Are vaccines the light at the end of the tunnel?

[nocl]

1 hour ago, Arizona Wildcat said:

Within 3 or 4 months there should be plenty of vaccine.  Pfizer will be online with doubled+ capacity in Belgium.  And J&J or another will have vaccine approved.  The issue shortly will be syringes.  Already in short supply locally.  Merck making the Moderna vaccine - that is a stretch.

The Belgium production is committed to contracts to other countries, primarily the EU, other than the US so it should not impact the US supply.

[deadzone1003]

29 minutes ago, nocl said:

They would only have to demonstrate equivalence from the new facility.  Pretty easily done. Same process as when a manufacturer start production in another plant.

 

It would be a manufacturing contract between the original company and the company that will manufacture.  Same as if they decided to do it outside of the DPA.

Usually those arrangements are on voluntary basis, but with the DPA it is involuntary.  If I was Moderna, I would at a minimum demand it be labeled as Moderna vaccine not manufactured by Moderna or whatever it takes to make Moderna feel comfortable about the situation.  If Moderna was your company, how would you do?

[nocl]

1 minute ago, deadzone1003 said:

Usually those arrangements are on voluntary basis, but with the DPA it is involuntary.  If I was Moderna, I would at a minimum demand it be labeled as Moderna vaccine not manufactured by Moderna or whatever it takes to make Moderna feel comfortable about the situation.  If Moderna was your company, how would you do?

With DPA the government can force to some degree to convert facilities, however, it still will require a contract with the host company.  It will not bypass the normal FDA requirements.

 

It does not bypass property rights, it does not bypass intellectual property, etc.  

 

So you can expect that the process will be one or more companies offer manufacturing facilities which will then be contracted to manufacture the vaccine under the original vaccine companies direction.  The only real differences are that 1. the original company will need to find another company to manufacture and 2. the manufacturer will need to preempt one or more of there facilities to offer to manufacturer.  Contract negotiations will be streamlined, but really not that much of an issue.  The vaccines company will still provide the manufacturing process information and over site, they will still own the product produced (though will need to pay a fee for the contract manufacturing), FDA will still inspect, QA checks on the product will still be performed, the lot numbers will still be under the control of the original company.

 

No one is going to start up manufacturing Pfizer or Moderna product outside of their control.

[markeb]

29 minutes ago, deadzone1003 said:

Usually those arrangements are on voluntary basis, but with the DPA it is involuntary.  If I was Moderna, I would at a minimum demand it be labeled as Moderna vaccine not manufactured by Moderna or whatever it takes to make Moderna feel comfortable about the situation.  If Moderna was your company, how would you do?

It happens all the time. Emergent in Baltimore is the Contract Manufacturing Organization for Astra Zeneca in the US, for instance. I assume that product will be labeled AZ with a production code for Emergent. While the DPA adds wrinkles, this is nothing new or unusual. 

Edited January 28, 2021 by markeb

[nocl]

20 minutes ago, nocl said:

With DPA the government can force to some degree to convert facilities, however, it still will require a contract with the host company.  It will not bypass the normal FDA requirements.

 

It does not bypass property rights, it does not bypass intellectual property, etc.  

 

So you can expect that the process will be one or more companies offer manufacturing facilities which will then be contracted to manufacture the vaccine under the original vaccine companies direction.  The only real differences are that 1. the original company will need to find another company to manufacture and 2. the manufacturer will need to preempt one or more of there facilities to offer to manufacturer.  Contract negotiations will be streamlined, but really not that much of an issue.  The vaccines company will still provide the manufacturing process information and over site, they will still own the product produced (though will need to pay a fee for the contract manufacturing), FDA will still inspect, QA checks on the product will still be performed, the lot numbers will still be under the control of the original company.

 

No one is going to start up manufacturing Pfizer or Moderna product outside of their control.

Forgot to mention one thing.  While the negotiations are going on the Government will be contributing money and other things to make worthwhile for both organizations to conclude the agreement quickly and accelerate production.

 

Just as a note Moderna does not really have its own manufacturing capability, they already contract with Lonza Ltd for manufacturing, and Catalent for fill finish in the US.

Edited January 28, 2021 by nocl

[deadzone1003]

6 minutes ago, markeb said:

It happens all the time. Emergent in Baltimore is the Contract Manufacturing Organization for Astra Zeneca in the US, for instance. I assume that product will be labeled AZ with a production code fo Emergent. While the DPA adds wrinkles, this is nothing new or unusual. 

Do, for example, Moderna have a say with whom it contract out its production of vaccine or, because of the DPA, the government makes that choice?  We really don't know what the government will do.  We have to let it all  play out.

