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Coronavirus Vaccine Roundup, Early September

It’s been a while since I went through the whole vaccine landscape (I’ve been putting it off!), but there’s a lot to catch up on. I’m going to incorporate some slightly reworked material from my July post in the introduction to each vaccine class, for reference, but everything on the candidates themselves is updated information. That earlier post includes more background on each specific candidate that I won’t be repeating here. Search for “update:” to see information added after this post was first published.

Update: (September 17) see here for a good roundup of lesser-known vaccine candidates.

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, these proteins 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), although it’s had a lot of work from a lot of groups over the years. Things have now accelerated, a phrase that you can just keep using these days. Another disadvantage is that if you pick a viral vector that infects people anyway, 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 your carefully engineered 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 one has been in thousands of patients in the UK, Brazil, and South Africa, and the team recently announced a trial in the US as well. And even though I just finished up talking about how booster shots with a viral vector can be tricky, that’s exactly what they’re studying: two doses, four weeks apart. Clinical results released in late July looked promising. There have been a number of supply deals announced, with this being the latest one, and both the EU and the US have paid to reserve hundreds of millions of doses if the clinical results are sufficient for a rollout. Update: (September 9) this trial has been paused as of September 8 on reports of a serious adverse event, likely transverse myelitis. More here, but this is an evolving story. Update: (September 17) the trial has resumed in the UK, but remains paused as of today in the US. See here for more. And a trial is starting to look at this one as an inhaled formulation as well.

CanSino/AMMS: we had clinical data from this one at about the same time as the Oxford publication. And you could indeed see the preexisting-immunity problem with this adenovirus (the more common human-infecting Ad5, as opposed to the Oxford chimpanzee adenovirus); the paper itself stated that this was a big concern. Update: (September 17) the company is defending their choice of vectors. CanSino has just cancelled plans for a Phase III trial in Canada, for reasons that frankly are still obscure – probably politics, but to be honest, Canada is doing pretty well with the pandemic and is probably not a good place to collect Phase III data to start with. But they’re starting a 5,000 patient trial in Saudi Arabia, and have announced a Phase III in Russia, with plans to go into Pakistan and Mexico as well. Now those populations could have plenty of coronavirus cases, unfortunately. But I remain skeptical that the Ad5 platform is going to come through – existing immunity varies in different populations around the world, but in general it looks like too many people already have antibodies to the vector itself. Update: (September 15) more on the role of China’s People’s Liberation Army in the development of this candidate.

Johnson & Johnson (Janssen): these folks have another obscure adenovirus (Ad26) in an attempt to avoid those problems. They’ve announced a Phase III trial starting this month that looks like the largest in the field (up to 60,000 patients) in locations all around the world. They’ve also been signing deals for reserving hundreds of millions of doses, should things work out, and continue to expand their manufacturing capacity. From what I can see, they’re the only ones at present who are not running a booster-shot trial, which could be an interested logistical advantage for them. Update: (September 15) looks like a trial has started in Spain as well. Considering how the coronavirus has come roaring back there, that’s good timing. But because of the AstraZeneca/Oxford problems, there are reports of people backing out.

Gamaleya Research Institute: this one is a two-shot dosing program, but one of them is an Ad5 vector and the other is an Ad26. This is the Russian vaccine that made so many headlines not long ago, and for the moment, I have no more to say than I said at the time: its “approval” in Russia was nothing more than a publicity stunt. Update: (September 10) the institute has published some data, but there are questions about their numbers in turn.

Reithera: this one is a gorilla adenovirus, for the same immune-evading reasons as the other unusual vectors above. The company has announced that the first human volunteer was dosed late in August in an Italian Phase I trial, and that they hope to go into Phase II/III by the end of the year.

Altimmune: this is another adenovirus vector, but this time administered intranasally (which can be a real logistic advantage over injections). The company also says that it expects the candidate to be storable at room temperature, another real advantage given what we’ve been hearing recently, but we’ll see how that holds up. They and their partners at Alabama-Birmingham have announced what look like solid results in mouse models, but they’re obviously behind the more highly publicized vaccine candidates when it comes to human dosing.

Merck/Themis: this is the first non-adenovirus vector candidate on this list – it uses the measles virus, actually. The company has said that it plans to start human trials in this quarter, which means this month, but we have very little data otherwise. Merck’s Roger Perlmutter has said, though, that with this one and the IAVI candidate (next paragraph!) that they’re trying for a one-dose vaccine rather than a booster shot regimen. Update: (September 9) note that in contrast to the other viral-vector candidates, this one and the Merck IAVI one below are both competent to replicate in the body. Update: (September 17) human dosing of this candidate has started in Belgium.

Merck/IAVI: the vector in this case is VSV, the virus used in the Ebola vaccine (which, as mentioned above, is the only one so far in humans that uses this viral-vector delivery idea). This one is said to be going into humans by the end of the year. The hope is that this one could be orally administered in a “swish-and-swallow” manner, which would certainly be an advantage. Update: (September 9) see note immediately above. Update: (September 30) Merck has begun their clinical trial on this one as well, in a single-dose protocol.

Vaxart: this company has also announced work on an oral coronavirus vaccine candidate, but information has been very hard to come by since then. I cannot find any data, nor any idea of when a trial might start. What I do find is lots of fans of the stock – not necessarily the company’s fault, because coronavirus therapy stocks have of course been an insane circus all year long, but it does make the signal/noise rather poor. We’ll see if some solid information appears eventually. Update: (September 17) the company has received clearance to start Phase I trials.

Washington University: a recent paper in Cell describes this chimpanzee adenovirus candidate. Interestingly, while an immune response was certainly induced in mice when the vaccine was given by injection, but an even more robust protective effect was seen when it was given intranasally. You have to wonder if the eventual coronavirus vaccine that people will take routinely will be a nasal one, but it’s for sure that whatever rolls out in the next few months will not be.

MediciNova: this Japanese company has an influenza-virus vector platform that they’re also using to try to develop an intranasal coronavirus vaccine. They’ve announced some mouse-model data; we’ll see if this one can make a place for itself in human trials.

Update: (September 17) Xiamen/HKU/Beijing Wantei: this is another influenza-vector intranasal vaccine candidate, which has just been approved for Phase I trials in China.

Genetic Vaccines:

These take DNA or RNA coding for coronavirus proteins and inject that directly into the bloodstream (all of the ones below are mRNA, except for Inovio, Genexine, Zydus Cadila, and AnGes). “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. Another one is that it looks like the ones under development will need to be stored under rather stringent cold-chain conditions.

Moderna: well, you can’t open up a news site without reading something about Moderna. So I’ll highlight that the company has released some data on their vaccine candidate’s performance in older patients (looks good). The company says that it is on target to complete enrollment in its Phase III trial by the end of this month, and (in response to some worries) is now publishing data on the diversity of its patient population. Like all the front-runners, we are waiting on efficacy data, and everything we have to say now will be outweighed by what those numbers tell us. Update: (September 17) the company has released its entire clinical trial protocol, the first of the companies involved in this to do so).

Pfizer/BioNTech: this one is also on track to complete enrollment late this month, and the company continues to stick with its optimistic timelines. Their CEO said today that they might have results in October, but that means the very end of October, surely. Update: (September 17) BioNTech has announced that they’ve substantially increased their production capacity, buying a plant in Germany from Novartis.

Inovio: I have been searching, but I have no new science results to talk about with this DNA vaccine candidate. It’s a stock-market fight, and another short-selling firm just came out with a very pessimistic report. And sure, that’s what short-sellers do, but they’re not always wrong, either. I have never been optimistic about these folks, and I have seen no reason to change my opinion. Hammer me for it, fanboys. Update: (September 17) more details from the judge on the recent court case that went against Inovio. Update: (September 28) the FDA has put the company’s Phase II/III trial on hold, with issues around the delivery device and perhaps more.

Curevac: they have a Phase I trial underway in Germany and Belgium, and it’ll be interesting to compare their data to Moderna and Pfizer/BioNTech when it completes. The company is already negotiating with the EU about supplying its candidate if it works, and says that its timeline would put that in the middle of next year. Update: (September 17) more funding from the German government.

Imperial College: I believe that this is the leading self-amplifying mRNA candidate left, after Pfizer and BioNTech dropped theirs. They’ve shown good results in mice, and a Phase I trial is underway in England, with reports of trials starting in Uganda by the end of the year. An advantage of the self-amplifying platform is (as you’d figure) that it takes lower dosages, but it’s not something that (to my knowledge) has been tried in humans until now. Update: (September 17) a trial is beginning studying this candidate and the Oxford/AZ one as inhaled formulations.

Arcturus/Duke-NUS: here’s the other self-amplifying candidate that I’m aware of, which went into humans just a couple of weeks ago in Singapore. Arcturus has both an mRNA platform and a lipid-based delivery platform, which have come together under the current conditions to get into the clinic very quickly indeed. Update: (September 9) here’s a preprint with early data on this candidate.

