A Wider Variety of Vaccine Platforms Report

 By Derek Lowe

Well, it’s definitely been a Vaccine Week around here, but it’s understandable. And we’ll finish off the week with a look at some types that we haven’t seen report yet. The news is. . .mixed.

First off is a preliminary report on the inactivated virus vaccine from Sinopharm – more specifically, their China National Biotec Group division, and even more specifically CNBG’s Beijing Institute of Biological Products. As a side note, if you find the organizational structure of these Chinese efforts somewhat confusing, come sit right over here next to me. A press release from the United Arab Emirates’ Ministry of Health and Prevention says that a trial there showed 86% efficacy and that there were no serious safety concerns. I would bet that this is a higher figure than most people expected from an inactivated-virus candidate – it’s an older technology that doesn’t always come through (but has certainly also generated some very useful vaccines in the past).

Unfortunately, that’s about all the release has to say – there are few further details. The 86% is said to be for preventing coronavirus infection, but we don’t know if this was measured by number of patients with symptoms or counting in asymptomatics via PCR testing. The release also says that the vaccine was 100% effective in preventing moderate or severe cases, which is also very good, of course. It’s a two-shot dosing regimen, and the vaccine itself is said to have no special storage requirements. So there’s a lot of promising stuff here, but there’s a lot to wonder about as well. I know that we’ve had a lot of press releases in this vaccine clinical trial business so far, but most of them have them have been a bit more informative than this. And although some of the Chinese development efforts have released and published good data sets, others have been very much lacking, and this is one of them.

For example, neither Sinopharm nor the Chinese authorities have had any comment on this announcement. And that’s odd. Indeed, the New York Times reports that one of their reporters got through to Sinopharm only to have them hang up the phone when asked for comment. So I’m not just being hard on this one because it’s from a Chinese company – this is weird by any nation’s standards. If I’m going to give Oxford and AstraZeneca grief for the way they rolled out their recent trial announcement – and I do, because they deserve some – then I’m going to give Sinopharm some for this. If they weren’t ready for a press release from the UAE government, they should say so. Hanging up the phone on people is not the way to build confidence in your organization and its skills. At any rate, the efficacy numbers from this single press release are good news. The UAE has now approved it, and shipments of it are already going to Egypt and Indonesia, among other countries. I would just feel better if I could hear the actual developers of the vaccine say something about it, and with some more numbers attached.

We also had news this morning from the GSK/Sanofi effort, but the news is not good. They have been working on a recombinant protein vaccine with the addition of GSK’s adjuvant, but the companies announced that a look at immunogenicity in Phase I volunteers showed an inadequate response in older patients. The 18-49 year old cohort apparently looked good, but when compared to convalescent plasma antibody levels, the levels in the older vaccinated patients were not. The companies plan to start up again in the clinic in February with an improved antigen formulation, but this will definitely delay their vaccine to (probably) the end of next year, and that’s assuming that the new version works as hoped.

That’s unfortunate. We need as many solid vaccines as we can get, and I don’t think anyone was really expecting something like this from the Sanofi/GSK team (they certainly weren’t). The two companies have a long track record in this area, but immunology is what it is – these results show that we can take nothing for granted. In fact, together with the lower efficacy seen in the Oxford/AZ candidate, I have to say that this is making the mRNA platforms look stronger all the time. More on this in a separate post next week. Anyway, in the same way that the Oxford/AZ data make me very curious about what we’ll see from J&J’s trial, these results make me similarly ready to see what Novavax will report with their own recombinant protein/adjuvant candidate. But they did have reasonable antigenicity numbers, at least. And in that first link in this post, the team at Science says that they believe that another inactivated-virus candidate (from Sinovac) may soon report on its trial in Brazil, so we’re going to have plenty of comparisons to think about.

Finally, word has come that an unusual vaccine candidate has had to stop development. In my earlier huge vaccine roundup posts, I mentioned the University of Queensland and their “molecular clamp” technique. Here’s more on how that is supposed to work. The idea is to use a trimeric protein that’s from HIV, a part of its gp41 glycoprotein, as a molecular platform to display the antigen proteins from whatever other virus you choose. The Queensland candidate (which was being developed with biotech company CSL) displayed the coronavirus spike protein this way, in what was believed to be exclusively its pre-fusion conformation. The idea looked like it would be readily adaptable to many viral proteins, and easier to realize than some of the other scaffolding ideas like this that have also been looked at.