[markeb]

5 minutes ago, deadzone1003 said:

Do, for example, Moderna have a say with whom it contract out its production of vaccine or, because of the DPA, the government makes that choice?  We really don't know what the government will do.  We have to let it all  play out.

That’s the wrinkle, but you’re not going to a CMO for a small molecule drug to make a viral vectored vaccine. It’s a small fraternity. And the government already has contracts for just this sort of contingency. That’s probably where they’ll start. 

Edited January 28, 2021 by markeb
Didn’t like the brand name for blue pills!

[nocl]

24 minutes ago, deadzone1003 said:

Do, for example, Moderna have a say with whom it contract out its production of vaccine or, because of the DPA, the government makes that choice?  We really don't know what the government will do.  We have to let it all  play out.

Under DPA the government encourages and greased the skids so to speak, it does not control.

[D C]

1 hour ago, nocl said:

They would only have to demonstrate equivalence from the new facility.  Pretty easily done. Same process as when a manufacturer start production in another plant.

 

It would be a manufacturing contract between the original company and the company that will manufacture.  Same as if they decided to do it outside of the DPA.

I don't think it's quite that easy, absent special covid stuff, even making generics of meds that have been around for decades involves countless hoops to jump through. 

[nocl]

15 minutes ago, D C said:

I don't think it's quite that easy, absent special covid stuff, even making generics of meds that have been around for decades involves countless hoops to jump through. 

Depends upon the type generic.  Biologics are a bit more difficult, CBER (Center for Biologics struggled with the process for generic biologics for a while before getting the guidance done).  But with chemical molecules a generic can be approved by showing bioequivalence. Pretty straight forward.  Was involved in a couple of those.

 

Most of the issues with generics are legal hurdles thrown up by the company that developed the original NCE. not getting approval of the generic by the FDA.

 

[nocl]

20 minutes ago, D C said:

I don't think it's quite that easy, absent special covid stuff, even making generics of meds that have been around for decades involves countless hoops to jump through. 

One other comment in this case we were talking about a new manufacturing facility, not approval of a generic.  New facilities come on line all of the time.  They just have to demonstrate equivalence, that is that product from plant A, is the same as product from plant B. and that the plant meets the requirements of Good Manufacturing Practices as defined by FDA guidance.

[Ken the cruiser]

With the thought that there may be a potential shortage of syringes, I kind of hope the J & J "one and done" vaccine with regular refrigeration requirements, would be the one chosen to be manufactured via the DPA process, if its efficacy is high enough. But, then again, I'm just sitting over in the peanut gallery with absolutely no background in the vaccine business.

[mayleeman]

WW2 involved lots of manufacturers making other competitors' equipment and weapons. The famous Jeep was orinally designed by Bantam, then the War Department had Willys and Ford bid to produce models based on Bantam's. The government chose Willys's model, and gave contracts to both Willys and Ford to manufacture them.

 

The best example was in aircraft production. Wikipedia's article is very interesting, especially this summary:

 

"Aircraft companies built other manufacturer's designs; the B-17 was built by Boeing (the designer), Lockheed Vega, and Douglas Aircraft. Automotive companies joined schemes to produce aircraft components and also complete aircraft. Ford set up the Willow Run production facility and built complete Consolidated B-24 Liberators as well as sections to be assembled at other plants."

 

https://en.m.wikipedia.org/wiki/United_States_aircraft_production_during_World_War_II

 

Interestingly, the Defense Production Act was first passed in 1950 for the Korean War. It was not in use in WW2. 

Edited January 28, 2021 by mayleeman

[TeeRick]

10 hours ago, nocl said:

One other comment in this case we were talking about a new manufacturing facility, not approval of a generic.  New facilities come on line all of the time.  They just have to demonstrate equivalence, that is that product from plant A, is the same as product from plant B. and that the plant meets the requirements of Good Manufacturing Practices as defined by FDA guidance.

nocl, That is a key point.  A new manufacturing or one newly-adapted to the mRNA production process is required.  It is one thing to make a protein subunit vaccine like the Novavax or GSK vaccines.  Lots of manufacturing facilities out there making proteins in various types of organisms and then purifying them.  But the mRNA technology, even if fairly simple, is a new manufacturing technology with not very many current players.  I suspect due to the success of the first two mRNA vaccines there will be a lot of demand for this technology and manufacturing plants for it in the future.  But it takes a significant time to set up and get approval for a new drug or biologics facility.  And approval from multiple worldwide regulatory agencies not just the FDA depending on where the vaccine would be used.

[TeeRick]

Here is a useful article with FAQ's on vaccine dosing and frequency of dosing for the mRNA vaccines from Pfizer and Moderna.