Sanofi/Translate: some slides have emerged in a regulatory filing that show immune responses in animal models. No idea when this one is going into humans, although it’s supposed to be soon.

Zydus Cadila: this DNA candidate has been through phase I, and early in August received approval to go into Phase II trials. Update: (September 17) these are apparently underway. To the best of my knowledge, though, we have no data other than the company’s statement that it was well tolerated in Phase I. The CEO has said that they hope to launch the vaccine itself next March.

Genexine: this DNA vaccine candidate has now been into primate models, and is approved to start clinical trials in Korea – but I can’t find a firm date when that’s supposed to happen.

AMMS/Abogen/Walvax: this one (China’s lone mRNA candidate, from what I can see) has been approved for human trials, but other than that, details are very hard to come by. I don’t even know if it’s been dosed yet, or what the timeline is.

AnGes/Osaka/Takara: this is a Japanese collaboration on another DNA vaccine candidate, which has begun recruiting for human trials. This one combines a DNA plasmid with a skin-penetrating jet injection device, so it’ll be a more complicated development to get through.

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 those proteins 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. Update: (September 17): for an overview of this area, see here.

Novavax: this company seems to be the leader in this area at the moment. They have just published results from their Phase I/II trials, and the antibody responses look good after the second dose of their adjuvant-containing vaccine. The results were, in fact, quite similar in the 5-microgram and 25-microgram dosage groups, which highlights the work that the adjuvant is doing. CD4+ T cells were also induced (Th1 phenotype, as in the other vaccines that have reported so far), but there were no data on CD8+. It looks like this one will be handled under standard refrigerator temperature shipping and storage. The safety profile looks good so far as well. So like the others in human trials, we’re going to have to wait for the key efficacy numbers to sort things out – in an interesting development, though, Novavax is the only vaccine developer (so far) to explicitly say that they would be willing to take the FDA up on Commissioner Hahn’s recent proposal to have companies file for approval before their Phase III trials are complete. Update: (September 17) the company has announced a production agreement with the Serum Institute in India to increase supplies.

Sanofi/GSK: coming up fast now is this Big Pharma competitor. The companies have announced today that they’ve started a Phase I/II trial at 11 sites across the US, with a Phase III to start in December. This one is using GSK’s adjuvant technology, which is already in human vaccines, and will also be shipped and stored at refrigerator temperatures (and not freezers or worse, like the mRNA candidates).

Update: (September 9) Finlay Institute (Cuba): the Cuban government has begun human trials with a protein subunit vaccine (Sobreana-01). Over six hundred people are being enrolled in a Phase I trial as of late August.

Clover Biopharmaceuticals: this company has already been in human trials for a while now, but there’s absolutely nothing new to report, from what I have seen. Not sure what’s going on here, and I hope to see some results soon.

Queensland/CFL/GSK: this one has been in human trials since back in July (no word yet). A preclinical animal study has been done in hamsters, though. It’s worth noting that this one uses a so-called “molecular clamp” technique to try to keep the viral protein in a more antigenic conformation, which is different from the other candidates in this area.Zydus Cadila: this Indian company is also in human trials.

Vaxine: this Australian company has partnered with Oxford Expression Technologies to try out recombinant Spike protein with Vaxine’s proprietary adjuvant. Phase II trials are supposed to begin this month.

Medigen: this is a Taiwan-based company with yet another mixture of Spike proteins and adjuvant from Dynavax. A human trial is set to begin this month.

Adimmune: another Taiwan effort with a Spike protein, and this one has already begun human dosing there.

UBI: still another Taiwan protein vaccine, but this one (from what I can see) is a mixture of several antigens. It has just received permission from Taiwan’s regulatory authorities to start human dosing.

Zhifei Biological Products: as far as I can see, there’s been nothing substantial about this one since the announcement of Phase II trials back in early July.

Stabilitech: no updates on this one, either, that I have been able to find.

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 only one company pursuing this route.

Meissa Vaccines: this small company announced back earlier in the summer that it had had a pre-IND meeting with the FDA about its attenuated coronavirus program, and was doing preclinical studies. If there has been more news since then, I have not been able to track it down.

Inactivated Virus Vaccines:

This is also a technique that’s 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 will very likely 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.

SinoPharm/Wuhan Institute of Biological Products: this candidate was the subject of a recent publication on a Phase I human trial, and that (while a bit light on details), was notable for a rather mild side effect profile. We’ll wait on efficacy data. This one is current being tested in the UAE. Update: (September17) the UAE has now approved use of this vaccine before clinical trials are complete.

SinoPharm/Beijing Institute: this one has sometimes been hard to distinguish from the other SinoPharm candidate, and I have been unable to locate any new information on it.

Sinovac: no new scientific data on this one, from what I can find. They’re in Phase III trials in Brazil and Indonesia, but that hasn’t stopped the Chinese government from authorizing its use in high-risk groups of government employees. Both governments have signed agreements to purchase the vaccine if it continues to show good clinical data. Update: (September 17) the company says that thousands of its employees have been given the vaccine as well. And there are reports that Indonesia is trying to develop its own vaccine rather than be completely reliant on this one.

Institute of Medical Biology (China): nothing new on this one since it was said to be entering clinical trials in June.

Bharat Biotech: this candidate is currently in Phase I/II trials at several locations in India, and the company has also received permission to conduct a separate trial with intradermal dosing (which should, in theory, use less vaccine per dose). What we’re not seeing is any more of the craziness back in July that would have had the vaccine theoretically launched two weeks ago, which is a relief. Update: (September 17) the company has provided data on this candidate’s prophylactic activity in a primate model.

Update: (September 17) Valneva: this French company is going to start Phase I trials of an inactivated-coronavirus vaccine, along with adjuvant from Dynavax, in December.

Virus-Like Particles

Here’s yet another category, which can be thought of as a “stripped virus”. A VLP has most or all of the surface proteins of the real virus, but doesn’t have the genetic payload inside, and therefore cannot replicate. But the immune response that develops to the surface antigens is still available. This technique is already used for vaccines against HPV and Hepatitis B, so it’s proven that it can work well. You have several options for preparing such VLPs, mixing and matching material from the natural virus (or more than one natural virus) and recombinant proteins.

Mitsubishi-Tanabe/Medicago: this is a plant-based candidate, coming from tobacco leaves (see the July post linked in the first paragraph today for more). Some plant-derived proteins can have very different immunogenic profiles than the “same” protein produced by other methods (different glycosylation patterns, generally). They’re currently in Phase I, with plans (I typed “plants” the first time) to go on to Phase II/III in October. They’re using adjuvants from both GSK and from Dynavax to go along with their proteins.

Kentucky BioProcessing: this is another tobacco-leaf protein production company, from R.J. Reynolds. I’m not sure whether to put them here in the VLPs or up in the recombinant protein section, but I’ll leave them here next to Medicago for convenience. They have completely preclinical testing on their candidate and are awaiting FDA approval to go into human trials.

Oxford/SpyBioTech: here’s a new one, based on a protein engineering system known as “Spytag/Spycatcher“. Molecular biology aficionados will know this one already – it’s an efficient protein conjugation method, with these two domains engineered to form a new covalent bond to each other when you express them in your desired targets and let them mix. That’s been used to put Spike antigen proteins (the RBD part) onto a known VLP called mi3, a technique that was already being investigated before the coronavirus epidemic even showed up. Mice given the RBD itself raised a detectable but not very strong immune response, but when the RBD was conjugated to the mi3 particles, that construct set off a much more potent and wide-ranging antibody response. I don’t know if this can get into human trials in time to help, but it looks quite interesting.


Dang, that’s a lot of vaccine candidates. And as you can see, it’s a long-tail distribution – there are some big ones that everyone knows about, but a lot of people are bringing a lot of technologies to bear on the problem. This makes me think that we’re going to have a multichapter story, in the end. There will be the first vaccines approved, then the second wave, then the improvements on those, until we have (with luck, hard work, skill, and lots of money) tossed this virus out of the human population and back to the bats, pangolins, or whoever had it in the first place.

An excellent side effect is that vaccine technology will never be the same after this – it’s going to be like aircraft design before and after World War II, and for many of the same reasons. This whole pandemic has been awful, in many different ways, but we’re going to come out of it stronger and more capable than when we went in.

121 comments on “Coronavirus Vaccine Roundup, Early September”

  1. Mister B. says:

    Plenty of reason to believe that among these candidates, one or more will be efficient enough to offer a protection against Sars-cov-19 and congeners !

    Thanks again Derek for this great work !

    Masks up. Hands washed. Be patient and take care !


  2. Marko says:

    In Foreign Policy today :

    “Trump’s Vaccine Can’t Be Trusted : If a vaccine comes out before the election, there are very good reasons not to take it.”

