses mutate quickly it may be of a concern indeed that the first generation vaccin does not protect against the next CoV epidemic, but the SARS -CoV mutations may (hopefully) also attenuate the pathogenicity of infection. I read little about the possibility that the virus by spreading and mutating may loss its ‘fitness ‘over time and can disappear all in a sudden for a longer period as SARS did in 2004 (or was community quarantine more effective at that time!?).
    In this respect I wish to refer to an intersting article from 2018: https://doi.org/10.1038/s41598-018-33487-8
    Take notice of the conclusion:
    “Our data suggest that SARS-CoV has suffered an attenuating mutation by the 29 nt deletion that constitutes a landmark genetic change. The SARS epidemic in 2003 may have taken a more severe course if not involving this mutation”.

    1. Bannem says:

      >Take notice of the conclusion:
      “Our data suggest that SARS-CoV has suffered an attenuating mutation by the 29 nt deletion that constitutes a landmark genetic change. The SARS epidemic in 2003 may have taken a more severe course if not involving this mutation”.

      Just musing, would engineering this mutation (or similar) into SARS-CoV2 produce an attenuated virus, which could then be used as a vaccine ?

      1. Toni says:

        Christian Drosten was involved in this paper. He talked about it yesterday in the TWiV podcast, as apparently isolates with an orf8 deletion were found in Singapore.
        http://www.microbe.tv/twiv/

  13. Wilhelm Cody says:

    Another issue is whether the disease is so under control by September that recruiting enough patients for all the arms remains possible or economical. That was an issue, as I recall, with the first Ebola vaccines, which had to wait a while for the next outbreaks. Also SARS-CoV-1 disappeared altogether. You can still show development of neutralizing antibodies and test safety but may not be able to show efficacy in the field.

  14. jz78817 says:

    “It looks like Sanofi is bringing the spike protein and GSK is bringing the adjuvant”

    I asked them if they wanted me to bring the Holiday Chicken aspic.

    No response yet.

  15. Giannis says:

    I think that attenuated vaccines deserve more research. A lot has been done to create live attenuated SARS1 vaccine. While the wild type virus killed all mice, the attenuated virus lead to an almost asymptomatic infection that created a good antibody response.

    SARS-CoV-2 kills less than 1 out of 1000 people under 50 years of age. Disabling the same ORFs as the original attenuated SARS1 vaccine should reduce the lethality by several orders of magnitude. I think it is unethical to continue the lock downs which leads to massive issues both in the economy and the physical and mental health of people. The lockdown induced obesity will kill a lot of people.

    All in all a live attenuated SARS-CoV-2 (dNSP16/ExoN) vaccine given to all immunocompetent younger than 50 years of age is the ethical thing to do after a trial in a city.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096805/

    1. Toni says:

      “In pursuit of a platform to rapidly respond to an emerging threat, combination live attenuated vaccines employing NSP16 mutations may offer the safest path forward.”
      Very interesting. Is it known why (or if) this was not pursued further?

      1. Giannis says:

        Because SARS1 went extinct in 2003. Well technically there were a few SARS1 escapes later (1). But there were some grants for developing SARS and MERS vaccines. But if the private corporations don’t smell profit they (rightfully or not) will not pursuit a vaccine. This is why the WHO or another world organization should have a plan and take vaccines against emerging diseases very seriously. We need(ed) a plan.

        (1) https://www.the-scientist.com/news-analysis/sars-escaped-beijing-lab-twice-50137

      2. James Thomas says:

        …and that paper was published less than a year ago?

    2. Ian Malone says:

      There are a number of questions aren’t there? What’s the acceptable fatality rate for a vaccine? Does the vaccine in question actually provoke a lasting immune response? (Not guaranteed even with wild type virus.) Covid-19 pneumonia seems to lead to longer term lung damage (I suppose not enough time has passed to know if it’s permanent), so even non-fatal cases may lead to loss of years of life.

