Ranger222 said:

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Your also asking the body to take the genetic code injected (in this case messenger RNA) and produce a protein that is similar to what the virus has and the body encounters upon infection. Sounds simple, but there could be issues with how the protein is folded and then recognized by the immune system to start antibody production. You are also only producing one select protein instead of the others encoded and produced by the complete viral genome. It seems to be ok in this case as the spike protein being produced has been shown to lead to neutralizing antibodies as seen in other studies.

Two things I'm concerned about -- lack of T-cell response seen in supplemental data and then the fact you need two injections. Going to be a mess trying to get people to go back twice a month apart for both infections for adequate protection.

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Not likely an issue with the way the protein folds. The virus relies on the same mechanisms to make its protein. Once the mRNA is in the cell, doesn't matter if it is injected or created by the virus, cell will still take either mRNA and make the same protein.

amercer said:

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My wife is at AZ so that's probably good for the stick options, but not great for the US as we won't be first in line to get those vials as they roll off the production line

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Are you sure? US gov has struck deals with many of the lead vaccines. Europe is doing the same. Deals probably involving some guaranteed local production in exchange for up front payments to get local production established.

Here is a article on the deal for US production.

https://www.fiercepharma.com/manufacturing/astrazeneca-emergent-biosolutions-sign-87m-deal-to-produce-u-s-supply-covid-vaccine

AZ CEO has publicly said that the U.K. gets the first batches.

I'm sure there will be a ton of back room **** going down by December, but that's what he said.

I have seen little to suggest the vaccine development process will be straightforward.

Take the Oxford-AstroZeneca vaccine for instance. Back in May they reported their live challenge trials in monkeys failed to prevent infection.

https://www.forbes.com/sites/williamhaseltine/2020/05/16/did-the-oxford-covid-vaccine-work-in-monkeys-not-really/

and

https://www.telegraph.co.uk/global-health/science-and-disease/doubts-oxford-vaccine-fails-stop-coronavirus-animal-trials/

But Eleanor Riley, professor of Immunology and Infectious Disease at the University of Edinburgh, said there was both good and bad news in the most monkey trials:

"Whilst the vaccine induced neutralising antibodies and vaccinated animals experienced less severe clinical symptoms than unvaccinated animals (good), the neutralising antibody titres were low and insufficient to prevent infection and importantly insufficient to prevent viral shedding in nasal secretions (worrying).
"If similar results were obtained in humans, the vaccine would likely provide partial protection against disease in the vaccine recipient but would be unlikely to reduce transmission in the wider community."

They went ahead with their Human Phase 1, 2, and 3 program. The Bloomberg article talks about some of this but is mostly saying AZ is in Phase 3.

Perhaps the fact AZ is using a chimp adenovirus in humans might let something that doesn't work well in monkeys work better in humans.

Overall good news, can't wait to see the phase 2 results.

Adenovirus is VERY immunogenic in humans (a fact that nearly killed the whole field of gene therapy 20 years ago when someone died in a clinical trial) So I am optimistic they will get a good response.

Ranger222 said:

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Your also asking the body to take the genetic code injected (in this case messenger RNA) and produce a protein that is similar to what the virus has and the body encounters upon infection. Sounds simple, but there could be issues with how the protein is folded and then recognized by the immune system to start antibody production. You are also only producing one select protein instead of the others encoded and produced by the complete viral genome. It seems to be ok in this case as the spike protein being produced has been shown to lead to neutralizing antibodies as seen in other studies.

Two things I'm concerned about -- lack of T-cell response seen in supplemental data and then the fact you need two injections. Going to be a mess trying to get people to go back twice a month apart for both infections for adequate protection.

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I think the Pfizer/BioNTech vaccine will be more effective. The Moderna vaccine is only targeting B-Cells, whereas the Pfizer patent will activate helper-TCells and B-cells. It's like having a backup plan. In the future of mRNA, I do believe they will be creating cocktails that will encode multiple proteins.

Some information from a recent Moderna press release

https://investors.modernatx.com/news-releases/news-release-details/moderna-completes-enrollment-phase-2-study-its-mrna-vaccine


They are going to use the 100ug dose in the Phase 3

Moderna has finalized the Phase 3 study protocol based on feedback from the U.S. Food and Drug Administration (FDA). The randomized, 1:1 placebo-controlled trial is expected to include approximately 30,000 participants at the 100 g dose level in the U.S. and is expected to be conducted in collaboration with NIAID, subject to regulatory approval.

They are including older folks in aspects of the trials.

On June 11, 13 days after the first participant was dosed, the Company announced that the cohort of healthy younger adults ages 18-55 (n=300) and the sentinel group of older adults ages 55 years and above (n=50) in the Phase 2 study of mRNA-1273 was complete. After reviewing the safety data from the sentinel cohort of older adults, on June 25, the Data and Safety Monitoring Committee of the study recommended Moderna to proceed with enrollment for the remainder of the Phase 2 study. The cohort of older adults (n=300) has now been fully enrolled. This Phase 2 placebo-controlled, dose-confirmation study is evaluating the safety, reactogenicity and immunogenicity of two vaccinations of mRNA-1273 given 28 days apart. Each participant is receiving placebo, a 50 g or a 100 g dose at both vaccinations.

The Company also announced that the cohorts of older adults (ages 56-70, n=30) and elderly adults (ages 71 and above, n=30) in NIH-led Phase 1 study have completed enrollment. Results are expected to be published once available.

amercer said:

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AZ CEO has publicly said that the U.K. gets the first batches.

I'm sure there will be a ton of back room **** going down by December, but that's what he said.