    1. confused says:

      It’s not like the US will be the only nation looking at/interested in a vaccine that seems to work…

      If data comes back showing a vaccine is maybe-barely-effective, perhaps. But if efficacy is decent wouldn’t that be fairly clear-cut (ie, if it works it works)?

      1. Marko says:

        I think the major concern is in regard to safety rather than efficacy. If you’re under the age of 40 or so , Covid-19 itself poses a vanishingly small risk to you. A fairly rare but serious side effect of the vaccine is something you’d want to know about. It takes numbers and time to pick those up.

        1. confused says:

          To a degree.

          But, I mean, what is a realistic risk of bad side effects? Wasn’t even the 1977 swine flu vaccine Guillain-Barre incidence a couple cases in a million?

          USS Theodore Roosevelt shows hospitalization rates maybe 1% or a bit less (?) and ICU/death rates ~0.1% in a population of relatively healthy relatively young adults.

          Which aren’t particularly scary numbers for a high-risk-tolerance young adult, but still, I can’t see vaccine side effects being comparable to that.

          I can see maybe not approving vaccine for say <20 age group at first, though, where the risk is incredibly low. But definitely for 20-40, IMO.

          I agree that a vaccine shouldn't be rushed *for political reasons*.

          But I *do* believe a COVID vaccine should be approved and distributed as soon as there is decent data showing efficacy.

          Unfortunately, given when the first Phase III trials started, if the first ones to start Phase III work, the timeline for the arrival of Phase III data might easily end up being "immediately before the US election".

          Although, given early voting, a late-October approval would probably not actually have nearly as much impact on the election as many people would expect/assume.

          1. Tony says:

            Even with Guillain-Barre (GBS) even a “bad” vaccine the incidence would probably be 1 in 100,000. We can assume that 5% of people will die from GBS. If we vaccinated 2 million people, 20 will get GBS and one person will die.

            Conversely, in my country, if 2 million people got infected, 4% would be hospitalised, so 80,000 people. 15% of hospitalisations would die, so 12,000 deaths. Even if better treatments reduce deaths by three orders of magnitude, that is still 12 deaths. So, getting the bad vaccine (assuming its 100% effective) is still worthwhile even with reasonably high side effects.

          2. Marko says:

            Assume the risk of dying from Covid-19 for those less that 40 yrs. old is 1 in 5000. Now , assume that the vaccine does not provide sterilizing immunity or does so only briefly, but does protect against moderate to severe disease. Then , assume that 1 in 2500 of those less than 40 yrs old who is vaccinated and subsequently infected dies from ADE , immune complex disease , etc. For that group , they now face double the risk of death from Covid-19 if they were vaccinated than if they were not.

            This isn’t likely to be the case , perhaps , but to detect such a risk , you need to carry on the trials well beyond the 150-175 events that can theoretically demonstrate efficacy. For meaningful safety information , you need many more events , across risk groups.

          3. PS says:

            As I have stated before, when the choice is being hooked upto a ventilator for 2 wks and then dying, alone in a room, AND getting a vaccine. The choice is quite simple and obvious.

          4. confused says:

            @Tony: yeah. The risk of COVID to young adults is not all that high, but it’s not 1-in-a-million low.

            It’s probably lower than the risk of dying in a car accident (I wish I had good numbers on car accident deaths by age… but TX has something like 3,000 car accident deaths/year and surely a large fraction of these must be in younger adults, given insurance pricing and age distribution of the TX population.)

            But car accidents are one of the most dangerous things to younger adults. COVID is still significant relative to the quite low baseline risk of death in this age group.

            @PS: the thing is, though, risk of being on a ventilator/dying from COVID is quite low for young people. USS Theodore Roosevelt had one ICU case (not sure if ventilator was used) and one death (not the same person) out of over 1,000 infections.

            @Marko: yeah if risk of 1 in 2500 was plausible, then maybe. But is that plausible?

          5. Marko says:

            “@Marko: yeah if risk of 1 in 2500 was plausible, then maybe. But is that plausible?”

            If you haven’t looked at enough cases to see it , you can’t even begin to speculate. What we do know is that evidence of ADE was seen in SARS and MERS vaccine studies. That should give us pause , at least , don’tcha think ?

            You don’t have to look for the 1 in a million , or even 1 in 100,000 , deadly adverse events to safely administer the vaccine to the broad population. But when you get down to adverse event death rates of 1 in 1000-5000 or so , you’re in danger of exceeding the threat of Covid-19 itself when you vaccinate the younger age groups. It might still make sense on a population-wide scale , but those younger groups should have the right to know they’re taking on additional risk for the greater good , and should have the opportunity to opt out if they so choose.

            BTW , here’s what you were looking for. See Table 4 on p.20 :


          6. Marko says:

            I should say that I don’t foresee any danger of excessive risk to vaccinated individuals as long as science , rather than politics , guides the vaccine rollout.

            If a signal showing 50% or greater reduction in infections or disease severity is shown for high-risk groups ( say , over 70 years old ) , then the rollout begins in that group(s). Meanwhile , the P3 data collection continues. Rollout then advances to other relatively high-risk groups. By the time you get to vaccinating the younger , lower-risk groups , your P3 data is sufficiently matured to allow parsing of the risk of vaccination to those groups.

            What I’m against is looking at 150 events and saying : “We’re done. Everybody can get vaccinated.”

          7. confused says:

            Yeah as long as we start vaccinating *high-risk groups* as soon as a vaccine shows efficacy waiting on a larger sample size for lower-risk groups would be fine. We could probably “go back to normal life” once the high risk people are vaccinated anyway, there are very few COVID deaths in the say under-40 age group.

            Though personally I’m under 40 and I would want a vaccine that showed efficacy ASAP.

            >>If you haven’t looked at enough cases to see it , you can’t even begin to speculate.

            Well, there’s prior biological plausibility, IMO.

            >>What we do know is that evidence of ADE was seen in SARS and MERS vaccine studies. That should give us pause , at least , don’tcha think ?

            Wait, MERS too? I’d heard about the SARS one… but I thought there was some question (discussed earlier on one of the comment threads on one of the other COVID vaccine posts) whether the in-vitro ADE seen in the SARS case would actually correspond to ADE of disease severity in humans.

            Also… this might be a stupid question, I’m not an expert on this *at all*… but if ADE was likely why aren’t we seeing it from natural infection? (Why would vaccine-induced antibodies be worse than naturally-developed ones?)

          8. confused says:

            Oh, and thanks, those accident fatality rate numbers are helpful.

            It seems a bit odd to compare *infection* fatality rate of COVID to *whole-population* accident fatality rates, though! Surely one wouldn’t expect 100% infection in any age group…

          9. Marko says:

            “..but if ADE was likely why aren’t we seeing it from natural infection?”

            ADE from natural infection would be detected upon COV2 reinfection. We’ve only seen a few cases of documented reinfection , so we don’t have the data yet , but in one of those few reinfections the second infection was indeed more symptomatic than the first.

            The issues discussed in this June article about ADE are as yet unresolved. Only safety data from large numbers in the trials will give us confidence that ADE will not be a problem :


          10. confused says:

            Hmm, yeah.

            I suppose I was basically thinking that given that reinfection is at least possible, but we see very little of it, it should be either incredibly rare (in which case its severity is less relevant; if a vaccine causes 1 in 100,000 cases of bad ADE that’s not really that significant relative to normal COVID) or normally asymptomatic (in which case there might be lots but it’s rarely detected since reinfected people don’t seek testing).

            But it could just be a time thing.

            I guess the real question is, are we seeing a few reinfections now because people are just starting to lose protection (so in say 2 months reinfections will be common)?

            Or are reinfections incredibly rare and we’re just finding a few fluke cases that have no meaningful implications for the larger picture?

          11. John Dallman says:

            “Although, given early voting, a late-October approval would probably not actually have nearly as much impact on the election as many people would expect/assume.”

            Early voters are people who’ve made up their minds. For voting, this is about people who vote on “gut feelings” (emotionally) and thus don’t decide until they day, or until they’re in the booth. These are often the people who decide a close election.

            The other side of this is about the blame, not the voting. If he looses, Trump needs a narrative about how he was cheated, and “Deep State prevented a life-saving vaccine so that I’d lose” is a strong one for his target audience. He needs that for his own self-esteem, which is the most important thing in the world for him. Yes, it’s a ridiculous narrative. If you read this blog, you are hugely biased towards scientific rationalism as compared with the average American, and that’s why the narrative is ridiculous.

          12. Dark Day says:

            “I guess the real question is, are we seeing a few reinfections now because people are just starting to lose protection (so in say 2 months reinfections will be common)? Or are reinfections incredibly rare and we’re just finding a few fluke cases that have no meaningful implications for the larger picture?”

            My understanding is that in at least one of these cases, the culprit was a new mutation of the COVID-19 virus that was markedly different from the old one — so in essence, it wasn’t a reinfection at all, but an entirely new infection.

