More vaccine news to catch up on – previous updates and specific topic posts on this subject were on June 15, on June 11, on May 26, on May 18 (with two other posts), on May 14, on May 1, on April 23, and on April 15 (author’s note: yikes). Keep in mind that some of those posts were updated after their original publication data as well.
Here’s the latest on the ones I’ve covered before and with new efforts added. There are now so many of these running that unless the program is especially noteworthy I’ll only touch on the ones that are in trials right now, or about to start soon. And I’m going to arrange them by vaccine class – the April 15 background post goes into some more detail on these, but I’ll start each group off with a short scientific summary. Neither the order in which these different mechanisms are presented nor the order in which companies are listed within them is meant to reflect any horserace handicapping on my part.
This class uses some other infectious virus, but with its original genetic material removed. In its place goes genetic instructions to make coronavirus proteins, and when your infected cells do that, it will set off an immune response. Note that this is different than being infected with a “real” virus, whose instructions are (naturally enough) to produce more virus, which go off and infect more cells. No, in this case each viral particle that you’re injected with will be able to infect one cell, and that’s it. An advantage of this approach is that it should appear to your immune system like a pretty realistic viral attack, and set off a full range of responses. A disadvantage is that this technique (as far as I can tell) has only once been used in human therapy (the Ebola vaccine, see below – update: edited this section to reflect this) – a lot of people have been working on it over the years, but things have now accelerated. Another disadvantage is that (depending on which virus you pick as a vector) some of your patients may already have antibodies to that one. That can mean that your attempt to repurpose it might crash and burn as the carefully designed vector gets attacked by antibodies and eaten by immune cells before it can even do its work. It also means that booster shots would have an uphill battle, since the antibodies from that first dose will be waiting for the second one. Antibodies to the viral payload: good. Antibodies to the viral vector itself: not so much.
Oxford/AstraZeneca: ChAdOx1-nCov19/AZD122: This is one of the frontrunning candidates in human trials (the WHO agrees), and it’s recently started dosing in South Africa and Brazil as well as the ongoing trials in the UK, etc. We’re going to be seeing a lot of that jump-around-the world pattern, tracking the places that have significant outbreaks in order to get the best statistics. That means that the organizations behind each candidate either have to have substantial resources themselves, or partner with those who do (pharma, the WHO, groups such as CEPI and the Gates Foundation, etc.) I don’t know when the next report of human data will be on this one, but it will be very closely watched indeed – see the May 18 post for the reaction to the last big data drop, which had some observers (not all) worried about the vaccine’s effectiveness. This one tries to get around the pre-existing antibody problem by using an adenovirus from chimpanzees (the “Ch” in the name).
CanSino/AMMS: their Ad5-nCov, we find out this morning, has been approved for use in the Chinese military “after clinical trials proved it was safe and showed some efficacy”. That’s probably how I would put it, too – the company reported on the Phase I data a few weeks ago, and one of the notable features was that about half the patients that they dosed, in all age cohorts, had pre-existing antibodies to the vector. That’s adenovirus-5, as the name implies, and it’s a pretty common human pathogen. This one was widely used earlier (back to the 1980s) in the viral-vector field (which encompasses both vaccines and gene therapy) and a great deal is known about its behavior in humans, but the existing immune response has been a problem every step of the way. Ad5 is also considered a good choice if you want your payloads delivered to the liver and not much of anywhere else – it tends to concentrate there, and it wouldn’t surprise me if a lot of the coronavirus protein production with the CanSino vaccine is taking place in that tissue. At any rate, an executive with the company has said that their Phase II results will be published very soon, while not missing a chance to take a shot at Moderna for not doing the same (see below), so it’s going to be very interesting to dig through those. Update: apparently the company is looking at a booster-shot regimen, and the same article quotes a Canadian hospital as saying that they are preparing to help with Phase III trials “in the fall”. How well booster shots will work with an Ad5 vector remains to be seen.
Johnson & Johnson (Janssen): J&J, on the other hand, is working with a different adenovirus platform, Ad26. That’s a much rarer strain, and very few people have pre-existing antibodies to it. They’ve been investing in this for years now, and the coronavirus epidemic has, as it has for so many other areas, accelerated things past anything that was contemplated before. This is the time to mention, though, that it’s not just the pre-existing response that can be a problem – if you raise too vigorous a response to the new viral vector you can cause trouble, too (and, as mentioned, perhaps wipe out the chances to ever use that particular vector for anything again). No big announcements since the company said that they were speeding up human trials to first dosing in July.
