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Coronavirus Vaccine Update, July 1

More vaccine news to catch up on – previous updates and specific topic posts on this subject were on June 15, on June 11, on May 26, on May 18 (with two other posts), on May 14, on May 1, on April 23, and on April 15 (author’s note: yikes). Keep in mind that some of those posts were updated after their original publication data as well.

Here’s the latest on the ones I’ve covered before and with new efforts added. There are now so many of these running that unless the program is especially noteworthy I’ll only touch on the ones that are in trials right now, or about to start soon. And I’m going to arrange them by vaccine class – the April 15 background post goes into some more detail on these, but I’ll start each group off with a short scientific summary. Neither the order in which these different mechanisms are presented nor the order in which companies are listed within them is meant to reflect any horserace handicapping on my part.

Viral Vectors:

This class uses some other infectious virus, but with its original genetic material removed. In its place goes genetic instructions to make coronavirus proteins, and when your infected cells do that, it will set off an immune response. Note that this is different than being infected with a “real” virus, whose instructions are (naturally enough) to produce more virus, which go off and infect more cells. No, in this case each viral particle that you’re injected with will be able to infect one cell, and that’s it. An advantage of this approach is that it should appear to your immune system like a pretty realistic viral attack, and set off a full range of responses. A disadvantage is that this technique (as far as I can tell) has only once been used in human therapy (the Ebola vaccine, see below – update: edited this section to reflect this) – a lot of people have been working on it over the years, but things have now accelerated. Another disadvantage is that (depending on which virus you pick as a vector) some of your patients may already have antibodies to that one. That can mean that your attempt to repurpose it might crash and burn as the carefully designed vector gets attacked by antibodies and eaten by immune cells before it can even do its work. It also means that booster shots would have an uphill battle, since the antibodies from that first dose will be waiting for the second one. Antibodies to the viral payload: good. Antibodies to the viral vector itself: not so much.

Oxford/AstraZeneca: ChAdOx1-nCov19/AZD122: This is one of the frontrunning candidates in human trials (the WHO agrees), and it’s recently started dosing in South Africa and Brazil as well as the ongoing trials in the UK, etc. We’re going to be seeing a lot of that jump-around-the world pattern, tracking the places that have significant outbreaks in order to get the best statistics. That means that the organizations behind each candidate either have to have substantial resources themselves, or partner with those who do (pharma, the WHO, groups such as CEPI and the Gates Foundation, etc.) I don’t know when the next report of human data will be on this one, but it will be very closely watched indeed – see the May 18 post for the reaction to the last big data drop, which had some observers (not all) worried about the vaccine’s effectiveness. This one tries to get around the pre-existing antibody problem by using an adenovirus from chimpanzees (the “Ch” in the name).

CanSino/AMMS: their Ad5-nCov, we find out this morning, has been approved for use in the Chinese military “after clinical trials proved it was safe and showed some efficacy”. That’s probably how I would put it, too – the company reported on the Phase I data a few weeks ago, and one of the notable features was that about half the patients that they dosed, in all age cohorts, had pre-existing antibodies to the vector. That’s adenovirus-5, as the name implies, and it’s a pretty common human pathogen. This one was widely used earlier (back to the 1980s) in the viral-vector field (which encompasses both vaccines and gene therapy) and a great deal is known about its behavior in humans, but the existing immune response has been a problem every step of the way. Ad5 is also considered a good choice if you want your payloads delivered to the liver and not much of anywhere else – it tends to concentrate there, and it wouldn’t surprise me if a lot of the coronavirus protein production with the CanSino vaccine is taking place in that tissue. At any rate, an executive with the company has said that their Phase II results will be published very soon, while not missing a chance to take a shot at Moderna for not doing the same (see below), so it’s going to be very interesting to dig through those. Update: apparently the company is looking at a booster-shot regimen, and the same article quotes a Canadian hospital as saying that they are preparing to help with Phase III trials “in the fall”. How well booster shots will work with an Ad5 vector remains to be seen.

Johnson & Johnson (Janssen): J&J, on the other hand, is working with a different adenovirus platform, Ad26. That’s a much rarer strain, and very few people have pre-existing antibodies to it. They’ve been investing in this for years now, and the coronavirus epidemic has, as it has for so many other areas, accelerated things past anything that was contemplated before. This is the time to mention, though, that it’s not just the pre-existing response that can be a problem – if you raise too vigorous a response to the new viral vector you can cause trouble, too (and, as mentioned, perhaps wipe out the chances to ever use that particular vector for anything again). No big announcements since the company said that they were speeding up human trials to first dosing in July.

Gamaleya Research Institute: Those previous entries are a good lead-up to this one, because the Russian GRI vaccine is a mixture of Ad5 and Ad26 vectors. To be honest, I’m not sure of the thinking behind giving both, but it will be an interesting comparison with the Chinese and J&J efforts, for sure. This work made headlines not long ago when the head of the institute let it be known that he and other workers there had actually injected themselves with their own candidate vaccine (!) This was not, he said, an attempt to prove safety, but rather a means to protect the staff while they were working with the coronavirus itself. One would suspect that the Russian language, with its rich stockpile of phrases, would have a metaphor similar to the English “putting the cart before the horse”, wouldn’t it? At any rate, this one has gone into human dosing in Russia.

Reithera: This Rome-based company is taking a similar approach to the Oxford group, in that they have a gorilla-infecting coronavirus platform that should be immunologically novel in a human population. Data are scarce, although the company has said that they expect to go into human trials “this summer”, and some stories on them say July.

Altimmune: Here’s another adenovirus vector, but administered via a different route. They’re going intranasal, and thus hoping to bring in a mucosal immune response as well. Since this seems to be the same platform as their earlier Nasovax influenza vaccine program, I will assume that this is also an Ad5 vector. This one is still listed as “preclinical” on the company’s web site, with such studies taking place partly at the University of Alabama-Birmingham. It’s good to see another technique being applied here; we’re going to need all the shots on goal that we can get.

Merck/Iavi: Now here’s a non-adenovirus vector. Merck’s partnership with nonprofit Iavi is around vesicular stomatitis virus (VSV), which is what was successful in the development of the Ebola vaccine. In that case, the gene for the VSV glycoprotein was replaced by one for the Ebola protein, and I would assume that something similar will be done to swap in the coronavirus spike protein here. Merck is expected to use the same Vero cell line production for this that they used for making the Ebola vaccine and for their rotavirus vaccine. That last one isn’t a VSV vector, but rather a group of mixed bovine-human rotavirus strains – but for all of these you need cells to serve as factories to crank out viral particles for you. I have seen no projected date for first-in-human dosing for this one, though

Merck/Themis: In another non-adenovirus move, Merck had been collaborating with Themis on using attenuated measles virus as a therapeutic, platform, and about a month ago they announced that they were buying them outright. The attenuated measles vaccine (see below for attenuated viruses in general) has a very good safety record and has long been considered an attractive candidate for repurposing, and now we’re going to find out how that works rather before we thought we would. The plan is for this to go into patients sometime later this year.

Vaxart: Now, these folks I had not heard much until the other day, when they popped up with a surprise press release saying that their vaccine candidate had been selected as part of the government’s “Operation Warp Speed” for a challenge test in primates. They have a platform developing oral vaccines – an adenovirus vector delivered in a coated tablet to get past the stomach and into the small intestine. (There’s an immediately obvious difference this route and the injectables in ease of storage and administration, which might be quite advantageous). This “mucosal immunity” technique will be familiar to many via its use in the oral polio vaccine, and the differences between it and the immune response generated by injection are quite complex. Vaxart hopes to go into Phase I later this year, and it will be very interesting to see what happens in the primate study and in humans. This route could turn out to be noticeably better or noticeably worse than other the efforts in the category, or might even end up as an adjunct to another vaccination route. I’m very glad that we have a completely different approach being looked at. (Update: corrected and moved the category on this one; I’d initially thought they were using just recombinant proteins).