          13. FrankN says:

            I understand that the issue of early, maybe premature vaccine approval in October is getting highly politicised. In this context, there are two things to consider:

            1. There are only two vaccines with a realistic chance to assemble the required documentation before November: a) BionTech/ Pfizer, and b) AstraZeneca. Moderna is trailing behind in proband enrollment. More importantly – Moderna is conducting Phase 3 only in the USA, where infection rates, albeit still high, have decreased to such a level that a statistically significant demonstration of vaccine effectiveness will acc. to my calculation require at least 51 days of post – boost injection observation.

            Now, while people tend to talk about the “Pfizer vaccine”, it is actually a BioNTech vaccine, licensed to Fosun (China) and Pfizer (rest of the world). This means that the ultimate decision about whether, when and what to submit to the FDA for approval will not be taken in the Pfizer HQ in NYC, but in Mainz, Germany. The same applies to the AZ vaccine, where the decision will be taken in Cambridge, UK.

            I am certain that the decision makers in Mainz and Cambridge will closely follow the US discussion, and consider pros and cons of an earlier or somewhat delayed submission. Nevertheless, ultimately the timetable will be set outside the US, and outside of President Trump’s immediate sphere of influence (in the case of BioNTech, which hasn’t collected any OWS subsidies so far, completely independent from US Government influence).

            2. As far as I understand (to be corrected, if wrong), an Emergency Use Authorization is independent of, and no prejudice for, eventual subsequent regular vaccine approval. I also believe (to again be corrected, if wrong) that it requires application by the owner of the medication/ vaccine to be authorised.
            Looks like a lot of additional paperwork, for little benefit to be gained, especially if one is confident that the assembled data should suffice for regular approval in due time..

            I just try to think from an industry perspective. The Trump Administration’s perspective, of course, is different. But in this case, as much as they hope (and pretend) to be so, they don’t seem to be in the driver’s seat..

          14. Hopeful Layman says:

            This occurred to me as almost a random thought, so make of it what you will, but for all the cynicism out there about government-“Big Pharma” collusion and profiteering, it seems to me that a very significant element of self-interest for the pharmaceutical companies would be the financial and public relations disaster that would arise if a Thalidomide-type catastrophe resulted from an early rollout of an insufficiently tested vaccine. The lawsuits along would probably bankrupt the company, and even if they didn’t, it would never survivie the blow to its reputation. Wouldn’t this be motivation enough to ensure caution in petitioning for EUA?

          15. Kevin C. Smith says:

            The sailors on USS Theodore Roosevelt had ALL had MMR vaccine during training, and it is thought that this stimulated their TH1 response and so reduced the morbidity/mortality far below what was expected.

        2. Alex says:

          “Yeah as long as we start vaccinating *high-risk groups* as soon as a vaccine shows efficacy waiting on a larger sample size for lower-risk groups would be fine. We could probably “go back to normal life”

          I disagree with the policy of waiting living in fear until a vaccine comes along. We know who the high risk demographics are and we should isolate them. The rest of us should take precautions and move along. This is the reality. And just my opinion of course.

          Tony, I thought we stopped putting people on ventitllators given they were problematic and even contributing to deaths? In any event, this is not March anymore, the death rate has dropped to flu levels. Heck, I’m not even sure in a year or two from now we may even need a vaccine according virologists I’ve read.

          Also, there’s a lot of silly unsubstantiated shots at Trump here. We can’t escape it. I have my opinions but if I want political commentary I’ll go to the appropriate place.

          1. Metaphysician says:

            You do realize that about 34% of the US population is over 50, right? “Just make the people at risk isolate” doesn’t work when that is more than a third of the populace.

          2. DataWatcher says:

            ” In any event, this is not March anymore, the death rate has dropped to flu levels. Heck, I’m not even sure in a year or two from now we may even need a vaccine according virologists I’ve read. . . .”

            Not sure who those “virologists” are, but the predictions I’ve seen are for upwards of 400,000 deaths in the U.S. by the end of this year.

            I also echo the comments of the previous poster concerning forcing “at-risk” people to isolate. That wouild include, not just “older” people ( 8 out of 10 COVID deaths in the U.S. have been among adults aged 65 years and older), but anyone with one of many pre-existing conditions (even common ones like hypertension, asthma, diabetes, and “lifestyle” factors such as obesity and smoking). We’re talking about “isolating” over 50% of the population.

          3. confused says:

            I think it’s somewhere in between.

            Yes the IHME model predicts over 400,000 deaths by end of year… but that model has performed terribly so far, and that result is extremely implausible.

            Current rate is about 850/day and dropping… and it’s September 5.

            210,000+ more deaths in a bit under 4 months would require an average rate more than double the current one, and the current rate is dropping (and will continue to do so for at least several weeks, given that hospitalizations are also falling).

            So an *average* rate over the next 4 months that high would require the rate to rise notably higher than what we saw in March-April, which seems completely implausible given better treatments/understanding of the disease. (And most high-population areas of the US are probably at at least 10-20% immunity by now.)

            But yeah, high-risk people are not that small a segment of the population.

            Although, a lot of people in their 50s or even 60s are not isolating or even necessarily being particularly careful, from personal/anecdotal experience. What counts as “high risk” is an issue of risk tolerance; it’s not like there’s a dramatic shift at age 50 or 65 or whatever.

          4. Hopeful Layman says:

            ” . . . a lot of people in their 50s or even 60s are not isolating or even necessarily being particularly careful, from personal/anecdotal experience.”

            In my experience, they are, and they’re my age group. But maybe it’s a regional thing; where you live, there might be more resistance to such things.

            By the way, with all the publicity about the possibility of an early EUA roll-out, Moncef Slaoui himself seems to be trying to downplay Trump’s promises, saying the chance for an early pre-election vaccine approval are “very low.” The quote is from an article in The Guardian. which unfortunately I can’t provide a link to, because it’s subscription-only.

          5. fajensen says:

            We know who the high risk demographics are and we should isolate them.
            Do we now? How does that isolation work in practice?

            It does seem the “high risk demographics” in Sweden and Denmark are people who work in service jobs where they must meet lots of people all the time and they probably get high doses of the Corona virus when they get it, with proportionally worse outcomes.

            It is pretty hard to isolate those people, they are doing more essential work than us symbol manipulators, who can work from home.

            In Denmark they had about 600 dead and 600 *disabled* during the first peak, that is nasty!

      2. zero says:

        You assume there would be data. That is not how this administration operates.

        There would be a breathless and partially-incoherent press release about some ‘miracle cure’ like convalescent plasma, a company with financial ties to Trump would be named, friendly press would push articles about how dear leader defeated the pandemic and his pack of nuts and dolts would line up to spend their money.

        The rest of us (and the rest of the world) will be fully aware that it’s empty spin, a grift play and nothing more. Still, it might be enough to affect the election. If there’s even the slightest chance of that happening, believe that Trump would sacrifice as many people as he thought it would take. Look at how many deaths he’s already enabled simply to keep the headlines less negative.

        1. confused says:

          If there were no data, yeah that would be different.

          But a vaccine isn’t going to come from the federal government by itself. Whichever company (Moderna or AstraZeneca or whoever) would have actual data, because they are in fact doing a Phase III trial. It would just be a question of whether it is released.

          And if the data shows the vaccine seems to work, why not release it?

          (I guess maybe the difference here is that I’d be *extremely* surprised if none of the first few vaccines prove to work, so I think the data will look quite good for at least one if not all.)

          And something that would *only be believed by those who were going to vote for him anyway* wouldn’t help in the election at all, in any case.

    2. enl says:

      Which of these (if any) is the one the el presidente Donaldo the Emoliated is betting on?

      Re: those under 40: See with the appropriate grain of salt referred to. Then again, in early april, a former student of mine (22, athelete) went down to covid via a coronary event….

    3. nobody says:

      For those who haven’t clicked-through on that link, the key point is that the Trump administration is planning to start mass vaccinations a few days before the US election, without waiting for full stage III results.

      There is an argument to be made that urgent need justifies cutting short ordinary testing procedures and that a handful of deaths would be an acceptable loss in the face of reduced population-level risk.

      There is, however, no argument that testing procedures should be cut short to help re-elect an incumbent. Risking lives to keep a ruler in power smacks of something from a totalitarian state.

      No one should take an October surprise vaccine unless it’s been approved by non-US regulators.

      1. confused says:

        Personally, I’d be more interested in what the data says than any regulatory decision. Even if the approval process was politically questionable, if the data shows that it probably works, I’d take it as soon as I could.

      2. Phil says:

        Trump’s own “vaccine chief” says it’s very very unlikely that anyone’s going to be getting vaccinated by the end of October, and that he only even heard about that from reading the news. Which seems typical for this Administration…

      3. Spectator says:

        He just doesn’t understand such processes. He knows make a deal, manage an organization, branding and entertainment. Those are valuable skills, but they’re beneath useless when applied to the current problem. He’s also got some obvious flaws, discourse on which doesn’t aid solving this problem.

