A Close Look at the Frontrunning Coronavirus Vaccines As of April 23 – Science Magazine

Theres plenty of news on the coronavirus vaccine front, so lets have a look. If you need some details on the different sorts of vaccines in general, heres the background post, which should help this one make sense. This is a rapidly advancing field, with a huge number of programs. Some of the players are doing a lot more than theyre talking about, while others (as is always the case) are talking much more loudly than their actions really justify. The signal/noise isnt great, but this will be an attempt to make sense of the landscape as of today.

Update:I should put in the links to the larger vaccine lists, as I did in the earlier post. Heres a good overview of the coronavirus vaccine world in a recentNature Reviews Drug Discovery. The official WHO list is here, and at BioCentury they have constantly updated open-access summaries of the vaccines and other therapies that are in the clinic and the ones that are still preclinical. Theyve also recently published this excellent overview of vaccine issues in this area.

CanSinos Ad5-nCov

Probably the most advanced candidate at the moment is CanSino BiosAd5-nCoV. This one has completed Phase I studies and the company has apparently started enrolling patients for a Phase II trial, making them the first to do that, to my knowledge. That one is of the kind mentioned in the background post under DNA vaccines, because what its doing is using a different virus entirely (adenovirus, which infects human cells readily) to deliver the DNA for a coronavirus protein (or proteins). You can also look at this as a hybrid of live virus and recombinant protein approaches, because you have a real infectious virus (just not the one causing the disease) being used to generate protein antigens that will call up antibodies to the real disease virus. Heres a review of the approach (open access), which has had a lot of work put into it over the years. Adenovirus vector vaccines of various sorts have gone into human trials for HIV, influenza, Ebola, tuberculosis, and malaria, but none have made it all the way through yet. Thats partly because those are some damned hard immunization targets people have been trying to come up with a decent tuberculosis vaccine since before any of us were alive but that also tells you how seriously people take this technique. There are vaccines that use this different-DNA-in-another-virus technique (such as the MerckEbola vaccine) but Im not aware of any adenovirus vector vaccines that have been approved anywhere for human use yet. CanSino has an adenovirus-vector Ebola vaccine of its own (Ad5-EBOV) thats already in Phase II trials; work on that one surely provided the boost needed for the company to advance this candidate so quickly.

No one outside CanSino has seen the Phase I results, and the main thing that we know about the Phase II trial is that the company is planning to enroll 500 patients in Wuhan, and that the highest dose from the Phase I protocol has been dropped. 250 people will get the Phase I middle dose, 125 will get the low dose, and 125 will get a placebo injection. Were likely not going to hear much about this until the conclusion of the trial; any sudden news before then has a better chance of being bad.

The Oxford vaccine,ChAdOx1-nCov19

Meanwhile, Oxford University has its own candidate, which is in a very aggressive clinical development program. Theyre telescoping Phase I safety and dosing and Phase II efficacy measurements into one 510-patient trial, with numerous endpoints. This one is another adenovirus vector which will set off production of the coronavirus Spike protein and (one hopes) raise a vigorous antibody response to it. The vector is a chimpanzee adenovirus from Vaccitech, so although the concept is similar to the CanSino vaccine, this will be a different beast. There is literally no way to know which of these competing efforts will yield a better vaccine, or if either will work at all: thats why we dose human beings, and in this case those humans are (I believe) beginning to be dosed right now (Thursday!) Oxford is definitely taking a chance with their trial design, but then, everyone else is taking chances of one kind or another here.

The good news is that the Oxford group had also put work into developing a MERS vaccine (yet another coronavirus) using this same platform. Their ChAdOx-MERS vaccine also expressed that viruss spike protein, and in Phase I human trials there were no safety problems, and they did indeed elicit the desired immune response. The group has a new preprint out that shows that a dose of vaccine in animals (up to monkeys) also provided immunity against a whole suite of known MERS mutational strains, which is good to see as well. (For more on this vaccine, see the Sinovac section below).

Modernas mRNA1273

This is another one thats progressing rapidly in the clinic, and if youre keeping score, is the most advanced vaccine candidate from a US company. Modernas expertise is in messenger RNA-based therapies, and this one is indeed an mRNA vaccine, developed in collaboration with the NIH. The hope is that this engineered RNA will enter cells and make them produce coronavirus spike proteins, which will then set off an immune response. As mentioned in the background post, this is a relatively new vaccine technology, and no vaccines have been approved yet using it. It has the advantage of being fast, though, which is why this candidate is in the position it is.