 

Genetic Vaccines:

These take DNA or RNA coding for coronavirus proteins and inject that directly into the bloodstream. “Directly” isn’t quite the right word, though – for these things to work, they have to be formulated and modified to survive destruction in the blood, to be taken up through cell membranes, and to be used for protein production once they’re inside. There have been extensive experiments in animal models over the years, but this is another category where no existing human vaccine uses the technology (yet!) Advantages include fast development and (possibly) ease of manufacture, depending on how exotic the final form turns out to be, and lack of an existing immune response to the vaccine itself (as seen with some of the viral vectors above). The big disadvantage is, well, once again no one has taken these things into humans yet. And another one is that some of these may need to be stored at not even the usual cold-chain conditions (which are enough of a logistical problem, thanks, particularly outside the industrialized countries) but even colder than that to keep them stable (for example) – an underappreciated problem, perhaps, that we’ll have to keep an eye on. Others have been shown to be stable without cold chain storage, so there’s clearly a wide variation.

Moderna: mRNA1273: this one, the leading mRNA vaccine candidate has been getting a lot of the coronavirus vaccine headlines, of course. They’re still heading for Phase III in July, and have signed up with Catalent (who are also working with J&J) for support in vaccine production, labeling, and distribution for that effort. This in addition to their own production work and the deal that they’ve already signed with Lonza in Europe. The company’s CEO said earlier this week that the best-case timeline had them with efficacy data before Thanksgiving, and yeah, I believe that would be the “everything goes flawlessly the first time through” situation. What we haven’t seen are many more details about how the vaccine has been performing so far. All we have is that small mid-May press release, and it’s been a while, hasn’t it? At some point, there’s going to be a dumptruck of data that will have to be released on this one, and until then we’re all just sort of tapping our collective feet.

Pfizer/BioNTech: Not much news here, but we definitely will be getting some. This effort started out with four different mRNA approaches, and there’s no word on if they’ve narrowed things down yet. Pfizer’s CEO Albert Bourla said recently that they’re sticking to a strict policy of not commenting on their vaccine results until they’re published in a journal. He also emphasized that they are not part of the government’s “Operation Warp Speed” effort, saying “We don’t take the money because we don’t need the money”, and believes that doing so would just slow down the company’s own efforts. They’re also planning for about 30,000 patients in their eventual Phase III trial, with about 100 sites (US and international). The number of drug companies that can organize (and pay for) something like that with cash-on-hand can be easily counted on your fingers, and Pfizer is certainly one of them. The company has also said that their best-cast timeline has a possible emergency use authorization in October (!), which will also require everything to ring the bells exactly on time. Not everyone believes that’s possible, but hey, we’ll find out pretty damn soon, won’t we? Update: initial Phase I data are out the first of their four candidates, and look good so far.

Inovio: this DNA vaccine candidate (INO-4800) is getting messy. The company had sued their manufacturing partner, VGXI, claiming that they were in breach of contract and holding up Inovio’s program because they could not fulfill their targets for delivery. A judge has just ruled against Inovio’s request to force disclosure of VGXI’s proprietary manufacturing techniques. For my part, I was already out of sympathy with Inovio after their announced early on in the pandemic that they had produced a vaccine in about three hours, when what he was actually talking about – as people who know any molecular biology whatsoever realized instantly – was a candidate construct for a possible vaccine. That brought on shareholder lawsuits, as the shares were whacked back and forth like a tennis ball between enthusiastic dice-rolling long investors and you-gotta-be-kidding-me short-sellers. I should note that the company has a stock market following that is need of therapy all by itself. Anyway, at this stage, a serious vaccine player should be talking about where they’re going to round up all the glass vials, where the sterile production lines are, how they’re going to handle the logistics for tens of thousands of clinical trial doses, and so on. Not off hammering on their contractual partners in the Montgomery County Court of Common Pleas.

CureVac: hey, remember these guys? Back in March, there was a flare of a story about how the US had allegedly tried to buy up the company (or the rights to any mRNA vaccine they produced), with sourcing of the news to irate members of the German government. There hasn’t been anything quite that lively around them since, but they recently got a 300 million Euro investment from the German government (who now own 23% of the company). They have continued to state that they expect to go into Phase I human trials before the end of June, which means that they have about 28 hours to go (Central European Time), as I write this.

Imperial College: this is another mRNA candidate, but it’s a self-amplifying one, like one of the four Pfizer/BioNTech variations – these are the only two that I know of using this technique. The vaccine went into human volunteers just a few days ago. The way these things work is to deliver messenger RNA that codes not only for the antigen protein of interest, but for an RNA polymerase enzyme (there’s a useful one that’s been borrow from alphaviruses) that will turn around and make more copies of the mRNA itself. The idea is that you can then dose with much smaller amounts of material, since it’s going to go out and make more of itself anyway.

Sanofi/Translate: this one is still scheduled to go into human trials in December. Sanofi has recently expanded their collaboration with Translate in this area, but I haven’t been able to track down details on the vaccine itself. There are an awful lot of ways to deal with the problem mentioned in the intro to this section, though, and I would expect this to be a different run at them than the other mRNA players have taken. Given that we have no idea how these things are going to perform in human subjects, a diversity of opinion is no bad thing.

Genexine: this South Korean company’s DNA vaccine, GX-19, has started human dosing. These folks and Inovio seem to be the front-running DNA vaccine players for now; everyone else in this category is RNA. I would assume that none of this testing is going to be done in Korea itself, though, since COVID-19 levels are so low there (and good for them).

AMMS/Abogen/Walvax: this is the first mRNA coronavirus vaccine in China, and was recently approved for human trials there. An interesting feature is that it’s said to be stable at room temperature for up to a week – rather surprising for an mRNA construct, but something to keep an eye on.

 

Recombinant protein vaccines

Here we get to a technique that really is used for human vaccines. The previous two categories force your own cells to make viral antigen proteins, but here you’re making them industrially and just injecting them directly. The advantage can be that such protein production can be accomplished in many different ways and is already done on a large scale. That said, every new protein is a new project, with its own idiosyncrasies. A disadvantage is that this technique sometimes does not produce enough of a robust immune response by itself (at reasonable doses of protein, anyway), and needs added “adjuvants” as part of the vaccine formulation. These are substances that increase immunologic reaction – through mechanisms that honestly have not always been so well understood over the years (more here) and you’ll see these in the entries below.

Novavax: The company has been raising significant amounts of money as they push on with their recombinant vaccine (a Spike protein produced in an Sf9 insect cell system). Otherwise, there’s very little news – now everyone waits to see their Phase I results!

Clover Biopharmaceuticals: These folks are also teaming up with GSK to use their adjuvant, as well as testing their recombinant glycoprotein with another adjuvant from Dynavax. Dosing of these trial arms has already started; they were the second effort in the recombinant protein space to go into humans after Novavax.

Sanofi/GSK: This one, a recombinant version of the Spike protein along with GSK’s own adjuvant, has also had its timeline pushed up. Dosing was scheduled to start in December, but’s now slated for September, with rollout in mid-2021 if everything works. The GSK adjuvant is the one used in their shingles vaccine, and even before the pandemic the company had planned to make this the centerpiece of their vaccine programs. It’s a mixture of a bacterial lipid from a strain of Salmonella and an extract of the Chilean soapbark tree. “Saponin” compounds of that sort have long been known as adjuvants, but this one really seems to ring the bells. I certainly noticed a reaction when I got the shingles vaccine myself (particularly the second dose).