        However, with sufficient pushback from people he relies on I suspect that an excessive haste error won’t happen. We could simply have a large Phase III, with some groups (nursing home staff, grocery store clerks, bus & subway operators being the initial recipients. Those groups are employed and either on their feet or needing to be alert and thus has passed some minimum health bar. Vaccinating them would have a disproportionate benefit AND provide good (even yuuge) Phase III data.

      4. Informed says:

        @Nobody: It is just false to say that the Trump administration is planning mass vaccinations before the election. Being prepared to distribute the vaccine at the earliest possible date when it might be available and approved is just commonsense. There is no need to muddy the waters with false statements and conspiracy theories.

        1. Nanobodaddy says:

          I’m a little less sanguine than you are, @Informed, but overall I agree with you. As much as I detest the way the Trump administration has politicized this, even Trump’s own people are saying that if an EUA were given, it would only be for a limited number of vaccines distributed to the most essential healthcare providers and other first responders. In the meantime, Phase III tests would continue, and final approval for the general population would be given later. (Obviously, not too unlike what the Russians did with their “Sputnik V”.)

          I hope that doesn’t happen for myriad ethical, scientific, medial, and human-health reasons, but we do need to keep it in perspective. They’re not going to be shipping tens of millions of doses of “Explorer V” to clinics and pharmacies throughout America.

  3. StrangeQuark says:

    I know that we need to do Phase III trials, and that Phase II trials aren’t sufficient to prove efficacy, but I’d like to be able to explain why this is true to a friend of mine. (He is asking why we aren’t just dosing people with vaccines that have passed Phase II.) I recall seeing a good summary of why elsewhere on this blog, but I’m having trouble finding it at the moment. Can anyone help me out?

    1. metaphysician says:

      Consider showing your friend this comic:

      . . . and explaining that a Phase 3 trial is how you tell if your Phase 2 trial is just a green jellybean.

    2. FrankN says:

      On the cold chain issue: I just talked discussed with an acquaintance, who is directly involved in BioNTech’s CoVid-19 vaccine development and testing (and may in fact even be the person to have instigated the -80° C cold chain requirement).

      The issue is that BioNTech (as Moderna and CureVac) “package” their mRNA vaccine in nano-lipids. Since you can’t directly applicate just 30 microgramms of vaccine, it is provided in a carrier substance, namely saline solution. It is well known that you can’t dissolve lipids in water – the best you can achieve is a homogene emulsion that, however, isn’t stable over time. Any separation of this emulsion inside the (multi-dose) vial could mean that invidual Phase-3 probands may get more or less than the intended 30 microgramm vaccine dose, which in turn could make Phase 3 results questionable. That’s a risk BioNTech and Pfizer weren’t willing to take.

      The best way to minimise this risk is to keep the original emulsion of vaccine and saline solution frozen for as long as possible. To achieve this, the transport and storage regime should ensure that the dew point of saturated saline solution, -21°C, will never be surpassed. This can probably be achieved at less than 80°C cold chain temperature (and, apparently, tests are already underway to identify the best compromise between temperature regime and emulsion stability). Nevertheless, with a -80° C cold chain already existing (UPS) and/or reasonably easily installable, BioNTech / Pfizer have for the time being decided to play it safe.

      As concerns protein-packed vaccines (Novavax etc.): While I am not aware of any allergic reaction to (nano-)lipids, the allergenic potential of proteins is well known (Gluten, nuts, egg white etc.). To me, using a protein in order to induce an immune reaction looks like a pretty good way to stimulate allergies, and of course an immune reaction against the protein packaging itself. As such, I wonder whether protein-packaged vaccines will not ultimately share the same fate as vector vaccines: Good for one shot, possibly two, but that’s about it.

      I hope Novavax etc. will prove my assumption wrong, although I don’t think they can do it through their Phase 3 trial. The real test will come, should the need for some kind of (bi-)annual refresher vaccination against SARS-CoV2 mutations arise (or SARS-CoV3 shows up in, say, 2025). Should the refresher then fail because of immunity against the protein packaging, we’re potentially bound for new disaster…

    3. johnnyboy says:

      @StrangeQuark: I think you are assuming that because a vaccine passes ph2, then it is safe – and then you just need to prove efficacy in ph3. This is not the case. Although ph3 is mainly about efficacy, it’s also about safety, as the larger numbers allow revealing less frequent side effects. And ph2 is not only about safety, as it’s often used to get efficacy data as well. So in short the ‘phase 2 for safety/phase 3 for efficacy’ that is often used to summarise the process oversimplifies it a bit.

    4. On Paper says:

      Because Phase II isn’t big enough to find out how reliable results would be in the general population, and large scale vaccinations are expensive. We don’t want to put all our manufacturing, distribution, and point-of-delivery resources into something that doesn’t work well broadly. And we really can’t afford to repeat that error with every vaccine that is going to pass Phase II but fail Phase III.

  4. Marko says:

    The Captain Picard of “Operation Warp Speed” says he’ll quit if politics “Trumps” science :

    1. Ye ol' Bone Spurs says:

      It already has. But if there’s one thing Moncef is excellent at, it’s politics. No doubt his training at GSK is being put to the test, but to benefit who?

      p.s. Derek – many thanks for all the insightful information!

      1. Calvin says:

        Moncef may be many things but he’s not a nasty man. He’s one of the good guys even if you don’t agree with his decisions. And as the Science article alludes to his politics is not aligned with those of the current administration. He’s been fairly public about his motives and they aren’t about making money. It’s hard to believe that somebody would work for the Trump administration on this with an entirely philanthropic view but that is actually the situation in this case. It is easy to be cynical but let the man do his job and in the fullness of time when we have some data make a judgement.

    2. PV=nRT says:

      Too bad Moncef didn’t quit science before getting GSK out of oncology and buying Sirtris.

      1. johnnyboy says:

        It sure is interesting to see both Slaoui and Vallance being in charge of the blundering efforts of the 2 worst performing countries on the Covid front. GSK seems to be a great training ground for world-classe executive failures.

        1. PV=nRT says:

          I wonder which of Vallances’ blunders killed more people: A- Terminating GSKs IO and NOAC programs, or B- Pushing ‘herd immunity’ as a strategy to fight covid in Feb & March. It’s easier to get a number for ‘B’.

  5. Bill says:

    Confused said: I can see maybe not approving vaccine for say <20 age group at first, though, where the risk is incredibly low. But definitely for 20-40, IMO.

    I think just the opposite. If a primary goal is to stop the spread of the disease, it would seem critical to vaccinate the primary spreaders. Take them out of the loop. College students in particular are making daily headlines on their unwillingness to behave and resulting outbreaks closing campuses left and right. Besides closing their campuses, they're taking it out to home and community. How could it be otherwise?

    1. Scott MacHaffie says:

      I skimmed the draft vaccine priority guide (it’s 155 pages, so not really light reading), and somewhere in there it made the point that we won’t have enough doses available quickly enough to really shut down transmission.

      Instead, it recommends prioritizing by risk, something along the lines of:
      – First responders and hospital personnel
      – Elderly, people with significant co-morbidities, and caregivers for those groups
      – Essentially everyone else (it’s actually broken down quite a bit more than this, but I think this is the gist)

      1. DrivingAround says:

        You’d think grocery store clerks and restaurant workers would be high on the list. Short exposure time, but multiplied by a very large numbers of stranger contacts.

        1. DataWatcher says:

          Some suggestions also include prioritizing people who work in meat and poultry processing plants. They’re at high risk for transmission and infection — and, because many of them are African-American or Latino, if they’re included early, and their vaccines get good results, this could be an important step in cultivating trust in populations that are currently very skeptical about accepting a vaccine.

    2. zero says:

      College students make daily headlines all the time whether or not there’s anything newsworthy happening, at least for a certain sector of ‘news’ sources on a quest to stir up panic about societal change.

      Employers force their service-industry employees back to work with insufficient safety equipment.
      Conservative legislators and elected officials force in-person voting and in-person school openings.
      Deniers refuse to wear masks, spreading the disease through churches and birthday parties across the country.
      Public figures spread misinformation about everything: death tolls, infection rates, risks, treatments, etc.

      If college students ‘refusing to behave’ are such a risk, why are the colleges holding in-person classes? I guarantee it’s not the students making that decision.

    3. confused says:

      Ok fine make it 18 and up then, or whatever.

      But the primary goal *at the beginning*, IE before everyone can be vaccinated, should probably be protection of high-risk groups.

      (Frankly, if the vaccine is quite effective, not just 50%, that might be enough to make COVID not that significant. If only people under 40 caught COVID, we probably wouldn’t be that aware of it…)

    4. Dark Day says:

      What’s happening on campuses does not make one optimistic about what life is really going to look like even after a vaccine is rolled out. No vaccine will be 100% effective, and given the virulence of COVID, true herd immunity is, at best, probably far in the future (and probably not even then, if reinfection and/or infection from new mutant strains is as likely as it’s starting to appear). The old civil rights anthem, “None of us is free until all of us are free” comes to mind — none of us is safe until all of us are safe. That probably means a not-entirely-reopened economy, continued mandatory masking and restrictions on public gatherings, etc., even after a vaccine and/or treatment might become available.