      I do agree about the need to find ways to end lockdown. Though different countries have different approaches; in the UK we can go out for exercise, and as it’s one of the few reasons to go out people seem to be exercising a lot more. We may even get /fitter/ overall. There is some suggestion that non-coronavirus deaths are up here however, and one possible explanation is people with serious conditions avoiding hospital.

      1. JustVisitingHere says:

        Otoh, the Mayor of Chicago prohibited any useful amount of exercise “you can go out for a run, but not a whole 5K”. 5K is barely a warmup for a fit person of any age. Same Mayor also closed the huge running/cycling path on their lakefront.
        The result is that residents will spend more time jammed into the city’s high density housing, an excellent place to friendly new hosts, if you are a virus.

        1. huh says:

          “prohibited a useful amount of exercise”! Seriously? Do a lot of the locals suffer from some sort of impediment that stops them from slowing down and turning around?

  16. Lothar Lindemann says:

    Hi Derek,
    Thanks a lot for this excellent summary and introduction!
    On the topic of mutations / how long and broad vaccines might work:
    Is it correct to assume that life-attenuated virus vaccines have the potential to offer the broadest / longest lasting protection – compared to vaccines based on single proteins, given that the human immune response will be directed against a whole range of viral proteins and epitopes (i.e. if there is a mutation in one or two proteins, there is still a vaccine effect against all the other viral proteins that didn’t mutate)?
    On the same topic, there are different virus strains being discussed (A/B/C, and L/S, depending on the literature). Would an effective life-attenuated vaccine need to consist of a mixture of all the strains, like the flue vaccine typically mixes between different strains each season?
    Lastly: Why would a test start with an attenuated life vaccine take so long, given that we already now work with the viruses (produced inc ell culture) sine a while?
    Thanks a lot for your insights, much appreciated!

    1. dwh says:

      @Lothar

      To provide some feedback on your questions re: live-attenuated vaccines:

      1. In general, live-attenuated vaccines generate the broadest (both in terms of cellular and humoral immunity and antigen diversity) and longest lived responses. However, they generally have the most safety risk associated with them and sometimes antigenic diversity can be a problem if the responses are not directed at the antigens most associated with protection. Having a broad range of antigens can also make them susceptible to inhibition if there is pre-existing immunity to conserved antigens of related viruses that the recipient may have already been exposed to (see, for example, the lower efficacy of the intranasal FluMist influenza live attenuated vaccine in adults vs. children)

      2. Regarding the different strains, SARS-CoV-2 is a non-segmented RNA virus which means it is more stable than a non-segmented virus like influenza. At this point, the SARS-CoV-2 mutations do not appear to be drastic enough to necessitate a multi-strain vaccine (but that could obviously change!). As outlined above, a live attenuated vaccine would likely be more resistant to the effects of mutation because it induces both antibody and T-cell responses and due to a broader range of antigen targets.

      3. Live-attenuated vaccines represent the highest safety hurdle. Since this is such a new virus, we do not understand the effects of all of the different viral proteins, so there is the potential for doing more harm than good in vaccinating large populations. While there are a couple of potential strategies for attenuation originally developed for the SARS and MERS live attenuated vaccine candidates, we also do not know how to grow up the SARS-CoV-2 attenuated strain with the kind of consistency and control expected for a vaccine. Without that, there is always a risk of reversion to virulence.

      1. dwh says:

        Typo: “….is more stable than a non-segmented virus like influenza.” should be “is more stable than a segmented virus like influenza.”

  17. Peter S. Shenkin says:

    Lovely summary.

    I just want to point a possible issue with the assertion:

    “The mention the other day of younger recovering Covid-19 patient who don’t seem to have developed antibodies is an example of that very problem: a really robust innate response could clear the virus in an infected person, but leave them without much long-term immunity.”

    How sure are we that the original coronavirus test which showed that he had COVID-19 was not a false positive? I’m not sure whether the false-positive rate for the (several) tests for the active virus is actually known, but I think the possibility needs to be considered.

