Well said. I misunderstood your post.

ElephantRider said:

---

What are "grade 3 systemic symptoms"?

---

A good reason not to give the 250 dose.

With the 25 dose effective and the 100 dose well tolerated, there is no reason to do a 250 dose.

amercer said:

---

My biggest question for Moderna is how much they can scale manufacturing. They've been around for a while, but they've never really brought a drug to market. I don't think anyone in the world has manufactured RNA on the scale that will be required.

---

Startup biotechs don't really do pharma manufacturing. Instead they turn to a number of companies that do contract pharma manufacturing. Big pharma used contract manufacturing as well. Moderna already has a manufacturer who I expect could scale reasonably well. In this case, I could also see expanding that to other contract manufactures if necessary. There are some other resources the govt can tap into as well, such as CIADM at TAMU.

The govt has given a green light to start manufacturing at scale prior to completion of the phase 3 so it is ready to go when approved.

amercer said:

---

Windy City Ag said:

---

https://www.fiercepharma.com/manufacturing/moderna-aims-for-a-billion-covid-19-shots-a-year-lonza-manufacturing-tie-up

Quote:

---

Moderna aims for a billion COVID-19 shots a year with Lonza manufacturing tie-up

If all goes to plan, the partners will continue to build out additional manufacturing sites that could bring Moderna's capacity up to 1 billion shots per year, the drugmakers said.

"This long-term strategic collaboration agreement will enable Moderna to accelerate, by 10 times, our manufacturing capacity for mRNA-1273 and additional products in Moderna's large clinical portfolio," Moderna CEO Stphane Bancel said in a release. "Lonza's global presence and expertise are critical as we scale at unprecedented speed."

---

---

I've worked with Lonza. They do have a lot of capacity.

I think it's really important for people to know that "fast" means vastly different things to people in lockdown than to biomanufacturing.

Getting a vaccine to market in 3 years would be incredibly fast. So what people are talking about here is borderline physically impossible. My guess is that anything available by the end of the year is probably in the tens of thousands of doses which will go to healthcare workers.

---

Manufacturing isn't the bottle neck for getting a vaccine to market. Getting FDA approval is.

While it takes a while to get the annual flu vaccine manufactured, that involves a complicated process with growing stuff in chicken eggs. This is an mRNA vaccine. One of the big advantages would be easier manufacturing. Get some yeast, insert the gene, and then grow it by the vat.

for reference, TAMU CIADM has the capacity to produce 50 million doses of vaccine in 4 months. If they can only produce tens of thousands by the end of the year, then someone will step in and make a change.

That said, if we don't have more than a few hundred million doses by the end of the year, it is going to be prioritized to healthcare workers, military, and elderly.

fightingfarmer09 said:

---

So 1.2% of pre selected healthy folks had some pretty rough symptoms after their vaccine, for a disease that in the vast majority of folks will be asymptomatic or extremely mild.

Success!

---

Only in a dose 10 times higher than what appears to be the effective dose.

Keegan99 said:

---

slacker00 said:

---

Keegan99 said:

---

The vaccine also produced neutralizing antibodies against Covid-19 in at least eight participants, the company said.

---

Isn't this is the critical part? Perhaps not enough time has gone along for them to develop and/or the data hasn't been collected yet, but if that percentage doesn't grow (8 out of 45) this seems less than useful. I know that's not the goal of a Phase I study, but they are collecting data and reporting.

---

Binding antibodies mark the virus for targeting by the immune system. That is extremely useful.

---

And binding antibodies were found at levels of a recovered patient at the 25 dose.

This is a dumb dumb question because I have no science background: can a vaccine help a sick person recover?

Fitch said:

---

This will be interesting to watch. Phase 2 testing is how long / many people?

---

Hundreds (600 I think). Ongoing. Doubt they use the 250 dose, might try something between 25 and 100.

They are planning to start phase 3 (thousands) in July.