Unfortunately, the use of this protein fragment also caused antibodies to be raised to it as well as to the Spike protein part, and that led to false-positive HIV tests in the trial participants. It’s important to note that these are indeed false positives – the vaccines used only a piece of one HIV protein and this has nothing to do with an actual HIV infection, of course. But wide use of such a vaccine would basically blow up the ability to do routine HIV blood screening, and that’s not good. Especially when there are other vaccine candidates out there with no such liability. Work on this one has ceased, and this would appear to throw into doubt any further plans to use the gp41 platform for future vaccines.

Update: there’s some more news. AstraZeneca today says they’re looking at combinations of the Oxford/AZ adenovirus vector vaccine with others. That includes the mRNA candidates and (interestingly) the Russian “Sputnik” vaccine from Gamaleya. Details on that latter one have been very much lacking. I’ve written here about the possibility of people getting more than one type of vaccine, so I’ll be glad to see some controlled data on the mix-and-match approach in general, while keeping in mind that (immunology!) every one of these situations could be different, all the way down to what order the vaccines are given in. To me, this also suggests that AstraZeneca is hedging against the possibility that their candidate may simply not be able to compete as a standalone agent in the eventual coronavirus vaccine landscape. . .

https://blogs.sciencemag.org/pipeline/archives/2020/12/11/a-wider-variety-of-vaccine-platforms-report

Latest on Coronavirus Mutations

 By Derek Lowe

For people looking for an accessible writeup on the coronavirus mutational landscape, I can recommend this Reuters article that came out today. It has a lot of good information in it, and a lot of very well-made graphics to show what’s going on. Past blog posts on this subject are here, here, here, here, and here.

And what’s going on, of course, is that the virus is mutating. It’s what viruses do. They don’t have a lot of overhead for lots of redundant error-checking machinery (although some have more of that than others), and honestly, total fidelity is not really an evolutionary advantage. A little sloppiness in copying the genetic material gives a more diverse population of viruses, with members that are more likely to be able to meet new threats or take advantage of new opportunities for infection. You would expect, over time, the viruses that can do a better job of that to be more represented. And remember, evolutionary time works different for viruses than it does for us. They turn around a new generation so quickly and in such huge numbers; they’re mashed down on fast-forward constantly.

So the mutational background is constant, but it’s important not to make the teleological error of picturing this all as being due to calculation, with the virus outwitting its adversaries. It can look like that, for sure, but it’s just millions of random chances spewing out everywhere – some work, some don’t, and what we see is the residue of some stuff that worked. You’ll see from the Reuters article that strains with a Gly in position 614 (the D614G one and its further offshoots) have become much more prominent. And those do seem to have a bit of an advantage in the binding behavior of the Spike protein – but if you look at some other situations around the world, you can see that other factors are at work. Singapore, for example, showed a lot of low-frequency mutations for a long time, apparently because these were showing up in foreign worker dormitory buildings which were then hit with vigorous quarantine measures. South Korea, for its part, had a lot more “V” family strains for a while due to a single superspreader event, which stood out against the country’s generally strong response. So there are a lot of extraneous factors and sheer accidents mixed into the data landscape.

The good news continues to be that none of the mutations studied so far in the general population seem to be able to evade the antibodies raised by the current vaccines. That doesn’t mean that it can’t happen – and as we start putting selection pressure on the virus by vaccinating people we’ll have to keep a close eye out for anything like that developing. But then we have to consider transmission. If an antibody-evading form of the virus also becomes harder to catch, well, it’s going to be less of a worry. But if we were to start doing a better job at not spreading the virus in general, that would be sort of nice, because that would reduce the chance that any nasty mutated forms get any kind of traction in general. If some sort of supervirus mutation occurs in a single patient who doesn’t then get close enough to other people for it to spread, then it’s a tree falling in a forest that doesn’t make much of a sound.