Gamaleya Research Institute: Those previous entries are a good lead-up to this one, because the Russian GRI vaccine is a mixture of Ad5 and Ad26 vectors. To be honest, I’m not sure of the thinking behind giving both, but it will be an interesting comparison with the Chinese and J&J efforts, for sure. This work made headlines not long ago when the head of the institute let it be known that he and other workers there had actually injected themselves with their own candidate vaccine (!) This was not, he said, an attempt to prove safety, but rather a means to protect the staff while they were working with the coronavirus itself. One would suspect that the Russian language, with its rich stockpile of phrases, would have a metaphor similar to the English “putting the cart before the horse”, wouldn’t it? At any rate, this one has gone into human dosing in Russia.
Reithera: This Rome-based company is taking a similar approach to the Oxford group, in that they have a gorilla-infecting coronavirus platform that should be immunologically novel in a human population. Data are scarce, although the company has said that they expect to go into human trials “this summer”, and some stories on them say July.
Altimmune: Here’s another adenovirus vector, but administered via a different route. They’re going intranasal, and thus hoping to bring in a mucosal immune response as well. Since this seems to be the same platform as their earlier Nasovax influenza vaccine program, I will assume that this is also an Ad5 vector. This one is still listed as “preclinical” on the company’s web site, with such studies taking place partly at the University of Alabama-Birmingham. It’s good to see another technique being applied here; we’re going to need all the shots on goal that we can get.
Merck/Iavi: Now here’s a non-adenovirus vector. Merck’s partnership with nonprofit Iavi is around vesicular stomatitis virus (VSV), which is what was successful in the development of the Ebola vaccine. In that case, the gene for the VSV glycoprotein was replaced by one for the Ebola protein, and I would assume that something similar will be done to swap in the coronavirus spike protein here. Merck is expected to use the same Vero cell line production for this that they used for making the Ebola vaccine and for their rotavirus vaccine. That last one isn’t a VSV vector, but rather a group of mixed bovine-human rotavirus strains – but for all of these you need cells to serve as factories to crank out viral particles for you. I have seen no projected date for first-in-human dosing for this one, though
Merck/Themis: In another non-adenovirus move, Merck had been collaborating with Themis on using attenuated measles virus as a therapeutic, platform, and about a month ago they announced that they were buying them outright. The attenuated measles vaccine (see below for attenuated viruses in general) has a very good safety record and has long been considered an attractive candidate for repurposing, and now we’re going to find out how that works rather before we thought we would. The plan is for this to go into patients sometime later this year.
Vaxart: Now, these folks I had not heard much until the other day, when they popped up with a surprise press release saying that their vaccine candidate had been selected as part of the government’s “Operation Warp Speed” for a challenge test in primates. They have a platform developing oral vaccines – an adenovirus vector delivered in a coated tablet to get past the stomach and into the small intestine. (There’s an immediately obvious difference this route and the injectables in ease of storage and administration, which might be quite advantageous). This “mucosal immunity” technique will be familiar to many via its use in the oral polio vaccine, and the differences between it and the immune response generated by injection are quite complex. Vaxart hopes to go into Phase I later this year, and it will be very interesting to see what happens in the primate study and in humans. This route could turn out to be noticeably better or noticeably worse than other the efforts in the category, or might even end up as an adjunct to another vaccination route. I’m very glad that we have a completely different approach being looked at. (Update: corrected and moved the category on this one; I’d initially thought they were using just recombinant proteins).
These take DNA or RNA coding for coronavirus proteins and inject that directly into the bloodstream. “Directly” isn’t quite the right word, though – for these things to work, they have to be formulated and modified to survive destruction in the blood, to be taken up through cell membranes, and to be used for protein production once they’re inside. There have been extensive experiments in animal models over the years, but this is another category where no existing human vaccine uses the technology (yet!) Advantages include fast development and (possibly) ease of manufacture, depending on how exotic the final form turns out to be, and lack of an existing immune response to the vaccine itself (as seen with some of the viral vectors above). The big disadvantage is, well, once again no one has taken these things into humans yet. And another one is that some of these may need to be stored at not even the usual cold-chain conditions (which are enough of a logistical problem, thanks, particularly outside the industrialized countries) but even colder than that to keep them stable (for example) – an underappreciated problem, perhaps, that we’ll have to keep an eye on. Others have been shown to be stable without cold chain storage, so there’s clearly a wide variation.
