There would seem to be a hierarchy of outcomes Moderna is looking for

Limits Deaths?

Limits Severe Cases per their definition (basically ICU admissions)?

Limits Cases with symptoms?

Limits Asymptomatic Cases?


I think I made the following back of the envelope calculation once before to suggest 30,000 might not yield
definitive results.

15,000 receive the placebo and 15,000, the vaccine. Assume across the whole of the
winter flu and cold season thru April, 30% of the participants are exposed to SARS-CoV2.
I think that is high but let's use it.

That means 4500 cases in each group. These are not high risk groups. I think it is possible the mortality rate is as low as 0.1%. That is 4.5 deaths expected in the placebo group. Teasing something out of such small numbers seems iffy.

ICU admissions might be 2-3 times deaths. So if that is close to the Severe Case definition you might see
10-15 in the placebo arm.

Hospitalizations might be a helpful measure but the scale is still pretty small. Maybe 60 or so in the
Placebo group.

So how many will test positive and have symptoms? People in the trial are probably more likely to get tested than the average person with mild symptoms. So, maybe you get 600-1000 testing positive and with symptoms.

Perhaps it will be a slam dunk and the vaccinated group will have no deaths, a vastly better severe case rate, and a much lower symptomatic case rate. Perhaps not. How low does that attack rate of 30% go if you only wait until November?

The primary endpoint is a reduction in cases. The reduction in hospitalizations, ICU, and deaths are nice data to have for marketing. If they factored in asymptomatic cases and were able to show a significant reduction in cases + asymptomatic cases, I think that would work too. But I would be concerned about people testing positive just because of exposure and not an actual infection. Certainly seems that could be the case.

FDA will sometime approve things based on very strong secondary endpoints, but generally if you miss on the primary endpoint, you aren't getting approved.


And it was always going to be a problem with a decreasing case count. Part of the rush to get through testing. SARS vaccines never made it through because there weren't people getting sick with SARS.


It does create a challenge with Trump saying weeks. It is entirely possible they just don't get enough data to approve in 4-8 weeks. That isn't a failure of the vaccine, but the media will spin it that way. We put all this money and effort into a vaccine and it didn't work. But if you wait a few more weeks or months, the data might be there.

BiochemAg97 said:

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The primary endpoint is a reduction in cases. The reduction in hospitalizations, ICU, and deaths are nice data to have for marketing. If they factored in asymptomatic cases and were able to show a significant reduction in cases + asymptomatic cases, I think that would work too. But I would be concerned about people testing positive just because of exposure and not an actual infection. Certainly seems that could be the case.

---

Here is what I was thinking. Maybe this take isn't helpful.....

With a disease like Covid-19 that has such a non-uniform risk across a population it matters which cases a vaccine prevents. It is possible that whatever issues make one vulnerable to a severe case limit the effectiveness of a vaccine in that person. If this were true a vaccine could be quite effective in the otherwise healthy and/or younger subset and less effective in the more vulnerable less healthy portion of the population.

So looking at the Primary Endpoint it is approvable by the FDA. And there is nothing wrong with that. However, it isn't as positive a result as one that hits the secondary endpoints of reducing deaths, severe cases, and hospitalizations. In fact differences in secondary endpoints might end up distinguishing between the various vaccines and approaches.

I'm hoping for clear evidence of a vaccine that is uniformly effective across the population.

KlinkerAg11 said:

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I think the Mnra vaccine has potential to be a gateway to new medicine that will help a lot of people.

---

Most of my life savings are banking on this.

Pfizer posted their Vaccine Protocol document. 137 pages. Outpacing Moderna by two pages. :-)

https://pfe-pfizercom-d8-prod.s3.amazonaws.com/2020-09/C4591001_Clinical_Protocol_0.pdf

And for comparison, here is some discussion around determining effectiveness and the definitions for what constitutes a case and a severe case.

Looks at previous SARS vaccine studies, that they have been trying to make since 2003. Its pretty much the same virus...


Some of the research is not good. Several times they rushed to human trials then nothing. The problem seems to be getting exposed to a virus again after you have had the vaccine.


Remember also, it takes many years of vaccine safety studies to determine one is safe before its released.

daggertx said:

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Looks at previous SARS vaccine studies, that they have been trying to make since 2003. Its pretty much the same virus...


Some of the research is not good. Several times they rushed to human trials then nothing. The problem seems to be getting exposed to a virus again after you have had the vaccine.


Remember also, it takes many years of vaccine safety studies to determine one is safe before its released.