    1. gcc says:

      It might also be possible that these people developed a T cell response that could provide some long-term protection, even though they don’t have high levels of circulating antibodies. That probably wouldn’t prevent infection the way neutralizing antibodies would, but might lead to a mild infection that is quickly cleared.

      1. dwh says:

        I think this is correct. I have not seen too much indication that false positive quantitative PCR tests would be occurring at the level where this would explain the absence of neutralizing antibodies in ~30% of patients. The Chinese paper that first described this could have been a lot better in that they indicated that they looked for IgG antibodies but they did not show the data. My guess is that those subjects developed IgG against at least the capsid protein, but the responses were non-neutralizing. Although T-cell responses were not measured, they did acknowledge that they played a likely role in viral clearance. The role of T-cell responses in vaccine and post infection immunity will become a very important topic as we move forward. While T-cell immunity may not prevent infection, it can play a vital role in limiting disease and viral shedding. Cell mediated immunity is also less sensitive to mutations in the binding domains to which antibody responses are directed. One of the key factors supporting the recombinant viral vector and DNA/RNA vaccine strategies is that they are capable of inducing both humoral and cell mediated immunity. Protein subunit and inactivated pathogens typically induce weak cell mediated responses. However, given the present focus of just including the spike protein in the current batch of candidates, I am not sure how good the vaccine induced T-cell immunity will be even in the viral vector / DNA/RNA vaccines.

        1. gcc says:

          I really appreciate all the detailed responses here in addition to the excellent post itself. I’ve followed this blog for years despite having left science for a different field several years ago and it’s always interesting and informative. Many thanks!

  18. Alan Goldhammer says:

    Hi Derek – I really liked your description of the reaction to Shingrix. My first shot was rather inconsequential. The second one gave me every single side effect on the product label. As the label noted, most symptoms disappear after 24 hours and that was my experience but those 24 hours were a mite uncomfortable.

    For me the big question is what level of safety is society willing to tolerate. Most vaccine trials end up with 50,000 patients so that the 1 in 10,000 AE can be detected. Maybe that step gets shortened but then you get into liability indemnification if something goes bad. It’s going to be a hard policy call, particularly if hot spots of breakout continue to appear.

    1. Alex says:

      That’s a really good thing to keep in mind – I’m going to review the SARS vaccine experience in an upcoming post to highlight this some more.

  19. Miles Gould says:

    “Bill Gates has already indicated willingness to fund factories for up to seven vaccines up front. The live-virus, attenuated virus, recombinant protein, and nucleic acid vaccines will all involve completely different production methods and formulations, and since we don’t know which way we’ll be going, this would seem the only way to address the issue.”

    How much do the production processes have in common within a family? Does Bill Gates have to pick seven candidates out of the 115 and hope the exact winners are among them, or if (say) his mRNA candidate doesn’t pan out and some other mRNA vaccine does, will he be able to rapidly retool to produce the winner? I suppose it’s too much to hope that he could build a generic live-virus factory, a generic DNA plasmid factory, etc, and then specialize them to the exact winning vaccines closer to the end when we have more information about what works?

    1. dwh says:

      The physical infrastructure required is fairly similar across most of the vaccine platforms. However, the process and scale up issues can vary significantly. mRNA and DNA are the most straightforward to implement at small scale because you are making the same chemical product (varying only in the encoded nucleic acid sequence) whether it is an HIV vaccine or SARS-CoV-2 vaccine. That is part of the reason why those were the first vaccines into testing. The DNA production is probably the most portable across candidates. mRNA is a little less so primarily because the major players have specific IP around production processes. Viral vector production uses common equipment platforms but fairly specialized processes for each candidate. For recombinant protein production, the needed infrastructure will depend on what your expression platform is. Obviously a mammalian cell culture or a tobacco plant production process will require very different bulk production facilities. Once you get the proteins, then the purification and formulation are fairly similar in terms of equipment, but the processes themselves are likely to be highly specialized for each product. Bottom line is that he should be able to make some broad based infrastructure investments that are somewhat portable across platforms, but, outside of the nucleic acid candidates, the process investments will be harder to leverage between candidates.