It’s all a race between several different factors. But here in the US we have so many people infected (and so much transmission going on) that frankly we’re making ourselves vulnerable to any more dangerous mutations that might crop up. In fact, if something like that were to emerge, the odds are better that it would do so here, from what I can see. We’re giving the virus every opportunity to reproduce and for the subsequent viral variations to then go out and try their luck infecting lots of other people. Vaccinating enough people quickly enough would interrupt these processes, and so would doing the sorts of public health measures that we’ve all been hearing about for months. But the first is going to depend on vaccine supplies, logistics, and public acceptance, and the second, well, look around you, si monumentum requiris.

It’s good news that no profoundly worse mutations have spread so far, and that might be a sign that they’re not so easy to come by. But then again, this virus has a relatively short acquaintance with human beings, so I think it would be prudent to assume that there are still a lot of things that we don’t know about its interactions with us. Let’s do everything we can to give it as few chances as possible.

https://blogs.sciencemag.org/pipeline/archives/2020/12/10/the-latest-on-coronavirus-mutations

Just Under 3M Will Get COVID-19 Vaccine in First Week

 The federal government says it will distribute only enough doses of Pfizer's COVID-19 vaccine to immunize 2.9 million Americans in the first week after the US Food and Drug Administration (FDA) authorizes it, far less than the initially discussed 6.4 million doses.

Theoretically, states have already formulated plans for distribution based on the revised lower amount. But in a briefing with reporters on December 9, officials from Operation Warp Speed and the Department of Health and Human Services (HHS) didn't make clear exactly what the states were expecting.

Vaccine will be shipped to and allocated by 64 jurisdictions and five federal agencies — the Bureau of Prisons, the Department of Defense, the Department of State, the Indian Health Service, and the Veterans Health Administration — according to the Centers for Disease Control and Prevention's COVID-19 Vaccination Program Interim Playbook.

It will be up to states — which will receive a supply prorated to population — and these agencies to determine how to prioritize distribution of the 2.9 million doses. Each state and agency has its own plan. Gen. Gustave Perna, the chief operating officer for Operation Warp Speed, said in the briefing that 30 states have told the federal government they will prioritize initial doses for residents and staff of long-term care facilities.

The distribution is contingent on FDA authorization, which could happen soon. The FDA's Vaccines and Related Biologics Advisory Committee weighed the effectiveness data for the Pfizer vaccine on December 10 and recommended that the agency grant emergency authorization. The FDA could issue a decision at any time.

Fewer Doses Out of the Gate

Perna said the federal government will begin shipping the Pfizer vaccine within 24 hours of an FDA authorization.

He said those shipments will include a total of 2.9 million doses — not the 6.4 million that will be available. The government is holding 500,000 doses in reserve and another 2.9 million to guarantee that the first few million people who are vaccinated will be able to receive a second dose 21 days later, said Perna.

In part, that is because the FDA labeling will require that a first dose be followed by a second exactly 21 days later, said HHS Secretary Alex Azar in the briefing.

Federal officials have calculated how much to hold back on the basis of Pfizer's production, said Azar. At least initially, "we will not distribute a vaccine knowing that the booster will not be available either from reserve supply by us or ongoing expected predicted production," he said.

Even with Pfizer having reduced its estimates of how much vaccine it can deliver in December, Azar said, "There will be enough vaccine available for 20 million first vaccinations in the month of December."

That estimate is predicated, however, on the idea that a vaccine under development by Moderna will receive clearance shortly after the FDA assesses that vaccine's safety and effectiveness on December 17.

https://www.medscape.com/viewarticle/942491

Timeline for Covid-19 vaccine distribution keeps slipping

 When Bruce Y. Lee was helping the U.S. government model delivery plans for H1N1 influenza vaccines, he came to expect one constant: The schedule would always change.

“We’d constantly have to update the models as new production numbers came out,” said Lee, a professor at CUNY Graduate School of Public Health & Health Policy, who developed computational models to guide the national response to the H1N1 flu pandemic in 2009. “That just became accepted.”