---

a large part of the issue with the SARS vaccine is no one was getting sick when they were ready to do phase 2/3 testing. Can't test efficacy if the test to control ratio is 0/0.

Well, if you are concerned about the many years of vaccine safety studies... might want to stick to the AZ vaccine.

The issue of whether it is helpful to release Interim results of the Phase 3 Trials is in the news.
Potentially you can make statistical arguments for effectiveness from very small numbers of cases in the trial.

This is in the Pfizer protocol.

BiochemAg97 said:

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daggertx said:

---

Looks at previous SARS vaccine studies, that they have been trying to make since 2003. Its pretty much the same virus...


Some of the research is not good. Several times they rushed to human trials then nothing. The problem seems to be getting exposed to a virus again after you have had the vaccine.


Remember also, it takes many years of vaccine safety studies to determine one is safe before its released.

---

a large part of the issue with the SARS vaccine is no one was getting sick when they were ready to do phase 2/3 testing. Can't test efficacy if the test to control ratio is 0/0.

Well, if you are concerned about the many years of vaccine safety studies... might want to stick to the AZ vaccine.

---

Just curious but why do you think AZ vaccine will be safer? AFAIK we don't have any current Adenovirus based vaccines.

IMO the mRNA is most likely to be the safest vehicle as it actually tells your immune system exactly which antibody to generate.

The military has been administering a live adenovirus vaccine for the last 40 years. Not exactly the same thing, but one good sign for the safety of the approach

Mechanistically the mRNA and adenovirus vaccines are similar. Both are delivering instructions for your body to make part of the coronavirus so that your immune system can recognize it.

amercer said:

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The military has been administering a live adenovirus vaccine for the last 40 years. Not exactly the same thing, but one good sign for the safety of the approach

Mechanistically the mRNA and adenovirus vaccines are similar. Both are delivering instructions for your body to make part of the coronavirus so that your immune system can recognize it.

---

Thanks I was not aware of that!

However that live adenovirus vaccine in pill form is very different from an injectible vaccine that is using Adeno to piggy back on and trigger the immune system. I expect we will see the rare post viral complications we see with other viral vaccines (GBS, Transverse Myelitis, etc).

KidDoc said:

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BiochemAg97 said:

---

daggertx said:

---

Looks at previous SARS vaccine studies, that they have been trying to make since 2003. Its pretty much the same virus...


Some of the research is not good. Several times they rushed to human trials then nothing. The problem seems to be getting exposed to a virus again after you have had the vaccine.


Remember also, it takes many years of vaccine safety studies to determine one is safe before its released.

---

a large part of the issue with the SARS vaccine is no one was getting sick when they were ready to do phase 2/3 testing. Can't test efficacy if the test to control ratio is 0/0.

Well, if you are concerned about the many years of vaccine safety studies... might want to stick to the AZ vaccine.

---

Just curious but why do you think AZ vaccine will be safer? AFAIK we don't have any current Adenovirus based vaccines.

IMO the mRNA is most likely to be the safest vehicle as it actually tells your immune system exactly which antibody to generate.

---

I tend to agree that mRNA is probably a safer system. But we don't have "years of safety studies" on any mRNA vaccine. I was specifically addressing that concern.

Oxford has tested theirs in multiple other human (and animal) trials. Not sure if they have one that has passed phase 3 and has been approved using their vector, but the whole hype of the Oxford vaccine back around May was they had a history of safety data that would allow them to jump to later phases.

BiochemAg97 said:

---

KidDoc said:

---

BiochemAg97 said:

---

daggertx said:

---

Looks at previous SARS vaccine studies, that they have been trying to make since 2003. Its pretty much the same virus...


Some of the research is not good. Several times they rushed to human trials then nothing. The problem seems to be getting exposed to a virus again after you have had the vaccine.


Remember also, it takes many years of vaccine safety studies to determine one is safe before its released.

---

a large part of the issue with the SARS vaccine is no one was getting sick when they were ready to do phase 2/3 testing. Can't test efficacy if the test to control ratio is 0/0.

Well, if you are concerned about the many years of vaccine safety studies... might want to stick to the AZ vaccine.

---

Just curious but why do you think AZ vaccine will be safer? AFAIK we don't have any current Adenovirus based vaccines.

IMO the mRNA is most likely to be the safest vehicle as it actually tells your immune system exactly which antibody to generate.

---

I tend to agree that mRNA is probably a safer system. But we don't have "years of safety studies" on any mRNA vaccine. I was specifically addressing that concern.