They don't necessarily need final results from phase 2 to start phase 3. But from phase 1 we know 2 doses 28 days apart, and then follow up to test for antibodies as a preliminary dataset. There would be continued follow up to compare infection rates between control and test groups.


While a normal situation would take longer to ensure reduction of infection, it may be possible to get EUA after the phase 3 shows effective levels of antibodies while the later phase 2 data show protection at those levels of antibodies, if those benefits are dramatic enough and the phase 3 shows no side effects. They would need to follow the phase 2 and 3 out for a couple years to continue to monitor for antibody titter to determine if you need a annual booster or not. But we could start vaccinating before.

So if you start phase 3 in July and start manufacturing, maybe get EUA 3-4 months later and manufacturing should be ready to go with initial doses maybe with a phased rollout.


One thing to consider, they phase 1 was 18-55. Need to also test in 55+ individuals to determine side effects and effectiveness in the elderly (might require different dosing). And then work down into children, although that may be a low priority for this virus.

https://investors.modernatx.com/news-releases/news-release-details/moderna-and-lonza-announce-worldwide-strategic-collaboration

Reading between the lines of this press release, I'd be surprised if they get a commercial batch released this year, and next years capacity would be in the 100 million dose range, which doesn't even cover the whole US.

Not trying to pee in anyone's Cheerios this morning. But as someone who has occasionally put on a full Tyvec suit to go into a GMP bio manufacturing suite, I can tell you that most people have very little appreciation for how long it takes to make and release drug.

Now, if the results look promising I'm sure even more resources will be thrown at it (and that a lot of QA speed records will be broken) but those aren't instantaneous either. It takes time to build more manufacturing suites, and to tech transfer.

Harry Stone said:

---

amercer said:

---

My biggest question for Moderna is how much they can scale manufacturing. They've been around for a while, but they've never really brought a drug to market. I don't think anyone in the world has manufactured RNA on the scale that will be required.

---

the cost is enormous as well. a 30k base sequence may cost upwards of $40,000,000 per 10 gms, which could treat 200,000 patients if they go with 2
25 mcg doses.

---

It isn't the whole genome. I believe only spike protein.

Plus, you probably don't synthesize the thing. If you modify something like yeast to produce it, you can grow vats really cheap (think a batch of beer but with much more regulation). Purification is more tricky, but beads that specifically bind that sequence isn't hard to get. Basic purification outline would be separate the DNA/RNA from the other cell junk, crude separation the DNA/RNA based on size, then pull out the mRNA with the right sequence, possibly follow with sizing again.

Biggest challenge is RNA is easy to degrade. Everything will need to be and stay RNase free.

KlinkerAg11 said:

---

This is a dumb dumb question because I have no science background: can a vaccine help a sick person recover?

---

Not really. You are already exposed to the virus.

Longer answer: We give rabies vaccine immediately after a possible exposure. Give a big dose of vaccine to get the immune system going strong instead of waiting for the virus to build up. We give Tetanus boosters if you step on a rusty nail. If you got the vaccine the day you were exposed, might help. If you already have symptoms, immune system has enough to work with already.

Gotcha, appreciate the explanation.

amercer said:

---

https://investors.modernatx.com/news-releases/news-release-details/moderna-and-lonza-announce-worldwide-strategic-collaboration

Reading between the lines of this press release, I'd be surprised if they get a commercial batch released this year, and next years capacity would be in the 100 million dose range, which doesn't even cover the whole US.

Not trying to pee in anyone's Cheerios this morning. But as someone who has occasionally put on a full Tyvec suit to go into a GMP bio manufacturing suite, I can tell you that most people have very little appreciation for how long it takes to make and release drug.

Now, if the results look promising I'm sure even more resources will be thrown at it (and that a lot of QA speed records will be broken) but those aren't instantaneous either. It takes time to build more manufacturing suites, and to tech transfer.

---

Keep in mind, this is the first vaccine that was in trial and is the one Fauci has been telling us end of '21 for months now. They final end point of the trial is end of '21. Now we are taking early '21.