The shifting timelines are already apparent with Covid-19 vaccine distribution in the U.S. — even before the rollout starts in the coming days. The Trump administration declared in May that 300 million vaccine doses would be available by January 2021, with the first distributed in October of this year. By October, that had shifted to 100 million doses by the end of the year, according to Health and Human Services Secretary Alex Azar. Currently, the plan is for 40 million doses to be distributed in December, though some in health care are skeptical of even that prediction.

Pharmaceutical and vaccine production involves complex coordination, involving product development, manufacturing, packaging, storage, distribution, and regulatory review, and each stage can cause unexpected delays.

The manufacturing process can — and usually does — go awry at some point. “Manufacturing never goes 100%, there’s always issues and stock you have to throw out,” said Lee. “You bake a thousand cakes, you’re not going to get a thousand successful cakes.”

At every stage of production, manufacturers must test the product to show that each batch, from each different facility, is equivalent to the original. This will inevitably reveal issues that need addressing as Covid-19 vaccines are produced at unprecedented scale and speed. “Not only do we want it yesterday, but we need a lot of it yesterday,” said Thomas Denny, chief operating officer of the Duke Human Vaccine Institute. “If you try and do something quickly in your kitchen, even if you have a recipe, sometimes things go wrong.”

Every feature of the final vaccine, including buffers, glass, pipette tips, dry ice, and packaging, then comes with its own potential production issues. Pfizer recently had to cut its end-of-year supply projections for Covid-19 vaccines in half, because of delays in scaling up the raw material supply chain.

As more vaccines are rolled out, this will increase the pressure on available supplies. “You’re dealing with a limited supply chain,” said Denny. “I would not be surprised, as we get two or three vaccines being manufactured, if we see some challenges.”

Another challenge for those making predictions about vaccine availability is that manufacturing capacity is a closely guarded secret, and companies are unlikely to reveal precise details even to major buyers such as the U.S. government, said Lee.

“Vaccine manufacturers hold their production capacity pretty close to their vest because it’s a point of a negotiation.” he said. Companies want to have flexibility in their contracts so they can balance production of various drugs and vaccines. “These companies are businesses and want to maximize their revenue. They’ll continue to make other products they can sell while manufacturing their vaccine.”

“Manufacturing never goes 100% … You bake a thousand cakes, you’re not going to get a thousand successful cakes.”

BRUCE LEE, PROFESSOR AT CUNY GRADUATE SCHOOL OF PUBLIC HEALTH & HEALTH POLICY

Even during a medical emergency, companies won’t reveal this information, said Mark Capofari, who was director of global logistics at Merck from 1995 to 2007 and currently lectures on supply chain management at Penn State University. During the AIDS crisis, when Merck made a key treatment drug, Crixivan, production capacity wasn’t shared outside the company, he said.

Once vaccines have been fully prepared, some degree of waste is inevitable, said Lee, meaning it will take more than 80,000 vaccines to inoculate 40,000 people (each person gets two doses). Vaccine is wasted if vials are broken, stored at the wrong temperature, or opened and only a portion of the doses inside are used. Wastage of between 1% and 10% is fairly common, said Lee, and this adds unpredictability to the system.

Distributing vaccines to the right people, and at the required storage temperatures, is its own complex logistical feat. Any problems with distribution can affect manufacturing, and vice versa. “You have to match supply and demand. If you don’t, you can end up with vaccines not being used, and people not being vaccinated,” said Lee.

There’s a limited amount of storage where vaccines can be kept to one side before being sent out, meaning the entire system has to work smoothly to quickly send vaccines to locations where they can be used as soon as they’re produced. “Once you make it and pack it, you just have to move it,” said Capofari. “You only have so much time from a cold-chain perspective to get it to the clinic.”

The package delivery companies FedEx and UPS are involved in distributing Pfizer’s vaccine, and both face their own limitations, especially during the holiday season. These companies seem to be at capacity, said Capofari. “I don’t know how much you can put lift into the system now.”

Despite the many variabilities, the U.S. government is still making optimistic predictions. Earlier this week, Azar said the government is “very confident” there will be enough doses for everyone in the U.S. who wants to be vaccinated by the second quarter of 2021.

Others are less sure. “This is all the world of guesstimates. I would think you’ll see these estimates reissued and refined every couple of weeks as we go through this process,” said Denny.