  6. Philip B says:

    Aren’t there rather a lot of mostly harmless coronaviruses floating around? Isn’t there one we could just infect ourselves with that would provide immunity to SARS-CoV-2 that doesn’t cause Covid-19? Most Coronaviruses are rhinovirus tier harmless, so think vaccination vs variolation.

    1. Patrick says:

      Doesn’t seem that way – no particular evidence of significant pre-existing immunity yet. Some antibodies which react a little, but plenty of semi-closed environment situations with infection rates at like 70-90%. That suggests there’s nothing common that gives useful immunity.

    2. FrankN says:

      We don’t know which of those “mostly harmless coronaviruses” are actually responsible for the partial immunity that has been reported in several studies. In all likelyhood, we are not talking about “common cold” human alpha-/betacoronaviruses – otherwise we wouldn’t catch a “common cold” each autumn/ winter. Rather, we might be talking about some yet unrecognised spill-over from animal reservoirs. E.g., one of the closest known relative to the MERS Virus is the Hedgehog Coronavirus, first attested from N. Germany. Alternatively, one may consider cat/ dog/ murine/ bovine/ equine coronavirus. My personal suspicion goes towards bat coronaviruses, which are currently being re-assessed by UPenn, as well as in N. Germany. Might even be Goose Coronavirus: All of the Southern Baltic Sea coast, from Germany through to Estonia, has very low infection/ mortality rates not only in international, but even in intra-country (Germany, Poland) comparison (400 cases/1.7 deaths per million in the Uckermark, vs. 15,858 cases/1,903 deaths pM in Tirschenreuth / Bavarian Forest – for comparison: New York 24,120 cpM/ 1,699 dpM).

      1. daksya says:

        > we are not talking about “common cold” human alpha-/betacoronaviruses – otherwise we wouldn’t catch a “common cold” each autumn/ winter.

        There are close to 200 known common cold viruses. See ‘Cold’ coronaviruses are estimated to cause only around 5-15% of annual common colds, so they could be potentially infecting a different set of people each year.

      2. Claudio says:

        Your suspicion could be correct.In 1985 there was a Coronavirus swine infection in former DDR(North-east Germany ) which could have caused the spill-over-effect of partial immunity.
        Viren-Welle in der DDR Die Stasi-Akte
        Das Dokument stammt aus dem Juli 1985 – aber die Überschrift liest sich wie ein aktueller Lagebericht … Die Akte der Stasi-Hauptabteilung 18 trägt den Stempel „Nur für den Dienstgebrauch“ und hat den Titel: „Information zum Infektionszeitpunkt und zur Übertragung der Coronavireninfektion im Kreis Brandenburg.“
        see Video

    3. Joey says:

      Using another coronavirus as a vaccine to SARS-2 would require the same exact development and trial methodologies as any other vaccine, so the question of whether common-cold-severity coronaviruses can be used as a vaccine for SARS-2 is moot.

  7. Grahame Grieve says:

    Derek it would be great if you could survey our experience with immunizing against respiratory virii, and coronavirii in particular. What existing approaches work well, and what don’t? In particular I’m interested in what data we have to suggest that immunization will stop the upper respiratory infection / infectiousness vs just preventing escalation into the dangerous system disease.

  8. antipodean lurker says:

    Looking for potentially high rates of some pre-existing immunity? Look at the infection rates (or lack thereof) in Thailand, Laos, Vietnam, Cambodia. Thailand reported its first case in 100 days recently. Vietnam and Thailand in particular are middle income countries with some public health infrastructure, so you can’t just blame lack of testing for low case numbers. Taiwan also may have some natural advantages from its geographic location, and also look at China’s success in containment.
    These countries are all close to the natural SARS-CoV-2 reservoir of bats. I’d look at background coronaviruses from around there that circulated in the last 15 years (SARS) but trending to more recent waves.
    Certainly there was very little pre-existing immunity on that fishing boat in Washington.
    Historically, the 1918 Influenza also hit isolated populations differentially harder (mortality in Cook Islands 20%, New Zealand Maoris in New Zealand 4%, New Zealand Maori battalion that fought overseas ~1% mortality from memory).
    I still think a vaccine will be a better solution this time.

    1. On Paper says:

      Would be interesting to compare infection and mortality rates to a map of pangolin populations in SE Asia, too.

  9. A Nonny Mouse says:

    My daughter had the second shot of the Imperial vaccine a couple of weeks ago (second goup looking a 3 different doses).

    No obvious problems, but she did have a headache which they followed by phone over the next few days, so a possible side effect.

    Thanks for the comprehensive review.

  10. Duncan says:

    I have been very surprised by how little interest the internet science pages have taken in the limited approvals given in China and Russia. Yes, I know that there is much to be said about the US. But ultimately for all the fire and brimstone it is not the US that has gone first. China appears to have been giving something to a non-trivial group of people apparently outside of clinical trials for some time now. They announced that a vaccine was available for military use, but as far as I can see nothing has been put out there about distribution, safety, effectiveness. Or even if their military has actually used it at all. Similarly Russia announced some quite convoluted approval that I admit I didn’t really understand – but not much has been said about actual use and effects beyond the approval.

    Ultimately the US and US citizens are going to have to reconcile themselves to whatever comes next. Here in Europe politicians are talking about December/January for limited use of a vaccine: I take that as meaning limited to the highest risk groups with wider use to follow. That would be within the OWS timelines. Everyone will be sucking it and seeing what happens, but I would be interested to know more about what happened next in China and Russia.

    My coping strategy when the time comes will be 100% disengagement from social media. I recommend it highly.

    1. SteveM says:

      Gamaleya is also beginning a 40,000 subject Phase 3 clinical trial:

      Trump no doubt is trying to grease the accepted vaccine to an American Pharma company for nationalistic reasons. Gamaleya is also penalized by the Trump Hate => Russia Hate phenomenon in the U.S. which intrudes into the scientific domain. It can be safely assumed that U.S. politicians and Big Pharma will do everything possible to sabotage acceptance of the Gamaleya product regardless of how effective it is and will use Russia Hate as a primary lever.

      So the Big Question is, if the Gamaleya vaccine is proven to be both clinically effective and cost effective, would it be rejected by the FDA for both raw political and nationalistic reasons?

      1. FrankN says:

        Check out the Sputnik V production capacities: Currently 1.5 million doses/ year, expected to be ten-folded over the months to come.

        “.. start mass production in other countries in partnership with local sovereign wealth funds, including India, South Korea and Brazil, as well as, in Saudi Arabia, Turkey and Cuba.
        The plan is to ramp up the vaccine production to 200 million doses by the end of 2020 including 30 million doses in Russia.”
        “expected”, “plan is ..” Great!
        And even if all the plans work out: Russia alone will under the envisaged two-shot regime require more than those 200 million doses in order to achieve herd immunity. Add to this the countries Russia has already promised Sputnik V supply to (Kazakhstan, Vietnam, probably also Cuba and Belarus) – another 100 million doses.
        We are talking at earliest summer 2022 before it will make sense to consider the possibility of licensing Sputnik V in the USA (and/or the EU, UK, Canada etc.) in earnest. And if, by then, we will still be in need of another SARS-CoV2 vaccine, something should have seriously gone wrong in vaccine development. That “seriously gone wrong” would in all likelyhood apply to Sputnik V as well, as it is an Adenovirus-based vaccine similar to the ones developed by AstraZeneca, J&J and others.

  11. Niduterpenoid A says:

    Hi Derek,

    Thanks for the really great summary. I had a general question- based on the large number of vaccines in development and the presumably large investments involved. To my mind (non-industrial chemist) it looks like a risky venture for companies? With such competition and costs involved are we going to see real problems for companies that don’t have a successful vaccine outcome or do you think it’s inherently the same level of risk as with other projects?

    1. With the caveat that it’s drawn from a relatively small dataset, probability of success (regulatory approval) for vaccines is historically 30-40%, less risky than other areas of pharma development. Factors impacting on risk in the case of COVID-19 vaccines are unproven technology, varying levels of development experience, possibly lower regulatory hurdles with respect to efficacy, with scope for emergency authorisation), plus a dash of political expediency.

      Commercial risk, at least for some companies, has been ameliorated through federal funding (BARDA), regional (European Commission) and national initiatives, grants and loans for manufacturing scale-up, and pre-approval supply agreements. There’s also “non-pecuniary” benefit in that its an opportunity to up the profile of non-conventional vaccine technologies, making them front runners for the next “Disease X” response, and accelerating integration into mainstream vaccine development.