If I'm doing a corporate press release, I'm generally not promising a timeline that requires modifying govt regulations and starting manufacturing before FDA approval. So my timeline would be based on ramp up after approval at the primary endpoint of phase 3.

Trump has endorsed Gates plan of getting manufacturing going before approval. And Trump tapped to now former Moderna CEO to make it happen. That could accelerate the timeline a bit. And with the full weight of the US govt breathing down your neck, maybe you scale up and manufacture a bit faster. Risks for sure.

I just think the timeline gets accelerated a bit, maybe a couple months. Trump wants end of the year and I have to think someone said it might be possible if certain things happen. I also think by July if the current manufacturing scale up plan isn't going to give enough vaccine, then Trump is going to say more faster, which triggers expanding the plan to bring in more manufacturing capacity. That may be find a supplemental contract manufacturer or tap into CIADM and the 2 other similar centers that the Fed already set up for pandemic response.

The question is, can it physically go faster?

I think Moderna is using an in vitro transcription process to make their modified RNAs. That's great on the downstream side, but a nightmare upstream. Their GMP raw materials are expensive and probably not widely available since no one else does this. Without being in their building, I can't say for sure, but it certainly seems like there is high risk for supply chain bottlenecks.

My guess is by the time they scale up, the big boys going the traditional route will have caught up to them. It wouldn't be a bad thing to have a bunch of good vaccines of course, I just think getting any of them this year is unrealistic.

Best case, maybe in six months they start rolling out pre approval vaccines to healthcare workers and nursing homes. And, hey, that would be pretty awesome.

Thanks for the info. You gotta hope they have success in Phase 2 and 3. Still, it's interesting to think they'll be able to extrapolate from a couple hundred or few thousand to 1 billion / year.

I suspect there will be all kinds of twists and turns in the Great Vaccine Race.

Take the turn around yesterday between Moderna and Oxford's Jenner Institute

End of April we have Oxford "in the lead":

https://www.biospace.com/article/oxford-university-s-jenner-institute-ahead-of-the-curve-on-covid-19-vaccine/

There are more than 70 groups worldwide rushing to develop a vaccine against COVID-19, including Moderna, Johnson & Johnson, Pfizer and BioNTech, Novavax and many others. One of the groups that appears to be ahead of the race isn't a commercial biopharma company, but Oxford University's Jenner Institute. Their primary focus is vaccine development and they had already tested a vaccine for an earlier coronavirus last year, showing it was not harmful to humans.

and the promising news from tests on animals

Their virus has been tested in six rhesus macaque monkeys at the National Institutes of Health's Rocky Mountain Laboratory in Montana, that were then exposed to large volumes of the virus causing COVID-19. More than 28 days later, all six were still healthy.

Then late last week the study paper is released, a fuller picture is presented, and digested in the press

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."

So, Oxford is seemingly in a ditch but their human trial is going forward:


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

What then are the choices for the Oxford group? Steam ahead with a vaccine known to be partially effective at best, one which we already know elicits poor neutralizing responses? Work to improve the immunogenicity of the current vaccine? Attempt trials with combinations of two or more vaccines, a prime boost strategy?

These questions are all the more fraught by what we already know about the complexities of antibody reposes to natural infections. For example, we know in the case of SARS and other coronavirus infections that even high titers of neutralizing antibodies fade quickly over time. How long can we expect weakly neutralizing antibodies to protect?
We know what the public response is of the Oxford group and their collaborators. Proceed with full speed to human safety then efficacy trials. Time will tell if this is the best approach. I wouldn't bet on it.


Against the negative takes on the Oxford vaccine we have Moderna announcing they will raise a billion or so after their press release. It does include positive results in virus challenge against their mouse model. So that is encouraging.

Twists and turns....

why does the movie I Am Legend keep popping up in my head...

This is a prime example of why we need to take all these announcements with a large grain of salt.