Given the current information, it’s reasonable to expect that vaccine rollout in the U.S. will continue well into the third quarter of 2021, agreed Denny, Lee, and Capofari. But even this prediction is dependent on everything going to plan.

“This is a best guess with everything aligning with everything you hope it will align,” said Denny. “Rarely do we get everything to work out with that type of alignment.”

https://www.statnews.com/2020/12/11/covid19-vaccine-timeline-keeps-slipping-experts-say-it-will-change-again/

Lilly/Incyte announce peer-reviewed publication of Baricitinib/remdesivir trial data

 

• Eli Lilly and Company (NYSE:LLY) and Incyte Corporation (NASDAQ:INCY) announce that the New England Journal of Medicine has published peer-reviewed results of the Phase 3 trial for baricitinib with remdesivir in hospitalized patients with COVID-19. The results support the emergency use authorization issued for the therapy by the FDA last month for adults and pediatric patients requiring supplemental oxygen.
• The ACTT-2 study was a double-blind, placebo-controlled trial sponsored by the National Institute of Allergy and Infectious Diseases.
• Andre Kalil, M.D., a principal investigator of the ACTT studies and the lead study author of the ACTT-2 New England Journal of Medicine manuscript, says "Results of this study demonstrated baricitinib in combination with remdesivir provided a faster median recovery time and reduced progression to ventilation or death compared to remdesivir alone in hospitalized COVID-19 patients on oxygen."
• Baricitinib, discovered by Incyte and licensed to Lilly, is an oral JAK inhibitor, approved for adults with moderate to severe rheumatoid arthritis in the U.S., and for moderate to severe atopic dermatitis, in the EU.
• https://seekingalpha.com/news/3643811-eli-lilly-incyte-announce-peer-reviewed-publication-of-baricitinib-remdesivir-trial-data

Cortexyme weighed down by Citi sell rating

 

• Cortexyme, Inc. (NASDAQ:CRTX) dropped -19.4% as Citi initiated coverage on the stock with a ‘Sell’ rating.
• Noting that risks from ‘company’s “unique” Alzheimer’s disease approach are still not reflected in the stock even after the recent selloff’, the analyst Neena Bitritto-Garg has set a price target of $20 per share, a 45.7% discount to yesterday’s close.
• This month, the company announced, its Alzheimer’s candidate, atuzaginstat, currently undergoing a Phase 2/3 study, passed an interim analysis of data.
• Currently undergoing a Phase 2/3 study, atuzaginstat passed an interim analysis of data by an independent panel of experts, the company announced early this month.
• Last month, Biogen (NASDAQ:BIIB) fell -28.1% when an FDA advisory committee blocked the regulatory approval for aducanumab, its candidate to treat mild Alzheimer's disease, citing insufficient efficacy.
• https://seekingalpha.com/news/3643837-cortexyme-weighed-down-citi-downgrade

FDA's Pfizer COVID vaccine approval means Moderna's just days off

 The Food & Drug Administration’s approval of the Pfizer-BioNTech's COVID-19 vaccine for emergency use is paving the way for Moderna, which may get the nod in a matter of days.

“It is clear that if it had not been for Donald Trump’s personal leadership we would not be seeing a Pfizer vaccine and hopefully in the next week a Moderna approved vaccine,” said Health and Human Services Secretary Alex Azar during an interview with FOX Business’ Maria Bartiromo.

Azar also noted that while the profile of Moderna’s vaccine is similar to Pfizer’s it is more “flexible” on many fronts.

“The Pfizer and Moderna vaccine are both what are called messenger R&A vaccine, that is the vehicle used to create the immunogenicity. So very similar technological platforms but the Moderna vaccine doesn’t have the same cold chain storage requirements that the Pfizer one does and it also comes in a more flexible packaging size. We have a smaller number of doses. Everything about the Moderna one is more flexible and easier for us to administer than the Pfizer,” he explained.

“We’re talking to AstraZeneca and J&J as they look forward to possible approval and get their phase 3 data hopefully in the near term.”

https://www.foxbusiness.com/markets/pfizers-coronavirus-fdamoderna-vaccine-approval-days-away