Zhifei Biological Products: Basically, all I know about this one is that it’s just been approved to go into human trials. There’s a lot of stuff going on in China – some of it (like CanSino’s) being well published, and some of it almost totally in the dark.

Queensland/CFL/GSK: Back at the end of April, the team at the University of Queensland announced preclinical results on antibody response to their vaccine candidate. They’re also looking at adjuvants from both GSK and Dynavax, and have partnered with several other companies for production and logistics so far. From what I can see, they’re recruiting patients now to start dosing next month. I’m not sure what the coronavirus situation is in Queensland itself, though – where will the majority of dosing be done?

Stabilitech: Here’s another small company working on oral vaccines, in this case with recombinant proteins (from what I can see). Their web site seem to claim to have formulations that have been through animal dosing, and says that they are ready to start human clinical trials “pending secured funding”. With all the money sloshing around in this area, I would have to assume that they have knocked on some doors, so we’ll see if this goes anywhere.

 

Attenuated Virus Vaccines:

This is another well-precedented vaccination technique. It involves producing a weakened form of the actual infectious virus, one that is not capable of causing damage but can still set off the immune system. There are several ways to do this, and it’s a bit of an art form involving taking the virus through a huge number of replications in living cells as you select for variants that are less and less harmful. An advantage is that such vaccines can be quite effective at raising a response – ideally, the immune system reacts exactly as it would to the real pathogen, except you avoid all the getting-sick part. A disadvantage is that part about it being an art form: balancing the lack of harm with immunogenicity is not something that can always be achieved. Some viruses have a wider window for this sort of thing than others, and it’s not easy (or possible, really) to know if this is a feasible pathway up front. That may well be one reason why (at the moment) I know of no candidate vaccines for this coronavirus that are using this method.

 

Inactivated Virus Vaccines:

This is also one that’s also been used in medical practice for many years, and it’s another inactivation step beyond the attenuated viruses. Heat or chemical agents are used to damage the virus to the point that it can no longer infect cells at all, but the plan is for there to be enough of the viral material left unaltered to still raise an immune response. Not the most high-tech approach, but it can definitely work. Many times, though, vaccines of this don’t provide enough of a response in a single shot, so you may be looking at a booster vaccine schedule. Interestingly, the Chinese groups seem to have this field to themselves; I’m not aware of any inactivated-virus vaccine for the pandemic that’s in serious development anywhere else.

SinoVac: When last heard from, the company had released positive Phase II data – well, some data. The full report on the trial is not out yet, but two weeks ago they issued a statement saying that over 90% of the participants had neutralizing antibodies at 14 days after dosing. That’s good news, but you’d want to see a lot more detail, such as actual antibody titers, and it hasn’t shown up yet (although SinoVac says it’s coming). Their Phase III trial will be starting shortly in Brazil – which given the epidemic situation there at the moment seems like (sadly) a good choice of venue. More on this one when more data show up.

SinoPharm/Wuhan Institute of Biological Products: This is the one that’s already being given to employees of Chinese state-owned companies who are traveling to high-risk areas overseas, so hey, why bother with clinical trial results? Well, anyway, the organization has announced that antibody titers were “high” in the initial trials, and the the seroconversion rates (at 28 days) were a flat 100%. One would like to see a full paper on these data, but I don’t know when (or if) that will ever show up; SinPharm seems to like to announce these things on Weibo and move on. The Phase III trials will take place in the United Arab Emirates, (and likely other locations as well?)

SinoPharm/Beijing Institute: This is the other SinoPharm vaccine, and just today the company has announced that it also passed safety trials and generated neutralizing antibodies. But this was another Weibo posting, so that’s all we have. I also have no clear idea about the differences between this one and the Wuhan-originated vaccine – all I know is that they’re both some form of inactivated coronavirus.

Institute of Medical Biology (China): Last week there was an announcement that this one had moved into Phase II testing, but we don’t know much more. There was a Phase I trial in May (China Daily link) with 200 people, whose results (as far as I can tell) have not been reported, either. Nor do we know anything about the method used to inactivate the virus in this candidate (just like the other two, actually).

 

OK, sheesh. There’s the state of the business as of today. I hope to use this post as a standing reference point for a little while to come, so I will be coming back in to update it as more news shows up. Right now we’re at an awkward age for vaccine development against this pathogen. Not all of these approaches are going to work, or at least not well enough to be useful. And we don’t have enough data on any of them to even start to guess which those might be. We can’t even do Phase II data comparisons, and the crucial Phase III data don’t even exist yet. So we’re going to be hanging in this limbo of “lots of things going, not sure about any of them yet” for quite a while. It’s going to get exhausting – what’s that, you say it’s kind of exhausting already? Hah – just you wait. . .

98 comments on “Coronavirus Vaccine Update, July 1”

  1. Barry says:

    Sounds like Altimmune (at least) takes the balance of IgA/IgG seriously, and aims for immunity at the lung surface (where infection happens) rather than in the plasma (where it’s convenient to measure).
    I’m sure recombinant protein vaccines can elicit IgG. I have no faith that that will protect against infection.

    1. Giannis says:

      All the vaccines that have been tried so far have protected lab animals from getting sick. That’s good enough for most of us.

      1. J says:

        I was worried about my pet rat. Glad to know that even if I get infected, there’s a way to keep him safe!

  2. evan says:

    How many of these efforts were begun with the original strain of sars-cov-2 and how many will be effective against the D614G strain dominant in the western hemisphere?

    1. Derek Lowe says:

      So far, there is no reason to think the antibodies for one do not cross-react with the other. But we do have to keep our eyes open. I know that Regeneron is dosing a cocktail of mAbs to try to forestall this sort of thing, for example.

    2. JasonP says:

      @evan

      check out this link as it describes how Regeneron expects to keep mutations from ‘escaping’ the ‘treatment.’

      https://science.sciencemag.org/content/early/2020/06/15/science.abd0831

  3. Steve Scott says:

    Vaxart is actually an adenovirus vaccine (AD5) and they claim it’s been formulated to overcome the problem of immunity to the AD5 including repeat doses. They also claim it has the potential to prevent infection altogether by stopping the invading virus in the upper mucosal system (nose, etc.) before it spreads. This is based on apparent success using this platform in a flu vaccine. And all in a pill. Yes, it all sounds too good to be true. Time will tell.
    https://vaxart.com/technology/

    1. Derek Lowe says:

      Ah, I saw them refer to their candidate as a “recombinant product”, but took that the wrong way. I’ll move them to the other category.

  4. Erik Dienemann says:

    Great stuff, thanks. Not sure if you traffic in predictions, but if you do, when do you think there will be a commercially available (launch at least, not doses for billions) vaccine, roughly speaking, i.e., 4Q20, 1Q21, etc.? I’ve been thinking by the end of the year, which I know is aggressive, but only because of the unprecedented sheer volume and quality of very well-funded scientific talent working on this in parallel in many companies/countries.

  5. nobody says:

    In other news, Gilead has jacked up the US price of Remdesivir from less than $20 for a course of treatment to over $2,000. Naturally, they’re claiming that this generous price is a humanitarian gesture and is not reflective of the true value of the drug. I’m sure the new price is completely reflective of the true desire of Gilead’s owners to buy multiple new houses each, however.

    I told you so.

    Concerns over finding the most effective COVID-19 treatments will be meaningless without measures to prevent price gouging. Even a 100% effective treatment or vaccine is useless if the industry is allowed to price such that the costs bankrupt patients, insurers, and national health providers (where applicable).