Moderna: mRNA1273: this one, the leading mRNA vaccine candidate has been getting a lot of the coronavirus vaccine headlines, of course. They’re still heading for Phase III in July, and have signed up with Catalent (who are also working with J&J) for support in vaccine production, labeling, and distribution for that effort. This in addition to their own production work and the deal that they’ve already signed with Lonza in Europe. The company’s CEO said earlier this week that the best-case timeline had them with efficacy data before Thanksgiving, and yeah, I believe that would be the “everything goes flawlessly the first time through” situation. What we haven’t seen are many more details about how the vaccine has been performing so far. All we have is that small mid-May press release, and it’s been a while, hasn’t it? At some point, there’s going to be a dumptruck of data that will have to be released on this one, and until then we’re all just sort of tapping our collective feet. Update: well, it turns out that Moderna’s Phase III will be delayed a couple of of weeks – and it appears from this story that one reason is that the company has been arguing with the NIH and the FDA over how that trial should be run. As of July 7, their Phase I data have yet to be published.
Pfizer/BioNTech: Not much news here, but we definitely will be getting some. This effort started out with four different mRNA approaches, and there’s no word on if they’ve narrowed things down yet. Pfizer’s CEO Albert Bourla said recently that they’re sticking to a strict policy of not commenting on their vaccine results until they’re published in a journal. He also emphasized that they are not part of the government’s “Operation Warp Speed” effort, saying “We don’t take the money because we don’t need the money”, and believes that doing so would just slow down the company’s own efforts. They’re also planning for about 30,000 patients in their eventual Phase III trial, with about 100 sites (US and international). The number of drug companies that can organize (and pay for) something like that with cash-on-hand can be easily counted on your fingers, and Pfizer is certainly one of them. The company has also said that their best-cast timeline has a possible emergency use authorization in October (!), which will also require everything to ring the bells exactly on time. Not everyone believes that’s possible, but hey, we’ll find out pretty damn soon, won’t we? Update: initial Phase I data are out the first of their four candidates, and look good so far.
Inovio: this DNA vaccine candidate (INO-4800) is getting messy. The company had sued their manufacturing partner, VGXI, claiming that they were in breach of contract and holding up Inovio’s program because they could not fulfill their targets for delivery. A judge has just ruled against Inovio’s request to force disclosure of VGXI’s proprietary manufacturing techniques. For my part, I was already out of sympathy with Inovio after their announced early on in the pandemic that they had produced a vaccine in about three hours, when what he was actually talking about – as people who know any molecular biology whatsoever realized instantly – was a candidate construct for a possible vaccine. That brought on shareholder lawsuits, as the shares were whacked back and forth like a tennis ball between enthusiastic dice-rolling long investors and you-gotta-be-kidding-me short-sellers. I should note that the company has a stock market following that is need of therapy all by itself. Anyway, at this stage, a serious vaccine player should be talking about where they’re going to round up all the glass vials, where the sterile production lines are, how they’re going to handle the logistics for tens of thousands of clinical trial doses, and so on. Not off hammering on their contractual partners in the Montgomery County Court of Common Pleas.
CureVac: hey, remember these guys? Back in March, there was a flare of a story about how the US had allegedly tried to buy up the company (or the rights to any mRNA vaccine they produced), with sourcing of the news to irate members of the German government. There hasn’t been anything quite that lively around them since, but they recently got a 300 million Euro investment from the German government (who now own 23% of the company). They have continued to state that they expect to go into Phase I human trials before the end of June, which means that they have about 28 hours to go (Central European Time), as I write this.
Imperial College: this is another mRNA candidate, but it’s a self-amplifying one, like one of the four Pfizer/BioNTech variations – these are the only two that I know of using this technique. The vaccine went into human volunteers just a few days ago. The way these things work is to deliver messenger RNA that codes not only for the antigen protein of interest, but for an RNA polymerase enzyme (there’s a useful one that’s been borrow from alphaviruses) that will turn around and make more copies of the mRNA itself. The idea is that you can then dose with much smaller amounts of material, since it’s going to go out and make more of itself anyway.