BCG is an adenovirus vector. TB but used outside the US.

Not the same vector as Oxford, but Oxford had tested theirs in multiple other human (and animal) trials. Not sure if they have one that has passed phase 3 and has been approved using their vector, but the whole hype of the Oxford vaccine back around May was they had a history of safety data that would allow them to jump to later phases.

---

I double checked the BCG vector (especially since I got it a few months ago as part of the BADAS study)- it is not adenovirus it is just weakened TB: https://www.nhs.uk/conditions/vaccinations/bcg-tb-vaccine-questions-answers/

I 100% agree there are no long term mRNA studies- just theoretically seems safer.

Oxford & AZ vaccine are the same vaccine- they are partners. It is the Adenorvirus piggy back technique.

KidDoc said:

---

BiochemAg97 said:

---

KidDoc said:

---

BiochemAg97 said:

---

daggertx said:

---

Looks at previous SARS vaccine studies, that they have been trying to make since 2003. Its pretty much the same virus...


Some of the research is not good. Several times they rushed to human trials then nothing. The problem seems to be getting exposed to a virus again after you have had the vaccine.


Remember also, it takes many years of vaccine safety studies to determine one is safe before its released.

---

a large part of the issue with the SARS vaccine is no one was getting sick when they were ready to do phase 2/3 testing. Can't test efficacy if the test to control ratio is 0/0.

Well, if you are concerned about the many years of vaccine safety studies... might want to stick to the AZ vaccine.

---

Just curious but why do you think AZ vaccine will be safer? AFAIK we don't have any current Adenovirus based vaccines.

IMO the mRNA is most likely to be the safest vehicle as it actually tells your immune system exactly which antibody to generate.

---

I tend to agree that mRNA is probably a safer system. But we don't have "years of safety studies" on any mRNA vaccine. I was specifically addressing that concern.

BCG is an adenovirus vector. TB but used outside the US.

Not the same vector as Oxford, but Oxford had tested theirs in multiple other human (and animal) trials. Not sure if they have one that has passed phase 3 and has been approved using their vector, but the whole hype of the Oxford vaccine back around May was they had a history of safety data that would allow them to jump to later phases.

---

I double checked the BCG vector (especially since I got it a few months ago as part of the BADAS study)- it is not adenovirus it is just weakened TB: https://www.nhs.uk/conditions/vaccinations/bcg-tb-vaccine-questions-answers/

I 100% agree there are no long term mRNA studies- just theoretically seems safer.

Oxford & AZ vaccine are the same vaccine- they are partners. It is the Adenorvirus piggy back technique.

---

Thanks for the clarification on BCG. Looks like I misread the adenovirus BCG connection. There was some work on enhancing BCG with anadenovirus. Not sure what became of it. https://stm.sciencemag.org/content/5/205/205ra134 It was using a human adenovirus rather than the chimp one Oxford uses.

I know Oxford & AZ are partners, but the early Oxford hype was before anyone mentioned an AZ partnership, I assume before they agreed to the partnership. Maybe the hype was really just because there were lots of trials of other vaccines.

BiochemAg97 said:

---

KidDoc said:

---

BiochemAg97 said:

---

KidDoc said:

---

BiochemAg97 said:

---

daggertx said:

---

Looks at previous SARS vaccine studies, that they have been trying to make since 2003. Its pretty much the same virus...


Some of the research is not good. Several times they rushed to human trials then nothing. The problem seems to be getting exposed to a virus again after you have had the vaccine.


Remember also, it takes many years of vaccine safety studies to determine one is safe before its released.

---

a large part of the issue with the SARS vaccine is no one was getting sick when they were ready to do phase 2/3 testing. Can't test efficacy if the test to control ratio is 0/0.

Well, if you are concerned about the many years of vaccine safety studies... might want to stick to the AZ vaccine.

---

Just curious but why do you think AZ vaccine will be safer? AFAIK we don't have any current Adenovirus based vaccines.

IMO the mRNA is most likely to be the safest vehicle as it actually tells your immune system exactly which antibody to generate.

---

I tend to agree that mRNA is probably a safer system. But we don't have "years of safety studies" on any mRNA vaccine. I was specifically addressing that concern.

BCG is an adenovirus vector. TB but used outside the US.

Not the same vector as Oxford, but Oxford had tested theirs in multiple other human (and animal) trials. Not sure if they have one that has passed phase 3 and has been approved using their vector, but the whole hype of the Oxford vaccine back around May was they had a history of safety data that would allow them to jump to later phases.