      1. James Millar says:

        It reminds me of the Manhattan project in a way, where Groves had to approve massive construction without knowing for sure exactly what would work.

      2. Vladimir says:

        Hi, what would be typical cycle time and probability of success for clinical trials for different types of vaccines?
        Thank you,

  20. KRL says:

    Excellent summary, Derek. I noted your mention of the discomfort following a second administration of the Shingrix vaccine, which I experienced also. And I was amused at your typo – the soreness is at the site of injection, not infection. MY infection with VZV occurred long ago, perhaps at a chickenpox party.

  21. J Severs says:

    Very well done, especially for mentioning possible logistic difficulties.

  22. Tom says:

    I know there was some discussion that from an ethical perspective, challenging healthy volunteers with actual live SARS-CoV-2 after being test vaccinated, may be worth it in terms of validating the vaccine far faster (and thus getting it to people faster), vs the risk to those volunteers. It seems like that’s the fastest case outcome here – if we did a rolling phase 3 out of the phase 1 and 2 trials on one of the early vaccine candidates. Normally we’d never consider that, but with the life cost and $$$ cost of this disease, it seems correct that gradually challenging a few thousand volunteers (as we gradually learn the vaccine is safe, if it is) with the virus is going to save more lives and money in the long run. I’m sure we can find people to volunteer if we get to that.

  23. Anonymous says:

    I have seen a doctor comment about the vaccine development in public forums on the 2009 H1N1 swine flu pandemic. I quote “the pandemic started in January 2009. Vaccine trials started in July 2009 and 3 billion doses delivered in November 2009. Does anyone have any information on this? Something isn’t adding up.

    1. Derek Lowe says:

      That’s because H1N1 piggybacked on years of successful yearly influenza vaccine work. Ebola is still the record for a “standing start”; there are no coronavirus vaccines at the moment.

      1. Anonymous says:

        That makes sense. Thank you for the information.

      2. Paul D. says:

        There are no coronavirus vaccines in humans. I believe there are some for other animals.

        1. Mark says:

          There is a vaccine for feline infectious peritonitis (FIP), which is caused by the feline enteric coronavirus. It has been out for many years but supposedly has problems. More than one veterinarian has told me they don’t recommend it and don’t give it to their own animals.

  24. Barry says:

    I have grumbled for decades that chicken eggs are obsolete–influenza viruses raised in them are selected to grow well in chickens, often quite different from the virus first isolated from humans, to which we want the vaccine. But maybe we should acknowledge that this technology isn’t going away yet.
    Can we humanize a chicken line for the proteins influenza needs for cell entry? Eggs from such chickens might produce vaccines more protective against the ‘flus we care about.

  25. Anon the II says:

    I don’t know if this post was meant to be a survey, but the first Shingrix nailed me. > 101 for about 10 h. Then it was all better. Got the booster about a month ago and it wasn’t as bad..

    1. Barry says:

      Funny, the first dose of Shingrix got me a sore arm (20hr) but the second got me the fever, myalgia…Certainly a bargain relative to all the stories I’ve heard of shingles. But two unpleasant days

      1. Giannis says:

        All this sounds similar to the response I have to the seasonal flu vaccine. 12 hours after the injection I have 38 C fever for a few hours. Then after a few hours the response stops completely. Totally worth it for reducing my chance of getting the real flu.

  26. Edmar Wiggers says:

    Indeed, you do provide most invaluable reading for (thousands of) laymen like me, looking for quality info on the Covid-19 situation. I’m an industrial engineer in Brazil, by the way.

    Your expertise in the pharma industry and skilful writing are most appreciated.

    Thank you, really, thank you for your blog.