Sanofi/Translate: this one is still scheduled to go into human trials in December. Sanofi has recently expanded their collaboration with Translate in this area, but I haven’t been able to track down details on the vaccine itself. There are an awful lot of ways to deal with the problem mentioned in the intro to this section, though, and I would expect this to be a different run at them than the other mRNA players have taken. Given that we have no idea how these things are going to perform in human subjects, a diversity of opinion is no bad thing.
Genexine: this South Korean company’s DNA vaccine, GX-19, has started human dosing. These folks and Inovio seem to be the front-running DNA vaccine players for now; everyone else in this category is RNA. I would assume that none of this testing is going to be done in Korea itself, though, since COVID-19 levels are so low there (and good for them).
AMMS/Abogen/Walvax: this is the first mRNA coronavirus vaccine in China, and was recently approved for human trials there. An interesting feature is that it’s said to be stable at room temperature for up to a week – rather surprising for an mRNA construct, but something to keep an eye on.
Recombinant protein vaccines
Here we get to a technique that really is used for human vaccines. The previous two categories force your own cells to make viral antigen proteins, but here you’re making them industrially and just injecting them directly. The advantage can be that such protein production can be accomplished in many different ways and is already done on a large scale. That said, every new protein is a new project, with its own idiosyncrasies. A disadvantage is that this technique sometimes does not produce enough of a robust immune response by itself (at reasonable doses of protein, anyway), and needs added “adjuvants” as part of the vaccine formulation. These are substances that increase immunologic reaction – through mechanisms that honestly have not always been so well understood over the years (more here) and you’ll see these in the entries below.
Novavax: The company has been raising significant amounts of money as they push on with their recombinant vaccine (a Spike protein produced in an Sf9 insect cell system). Otherwise, there’s very little news – now everyone waits to see their Phase I results! Update: the company has published preclinical results in baboons and mice. And they have received up to 1.6 billion in funding from the US government, bringing their vaccine candidate into the “Operation Warp Speed” portfolio.
Clover Biopharmaceuticals: These folks are also teaming up with GSK to use their adjuvant, as well as testing their recombinant glycoprotein with another adjuvant from Dynavax. Dosing of these trial arms has already started; they were the second effort in the recombinant protein space to go into humans after Novavax.
Sanofi/GSK: This one, a recombinant version of the Spike protein along with GSK’s own adjuvant, has also had its timeline pushed up. Dosing was scheduled to start in December, but’s now slated for September, with rollout in mid-2021 if everything works. The GSK adjuvant is the one used in their shingles vaccine, and even before the pandemic the company had planned to make this the centerpiece of their vaccine programs. It’s a mixture of a bacterial lipid from a strain of Salmonella and an extract of the Chilean soapbark tree. “Saponin” compounds of that sort have long been known as adjuvants, but this one really seems to ring the bells. I certainly noticed a reaction when I got the shingles vaccine myself (particularly the second dose).
Zhifei Biological Products: Basically, all I know about this one is that it’s just been approved to go into human trials. There’s a lot of stuff going on in China – some of it (like CanSino’s) being well published, and some of it almost totally in the dark.
Queensland/CFL/GSK: Back at the end of April, the team at the University of Queensland announced preclinical results on antibody response to their vaccine candidate. They’re also looking at adjuvants from both GSK and Dynavax, and have partnered with several other companies for production and logistics so far. From what I can see, they’re recruiting patients now to start dosing next month. I’m not sure what the coronavirus situation is in Queensland itself, though – where will the majority of dosing be done?
Stabilitech: Here’s another small company working on oral vaccines, in this case with recombinant proteins (from what I can see). Their web site seem to claim to have formulations that have been through animal dosing, and says that they are ready to start human clinical trials “pending secured funding”. With all the money sloshing around in this area, I would have to assume that they have knocked on some doors, so we’ll see if this goes anywhere.
Zydus Cadila: (update) this Indian company has now received authorization from the government to move their first vaccine candidate (ZyCov-D) into human trials. They’re talking up a very aggressive timeline; we’ll see how that goes. They are also, according to that interview, working on some other vaccine platforms against the coronavirus, and I’ll update those as more information becomes available.