---

I double checked the BCG vector (especially since I got it a few months ago as part of the BADAS study)- it is not adenovirus it is just weakened TB: https://www.nhs.uk/conditions/vaccinations/bcg-tb-vaccine-questions-answers/

I 100% agree there are no long term mRNA studies- just theoretically seems safer.

Oxford & AZ vaccine are the same vaccine- they are partners. It is the Adenorvirus piggy back technique.

---

Thanks for the clarification on BCG. Looks like I misread the adenovirus BCG connection. There was some work on enhancing BCG with anadenovirus. Not sure what became of it. https://stm.sciencemag.org/content/5/205/205ra134 It was using a human adenovirus rather than the chimp one Oxford uses.

I know Oxford & AZ are partners, but the early Oxford hype was before anyone mentioned an AZ partnership, I assume before they agreed to the partnership. Maybe the hype was really just because there were lots of trials of other vaccines.

---

Out of curiosity, what do you do for a living? I really enjoy reading your insights.

Harry Stone said:

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BiochemAg97 said:

---

KidDoc said:

---

BiochemAg97 said:

---

KidDoc said:

---

BiochemAg97 said:

---

daggertx said:

---

Looks at previous SARS vaccine studies, that they have been trying to make since 2003. Its pretty much the same virus...


Some of the research is not good. Several times they rushed to human trials then nothing. The problem seems to be getting exposed to a virus again after you have had the vaccine.


Remember also, it takes many years of vaccine safety studies to determine one is safe before its released.

---

a large part of the issue with the SARS vaccine is no one was getting sick when they were ready to do phase 2/3 testing. Can't test efficacy if the test to control ratio is 0/0.

Well, if you are concerned about the many years of vaccine safety studies... might want to stick to the AZ vaccine.

---

Just curious but why do you think AZ vaccine will be safer? AFAIK we don't have any current Adenovirus based vaccines.

IMO the mRNA is most likely to be the safest vehicle as it actually tells your immune system exactly which antibody to generate.

---

I tend to agree that mRNA is probably a safer system. But we don't have "years of safety studies" on any mRNA vaccine. I was specifically addressing that concern.

BCG is an adenovirus vector. TB but used outside the US.

Not the same vector as Oxford, but Oxford had tested theirs in multiple other human (and animal) trials. Not sure if they have one that has passed phase 3 and has been approved using their vector, but the whole hype of the Oxford vaccine back around May was they had a history of safety data that would allow them to jump to later phases.

---

I double checked the BCG vector (especially since I got it a few months ago as part of the BADAS study)- it is not adenovirus it is just weakened TB: https://www.nhs.uk/conditions/vaccinations/bcg-tb-vaccine-questions-answers/

I 100% agree there are no long term mRNA studies- just theoretically seems safer.

Oxford & AZ vaccine are the same vaccine- they are partners. It is the Adenorvirus piggy back technique.

---

Thanks for the clarification on BCG. Looks like I misread the adenovirus BCG connection. There was some work on enhancing BCG with anadenovirus. Not sure what became of it. https://stm.sciencemag.org/content/5/205/205ra134 It was using a human adenovirus rather than the chimp one Oxford uses.

I know Oxford & AZ are partners, but the early Oxford hype was before anyone mentioned an AZ partnership, I assume before they agreed to the partnership. Maybe the hype was really just because there were lots of trials of other vaccines.

---

Out of curiosity, what do you do for a living? I really enjoy reading your insights.

---

I am a patent agent working for a company that supplies scientific instrumentation, reagents and consumables, and software and services to healthcare, life science, and other laboratories in academia, government, and industry (including in the biotech and pharma sectors).

It get a broad look at some of the technologies we develop, and a very detailed look when writing a patent application.

Got my 2nd shot at 9am yesterday, wasn't sure i had the vaccine or placebo. Well I'm sure now. 102 fever last night, pretty bad headache but it was mostly my fault as I didn't make sure we had advil on hand. My wife is at the gym so I just got back from HEB with supplies. *facepalm*

But I'm very pumped I got it and interesting that it's a pretty strong reaction.

BiochemAg97 said:

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Harry Stone said:

---

BiochemAg97 said:

---

KidDoc said:

---

BiochemAg97 said:

---

KidDoc said:

---

BiochemAg97 said:

---

daggertx said:

---

Looks at previous SARS vaccine studies, that they have been trying to make since 2003. Its pretty much the same virus...