  27. Luis says:

    Hello,could you tell us what kind of Vaccine is being developed by the Oxford University in the UK please. Professor Sarah Gilbert is 80% confident that the vaccine will work and if everything goes to plan then mass production can start by September 2020 which is way ahead of the usual 18 months mentioned for any other vaccine.
    Thank you.

    1. Tomas says:

      It is adenovirus-based with the spike of SARS-CoV-2 as an antigen. Google “The Oxford Vaccine Centre’s COVID-19 vaccine trial”.

  28. loupgarous says:

    Always an education, Derek – thanks for a thorough run-down on the salient issues in vaccine development and manufacture!

  29. Jim Palmer says:

    Given that incarcerated populations are likely to be quite susceptible to infection, is there a movement to recruit prisoners as volunteers for vaccine trials? (One incentive might be sentence-shortening, another might be self-preservation.)

    Disclaimer — I’m not advocating this as much as inquiring about whether it’s already being done!

    1. HU says:

      I am sure that the CCP has already “recruited” many of their incarcerated to participate in vaccine trials that are followed by a challenge of the live virus. The primary endpoint being the number of people alive without intensive care, 1 month after challenge.
      Note that I have no proof for this at all, but something I fully expect the CCP to do, given how they have already had the concentration camps set up for a long time…

    2. SirWired says:

      Of all the issues involved with nCoV vaccine development, I don’t think an ability to recruit volunteers will be one of them. (Meaning we can sidestep the *beyond* thorny ethical dilemmas of deciding how “voluntary” an imprisoned trial subject is.)

  30. TfreakPI says:

    So here is basically what is bothering me right now……we have a safe drug that is used around the world, that has been investigated as an antiviral for decades, that the FDA approved for EUA, and has clinical trial backing (how much is debatable). Nevertheless, 50+% of scientists or medical technicians oppose using it in an emergency simply because trump advocated its investigation. There was no such debate at all in the obama handling of the super flimsy ebola vaccine. That my friends is totally insane and I will no longer trust scientists to be impartial again ever.

    1. SirWired says:

      It’s not just “because Trump” that there is reluctance to use HCQ/Zithro. Derek has covered why extensively in this space. (Namely, they are not harmless drugs, and may very well kill a patient that would otherwise survive the illness.)

      (And why would Medical Technicians have anything to do with it at all? It’s a prescription drug given over days, not something you inject into somebody’s arm in an ambulance as a last-second intervention.)

      1. David Marilley says:

        It is being done. The best course for even older subjects is to control blood zinc level way up, dose hydrocl. correctly, then inject the S strain of the virus in the arm (better place than the lungs to meet your immune system). The virus dose has not been learned, which is unbelievable.
        This way you build an army of immune humans and don’t kill impoverished people by killing the economy. But we are fighting the last war against a very weak enemy. It is really idiotic. But then the FED for decades DOD stewardship etc. We have failed to develop leaders.

        1. Lappan says:

          That would be a very exciting outcome – where is this being done, and where are the results being published?

          1. George says:

            In his deranged head

  31. Iain Welsby says:

    Ad5-nCoV is not a traditional “protein fragment vaccine”, it is a recombinant adenovirus type-5 vector (Ad5) vaccine.

    1. David Marilley says:

      NVAX has the answer. They don’t have billion dollars to implement.

  32. yyz says:

    If Rabies and tetanus have an immune globulin, why cant the covid-19 have one ? I understand that it is not a vaccine but it is good enough as a cure ?

    1. Gibbon1 says:

      Coming in about a week late, but companies are working that angle as well. I have no idea but could be a stop gap while a vaccine is developed. As long as it can be rolled out sooner. Might be able to use that as an adjunct to contract tracing. Advantage you’re giving to at risk people not the general population.

  33. JasonP says:

    Who needs baseball when we can watch Derek consistently knock these posts out of the park?

    Thanks for the education at a level most can assimilate!