    Naturally, the people who develop medications certainly shouldn’t be expected to work for free, but it’s entirely reasonable that the investors who “own” them shouldn’t be permitted to extract enough money from the pandemic to buy several countries outright.

    1. Aleksei Besogonov says:

      This is not out of line with actual drug development and production costs. They are likely not going to make a lot of profit on it.

      1. Marko says:

        They’ll make a lot more profit than they would have absent Covid-19 :

        “…Remdesivir was developed with research funded by a $37.5 million NIH grant. The NIH plans to spend at least an additional $30 million on phase II trials of the medication this year. Since we’ve all paid for remdesivir’s development through our taxpayer dollars, it should be available to everyone who needs it at no cost.
        Instead, the Trump administration just granted Gilead, a giant pharmaceutical corporation, “orphan” drug status for remdesivir. That means that Gilead is free to charge outrageous prices for the drug, with their government-granted exclusivity ensuring that there will be no competition for years to come….”

        https://www.salon.com/2020/03/29/we-already-paid-for-covid-19-treatments-we-cannot-let-gilead-make-us-pay-again_partner/

        1. CantRememberSBhandle says:

          I do not work in the industry, so I’m guessing. BUT I would guess that Remdesivir cost many times that $37M government grant to develop; that might be been for some specific stage of development. New drugs today seem to cost billions, at least in the West.

        2. Derek Freyberg says:

          Gilead turned down (withdrew their application for) orphan drug status very soon after the story you mention.

          1. Marko says:

            Thanks , I hadn’t heard. That’s one big pharma abuse avoided , anyway.

            I guess they couldn’t take the heat , so exited the kitchen….

        3. Warren Thomas says:

          That’s not the M.O. of Orphan Drug Status, the purpose of that designation is to fast track FDA approval from 10 years down to 9 years and 363 days. Apart from the travel ban, Trump has been effectively immaterial to all things CoV since January, deferring leadership to that consummate putz, Fauci, whose inconsistency, conflicts of interest, and utter lack of peripheral vision in the midst of Remdesivir’s repeated clinical failures as to emergent therapies are staggering.

        4. Warren says:

          That’s not the M.O. of Orphan Drug Status, the purpose of that designation is to fast track FDA approval from 10 years down to 9 years and 363 days. Apart from the travel ban, Trump has been effectively immaterial to all things CoV since January, deferring leadership to that consummate putz, Fauci, whose inconsistency, conflicts of interest, and utter lack of peripheral vision in the midst of Remdesivir’s repeated clinical failures as to emergent therapies are staggering.

  6. Erik Dienemann says:

    Minor point, but your “Viral Vector” section states that, “A disadvantage is that this technique has not yet been used in human therapy.” Given that, I think the Merck vaccine collaborations with Iavi using the platform used successfully for Ebola shouldn’t be in this category, since obviously it’s a proven approach. Not sure on the Themis modified measles vector approach (i.e., whether that’s been approved for any viral disease yet).

    1. Derek Lowe says:

      No, that’s true! I was thinking of adenovirus vectors, but that’s quite right. I’ll reword. . .

  7. Mantis Toboggan says:

    I remember that nasal flu vaccine was generally inneffective, at least recently. Is there any reason why nasal COVID vaccines would be better?

  8. JasonP says:

    Thank you Derek! I can not imagine how many hours you have into research & reading in order to produce this thorough review! Much appreciated!

  9. Tony says:

    Queensland has virtually no covid cases. They might be able to dose down in Victoria, but even in that location results will be hard to see – maybe in healthcare workers on covid wards etc.

    1. Paul Young says:

      Phase 1 for the Molecular Clamp protein subunit will be in Brisbane, Queensland. We are only looking at safety and immunogenicity in this study so the fact that Australia has been successful at fully flattening the curve will not be an issue. Phase 2/3 will of course need to be conducted overseas.

  10. RA says:

    Thanks for an amazing summary of a lot of information!

    The differences between China and the rest of the world are striking. China is already deploying vaccines in some populations…is this because they are being “reckless” and/or do they have data (secret challenge trials?) that give them confidence. Or is it propaganda and they are not really administering their vaccines to travelers and military?

    And strange that is China the only one pursuing a tried and true strategy…inactivated virus vaccines….there are so many western efforts…weird why there is not one western company using this strategy.

    Was also pleased to see that there is an intranasal option being looked at…seems like we need more attention to the defenses where the infection actually enters the body! It’s too bad that it is so early stage and only a viral vector approach…wish that there where more of these efforts with different mechanisms…is it plausible to do mRNA, Protein, inactivated virus, etc through intranasal administration. To be clear, I am skeptical anything intranasal would be effective by itself…but I wonder whether it would be helpful as an adjunct to an IM vaccine to get to sterilizing immunity so that the vaccinated don’t spread the virus to the unprotected.

    The vaxart effort is intriguing, but I am unclear on how increasing enteral mucosal response through a pill would do much to improve respiratory mucosal response. I can see how an oral route makes sense for an enteric virus, but not for a respiratory virus. I have heard there is work on an oral flu vaccine too, so I guess there must be some promising mechanism to pursue…but I find it surprising!

    1. Marko says:

      “… I am unclear on how increasing enteral mucosal response through a pill would do much to improve respiratory mucosal response. ”

      I think the general idea behind oral administration ( as well as nasal ) is its tendency to stimulate a secretory immune response , regardless of the target mucosa.

      1. nobody says:

        Would a vaccine designed to provoke a mucosal response provide any protection against infection through open cuts or other entry points that are not protected by mucous membranes?

        1. Barry says:

          Which class of antibody is evoked depends on Class Switching
          https://en.wikipedia.org/wiki/Immunoglobulin_class_switching#:~:text=Class%20switching%20occurs%20after%20activation,D)J%20recombination%2C%20but%20possessing

          but yes, IgG seems to be the default that will be elicited by any antigen. It’s the IgA that’s elective.And IgG would have a play on any pathogen introduced through broken skin.

      2. Barry says:

        I’m no immunologist, but if I have this right, IgA are produced by leukocytes and dumped initially into the plasma compartment. From there, their Fc is recognized by “secretory component” displayed on the basolateral surface of mucosal epithelial cells. That SecretoryComponent/IgA complex then transits the epithelial cytosol* and the IgA is secreted from the apical side of the cell.
        So it shouldn’t matter which mucosal membrane you immunize. If you elicit a robust IgA response, all the mucosa should be protected.

        *so yes, at least transiently, these antibodies to get to patrol the cytosol

    2. confused says:

      >>China is already deploying vaccines in some populations…is this because they are being “reckless”

      Well, military are expected to take higher risks than the average person anyway. Arguably testing a vaccine isn’t that different … ultimately it’s exposing a relatively few people to more risk to protect everyone else.

      Perhaps they would think that we are being excessively over-cautious and thus extending the pandemic longer than necessary.

      And China’s society and government likely finds this sort of thing much more palatable than most of the Western world. The balance of government authority vs individual rights is quite different.

      (Although I’d really feel a lot better about it if it were non-military, so genuine consent was more clear. I’d be perfectly willing to get an experimental COVID vaccine, and think that the US is generally over-cautious about this sort of thing, but informed consent is absolutely critical.)

    3. Thomas Kunz says:

      Another cause for concern this fall:

      ⁦‪@CNBC‬⁩
      New strain of flu in China has potential to become a pandemic, scientists warn cnb.cx/31u4DJX

      6/30/20, 4:42 AM

      1. Barry says:

        This “new strain” is H1N1. It would not arrive in a naive population; many of us (20% of the U.S.) survived H1N1 in 2009

        1. eub says:

          “Avian-line” EA H1N1 is not your stock human-circulating H1N1 and apparently shows some level of antigenic difference, is the stated concern.