The pub on the Jenner Group being ahead always seemed off to me given Moderna was well into phase 1 trials and Jenner Group was still doing animal tests but just planning to skip right to phase 3.

Moderna is now ahead because they had good phase 1 results. Triggers immune response and no side effects at the still effective low dose. But still a small study. If there was a side effect that was 1 in 100 or 1 in 1000, we likely wouldn't know from this study. Let alone a side effect that is 1 in a million. We also haven't followed this first batch to identify any long term issues. All of those could potentially end this vaccine.


Still a long way to go and a lot of possible stumbling blocks.

Also, raising money after a successful phase 1 result is pretty typical of pharma companies of this type. Phase 2 and 3 trials are a considerable expense. Either you raise money (preferably right after good news) or you partner (and then probably get bought out) with one of the big guys.

Still high risk as a lot of these type of companies fail with a failed phase2/3 trial.

This is really exciting technology. Being able to inject mRNA so your own cells start cranking out antibodies is brilliant, innovative, and very exciting for future vaccines. It is outside of the realm of possibility that this same technique could be used to target specific cancer cells not just viral proteins.

BiochemAg97 said:

---

Still a long way to go and a lot of possible stumbling blocks.

---

To me, a significant motivation for skepticism is that we don't seem to have a great grasp on the underlying pathology of the disease. Is it naive immunity which can be fixed by "controlled exposure" via vaccination? That certainly exists but is that what drives the severe cases? The disease progression seems very different in those that end up hospitalized or dying. What is truly going on there? Is that a immune deficiency or pathology (not sure the proper terminology) that can be corrected by vaccination?

As you note above, these early trials involve healthy 18-55 yr olds. I understand that is where you start in determining dosages and tolerance. Yet I'd be more impressed if they were reporting on tests on old overweight monkeys. :-)

BiochemAg97 said:

---

Harry Stone said:

---

amercer said:

---

My biggest question for Moderna is how much they can scale manufacturing. They've been around for a while, but they've never really brought a drug to market. I don't think anyone in the world has manufactured RNA on the scale that will be required.

---

the cost is enormous as well. a 30k base sequence may cost upwards of $40,000,000 per 10 gms, which could treat 200,000 patients if they go with 2
25 mcg doses.

---

It isn't the whole genome. I believe only spike protein.

Plus, you probably don't synthesize the thing. If you modify something like yeast to produce it, you can grow vats really cheap (think a batch of beer but with much more regulation). Purification is more tricky, but beads that specifically bind that sequence isn't hard to get. Basic purification outline would be separate the DNA/RNA from the other cell junk, crude separation the DNA/RNA based on size, then pull out the mRNA with the right sequence, possibly follow with sizing again.

Biggest challenge is RNA is easy to degrade. Everything will need to be and stay RNase free.

---

Im doubting they will modify yeast to produce it.

Didn't take long for cold water to be thrown on those results.

https://www.thestreet.com/investing/moderna-shares-resume-slump-as-vaccine-questions-mount

KidDoc said:

---

This is really exciting technology. Being able to inject mRNA so your own cells start cranking out antibodies is brilliant, innovative, and very exciting for future vaccines. It is outside of the realm of possibility that this same technique could be used to target specific cancer cells not just viral proteins.

---

Yeah, but when we do this in plants everyone freaks the F out. Including numerous medical professionals.

fightingfarmer09 said:

---

KidDoc said:

---

This is really exciting technology. Being able to inject mRNA so your own cells start cranking out antibodies is brilliant, innovative, and very exciting for future vaccines. It is outside of the realm of possibility that this same technique could be used to target specific cancer cells not just viral proteins.

---

Yeah, but when we do this in plants everyone freaks the F out. Including numerous medical professionals.

---

People freak out when you do it in humans too. We had to have a long discussion over whether one of the patients in our clinical trial would be let back into Canada. After receiving gene therapy, some people wanted to label them as a transgenic organism.....