    1. Cooper S. Towne says:

      While I knew Derek Lowe did have a decent baseball career as a pitcher, your comment prompted me to check if he ever hit a home run, which he did! 1 career home run in 2011, his 14th of 17 season in the MLB: https://www.baseball-reference.com/players/l/lowede01.shtml

  34. wanderer says:

    We should definitely NOT weaken the safety studies/requirements of any Covid-19 vaccination. If only 0.1% of the vaccinated people develop serious side effects, we will end up with a bigger problem than we already have!!

  35. Paul Deems says:

    What is your opinion on this proposal to speed testing by using human challenge trials to replace conventional phase 3 testing?

    https://academic.oup.com/jid/article/doi/10.1093/infdis/jiaa152/5814216

    Would regulatory authorities allow it under existing regulations or would it require politicians to pass some sort of emergency measure giving greater latitude to COVID-19 related trials?

    1. Derek Lowe says:

      The FDA, CDC, and WHO all have guidelines for human challenge trials. It all comes down to risk/benefit, and that’ll be a tough call if we get to that point. We may not end up at that impasse, though. . .

  36. George Stanchev says:

    And CanSino goes in Phase II after 3 weeks. What could possibly go wrong?

    https://www.fiercepharma.com/vaccines/china-s-cansino-bio-advances-covid-19-vaccine-into-phase-2-preliminary-safety-data

    “It’s worth noting that the investigators have abandoned the highest dose used in the phase 1 trial. This time, 250 people will get the middle dose, and the remaining 250 will be split up to receive either the low dose or placebo.”

  37. Ted Martner says:

    Calcium Citrate question.
    We are 75+yr old. My wife is taking generic Calcium Citrate for GERD follow-ons.
    This generic includes Zinc Oxide 10mg Zn.
    Should I pop one of these zinc-ins daily, for now?
    Or is that a Really Zany Idea?

  38. Michael says:

    Derek,

    great article, as always!

    You write “Fortunately, testing for vaccine efficacy can be (fairly) straightforward…” Just one concern here: By the time the vaccine is ready for efficacy testing, we very likely have he following situation. In the developed countries the virus is under control, with relatively few cases due to continued hygienic precautions, isolation etc. In the non-developed contries, the pandemic will have caused herd immunity due to nearly uncontrolled spreading (unfortunately). So incidence will be quite low. In this setting a trial for efficacy will have to be really huge, won’t it?

    1. Derek Lowe says:

      That is a possibility. I was surprised, though, by the news today that a serology survey among heath care workers in Wuhan came back only about 2% positive (!) So there may be less prevalence than we have been assuming. . .but we need more data.

      1. Current WHO estimate is around 2-3% of the general population have COVID-19 antibodies (with the caveat that this is, in part, estimated from blood donors, not the public in general).

        I need to delve deeper, but my understanding is that seroprevalence to the non-SARS coronaviruses (S-protein specific antibody) is high even from an early age, (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848659/), at least in urban China. If the current low level of seroprevalence is an accurate indicator of low COVID-19 exposure then we have a long way to go before we can count on herd immunity to contribute to lower infection rates.

  39. Jens says:

    I think it’s worth to mention one additional approach (perhaps you did, and I missed it?):

    The German Paul-Ehrlich-Institute (Federal Institute for Vaccines and Biomedicines) just started a clinical trial with COVID-19 convalescent plasma (CAPSID). The aim of the clinical trial is to gain insights into the efficacy and safety of COVID-19 convalescent plasma in the treatment of severe COVID-19 diseases.
    More infos can be found here: https://www.pei.de/EN/newsroom/press-releases/year/2020/07-pei-approves-first-covid-19-therapy-study-with-convalescent-plasma.html
    and here: https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001310-38/DE

  40. Great piece (coming from someone with 30+ years in vaccine development). With respect to safety, worth (re)flagging lessons learned from investigational SARS vaccines (hypersensitivity) and that COVID-19, like other coronaviruses, appears to benefit from antibody dependent enhancement. Natural infection seems to result in relatively short lived immunity and my gut feel is that we will need to be very lucky to have something even partially effective first time around.