          The PNAS paper’s abstract (linked) states “Moreover, low antigenic cross-reactivity of human influenza vaccine strains with G4 reassortant EA H1N1 virus indicates that preexisting population immunity does not provide protection against G4 viruses.”

          A 2013 paper (doi:10.3201/eid1910.130420) on EA H1N1 said it was antigenically “different from” seasonal H1N1, but the standard 2012-2013 vaccine was moderately protective.

  11. David says:

    I’m baffled as to how Merck/Themis intend to use a measles virus as a COVID-19 vaccine vector. Isn’t the measles vaccine, which most of us have received, the paradigm example of one that elicits a lifetime sterilizing immune reaction? Who are they going to test it on, the children of anti-vaxxers?

    1. eub says:

      They claim (linked from my name) “functionality of the technology in humans even in the presence of pre-existing anti-measles immunity” for their Chikungunya candidate.

      “Previous experiments in animal models had so far shown that pre-existing antibodies do not impair the ability of the MV vector to replicate and to induce humoral and cellular responses.”

      “To assess the impact of pre-existing measles-immunity, a group of [CD46-IFNAR] mice was immunized with the empty MV strain one month before immunization with MV-CHIKV. No impact was detected and all mice in this group were protected against challenge with CHIKV.”

      “To particularly address the question of impact of pre-existing measles immunity, this study included a group in which the [human, wild-type] subjects were immunized with the MMR vaccine Priorix®, one month before the first immunization with MV-CHIK (n = 34). No effect on the antibody response to chikungunya was found, confirming the previous results that pre-existing immunity to measles does not affect the immunogenicity of MV-CHIK.”

      I have no idea how this works! Or, well, as they put it:

      “The mechanism of the escape of the measles vector from pre-existing immunity needs to be further evaluated [31]. It could potentially be linked to the higher dose of recombinant MV vaccine used or to the fact that measles virus spreads from cell to cell by cell contact in vivo, thus escaping from neutralizing antibodies. Also, upon cell infection, recombinant MV express measles proteins as well as heterologous antigens in professional antigen-presenting cells. While the measles particles are assembled and released from infected cells, heterologous antigens are either secreted or expressed on the cell surface, depending on the nature of the antigen, and stimulate the immune response in spite of measles neutralizing antibodies. Lastly, it has recently been shown that antigens expressed from replicating MV vectors are naturally adjuvanted through defective interfering genomes produced by the recombinant virus, contributing to robust induction of interferon and conferring vaccine efficacy [72].”

  12. Chris h says:

    Your updates have been great!

    Do you have any thoughts why human challenge studies are not being pursued? It’s a puzzle to me.

  13. Nameless says:

    How do the mRNA/DNA vaccines end up in the cell to start the protein production process? Are there transporters to move through the membrane?

    All my med chem training screams that a nucleic acid is too large, polar and charged to even look at a membrane.

    1. Mammalian scale-up person says:

      Yes, they can be formulated as liposomes to facilitate membrane fusion. Coat it in detergent and grease.

      1. Steve Scott says:

        Here is a longer explanation of how mRNA vaccines penetrate into the outer layer of a cell. They do not go into the center of the cell where DNA is located.
        https://medium.com/beingwell/covid-19-vaccine-may-be-available-in-fall-a90692e9c441

  14. eub says:

    The way these things work is to deliver messenger RNA that codes not only for the antigen protein of interest, but for an RNA polymerase enzyme (there’s a useful one that’s been borrow from alphaviruses) that will turn around and make more copies of the mRNA itself.

    Well that sounds pretty Sorcerer’s Apprentice. A non-pathogenic pure-RNA virus, basically?

    What’s the endgame with this, that keeps it from replicating indefinitely? Does the alphavirus RNA polymerase get presented as an antigen?

    1. A Nonny Mouse says:

      My daughter has volunteered for this trial (Imperial) and it seems that there will be a second dose given after a month. Clearly, then, they don’t expect it to keep on replicating or this would not be needed.

      The first volunteer was, by the way, given 0.1 microgram of the material. Next 15 increasing dose and the next 300 mixed dosage.

      1. eub says:

        Yeah, it can’t, there’s bound to be something that stops it (or RNA would have eaten us all), but I am curious what it is!

        1. Thomas says:

          Perhaps, as a self-concocted RNA virus goes, it will be stopped in its tracks by our (innate) immune system?
          This virus would omit the ‘block the immune system’ parts that viruses tend to have.
          At least that is my guess; my understanding is that pathogenic viruses have these mechanisms or they do not stand a chance.

        2. Barry says:

          This is what biologists call “The RedQueen’s Race”. Pathogens mutate and succeed among some of the population. Others prove less susceptible, and have a better chance of passing their genes to future generations. Our species has survived many novel pathogens in the past. But many individual humans have succumbed. Until ca. 500yrs ago, a novel pathogen could arise locally, devastate or wipe out a whole population, and die out. In the 21st c., that sort of containment is much much harder.

          1. confused says:

            Well, I don’t think containment was very effective back then. There was basically no contact between Eurasia-Africa and the Americas, or between either of those and Australia, so novel pathogens didn’t go truly global before the Age of Discovery, sure.

            But things like the Plague of Justinian, the Black Death, and measles (which I’ve read is now thought from genetic evidence to have originated c. 900-1000 years ago) spread all across the Old World pretty effectively. That’s not really “containment”.

            Even things like the ‘English sweat’/’sweating sickness’ (sudor anglicus) which hasn’t been seen in centuries did spread outside England.

            Are there really cases of diseases dying out because they devastated or wiped out one isolated population? Certainly some Pacific islands and Native American groups were completely devastated by smallpox and measles, but those are cases where a disease was introduced into an isolated population from a larger more connected one, not where it originated in the isolated population.

          2. Derek Lowe says:

            I think if there were such diseases, we never heard about them – it could possibly have happened to relatively isolated populations in prehistory, who were never seen again.

            As an aside, contemporary accounts of the Plague of Justinian are fit to make your hair stand straight up.

          3. confused says:

            Oh yeah, it’s totally possible it could have happened several times and not been recorded. I just thought the implication was that we had evidence that this *did* happen.

            Yeah, reading about those sorts of things is really stark. The Black Death too.

  15. Lambchops says:

    If anyone is interested in proposals for how vaccines could be paid for it’s well worth having a look at some of the materials related to the Office of Health Economic’s Annual lecture: https://www.ohe.org/news/2020-ohe-annual-lecture-explores-question-how-should-world-pay-covid-19-vaccine

    The approach being advocated here is a value based advanced commitment, the idea being (in simplistic terms) that this will allow middle income countries to commit to vaccine spending (in the knowledge that it will scale in a predetermined way with the efficacy of any approved vaccine and their ability to pay). This will in turn mean that companies can be more confident in having a revenue stream from these countries that may have been far from guaranteed using other payment models, plus it will provide an incentive to companies who may be coming later to market, but with better efficacy as the value based element limits the spend on inferior products which don’t perform as hoped. More detail and a much better explantion in the following: https://www.cgdev.org/publication/leave-no-one-behind-using-benefit-based-advance-market-commitment-covid-vaccine

  16. Doug says:

    Stupid procedural question from non-science-person:

    Other than strategic withholding (for, say, economic or any other reasons), what is the hold-up on the release of data? Over and over again, you note that these companies have announced completion of this-or-that phase with “data coming soon.” I’m sure there’s lots of processing and statistical wizardry involved in producing data for consumption. But if someone knows beforehand the size of their trial and what data they’re collecting during it and what they want to show with it, why wouldn’t all the computational programming work be done so that you just have to feed the data into the computer and get your results? Surely it doesn’t take literally weeks to crunch numbers for trials of, say, 200 people?