      1. Niduterpenoid A says:

        Thanks Alex- interesting stuff to think about

  12. DrBob says:

    Does anyone know the prespecified assumptions to determine efficacy for interim analyses (IA) of the large PH3 trials? i.e. Does the DSMB(s) have a specific number of events that are supposed to trigger an IA? eg 100 cases, 200 cases, etc? and that would have statistical power to say vaccine is better than placebo (let’s say for a 50% reduction in infection)?

  13. Roy Badami says:

    Valneva’s vaccine is an inactivated virus. It’s one of the ones being funded by the UK Vaccine Task Force.

    1. Roy Badami says:

      Also, Bharat Biotech (which you list) is another example of an inactivated virus vaccine that is not Chinese.

  14. Bill says:

    I just read where WHO stated none of the vaccines in S3 trials has yet shown 50% efficacy. Is that a meaningful statement? Are trials continuously assessed along the way?

    1. Marko says:

      WHO communications must be managed by a 10-yr-old with Tourette’s. They’ve misused the phrase “no evidence” so many times in recent months that I have to think it’s some sort of pathological twitch or compulsion.

      In this case ” no evidence” means they haven’t seen the evidence. Nobody has. The trials are blinded to everyone but DSMBs , and WHO has no privileged access to DSMBs.

  15. Ezra Abrams says:

    Cause I have a PhD, I am the person family ask about any medical thing (as you all know, trying to explain “that’s not my area” doesn’t work)

    and my advice is always: if it is something new, unless you are in real pain or danger, you don’t want to be first; let someone else be a guinea pig for a new drug or surgery or whatever (vaginal hernia mesh anyone ?)

    And I think that holds for new technology in vaccines: unless you are in a hi risk group, don’t let them inject you with a nucleic acid vaccine (? pro immunogen)
    let someone else be the guinea pig

    1. dearieme says:

      Will the politicians decide that they will have priority access to the vaccine? You could call it a Pelosi Haircut effect.

    2. Joey says:

      If everyone thought “let someone else be the guinea pig”, there would be zero approved treatments for anything. Not everyone is so risk-averse, some are willing to take risks given an expectation of efficacy from Phase 1 and altruism.

  16. An Old Chemist says:

    This is a live website for the progress of all the covid-19 vaccines Updates (New York Times)-It was last updated on September 3:

    Coronavirus Vaccine Tracker

  17. Tony Warren says:

    A friend in the pharma game, well placed in one of the front runners, early on told me that if there was a good thing about Covid-19, it was that it had the magical power of cutting FDA red tape.

  18. Steve Scott says:

    Thank you Derek for being a guiding light for truth and reason. This is all about the data, and Covid-19 vs. the human immune system in all its complexities. The Phase III data, when it emerges, will allow informed decisions on whether distributing vaccines outweighs the alternative, given the growing human toll.

  19. Charles1 says:

    Question: There are reports that Moderna’s vaccine trial is being delayed because they haven’t met Dr. Fauci’s benchmark for African-American participation, which is that it be TWICE the percentage of African-Americans in the population, on the presumptive reasoning that they are especially hard hit by the virus. Does anyone think this is legitimate scientific reasoning? Surely there are some genetic differences between African-Americans and other demographics, such as a predisposition to sickle-cell anemia, but Africans on a global basis do not seem particularly predisposed to this virus. I assume that there is no conclusive answer yet as to why Black Americans have been disproportionately affected, but it seems that poverty, and living in densely populated cities, is a key factor everywhere in the world. Is there any rational scientific reason to believe that a vaccine that protects the general population, would not protect Black Americans as well? I pose the question as delicately as I can– does this not strike researchers as an awfully specious rationale for delaying a trial?

    1. sPh says:

      The effectiveness of the vaccine will in part be due to the universality and effectiveness of the vaccination campaign. If the US African-American population, which makes up a disproportionate percentage of service workers who are ‘at risk’ both for contracting COVID and for spreading the virus to others, do not get vaccinated due to distrust of how it was developed then the vaccination campaign as a whole could fail. Thus additional effort to ensure that perception does not get formed is justifiable.

      1. Hopeful Layman says:

        Yes: Uptake among Black Americans is absolutely crucial for the success — such as it may be — of a vaccine. Right now the polls are showing that under 50% of African-Americans would take a vaccine if it were available.

        Black Americans have many risk factors and pre-existing conditions, often stemming from social and economic inequality, and — as stated above — many also work in high-risk occupations. It is essential that major efforts be made to establish trust in a vaccine.

        I’d also add, at risk of being accused of “policizing” this further, that as long as Trump remains in the White House, trust among African-Americans, many Hispanics, and others who have come to see him as virtually an existential enemy, will be extremely low. When / if a new administration assumes office on January 20, a focused and dedicated education campaign can be launched to begin to try to allay some of the fears and misigivings. It will take some time, but if the people vaccinated during “Phase 1” of the program (health care workers and other “essential” workers, possibly including people who work in meat and poultry processing plants, many of whom are Black and Hispanic) are seen to be doing well, with few serious side effects and rapidly declining numbers of new cases, then other “mainstream” Americans may get off the fence and decide to be vaccinated when their time comes.

  20. RonH says:

    Are there issues with using a measles virus vector in the Merck/Themis vaccine? Would this have the same issues adenovirus vectors have, especially since a large part of the population has been vaccinated against measles?

    1. OneNeoEno says:

      I usually abide by rule 1 of the internet – don’t read the comments – but read through them to find out if this glaring question has been answered. Sadly no, but at least I’m not the only person asking it.

      I had measles when I child. My son was vaccinated. Is a vaccine with a measles vector going to do jack for either of us?

      1. Derek Lowe says:

        Good question! See the section “Influence of Pre-Existing Immunity” in this paper:

    2. FrankN says:

      Same question/ concern here. Probably, Phase 1, or at latest Phase 3 will tell us. That Chinese Ad5-based vaccine (forgot, which of those “Sinoxxx” companies developed it) revealed the pre-immunity problem already in Phase 1.

  21. Marko says:

    It’s official. We’re definitely living in Bizarro World.

    Drug industry pushes back against pending FDA under-regulation :

    “Covid-19 Vaccine Developers Prepare Joint Pledge on Safety, Standards”

    1. DataWatcher says:

      If this is true, it’s excellent news; the last thing we need is already-shaky public confidence shaken even more by an apparent “rush job” that’s suspected of being politically motivated. In the U.S., uptake will be at least as cricitical a consideration as the effectiveness of the vaccine itself, and actions like this can only serve to improve it.

    2. Ken says:

      The WSJ article is paywalled, but from a different site the companies making that pledge are Pfizer, Merck, AstraZeneca, Sanofi, GlaxoSmithKline, BioNTech, Johnson & Johnson, Moderna, and Novavax.

  22. Tirani says:

    I started reading this blog several years ago after being introduced to ‘Things I Won’t Work With.’ I used to tool by every three or four months to see what was new and interesting; now I come by weekly for your updates. Thank you for making this information understandable to lay folk like me. Keep up the good work!

  23. Nigel says:

    Hope you’ll forgive me for asking a stupid question . Am I right in thinking that the viral vector vaccines (oxford) and the genetic vaccines (moderna) are in some ways much the same ? One having mRNA packaged in a virus , the other having it packaged in an artificial envelope ?

    1. No such thing as a “stupid question”…

      The Oxford/AZ and most of the other viral vaccines use different strains of non-replicating adenovirus engineered to produce COVID-19 virus proteins (generally the “spike” or S protein). The Moderna, BioNTech/Pfizer, CureVac candidates are chemically-modified mRNA encoding viral protein (again, the S protein) delivered in a lipid nanoparticle formulation.

      Viral vectors have a long (and somewhat chequered) development history, the major drawback being pre-existing immunity to the vector itself, or the generation of a vector-specific immune response on vaccination. The Oxford vaccine gets around this by using a chimpanzee adenovirus with low immunogenicity in humans; the Russian vaccine uses a “prime-boost” approach, with different vectors for the first and second immunisations. Early data suggests that pre-existing or induced vector antibodies do not compromise the response to COVID proteins.

      Prior to COVID, there was very limited clinical experience with mRNA vaccines. Main issues are preventing the mRNA from being degraded and ensuring that enough gets into host cells to be transcribed into DNA and translated into sufficient quantities of protein to induce an immune response. Early data is encouraging, but emphasis here on “early”.

    2. johnnyboy says:

      ‘Nigal: You could say the principle is the same (getting the host’s cells to produce viral proteins), but the method to get this to happen is quite different. A virus is not just an empty envelope, it has surface proteins to help getting inside cells, and enzymatic machinery evolutionarily designed to help integrating into the hosts’ RNA and producing the viral proteins. An enveloped RNA vaccine like Moderna’s just has that engineered lipid envelope and the mRNA inside – I think there’s a lot more ‘hoping and praying’ involved that the administered mRNA will get inside the cells and lead to sufficient protein transcription and expression. There’s evidence that the approach certainly works to a certain extent – the question is whether it works to a sufficient, sustained and consistent enough degree in everyone who gets it.