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And he can say that because AZ isn't manufacturing in the US. Emergent Biosolutions will be manufacturing in the US.

plain_o_llama said:

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I have seen little to suggest the vaccine development process will be straightforward.

Take the Oxford-AstroZeneca vaccine for instance. Back in May they reported their live challenge trials in monkeys failed to prevent infection.

https://www.forbes.com/sites/williamhaseltine/2020/05/16/did-the-oxford-covid-vaccine-work-in-monkeys-not-really/

and

https://www.telegraph.co.uk/global-health/science-and-disease/doubts-oxford-vaccine-fails-stop-coronavirus-animal-trials/

But Eleanor Riley, professor of Immunology and Infectious Disease at the University of Edinburgh, said there was both good and bad news in the most monkey trials:

"Whilst the vaccine induced neutralising antibodies and vaccinated animals experienced less severe clinical symptoms than unvaccinated animals (good), the neutralising antibody titres were low and insufficient to prevent infection and importantly insufficient to prevent viral shedding in nasal secretions (worrying).
"If similar results were obtained in humans, the vaccine would likely provide partial protection against disease in the vaccine recipient but would be unlikely to reduce transmission in the wider community."

They went ahead with their Human Phase 1, 2, and 3 program. The Bloomberg article talks about some of this but is mostly saying AZ is in Phase 3.

Perhaps the fact AZ is using a chimp adenovirus in humans might let something that doesn't work well in monkeys work better in humans.

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The Oxford vaccine actually skipped phase 1 and went straight to phase 2/3 which is why they are "in the lead". They were allowed to do this because the platform they use is well tested for safety.

So while we have some evidence of efficacy for the Moderna vaccine from the phase 1, we don't have that for the Oxford/AZ vaccine.

You're discounting other viral proteins/effectors produced during infection that may modify/assist translation and/or change protein stability.

May not matter in this particular case, who knows, but something that should be considered for mRNA vaccines in general. There are multiple reasons why there aren't any currently on the market.

I found this discussion about how T-Cell and Antibody responses will play into the potential success
of these vaccines really interesting. Start at 18:00 and listen for about 10 minutes where they conclude
that there are "lots of eggs in the Spike basket."

https://www.microbe.tv/twiv/twiv-631/

Doesn't seem simple.

BiochemAg97 said:

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amercer said:

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AZ CEO has publicly said that the U.K. gets the first batches.

I'm sure there will be a ton of back room **** going down by December, but that's what he said.

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And he can say that because AZ isn't manufacturing in the US. Emergent Biosolutions will be manufacturing in the US.

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The stuff hit the fan when the CEO of Sanofi said the US would get their first doses because we gave them funding. That got him hauled into the French Presidents office to explain himself. It's a good thing so many programs seem to be on about the same timelines because the political aspects of who gets what first could be nasty.

And Emergent is certainly a big boy, but I doubt any CMO can be faster than an internal big pharma effort.

I read/heard somewhere that Moderna has known for at least a few weeks that the immune response to the drug was looking really good with mild side effects. They started ramping up production already. By the time the trial is complete they are going to have MASS quantities of the vaccine.

CardiffGiant said:

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I read/heard somewhere that Moderna has known for at least a few weeks that the immune response to the drug was looking really good with mild side effects. They started ramping up production already. By the time the trial is complete they are going to have MASS quantities of the vaccine.

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Moderna provided a summary of the phase 1 results in May when they announced moving on to phase 2 and 3. The new news is really just the publication of those previously summarized results with some additional follow up (antibodies were not seen to drop off after an additional month of testing).

At that time, Trump started the Operation Warp Speed to roll out a vaccine by the end of 2020. Moderna at that time was saying early 2021. Trump's initiative has mostly involved paying the vaccine companies to secure production to have vaccine available shortly after FDA approval. That puts into practice what Bill Gates was saying about funding the top candidates to start production before testing was complete rather than waiting until approval, then getting the facilities in place and starting to make the vaccine.

As far as Moderna, it was announced with the completion of the phase 1 and the start of Operation Warp Speed that their contract pharma manufacturer was getting additional facilities set up to manufacture the vaccine.

tl;dr Moderna has been getting things in place to manufacture in volume since the end of Phase 1. It wouldn't surprise me if they start large scale manufacturing prior to completion of phase 3. Keep in mind, phase 3 is 30,000 people (60,000 doses) so they have scaled up a fair amount since phase 1 already. But 100s of millions is another big step.

amercer said:

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BiochemAg97 said:

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amercer said:

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AZ CEO has publicly said that the U.K. gets the first batches.

I'm sure there will be a ton of back room **** going down by December, but that's what he said.

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And he can say that because AZ isn't manufacturing in the US. Emergent Biosolutions will be manufacturing in the US.

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The stuff hit the fan when the CEO of Sanofi said the US would get their first doses because we gave them funding. That got him hauled into the French Presidents office to explain himself. It's a good thing so many programs seem to be on about the same timelines because the political aspects of who gets what first could be nasty.

And Emergent is certainly a big boy, but I doubt any CMO can be faster than an internal big pharma effort.

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I'm not worried about who wins the race to the first injection. In all likelihood, since the phase 3 testing is in UK, the vaccine will be first approved in UK/EU and then the FDA. But it isn't like US is going to be cut out because UK/EU gets first dibs on the vaccine. We will have domestic production to supply US even in UK/EU doesn't want to share their supplies. EU/UK will have domestic production of several of our vaccine candidates in case we don't want to share our supplies.

And it isn't like Emergent is setting up manufacturing all by themselves... they will have a lot of knowledge transfer from AZ.