Some of the research is not good. Several times they rushed to human trials then nothing. The problem seems to be getting exposed to a virus again after you have had the vaccine.


Remember also, it takes many years of vaccine safety studies to determine one is safe before its released.

---

a large part of the issue with the SARS vaccine is no one was getting sick when they were ready to do phase 2/3 testing. Can't test efficacy if the test to control ratio is 0/0.

Well, if you are concerned about the many years of vaccine safety studies... might want to stick to the AZ vaccine.

---

Just curious but why do you think AZ vaccine will be safer? AFAIK we don't have any current Adenovirus based vaccines.

IMO the mRNA is most likely to be the safest vehicle as it actually tells your immune system exactly which antibody to generate.

---

I tend to agree that mRNA is probably a safer system. But we don't have "years of safety studies" on any mRNA vaccine. I was specifically addressing that concern.

BCG is an adenovirus vector. TB but used outside the US.

Not the same vector as Oxford, but Oxford had tested theirs in multiple other human (and animal) trials. Not sure if they have one that has passed phase 3 and has been approved using their vector, but the whole hype of the Oxford vaccine back around May was they had a history of safety data that would allow them to jump to later phases.

---

I double checked the BCG vector (especially since I got it a few months ago as part of the BADAS study)- it is not adenovirus it is just weakened TB: https://www.nhs.uk/conditions/vaccinations/bcg-tb-vaccine-questions-answers/

I 100% agree there are no long term mRNA studies- just theoretically seems safer.

Oxford & AZ vaccine are the same vaccine- they are partners. It is the Adenorvirus piggy back technique.

---

Thanks for the clarification on BCG. Looks like I misread the adenovirus BCG connection. There was some work on enhancing BCG with anadenovirus. Not sure what became of it. https://stm.sciencemag.org/content/5/205/205ra134 It was using a human adenovirus rather than the chimp one Oxford uses.

I know Oxford & AZ are partners, but the early Oxford hype was before anyone mentioned an AZ partnership, I assume before they agreed to the partnership. Maybe the hype was really just because there were lots of trials of other vaccines.

---

Out of curiosity, what do you do for a living? I really enjoy reading your insights.

---

I am a patent agent working for a company that supplies scientific instrumentation, reagents and consumables, and software and services to healthcare, life science, and other laboratories in academia, government, and industry (including in the biotech and pharma sectors).

It get a broad look at some of the technologies we develop, and a very detailed look when writing a patent application.

---

very cool. i cofounded an mRNA company. these vaccines have changed the game for our company.

I think some folk's intuition is that the shot is putting something into their body that will fight the virus and the disease. They don't see vaccination is safely (hopefully) exposing us to something similar to the virus in order to train our bodies to effectively (hopefully) fight the virus/disease if we encounter it for real. One expects training might hurt, adding ammunition should not.

Of course when someone tells you a Hepatitis Immune Globulin injection is a vaccination then things stay confusing. But I wouldn't want to try to explain the difference.

Johnson and Johnson has started their Phase 3 trial and released a Protocol document.

https://www.jnj.com/coronavirus/covid-19-phase-3-study-clinical-protocol

If you are keeping score they are at 163 pgs. :-)

plain_o_llama said:

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Johnson and Johnson has started their Phase 3 trial and released a Protocol document.

https://www.jnj.com/coronavirus/covid-19-phase-3-study-clinical-protocol

If you are keeping score they are at 163 pgs. :-)

---

Another adenovirus vehicle. Pretty promising primate data, one dose efficacy is pretty exciting. It is really looking like we may end up with multiple viable vaccines.

Study is 18+ only which is what I expect to be for the majority of COVID vaccines as it is so benign in children.

Saw a brief interview on CNBC. They intend to have 60,000 volunteers in the Phase 3 and include older and less healthy participants. They are focused on the single dose but will have some subset at two doses for comparison. There is a suggestion that having a single dose will allow them to be on a similar timeline to the other 2 dose competitors who started a little earlier.

plain_o_llama said:

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Saw a brief interview on CNBC. They intend to have 60,000 volunteers in the Phase 3 and include older and less healthy participants. They are focused on the single dose but will have some subset at two doses for comparison. There is a suggestion that having a single dose will allow them to be on a similar timeline to the other 2 dose competitors who started a little earlier.

---

Thought I saw Moderna or Pfizer had the reverse, with some part of the study looking at if they could get by with 1 dose.


Also, AZ is also working towards a single dose. Not surprising since both are adenovirus.

From all of this, is there a better possibility for a cure for the common cold?