 

https://www.medscape.com/viewarticle/944321?src=wnl_edit_tpal&uac=370300SV&impID=3154598&faf=1#vp_1

 

Also a report from the CDC on severe allergic reactions - which seem to be very rare- in people vaccinated with Moderna or Pfizer vaccines to date.

 

https://www.cdc.gov/mmwr/volumes/70/wr/mm7004e1.htm?s_cid=mm7004e1_w

Edited January 28, 2021 by TeeRick

[TeeRick]

Review on the overall prevalence of asymptomatic SARS-CoV-2 infections from Annals of Internal Medicine.  Some interesting observations here. 

https://www.acpjournals.org/doi/10.7326/M20-6976

[Orator]

32 minutes ago, TeeRick said:

Here is a useful article with FAQ's on vaccine dosing and frequency of dosing for the mRNA vaccines from Pfizer and Moderna.

 

https://www.medscape.com/viewarticle/944321?src=wnl_edit_tpal&uac=370300SV&impID=3154598&faf=1#vp_1

 

Also a report from the CDC on severe allergic reactions - which seem to be very rare- in people vaccinated with Moderna or Pfizer vaccines to date.

 

https://www.cdc.gov/mmwr/volumes/70/wr/mm7004e1.htm?s_cid=mm7004e1_w

DW and I had our first shot of Pfizer on Tuesday and experienced only  slight side effects, like a brief headache. The second shot is scheduled for 4 weeks from the first. 

[mimbecky]

Those of you in the medical field...what are your thoughts on pain relievers and the vaccine?  Any logic to this?  Would be interested for when my number comes up.

 

Getting The COVID Vaccine? Don’t Do This Before Your Shot (ibtimes.com)

 

 

 

 

[TeeRick]

37 minutes ago, mimbecky said:

Those of you in the medical field...what are your thoughts on pain relievers and the vaccine?  Any logic to this?  Would be interested for when my number comes up.

 

Getting The COVID Vaccine? Don’t Do This Before Your Shot (ibtimes.com)

 

 

 

 

Here is another general article:

https://www.healthline.com/health-news/should-you-take-pain-relievers-after-covid-19-vaccine

 

From the CDC:

Antipyretic or analgesic medications (e.g., acetaminophen, non-steroidal anti-inflammatory drugs) may be taken for the treatment of post-vaccination local or systemic symptoms, if medically appropriate. However, routine prophylactic administration of these medications for the purpose of preventing post-vaccination symptoms is not currently recommended, as information on the impact of such use on mRNA COVID-19 vaccine-induced antibody responses is not available at this time.

https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html

 

It is in fact recommended that stronger anti-inflammatories like steroids should be avoided.

https://asipp.org/wp-content/uploads/2021/01/DRAFT-ASIPP-GUIDANCE-DOCUMENT-ON-COVID-19-VACCINE-AND-STEROIDS-01222021.pdf

 

Of note is that the approved vaccines at 95% efficacy did not exclude taking OTC pain relievers in the phase 3 clinical trials.  So that might tell you something.

 

[deadzone1003]

2 hours ago, TeeRick said:

nocl, That is a key point.  A new manufacturing or one newly-adapted to the mRNA production process is required.  It is one thing to make a protein subunit vaccine like the Novavax or GSK vaccines.  Lots of manufacturing facilities out there making proteins in various types of organisms and then purifying them.  But the mRNA technology, even if fairly simple, is a new manufacturing technology with not very many current players.  I suspect due to the success of the first two mRNA vaccines there will be a lot of demand for this technology and manufacturing plants for it in the future.  But it takes a significant time to set up and get approval for a new drug or biologics facility.  And approval from multiple worldwide regulatory agencies not just the FDA depending on where the vaccine would be used.

Agree with your line of reasoning.  By the time we even get these DPA vaccines, we may have already an excess of vaccines if J&J proves to be satisfactory and we don't get rid of the AZ vaccines.  Shipping and distributing Pfizer vaccine in the summer will be a more difficult.  Demand may be more uneven by then.  It would only make sense to get more mRNA vaccines only if the J&J vaccine's efficacy rate is much closer to AZ than to the current ones.  

 

For people commenting on side effects of their vaccination, the worst side effects occurs after your 2nd shot (as reported in the Phase III trials).  

[D C]

2 hours ago, TeeRick said:

Review on the overall prevalence of asymptomatic SARS-CoV-2 infections from Annals of Internal Medicine.  Some interesting observations here. 

https://www.acpjournals.org/doi/10.7326/M20-6976

I remain highly skeptical. The veracity of their conclusion relies on both the assumption of extremely high test accuracy (I didn't see anything in the report to suggest orthogonal testing of asymptomatic positives) and the validity of there being a complete and total lack of symptoms.   Besides, who is actually tracking symptoms of every positive test result?  