    I don’t get it. Someone please explain!

    1. bks says:

      Never attribute to malice that which can be explained by stupidity, but never attribute to stupidity that which can be explained by greed.

    2. Ian Malone says:

      From my limited perspective, a few possibilities.
      One is for less time critical situations, releasing the data is often a case of packaging the headline figure (efficacy) up with a lot of other measures, things like compliance, adverse advents, other related makers, sub-group analyses. You may have more complex statistical techniques you also want to apply if you find unusual things in the data (but this is unlikely in cases where the outcome was clear-cut). Early releases of results (rather than the full report) may need peer review.
      Data reconciliation and queries, you’re collecting multi-site data, depending what data you’re collecting there is potentially a process of checking what you’ve got is the correct data. There will be separate teams involved (statistics, labs, site coordinators) and you’ve got to be sure everyone has what they’re supposed to have, data cleaning is another step.
      The ideal is certainly that you pre-specify all your analysis and data processing, there are even tools that would let you just push raw figures in one end and have the numbers in your (otherwise pre-written) report filled in at the other. That requires a fair amount of work to set up in advance though, you’ve got to pre-specify all your data formats, shake out any issues in how things have been recorded and test it to death. To some degree this takes place as part of planned futility analysis and interim analysis, but you don’t want to be constantly calculating p-values as this is actually a form of multiple comparisons.
      Under normal circumstances the different teams and individuals involved are likely to be working on multiple things, so delays will crop up due to project schedules. If you’re in a situation where there’s one project that can take priority over all others then you might be able to commit the people to make sure everything is as ready as it can be in advance. The turnaround of the UK Recovery trial dexamethasone arm is an example.

  17. Tcell says:

    Imagine the T-cell response is most important (would explain why young people are less vulnerable: rich T-cell population in contrast with elderly). This paper shows that protective T-cells can be generated even without observing seroconversion: https://doi.org/10.1101/2020.06.21.20132449 . To this end inactivated virus vaccin may provide the best peptide antigen pool for activating T-cells directed to Sars Cov2 epitopes.

    1. RA says:

      Saw this twitter thread that makes the same point you do:

      https://twitter.com/BallouxFrancois/status/1277885591376535553

      Why on Earth is there little interest in inactivated vaccines outside of China, where there are multiple in development?!?!?!

      Is it that the Chinese are focused on reliably protecting their population while Western companies are more interested in using the pandemic as an opportunity to advance new technologies they have already been working on for other problems?!?!

      I would love a scientific explanation for why it is wise for western companies to put nearly all their eggs in unproven mechanistic “baskets!”

      1. Mammalian scale-up person says:

        Do you want to grow a 20,000L tank of a BSL-3, add some chaotropic buffer to release more virus particles (because you really, really, do NOT want to use a commercial homogenizer that uses a 1000psi pressure drop to lyse the cells), then run it slowly through a heat exchanger into a closed tank with a dash of detergent that nevertheless must be vented *somewhere*, hopefully via a lot of UV bulbs stuffed into the air break and hope very very much that 99.9999% of the viruses got killed and despite the massive hurry we are all in, all your seals and elastomers are virus-tight and absolutely nobody cut any corners on safety or complained about having to buy so many high-wattage UV bulbs and cheaped out on you? Nobody was in such an almighty hurry that they maybe skipped some limit switch testing to be sure that every single valve position for about 1000 valves in your facility was being correctly tracked by the automation?

        Me neither.

        Did it once, that was enough for a lifetime. Still have the scars from the time during PQ when a burst disk ruptured and sprayed everyone in the room with a mix of pressurized BSL-3 bugs and hot caustic wash. There was one safety shower for 10 people. If I’m going to get drenched in overpressurized process intermediate again, I’d rather it be some Ad5 that’ll just make me a little sneezy, or recombinant spike that’s like a shower of chicken broth.

        1. RA says:

          That is really illuminating….thanks for vividly showing us what is really involved behind the scenes! So, if I understand you correctly, you are saying that it is too dangerous to produce and scale up an inactivated vaccine when the virus is so virulent and our production safety processes inadequate.

          So, then is the reason that the Chinese are nearly monopolizing the inactivated vaccine space that they have better safety processes and/or they are more willing to sacrifice/expose some of the workers who would have to produce such a vaccine? Or is it something else?

          1. Mammalian scale-up person says:

            Correct, the virus doesn’t start off as inactivated…it starts very much alive (as much as viruses live, anyway) and has to be inactivated once the fermentation reaches a certain titer. Easiest thing is to run through a shell-and-tube heat exchanger and add some detergent, which can both be done as closed processes that don’t expose people *very much* but most of our sterile filtration systems are meant to filter bacteria, not viruses. There’s a lot of additional piping and infrastructure involved in adding virus inactivation traps to exhaust lines and biowaste drains. And it’s pretty difficult to find a pinhole leak in valve diaphragm #598 even though we routinely do pre-use pressure testing.

            Maybe they are willing to buy every UV light made in China, which is a lot to be sure. Maybe they already have some existing BSL-3 facility they can use to start production. Maybe they are going to use people whose safety they don’t care about to make the stuff, labor conditions in other industries (e.g. electronics) don’t seem to bother them much. Maybe they have enough recovered people who would have convalescent antibodies, that they can run a facility with no fear of infection. Maybe they’re going to automate the holy heck out of it, to a level we haven’t seen before, though this level of automation would have a longer build-out and validation time.

            There’s a few options for handling these things, but growing out anything a BSL-3 or on the Select Agents list at commercial scale is generally frowned upon in the US after 9/11. There’s a lot of additional security and monitoring, because the Department of Defense gets a bit, uh, ANXIOUS about uncontrolled lab strains being accessible to more than a handful of people (whether this is reasonable or not, given the natural abundance of such things, is a different debate). So you need additional facility controls around that, and it’s just…a lot. It’s not impossible, it’s just more crap to deal with, and more time and expense to get a facility up and running, and then you have to have it dedicated to only that one product, you can’t make other stuff without doing a total facility clearance, and how many live BSL-3s are you going to grow up at scale, really? The permitting for those buildings often takes years, with a lot of public hearings that are really no fun at all. Whatever time you save from using the proven efficacious method is wiped out by the need to build a whole new building with additional environmental controls from the ground up and not being able to use existing facilities.

          2. confused says:

            It does seem a bit odd that the permitting steps couldn’t be skipped or greatly expedited in “emergency conditions”, though. I mean, surely a lab-escape of COVID wouldn’t be very significant since the “wild” virus is already basically everywhere in the US?

          3. Mammalian scale-up person says:

            Confused – you know, if there were government support for such a thing, that would be wonderfully useful. There are many, many aspects of making vaccines that the government could be a huge help with, including logistics and other siting concerns (infrastructure for water supply etc). Unfortunately, we are not so lucky and can hardly get a comprehensive support for “wear a mask and keep your cooties to yourself,” let alone support for permit waivers…

          4. RA says:

            Thanks again for the insights! Seems like there are multiple barriers to making an inactivated vaccine. I learned a lot from what you wrote.

            When we put everything together, seems very possible that at the end of the day, we are going to be dependent on a Chinese vaccine to end the outbreak.

            Are we being duped in America?

            – High probability success approach pursued by Chinese, not American/western companies

            – Western companies, eager to show they are “working hard” to end the pandemic, actually taking advantage of taxpayer money to accelerate the technologies of the future…which even if they fail for COVID (who cares, no money to be made there!), will lead to patents and profits for other uses down the road….a long con, so to speak.