Attenuated Virus Vaccines:
This is another well-precedented vaccination technique. It involves producing a weakened form of the actual infectious virus, one that is not capable of causing damage but can still set off the immune system. There are several ways to do this, and it’s a bit of an art form involving taking the virus through a huge number of replications in living cells as you select for variants that are less and less harmful. An advantage is that such vaccines can be quite effective at raising a response – ideally, the immune system reacts exactly as it would to the real pathogen, except you avoid all the getting-sick part. A disadvantage is that part about it being an art form: balancing the lack of harm with immunogenicity is not something that can always be achieved. Some viruses have a wider window for this sort of thing than others, and it’s not easy (or possible, really) to know if this is a feasible pathway up front. That may well be one reason why (at the moment) I know of no candidate vaccines for this coronavirus that are using this method.
Inactivated Virus Vaccines:
This is also one that’s also been used in medical practice for many years, and it’s another inactivation step beyond the attenuated viruses. Heat or chemical agents are used to damage the virus to the point that it can no longer infect cells at all, but the plan is for there to be enough of the viral material left unaltered to still raise an immune response. Not the most high-tech approach, but it can definitely work. Many times, though, vaccines of this don’t provide enough of a response in a single shot, so you may be looking at a booster vaccine schedule. Interestingly, the Chinese groups seem to have this field to themselves; I’m not aware of any inactivated-virus vaccine for the pandemic that’s in serious development anywhere else.
SinoVac: When last heard from, the company had released positive Phase II data – well, some data. The full report on the trial is not out yet, but two weeks ago they issued a statement saying that over 90% of the participants had neutralizing antibodies at 14 days after dosing. That’s good news, but you’d want to see a lot more detail, such as actual antibody titers, and it hasn’t shown up yet (although SinoVac says it’s coming). Their Phase III trial will be starting shortly in Brazil – which given the epidemic situation there at the moment seems like (sadly) a good choice of venue. More on this one when more data show up. Update: dosing in Brazilian volunteers started July 6.
SinoPharm/Wuhan Institute of Biological Products: This is the one that’s already being given to employees of Chinese state-owned companies who are traveling to high-risk areas overseas, so hey, why bother with clinical trial results? Well, anyway, the organization has announced that antibody titers were “high” in the initial trials, and the the seroconversion rates (at 28 days) were a flat 100%. One would like to see a full paper on these data, but I don’t know when (or if) that will ever show up; SinPharm seems to like to announce these things on Weibo and move on. The Phase III trials will take place in the United Arab Emirates, (and likely other locations as well?)
SinoPharm/Beijing Institute: This is the other SinoPharm vaccine, and just today the company has announced that it also passed safety trials and generated neutralizing antibodies. But this was another Weibo posting, so that’s all we have. I also have no clear idea about the differences between this one and the Wuhan-originated vaccine – all I know is that they’re both some form of inactivated coronavirus.
Institute of Medical Biology (China): Last week there was an announcement that this one had moved into Phase II testing, but we don’t know much more. There was a Phase I trial in May (China Daily link) with 200 people, whose results (as far as I can tell) have not been reported, either. Nor do we know anything about the method used to inactivate the virus in this candidate (just like the other two, actually).
Bharat Biotech: (update) this Indian company has also just received the go-ahead to take their inactivated-virus candidate Covaxin into human trials. This is not without controversy: the Indian Council on Medical Research apparently communicated a timeline to hospitals taking part in the study that is completely unrealistic. How unrealistic? How about a launch by August 15? Which is India’s Independence Day, by what is no doubt a coincidence? This does not inspire confidence.
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 one of the companies that is producing recombinant proteins in tobacco leaves. This idea has been around a while, because the plant can produce reasonable yields of well-folded proteins that can have different glycosylation states than the ones produced by other platforms. As that last link shows, though, uptake of this technology has not been as quick as people once expected – improvements in the more traditional platforms (and the long experience with them) make this a difficult market to crack. But vaccines are a good place to be, because the plant-derived proteins may in fact be more immunogenic because of those glycosylation patterns. Medicago has announced that they are going into human trials with a plant-derived virus-like-particle coronavirus vaccine before August.
OK, sheesh. There’s the state of the business as of today. I hope to use this post as a standing reference point for a little while to come, so I will be coming back in to update it as more news shows up. Right now we’re at an awkward age for vaccine development against this pathogen. Not all of these approaches are going to work, or at least not well enough to be useful. And we don’t have enough data on any of them to even start to guess which those might be. We can’t even do Phase II data comparisons, and the crucial Phase III data don’t even exist yet. So we’re going to be hanging in this limbo of “lots of things going, not sure about any of them yet” for quite a while. It’s going to get exhausting – what’s that, you say it’s kind of exhausting already? Hah – just you wait. . .