[nocl]

4 hours ago, TeeRick said:

nocl, That is a key point.  A new manufacturing or one newly-adapted to the mRNA production process is required.  It is one thing to make a protein subunit vaccine like the Novavax or GSK vaccines.  Lots of manufacturing facilities out there making proteins in various types of organisms and then purifying them.  But the mRNA technology, even if fairly simple, is a new manufacturing technology with not very many current players.  I suspect due to the success of the first two mRNA vaccines there will be a lot of demand for this technology and manufacturing plants for it in the future.  But it takes a significant time to set up and get approval for a new drug or biologics facility.  And approval from multiple worldwide regulatory agencies not just the FDA depending on where the vaccine would be used.

No doubt it will take time to prepare and equip a new facility for mRNA production.  

 

However there are a few contract manufacturers that do have that capability in limited capacity now. There are some of the majors that also have been playing in this area, also with limited capacity.

 

The key advantage with existing companies is that the facilities are already operating under GMP and the change is basically one of installing new equipment.  Depending upon equipment availability I have seen a facility (complex biologics) go from making one product, getting cleared out, new equipment installed  and making another product (also complex biologic) in 30 days. All depends upon equipment availability.

 

Under DPA one would expect that any production will be marked for the US otherwise there would not be grounds for using the law.

 

However, when it comes to manufacturing sites, in most cases, you would not need approval from other regulatory authorities.  The product is the product which would already be approved.  Some countries may choose to inspect a new facility, but usually not.  Many countries have agreements to accept other countries certifications of manufacturing facilities.  So the regulatory side is not a major thing.

 

Here are a few contract manufacturers that advertise mRNA manufacturing capability

 

Creative Biolabs

Trilink Biotech

Lonza (currently used by Moderna)

Translate Bio

 

The biggest issue as described in one article is "For dose manufacturing of COVID-19 mRNA vaccines, sponsor companies are opting to partner with manufacturers, rather than outsource to CMOs."

 

Activation of DPA might change that approach.

 

 

The discussion was on supposed loss of control of the original company under DPA.  Which will not happen.

Edited January 28, 2021 by nocl

[TeeRick]

27 minutes ago, nocl said:

No doubt it will take time to prepare and equip a new facility for mRNA production.  

 

However there are a few contract manufacturers that do have that capability in limited capacity now. There are some of the majors that also have been playing in this area, also with limited capacity.

 

The key advantage with existing companies is that the facilities are already operating under GMP and the change is basically one of installing new equipment.  Depending upon equipment availability I have seen a facility (complex biologics) go from making one product, getting cleared out, new equipment installed  and making another product (also complex biologic) in 30 days. All depends upon equipment availability.

 

Under DPA one would expect that any production will be marked for the US otherwise there would not be grounds for using the law.

 

However, when it comes to manufacturing sites, in most cases, you would not need approval from other regulatory authorities.  The product is the product which would already be approved.  Some countries may choose to inspect a new facility, but usually not.  Many countries have agreements to accept other countries certifications of manufacturing facilities.  So the regulatory side is not a major thing.

 

Here are a few contract manufacturers that advertise mRNA manufacturing capability

 

Creative Biolabs

Trilink Biotech

Lonza (currently used by Moderna)

Translate Bio

 

The biggest issue as described in one article is "For dose manufacturing of COVID-19 mRNA vaccines, sponsor companies are opting to partner with manufacturers, rather than outsource to CMOs."

 

Activation of DPA might change that approach.

 

 

The discussion was on supposed loss of control of the original company under DPA.  Which will not happen.

Yes I agree with your points. But my concern is that the GMP - verified mRNA manufacturing players and capabilities are still very limited for the job at hand.  Hopefully much more capacity develops over time if COVID continues to be with us for a number of years.  And of course the vectored-vaccine approaches like from J&J and AZ also are a new technology (in terms of large scale manufacturing) and will be limited too.  But the world will get there!

[TeeRick]

1 hour ago, D C said:

I remain highly skeptical. The veracity of their conclusion relies on both the assumption of extremely high test accuracy (I didn't see anything in the report to suggest orthogonal testing of asymptomatic positives) and the validity of there being a complete and total lack of symptoms.   Besides, who is actually tracking symptoms of every positive test result?  

Skeptical of what specifically? The report of 1/3 of positive infected people being asymptomatic?  Or the methods and retrospective analysis used?  Thanks!

[D C]

12 minutes ago, TeeRick said:

Skeptical of what specifically? The report of 1/3 of positive infected people being asymptomatic?  Or the methods and retrospective analysis used?  Thanks!

Skeptical that true asymptomatic cases are that abundant.  Essentially every false-positive is factored in as an asymptomatic-positive.  They seem to acknowledge that only in passing.