    1. Derek Lowe says:

      That’s a really good thing to keep in mind – I’m going to review the SARS vaccine experience in an upcoming post to highlight this some more.

  41. Denise Gipson says:

    Thank you for a thorough article and good links. Given that there are already significant risks to getting COVID-19 (death and also evidence that, in some patients, there may be long-term effects on the lungs, heart, kidneys, etc.), I think it would be worth it to try vaccines on any willing volunteers NOW. I would volunteer. Many people are already working (health care workers, food suppliers, etc.) often with insufficient PPE (or why are they also getting sick?) Furthermore, not everyone can self-isolate until next year, particularly those in rural areas, where food delivery doesn’t exist. Or, they can’t afford food, let alone to have it delivered. So, vaccination risks are lower than getting the disease. By the way, I had chicken pox as a child (no vaccine then), and therefore, I am now at risk for shingles, so I don’t recommend the “get a wild-type infection” route. Testing everyone is ludicrous and doesn’t solve the problem; a vaccine does. Although a vaccine now might not be perfect and/or a booster shot later might be required, OK! Later, we would be better prepared and better equipped to vaccinate with a more ideal candidate, but we would be out of the situation we are in now. Yes, vaccines take time to produce, which is why MANY companies should be working on 2000-L. facilities NOW. I would like a “phase III” clinical trial of everyone who wanted the vaccine now, especially those at high-risk or in high-impact areas NOW. Under this plan, fewer people would be dying than are now.

    1. loupgarous says:

      Denise Gipson:

      “Testing everyone is ludicrous and doesn’t solve the problem; a vaccine does. Although a vaccine now might not be perfect and/or a booster shot later might be required, OK! Later, we would be better prepared and better equipped to vaccinate with a more ideal candidate, but we would be out of the situation we are in now. Yes, vaccines take time to produce, which is why MANY companies should be working on 2000-L. facilities NOW. “

      (1) Testing everyone can give us a snapshot of who’s been exposed, who hasn’t, and perhaps show how many asymptomatic cases are out there (though we’d be relying on self-reporting of symptoms). It’d also give us a fuller estimate of number of cases, so our estimates of case fatality ratio would be better. That’s worth knowing, so universal testing is worthwhile.
      (2) Without estimates of how the disease spreads in the absence of vaccines, we have no way of estimating the effectiveness of vaccines. We need to test as many people as possible to establish who has antibodies to SARS_CoV2, and which strain they have antibodies to in order to measure their response to any vaccine they receive. If you don’t have a way of measuring who already had antibodies pre-vaccine and who develops them after vaccination, you have no means of measuring each vaccine’s effectiveness in order to decide which vaccines work best and ought to be made. You also want to test different (say, attenuated and invactivated) kinds of vaccines to give those with immune deficiencies a safe alternative to vaccination with a live virus that might make them ill.
      (3)Testing of everyone is a thing you probably need after one or more vaccines are tested and proven, to be sure as many SARS_CoV2-näive people are vaccinated as possible so that herd immunity develops to as great a degree as possible (so as few people as possible are infected with the wild-type virus and fall ill with Covid-19.
      (3) Bill Gates has offered to finance up to seven vaccine production facilities, so we’d have at least that many different vaccines to work with.

  42. Benjamin says:

    January 2021 !!!! But it’s too late !!!! I wish the vaccine could be prepared earlier than this time and save the lives of humanity … and the next good news for everyone was that it was written that there are 78 corona vaccine programs that are currently correct and scientists are working on them. The detailed description of the types of vaccines was very exciting for me and gave me good information. And I hope that the final vaccine will be prepared and released as soon as possible. Thank you for posting any new news on your website.