Volunteers have already been given a low dose of the vaccine in a 45-patient Phase I trial in Seattle, and a larger one is enrolling at Emory, dosing 25, 100, and 250 micrograms of the mRNA in various age groups. That will set up the dosing protocols for the first Phase II trials, which Modernas management has been saying could begin in the spring. Of course, spring is a flexible concept! This is a big bet on a new technology the company has set up to receive as much as $483 million from HHSs BARDA to ramp up clinical work and manufacturing in an effort to not miss a beat should the vaccine show promising data.

BioNTech and Pfizer

More mRNA candidates are moving along briskly as well. BioNTech has a deal with Fudan to work on such coronavirus vaccines in China, and they signed up last month with Pfizer for the rest of the world. (The companies had already been working on an mRNA influenza vaccine). Word has just come that the companies have received clearance from German regulatory authorities to start a Phase I/II trial. Theyre spreading out the risk by adding to the work, taking four different candidates into the clinic more or less simultaneously.

Theyre varying both the payload and the method of delivering it. Two of the candidates use mRNAs with naturally occurring (but less common)modified nucleoside bases in them (presumably things like pseudouridine), a trick thats been tried over the years to increase stability and to cut down on the problem of developing antibodies to the mRNA vaccine itself (rather than to the protein it eventually produces!) The third has another modification, uridine-containing mRNA (presumably an extra tail of U residues?), which has been shown in some cases to increase the immune response to the protein product. And the fourth is a so-called self-amplifying mRNA, which has a sequence for a replicase enzyme in it as well. When this gets translated into protein, the replicase goes to work making more copies of the mRNA, including some double-stranded species that prime the immune system even more. As for the payload, two of these have the Spike protein (a popular choice, and for good reason), while the other two have just the receptor-binding domain from the spike (which came up in a recent post on coronavirus mutations here as well).

The trial will be dose-escalation design (1 to 100 micrograms), doing the usual range-finding for the later trials in up to 200 volunteers. Theyre also going to look at the effect of repeat vaccinations and will try some cohorts of higher-risk patients as well. This is an ambitious program indeed.

Sinovacs PiCoVacc

Meanwhile, back in China, Sinovac has received approval for human testing of an inactivated-virus vaccine (see that background post for more on these). You may recall that these sorts of vaccines often need an adjuvant to boost the immune response, since they can be less like a real infection as far as the body is concerned, and Sinovac has just recently partnered with US-based Dynavax. They have an adjuvant that theyve used in their own hepatitis B vaccine, and theyre bringing that in for Sinovac.

Sinovac themselves made news this week with a preprint that shows evidence that their vaccine produced neutralizing antibodies in mice, rats, and rhesus monkeys. The latter animals were significantly protected against challenge with the coronavirus itself, which successfully infected the control animals in what is a first report of a possible animal model in primates. Moreover, these antibodies appear to be effective against ten different mutational forms of the virus, which is good news in light of recent news about variant strains.

Perhaps the biggest news is that the company saw no evidence of antibody-dependent enhancement (ADE). This is an extremely annoying effect in which some of antibodies raised by a potential vaccine can actually be beneficial to the virus upon infection, helping it to enter cells such as monocytes and lymphocytes. ADE can be hard to get a handle on; it can depend on the antigen, the antibody titer induced in the patient, what the next viral pathogen is, etc. Indeed, its possible that antibodies to other coronaviruses might be helping the current one along in some people due to this effect. This was a major problem with attempted vaccination against dengue that virus comes in several closely related varieties, and it turned out that immunization against one could make subsequent infection with another one even worse. Its exactly what you dont want from a vaccine, and the only way to know if its happening is to try it and see.

ADE was seen in some SARS vaccine attempts, unfortunately, where its worth noting that those blood cell lines just mentioned dont even have the now-famous ACE2 protein on their surfaces at all (the virus enters through another pathway, perhaps complement receptors). There is a report of an inactivated-virus SARS vaccine that did not show ADE, though, and in the animal studies mentioned up in the section on the Oxford MERS vaccine, they didnt see this effect, either. And now it appears that this new nCov-19 vaccine doesnt have obvious ADE, which is good news.