  24. And to complement Derek’s excellent overview:

    Evolution of the COVID-19 vaccine development landscape (Nature, 4th September)

    1. Nigel says:

      Thank you for the answers people . Trying to keep track of the Covid situation is pushing my understanding to the limit on afraid !
      Thanks again.

  25. DataWatcher says:

    “No such thing as a ‘stupid question’ . . .”

    Well, I hope not, but — Will people have to get tested before they get vaccinated? If an asymptomatic person who actually has the virus gets vaccinated, what’s the point? Is that a “wasted” vaccine that could have gone to someone for whom it might have done some good? Will this be an additional logistical hurdle to getting as many people vaccinated as efficiently as possible?

    We’re already talking about upwards of 320 millinion in the U.S. alone, which will probably mean upwards of 640 million doses (two per person). Nationwide, over the course of a year, that averages out to approximately two million vaccinations per day. Is this even feasible?

  26. Right now, no one knows what constitutes protective immunity to COVID-19, whether resulting from natural infection or vaccination. Best guess is that infection (and probably) vaccination result in relatively short-lived neutralising antibody responses, which confer protection against infection/reinfection, or at least reduce severity of infection/reinfection. The cellular elements of the immune system and “immunological memory” may provide useful, longer-lasting protection.

    The goal with vaccination is to improve upon the response to natural infection, so no value in testing for active infection prior to vaccination, and assuming that active infection or pre-existing antibodies do not compromise vaccine efficacy, the shot would not be wasted.

    Supply and logistics are issues for mass vaccination. Supply of any flavour of vaccine is likely to be initially limited and restricted to high-risk populations and essential workers. As of April, US estimates for the initial target groups were: 17-20m healthcare personnel, rising to 80m when you add in other essential workers; around 100m considered to have high-risk medical conditions, with this group overlapping with those aged 65 or more (53m). Let’s say somewhere north of 200m on roll-out. Feasibility will of course depend on the nature of the vaccine(s) with respect to storage requirements and stability once a multidose vial had been popped. The need for -70C storage and distribution has already been flagged as a complication with regard to BioNTech/Pfizer’s mRNA vaccine candidate.

  27. Jonas S says:

    FYI aside from the virally vectored Ebola vaccines there are Dengvaxia against Dengue fever and IMOJEV against Japanese encephalitis according to this review:
    Have not looked much into this, but these seem to be termed “recombinant chimeric” virus vaccines, where yellow fever virus surface antigens are replaced with those of the target pathogen.

    1. That’s correct, although the FDA-approved ebola vaccine has a different viral “backbone”- vesicular stomatitis virus, engineered to express an ebola glycoprotein. A digression, but it had a twenty year development path before Merck took up the baton

      The Chinese approved ebola vaccine is adenovirus based.

  28. Reader says:

    Derek, The Lancet has published the results of a Phase 1/2 clinical trial of a vector vaccine from Gamaleya. Your list can be updated.

  29. SteveM says:

    Gamaleya answers questions about their Sputnik 5 vaccine:

    Questions on Russia’s Sputnik V Vaccine Answered, Time for Critics to Look for Plank in Own Eyes

    The Russian scientists respond to being attacked and delegitimatized because they are Russians. But their claims of course are still open to objective scientific scrutiny.

  30. debinski says:

    Interesting, Pfizer/BioNtech are developing a 5th vaccine that was not a part of their original BNT162 program. It’s BNT162b3. A phase 1/2 trial is starting this month in Germany.

  31. Marko says:

    Small ( 76 patients ) RCT on Vit D supplementation in hospitalized Covid-19 patients shows impressive reduction ( Odds Ratio 0.02 (95%CI 0.002-0.17) in admission to ICU , p=.001 :

    “Effect of Calcifediol Treatment and best Available Therapy versus best Available Therapy on Intensive Care Unit Admission and Mortality Among Patients Hospitalized for COVID-19: A Pilot Randomized Clinical study”

    Expect a collective huge yawn from the blue-check big pharma shills about this one. This has been out since 8/29 and barely a peep from any of them about it so far.

    1. TallDave says:

      holy cow thanks for that

      “Of 50 patients treated with calcifediol, one required admission to the ICU (2%), while of 26 untreated patients, 13 required admission (50%)”


      always said that mortality correlation was too crazy to ignore — 20:1 without adjustment, 10:1 with

      of course almost no one will notice b/c when they see “supplement” everyone’s rational filters just assume it must be nonsense (which, to be fair, happens enough to warrant a general skepticism)

  32. Marko says:

    AstraZeneca Covid-19 vaccine study put on hold due to suspected adverse reaction in participant in the U.K.

  33. Cole J. Batty says:

    Re: Janssen: “From what I can see, they’re the only ones at present who are not running a booster-shot trial, which could be an interested [sic] logistical advantage for them.”

    Among viral vectored candidates, Cansino is also running a Phase 3 with a prime-only schedule, as they did in their phase 1/2. From NCT04526990:

    “Experimental: Experimental group
    20000 participants, Ad5-nCoV , single dose, Intramuscular administration”

  34. TallDave says:

    thanks for the roundup

    it’s quite a pipeline, hope it’s enough to stamp out COVID globally in 2021

    must already be the greatest mass research effort ever

    no doubt it will be studied often in decades to come

    self-amplified intriguing

  35. Barry says:

    ” Deployment of a weakly effective vaccine could actually worsen the COVID-19 pandemic if authorities wrongly assume it causes a substantial reduction in risk, or if vaccinated individuals wrongly believe they are immune, hence reducing implementation of, or compliance with, other COVID-19 control measures. Deployment of a marginally effective vaccine could also interfere with the evaluation of other vaccines, as subsequent vaccines would then have to be compared with it rather than with a placebo. For a vaccine superior to the weakly effective vaccine, the increased sample size required could delay recognition of its efficacy. More importantly, if the weak vaccine is compared against an even weaker vaccine, the statistical criteria used to analyse non-inferiority trials could well endorse the even weaker vaccine as being non-inferior (so-called bio-creep).1
    The criteria used to define a successful vaccine in the initial clinical trials of vaccination versus placebo should therefore be strict enough to protect against the risk of a weakly effective vaccine being deployed, especially since there are already many candidate vaccines against COVID-19 to be tested,2 providing many chances to overestimate efficacy. Hence, the initial trials comparing COVID-19 vaccines versus placebo should seek reliable evidence not only of some efficacy but of worthwhile efficacy.”

  36. David Edwards says:

    The one question that worries me in this regard, centres upon two unpleasant facts.

    There does not exist a single “Covid-19” virus. What we refer to via shorthand as “Covid-19” actually has its own phylogenetic tree (the global phylogenetic tree here takes ages to load, but eventually reinforces the point). So we’re dealing with a population that’s acquired a host of mutations since the virus was first identified, and some members of that phylogenetic tree might already be outside the remit of vaccine protection thanks to the mutations acquired therein. There’s also the possibility that future additions to the phylogenetic tree could prove recalcitrant to combat with a vaccine.

    However, there are other Coronaviruses in existence, which raise another prospect: a recombinant virus emerging from individuals simultaneously infected with a Covid-19 serotype and one of the other Coronaviruses. I have an old textbook on genetics which covers recombinant viruses of this sort, with reference to bacteriophages, and which states that this is one of the means by which bacteriophages keep one step ahead of the bacteria they infect. A new, and even nastier, recombinant Coronavirus, containing the most virulent parts of both parents, might also prove recalcitrant to control by vaccine.

    This scenario is capable of keeping me awake at night. And should keep awake anyone recognising the potential contained therenin.

    1. Barry says:

      There are of course mutant coronaviruses. But it does seem that the spike protein–and the RBD of the Spike protein–must be preserved for virulence. Any vaccine that elicits immunity (Abs and TCRs) to the RBD of Spike should protect against any virulent mutants. And the non-virulent mutants aren’t as interesting.

    2. An Old Chemist says:

      @David Edwards & Barry: Does this refer to your query?:

      Stable SARS-CoV-2 genome is good news for vaccine developers

  37. debinski says:

    Pfizer has posted some preclinical data (macaques and mice) on a preprint server. It also includes background on characteristics of the vaccine itself. Would love to hear an expert analysis of the data.

    1. Marko says:

      “Pfizer and BioNTech are moving to enlarge the Phase 3 trial of their Covid-19 vaccine by 50%, which could allow the companies to collect more safety and efficacy data and to increase the diversity of the study’s participants…..”

  38. Barry says:

    If you want mucosal immunity (and you do!) inoculate the mucosa
    “This is a virus that’s transmitted through your respiratory tract, so if you want a vaccine that will really prevent infection and onward transmission you want to have an antibody response in your nose, in your lungs,” Shattock said. “The most efficient way to induce that is by inoculating through that route.”

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