  43. Jens says:

    The German Paul-Ehrlich-Institute (Federal Institute for Vaccines and Biomedicines) just announced the start of a trial of an RNA vaccine in healthy human volunteers.
    See https://www.pei.de/EN/newsroom/press-releases/year/2020/08-first-clinical-trial-sars-cov-2-germany.html

  44. Alan Meyers says:

    We don’t yet know if infection confers immunity, and thus if an antibody response signifies immunity; in the case of HIV infection, it doesn’t, and re-infection with HIV is possible. Is an effective vaccine possible if infection does *not* confer immunity?

  45. Vayare says:

    Really good content

  46. Toni says:

    Maybe it’s a bit of a weird question. But can we compare the problems we are facing in vaccinating against respiratory viruses with the problems in immunoncology?
    Yes, I know that on the one hand we have to fight with a poor mucosal immunity (and other things) while tumour cells can evade the immune defence by other means.
    But wouldn’t it at least be conceivable that some of the immunocheckpoints (PD-1, accessory immune receptors, TGF-beta etc.) should be given attention during vaccination against viruses – perhaps in the form of new adjuvants or as an accompanying therapy during vaccination?

  47. Frank says:

    Fascinating insight from many of the posters. I come from a science background, Mainly social sciences. I have always found the development of vaccinations such a complex field . What are the genuine chances of a vaccine this year being available worldwide ?

  48. Mark says:

    Or Sars-CoV-2 could go the way of Sars-CoV-1. When it first appeared in early 2003 it was so deadly that it killed 1 in 10 infected. By July 2003, it had basically mutated itself out of existence.

    1. Dale says:

      Funny how true this is even today after the sh*tshow that was the US handling the pandemic.

  49. Yuejin Huang says:

    The approach of Sanofi bringing the spike protein and GSK bringing the adjuvant may make sense. Any method that uses powerful immune cells to kill Covid-19 is dangerous.

  50. Milad says:

    You do need to know how long the immunity lasts in people. That takes as long as it lasts. I should think the minimum would be 70% effective after 6 months. Immunizing more often than once a year is challenging.

  51. Elena Angela Lusi says:

    If SARS CoV -2 will behave like the Spanish flu virus, disappearing after its epidemic cycle, do we still need a vaccine?

  52. Mary says:

    I still can’t believe that we do not have a vaccine for the virus yet! It makes me worried since I am in my 60’s. Do you think it will be covered under Medicare? I know Medicare covers some vaccines already, https://www.ez.insure/2020/04/4-vaccines-that-medicare-covers/ this was article was helpful to know which ones…but if it is not covered, then I do not know how to pay for it.

    1. JS says:

      It’s been more than 3 months now since many companies started research on COVID vaccine. Those 5 companies given money by US government, CEPI funding and so many other millions of dollars put in research. Is it all going down the drain?

  53. chartiran says:

    That’s a really good thing to keep in mind – I’m going to review the SARS vaccine experience in an upcoming post to highlight this some more

  54. “It looks like Sanofi is bringing the spike protein and GSK is bringing the adjuvant”

    I asked them if they wanted me to bring the Holiday Chicken aspic.

    No response yet

  55. Elizabeth Bradburn says:

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  56. JS says:

    It’s been more than 3 months now since many companies started research on COVID vaccine. Those 5 companies given money by US government, CEPI funding and so many other millions of dollars put in research. Is it all going down the drain?

  57. John says:

    I worry about COVID19 in winter and peak in autmn. I think thats very dangrous and its need to goverment take care about that.

  58. tahviehnegar says:

    nowadays HVAC systems in buildings are very important because COVID19 can carry easily in air and transfer to others. please pay attention to air condition systems of your building. ASHRAE (The American Society of Heating, Refrigerating and Air-Conditioning Engineers) have many good articles about the relation between corona virus and air condition systems.

    https://www.ashrae.org/file%20library/technical%20resources/covid-19/ashrae-covid19-infographic-.pdf

  59. Miranda says:

    What do you think about the Russian vaccine? Is the Russian claim to make the first Corona vaccine true?

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