The Wuhan Institute For Biological Products

This vaccine candidate was given the go-ahead for human trials at the same time as the SinoVac one, but its not easy to find any information about it. All I know at the moment is that its another inactivated-virus one, so it will be interesting to see what differences might show up between it and the SinoVac effort. I have been unable to find out more about the size of the trials, etc., but if anyone has information, Ill be glad to update.

Inovios INO-4800

The Inovio candidate is a DNA vaccine, the only one Im mentioning today. Thats a broadly similar idea to the mRNA vaccine, in that youre coming into the patients cells with genetic material and trying to get to them to make the antigen proteins for you. The company has been working on this platform for several years, and like several others their earlier efforts on MERS and/or SARS have jump-started their efforts on this new coronavirus. They started dosing 40 volunteers here in the US earlier in April, moving from younger, healthier participants now to older ones, and theyre moving into similar trials in South Korea. The regulatory authorities there have set up a number of fast-track procedures for accelerated safety and toxicology approvals in cases like this, where the general vaccine platform has been into human patients before.

One of their challenges is that theyre also developing a new delivery device to administer the vaccine through the skin. They have some Gates Foundation money for that, but if theyre going to get this working on a large scale there will, youd figure, be some significant manufacturing challenges in producing both a new vaccine and a new handheld device to dose it.

Johnson & Johnson (Janssen)

Now we get to the candidates that (as yet) do not have human trials set. J&J has another adenovirus platform of their own, Ad26 (see the CanSino and Oxford entries above for more on this technique), and theyve been working on a number of vaccines with that same vector. They have signed a huge deal with HHS/BARDA to help develop this one, and what we know so far is that they have run a whole series of gene constructs through the adenovirus and selected the most immunogenic candidate for dosing in primates. The company has some pretty serious manufacturing capability, and is ready to partner with others to get up to the number of doses needed theyre targeting a billion, on a not-for-profit basis.

Their Phase I trial is not going to start until September the company explains that with the adenovirus vector that you need to get the correct seeds to grow more viral vector. The stuff makes itself, but you have to be very sure that youve picked the one that you really want, and that its stable enough to keep giving you the same material over a big manufacturing run. (This is interesting to contrast with the full-speed-ahead approach taken by CanSino and Oxford one would like to know the differences between these adenovirus platforms and whos taking on the most risk with their programs)

One big difference could be that the Ad5 vector being used by CanSino has run into some problems with immunity showing up to the vector itself. (Update: I should clarify that this is because that variety of adenovirus is one that many people are already exposed to, without any particular disease being associated with it). You obviously dont want that (see the BioNTech/Pfizer entry above for similar worries). J&J has reported that their Ad26 Ebola vaccine candidate avoids this problem, so its a potential advantage. (Update: as per that last note, this adenovirus platform and the Oxford one have the advantage of humans not being as exposed to them already).

Sanofi/GSK

And heres another Big Pharma entry. Sanofi has a vaccine platform that uses insect cells to turn out recombinant antigen proteins, and this has already been used for an approved flu vaccine. Theyre bringing this technology and (as mentioned in the earlier vaccine roundup post) combining it with GSKs adjuvant (as used in their own shingles vaccine). Such adjuvants (immune-response boosting agents) are important when youre vaccinating with specific proteins like this, because otherwise the antibodies might not reach useful levels. Theyre also working with BARDA, and the companies have stated that they plan to move into human testing in the latter part of this year (similar to J&J).

Sanofis antigen is a Spike protein as well (the logical choice, as you can see from so many people using it), and their protein production platform is said to be able to deliver hundreds of millions of doses. Manufacturing capability is already being expanded on an at-risk basis, and at-risk basis is pretty much the slogan for the vaccine effort across the whole biopharma industry.

Summary

So by my count, the biggest and most advanced programs include two inactivated virus vaccines, three different adenovirus vector vaccines, two mRNA possibilities, a DNA vaccine, and a recombinant protein. Thats a pretty good spread of mechanisms, and there are of course plenty more coming up right behind these. You cannot do the tiniest search for such information without being inundated with press releases about companies working on coronavirus vaccines not complaining here and moving on to smaller companies would make this post multiple times longer. Ill update as more news comes out and add in more companies and candidates.

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A Close Look at the Frontrunning Coronavirus Vaccines As of April 23 - Science Magazine