            – Sketchy data release processes to string us along, amplified by a scientifically illiterate media ….i.e. incomplete results being released by press release (followed by stock dumping!). When results are released, focusing only on Abs, withholding data on tcell responses, etc. Que the headlines for promising results!

            – A sketchy process by the administration to pick 5 top candidates with little scientific input…main goal is to give false hope, get an EUA before election, whether or not it actually works well is not important as we won’t know that for sure until after the election. FDA laying the groundwork now by setting the bar low for vaccine approval…50% effectiveness needed only! Maybe that’s about what we can expect from the “new and improved” mechanisms! Great!!!!

            – Meanwhile, China gets a huge geopolitical boost by having a monopoly over the most effective vaccine…after they gave the world the virus in the first place!!!! Awesome! USA, USA!

            Hope this scenario does not come true. Hope the new approaches work in real life! But dang, if we get a crap vaccine and the Chinese have a good one, I wonder if there will be pitchforks for the US Pharma industry….not just from “socialists,” but national security hawks too….this BS leaves us so vulnerable to a bioattack.

            I mean, the justification for high prices for Americans is that we supposedly benefit from the innovation when Pharma can make huge profits. But if the industry (and the elected officials it has paid for) can’t out-perform the Chinese in securing our health and safety, then it will be interesting to see whether their big-money lobbying can save them from significant future regulation. If we give you all that money and the outcome is “inject them with the Wuhan Flu (vaccine),” to quote the great Sacha Baron Cohen, that is not going to go over well!!!

          5. Derek Lowe says:

            Today’s mRNA results poke a few holes in this theory, perhaps. We’ll see. . .

          6. RA says:

            Meh. Tea leaves, but not t-cells from Pfizer. We’ll see indeed! Gonna take more than IgG levels to take me off the cynical ledge! FREE THE DATA!!!!

          7. confused says:

            @Mammalian scale-up person: yeah, but I would have thought the current administration would be more likely to go along with waiving regulatory barriers than with broad population-affecting measures.

            @RA: 50% effectiveness is IIRC comparable to the flu vaccine. Not great, but a 50% effective vaccine, combined with treatment improvements that are already happening (and probably will be a lot farther along), could make this thing a lot less scary.

            Especially since IIRC the flu vaccine reduces the severity of flu even if you do catch it. If the same’s true here, even a fairly poor vaccine could knock COVID down to a severity more like a “regular respiratory virus” that we don’t worry about much.

          8. RA says:

            https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-takes-action-help-facilitate-timely-development-safe-effective-covid

            “It conveys that the FDA would expect that a COVID-19 vaccine would prevent disease or decrease its severity in at least 50% of people who are vaccinated.”

            So, I think it depends on what 50% we are talking about and how much. Seems like you could shorten the duration of illness by a few days in your younger participants, do nothing for your older ones, and meet the definition. A step in the right direction, yes. Worth taking if nothing better, yes. Equal or better than the best Chinese vaccine? Hmmmmm.

            I think of the hype about Remdesivir…yes, a step in the right direction for treatment, but not a game-changer. Worried about similar hype for a new-fangled mRNA vaccine while the Chinese make an inactivated virus vaccine that actually confers more protection. Hope I am wrong!!!!

          9. Mammalian scale-up person says:

            RA – I would not say we are being fooled to be reliant on the Chinese, no. Some of the platforms have previous demonstration of Ph 3 efficacy (Merck’s VSV platform is good, the JnJ platform is just about to be approved on Ebola as well). Recombinant spike that Sanofi-GSK are pursuing is no different a concept than other recombinant surface molecules (hep B, HPV, shingles vaccines are all recombinant capsid subunits). In terms of manufacturability, the adenovirus and VSV platforms are very easily scaled and the dosing is much lower – so easy enough to make quickly with existing equipment and facilities. It’s actually a lot easier to make the adenovirus stuff than the RNA things, we don’t have a ton of liposome pilot-scale facilities just laying around waiting for occupancy. If you told me I needed to make ONE of these vaccines starting tomorrow, those ones I can at least whip something up pretty quickly with what I have in the warehouse.

            @Confused – It seems to me that the current government has been all around incompetent in every imaginable way. Which isn’t terribly surprising, given their individual histories of failure.

        2. EJ says:

          I gotta say, I really enjoyed this thread.

  18. bofh says:

    I just came to thank you for your articles. They strike me as a great balance of science and popular – easy enough to be read by a layman, fact and information packed enough to be easily verifiable and thus trustworthy.

    Thank you very much, Derek!

  19. Lambchops says:

    Tired to post a link to something that may be of interest to those wondering how we could possibly be paying for these vaccines but I think it fell afoul of the spam filter.

    The Office for Health Economics annual lecture considered this very issue, there’s some good reading in the links of this news article:

    https://www.ohe.org/news/2020-ohe-annual-lecture-explores-question-how-should-world-pay-covid-19-vaccine

  20. Toni says:

    Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19
    https://www.biorxiv.org/content/10.1101/2020.06.29.174888v1

  21. JIA says:

    Hi Derek, you wrote about viral vectors: “A disadvantage is that this technique (as far as I can tell) has only once been used in human therapy (the Ebola vaccine, see below)”. But Adeno-associated virus (AAV)–mediated gene therapy is being used successfully* for gene therapy in hemophilia A & B, with one product (BioMarin, valoctocogene roxaparvovec (valrox)) that has been filed for approval with FDA in February. Competitors include Spark Therapeutics, Sangamo, Pfizer, and others — it’s a pretty healthy field.

    *I put an asterisk here, because BioMarin is seeing declining production of the FVIII therapeutic protein in their treated patients… whether the therapy will last for a patient’s lifetime remains to be seen.

  22. Squad Squad says:

    Please don’t use “pre-existing”. They were simply “existing antibodies”.

    1. dwh says:

      The term “pre-existing antibodies” is correct as used in the post. One could be a little more precise in terminology by using “pre-existing anti-vector antibodies”, but it is a commonly used term in the field to describe antibodies that the recipient exhibits prior to the initiation of the immunization regimen. The term is used to differentiate from the antibody response which is raised due to the vaccine administration itself. Its use is primarily directed at antibodies which are specific for the vector you are using to deliver the vaccine, but not the target antigen itself. In the context of SARS-CoV-2, this means the pre-existing antibodies against the surface antigens of the adenovirus (or other virus) carrying the sequence for the SARS-CoV-2 spike antigen. This is an important consideration for the use of live viruses as vaccine vectors since the “pre-existing” immune responses can inhibit the activity of the vector and prevent the recipient from developing the desired immune response. As pointed out by Derek, you need to consider that the administration of the vaccine itself will also elicit anti-vector immune responses that can inhibit subsequent dosing. These are typically referred to as “vector-induced antibodies”.

  23. Calvin says:

    Pfizer’s “We’re not part or Warp Speed, we don’t need the money” reeks of a company that has been rejected. Call me a cynic.

  24. Doug says:

    There seems to be a number of people who have made comments in this forum who are very knowledgeable about vaccines and the science behind them. What are your opinions about the best prospects for an effective and safe vaccine and the timeline it can be achieved.

  25. Jonathan B says:

    For how long do the nucleic acid and viral vector vaccines present antigen in the body?

    From “No, in this case each viral particle that you’re injected with will be able to infect one cell, and that’s it” I gather its not for very long… although my understanding is that the measles vector at the very least is replication competent?? Not sure about VSV and the adenos. My admittedly low level understanding of this field is that most adjuvants work by sustained release of the virus, enabling the long term presentation needed to train B cells – do these various rna and viral vectors provide sustained release of the antigen in the body? What kind of adjuvants do moderna et al use with these delivery methods?

  26. Jonathan B says:

    Anyone know what GSK’s special adjuvant is that everyone wants to use? Whats so good about it?
    Also, what are some examples of non-VLP subunit vaccines against viruses that have actually made it through clinical trials into production??

    1. Derek Lowe says:

      There’s a brief description of it and a couple of links later down in the post – it’s a mixture of two components.

      1. Jonathan B says:

        Thanks!

  27. Jonathan B says:

    Re University of Queensland “molecular clamp” technology how good is this really? Nice concept about holding the antigen in a native conformation like state, exposing the relevant residues to the immune system. But I am quite suspicious that a few simple alpha-helix are all thats needed to stabilise the conformation – and that one size fits all in that they apply the same helices to the various viruses theyve tested through their pipeline?? Can someone confirm this is actually what they do? Couldnt find many publications on this when i briefly looked into it, would be very interested to hear some opinions.

    1. Paul Young says:

      Can confirm this is what the Molecular Clamp does, but it’s 6 helices forming a very stable six-helical bundle. That’s what so effectively stabilises the structure. We were a bit surprised ourselves that it has worked so well for so many different viruses – but empirical testing shows that to be the case. We have been accumulating full data sets for publication which will hopefully be out soon.

  28. Calvin says:

    General consensus (in the virology community) still seems to be that the AZ-Oxford vaccine is ahead but unlikely to actually work. 2 doses are almost certainly going to be required which makes it quite a manufacturing challenge and deployment could be a massive hurdle. I can only assume they are continuing on the basis that if there is nothing else, then something is better than nothing.

  29. MagickChicken says:

    I volunteered for the Pfizer/BioNTech trial (two years), the packet is in the mail. I’ll let everyone know if it kills me.

    1. Some idiot says:

      How? 😉

  30. Ilya says:

    Of course we have “putting the cart before the horse” in Russian (ставить телегу впереди лошади), as it most certainly has antique roots. We also have “running in front of the steam train” metaphor, which suits the case even better.

    Many experts claimed this testing in Gamaleya institute a serious breach of the medical ethics. The staff isn’t independent from the director, and using the vaccines on them _before_ even testing it on mice is a serous misconduct. Moreover, they now have a strong incentive to forge the results, otherwise their reputation will suffer.

  31. Marko says:

    Gotta love the Pfizer CEO comment : He stayed away from “Operation Warp Speed” because he wants to move quickly.

    Ouch !

  32. Martin A says:

    Derek, thanks for the time and effort put into these blogs, really appreciate it.

    As a layman one thing I have been wondering about for a while is whether we would get any leaks from people involved in the various trials about the efficacy and effectiveness of the vaccines (good or bad). What are your thoughts, if a certain vaccine was to be performing really well (or badly for that matter) even at the earlier stages, do you think we will start to hear rumblings way before the trial ends?

  33. Lea Vogt says:

    Hi Derek,
    I’m studying in Tuebingen and as far as I know a first test person got Curevac’s vaccine last friday. More are going to follow and they are recruiting test persons in Munich as well.
    So, I would say they acctually started their phase I in June 😉

  34. ghost of q.mensch says:

    How do you tell when a Pfizer CEO is Lying?…

    June 29: “Pfizer/BioNTech: Not much news here, but we definitely will be getting some. This effort started out with four different mRNA approaches, and there’s no word on if they’ve narrowed things down yet.

    Pfizer’s CEO Albert Bourla said recently that they’re sticking to a strict policy of not commenting on their vaccine results until they’re published in a journal.

    July 1: ““We are encouraged by the clinical data of BNT162b1, one of four mRNA constructs we are evaluating clinically, and for which we have positive, preliminary, topline findings,” Kathrin Jansen, head of Pfizer’s vaccine research and development, said in a press release….”

    https://www.cnbc.com/2020/07/01/pfizer-stock-jumps-after-it-reports-positive-data-in-early-stage-coronavirus-vaccine-trial.html

    1. Derek Lowe says:

      At least it’s a preprint manuscript full of data, rather than a press release, right?

      1. ghost of q.mensch says:

        Found the submitted manuscript (16 pgs) : https://www.medrxiv.org/content/10.1101/2020.06.30.20142570v1.full.pdf

        Study was run on 45 healthy young adults (avg age 35.4yr) between 04 May 2020 and 19 June 2020.

        -“Study Design and Demographics
        Between 04 May 2020 and 19 June 2020, 76 subjects were screened, and 45 participants were randomized and vaccinated. Twelve participants per dose level (10 μg and 30 μg), were
        vaccinated with BNT162b1 on Days 1 and 21 and 12 participants received a 100 μg dose on Day1. Nine participants received placebo (Figure 1).

        The study population consisted of healthy male and nonpregnant female participants with a mean age of 35.4 years (range 19 to 54 years); 51.1%were male and 48.9% were female. Most participants were white (82.2%) and nonHispanic/non-Latino (93.3%) (Extended Data Table 1). “

        1. Derek Lowe says:

          There’s a whole post on this on the top of the blog now, actually. Very interesting stuff.

  35. Nathan Williams says:

    Do we expect there to be Phase I failures, generally – and would we hear about it if they did? I’m sure none of them want to, of course, but this seems like there’s so many different projects that statistically, one of them has to step on the rake, right? That all of them clear that stage starts to be a little worrying, but I don’t know what the expectation is.

    1. Derek Lowe says:

      Certainly possible, but honestly, I’d say that the mRNA vaccines are about the furthest-out-there platform of all the major efforts. So if those work (like today’s results), I think that the others will, too, if by “work” we mean “generate increased neutralizing antibodies”. How these correlate with actual protection from the virus is another thing entirely, but those will be Phase II and Phase III failures, won’t they?

    2. confused says:

      As a total lay observer (my field is environmental, not immunology) I wonder if this means that biotech has advanced enough in the last decade or so that the trial and error component of development is less?

  36. Jürgen Bosch says:

    CureVac’s trial: NCT04449276

    Thanks Derek for the detailed uodates – that’s a lot of work to stay on top of things that get published.

    *noticed that I posted it in the Pfizer section

  37. MissMoo says:

    I’m pretty sure the GSK/Sanofi vaccine uses the AS03 pandemic adjuvant not the AS01 (Shingrix) adjuvant. Their head of vaccines said on a call in late April “It’s a proven adjuvant that we had supplied before. It’s our adjuvant system number 3”.

  38. Not an immunologist, nor a financial guru but I think this information might shed light on Moderna and its COVID-19 vaccine:

    May/27/2020:
    https://www.statnews.com/2020/05/27/moderna-executives-cashed-out-shares-stock-price-soared/
    The day after the “breakthrough” in vaccine development was announced there was a major internal sell off of the Moderna shares. My thinking: If you think something is good, and will only gain in value, why do you sell it?

    July/02/2020:
    https://www.marketwatch.com/story/modernas-stock-falls-following-report-that-the-phase-3-coronavirus-vaccine-trial-has-been-delayed-2020-07-02
    Moderna’s stock falls following report that the Phase 3 coronavirus vaccine trial has been delayed

    Thank you for your attention. Peter

  39. daksya says:

    India looks to be aiming for an aggressive launch date for one of its vaccine candidates

    “The first made-in-India coronavirus vaccine may be launched by August 15, with the Indian Council of Medical Research (ICMR) fast-tracking efforts to develop “Covaxin” in partnership with Bharat Biotech International Limited.”

    “The ICMR talked about plans to launch the vaccine for public health use by August 15, Independence Day.

    “It is envisaged to launch the vaccine for public health use latest by 15th August 2020 after completion of all clinical trials,” said the research body.”

    https://www.ndtv.com/india-news/indias-first-coronavirus-vaccine-may-be-launched-by-august-15-2256269

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