Covid-19 #24: You Scream, I Scream, We all Scream for Vaccine

[Clueless Northman]

You mean, just what China and Russia were blamed for?

A key issue is that plenty of sceptical people just wouldn't get vaccinated in such a situation. They're already doubtful in places with emergency approval after phase 3 was completed. Were I a benevolent autocrat with massive repressive police apparatus, I might consider that indeed, but I'm not sure it would help in our Western societies.

[JoannaL]

1 hour ago, rotting sea cow said:

I don't know about you, but with the later polemics en relation to the Oxford/AZ vaccine and statements regarding the J&J, I get the feeling that the Phase 3 process has just become moot as these vaccines will be approved regardless of the data. Don't get me wrong, I do think they are effective and sorely needed but by getting political it's undermining the whole process. I think it would have been better and saving everybody precious time to approve the vaccine for emergency use after Phase 1 & 2 and do Phase 3 & 4 in parallel too.

 

No, what is necessary is to get quickly good reliable data of decent phase III trials and then get a regular -not an emergency use authorization. Everything else will destroy the credibility of these vaccines. It seems that AstraZeneca applied too quickly in Europe. In the US they are conducting a second phase III trial because of that and have not yet applied for authorisation because they know their data are not sufficient as of yet. They perhaps should have waited in Europe too. Just look at it from the other side: Yes it is bad to wait   longer because the data is not sufficient. But wouldnt it be worse to approve to fast and then have a vaccine which doesnt work or worse - which is unsafe?

[rotting sea cow]

17 minutes ago, Clueless Northman said:

You mean, just what China and Russia were blamed for?

A key issue is that plenty of sceptical people just wouldn't get vaccinated in such a situation. They're already doubtful in places with emergency approval after phase 3 was completed. Were I a benevolent autocrat with massive repressive police apparatus, I might consider that indeed, but I'm not sure it would help in our Western societies.

There are nevertheless not enough vaccines to vaccinate everybody. Just offer it to the people who are willing to take it. Probably it wouldn't have made a dent into the number of infections till new year, but it would have been better than running this show.

hard core antivaxers won't get vaccinated no matter what, the trick is convincing the ones.  in doubt and nothing better than hearing stories from their co-workers, friends and relatives.

[Mlle. Zabzie]

1 hour ago, rotting sea cow said:

I don't know about you, but with the later polemics en relation to the Oxford/AZ vaccine and statements regarding the J&J, I get the feeling that the Phase 3 process has just become moot as these vaccines will be approved regardless of the data. Don't get me wrong, I do think they are effective and sorely needed but by getting political it's undermining the whole process. I think it would have been better and saving everybody precious time to approve the vaccine for emergency use after Phase 1 & 2 and do Phase 3 & 4 in parallel too.

 

I’m not sure that is true at least in the states.  I mean AZ was required to actually go out and get good data to fix their botched earlier trial.  And Merck pulled its candidates.  I see the Merck example as actually proof of concept - the system is working because if the data were there you know Merck would be touting it.  The data aren’t there.  

That said, I do think we probably have a pretty good idea after phases 1 and 2.  But we don’t have the total picture, and I’d rather go through the last phase and into emergency use rather than rush an already rushed process. 

[rotting sea cow]

1 minute ago, JoannaL said:

No, what is necessary is to get quickly good reliable data of decent phase III trials and then get a regular -not an emergency use authorization. Everything else will destroy the credibility of these vaccines. It seems that AstraZeneca applied too quickly in Europe. In the US they are conducting a second phase III trial because of that and have not yet applied for authorisation because they know their data are not sufficient as of yet. They perhaps should have waited in Europe too. Just look at it from the other side: Yes it is bad to wait   longer because the data is not sufficient. But wouldnt it be worse to approve to fast and then have a vaccine which doesnt work or worse - which is unsafe?

Yes I agree. As things stand now AstraZeneca vaccine wouldn't be approved until the trial is rectified and solid data is produced. However, it seems that parts of the EU want the vaccine so badly that they forget that fact and so the vaccine is the facto approved regardless of the data. Notice, that the EU also placed pressure to get the Pfizer vaccine approved sooner or so the Le Monde reported. 

Similar things are happening with the J&J vaccine. Everybody acts like the vaccine is already approved.

[Fragile Bird]

Dr. Fauci, in an interview this morning, has spoken about the fear we've touched on - that soon there will be so many mutations to the virus that the current vaccines won't be as effective, or effective at all. Right now he is confident that the current vaccines can deal with all the existing variants, but that could change. The idea that any company would go all out and produce a billion doses of a vaccine that might not work 6 months from now does not sound like a thing most companies would do.

I don't mean to be depressing or anything, but I foresee a future with shorter lifespans and a very different lifestyle than what we previously had. I don't think it will last forever, history seems to tell us that, but it may last a lot longer than we've been contemplating so far.

On the bright side of things, we may be slowing climate change down!

eta: the interview was reported on CNBC this morning but I can't find it to post a link. Now that Trump is gone, though, he is popping up everywhere and speaking his mind, and his strongest message is the best way to prevent mutations is to stop the virus from replicating, so wear a mask, wash your hands, keep social distances and stay away from crowds. Oh, and get vaccinated ASAP.

[Padraig]

1 hour ago, rotting sea cow said:

Yes I agree. As things stand now AstraZeneca vaccine wouldn't be approved until the trial is rectified and solid data is produced. However, it seems that parts of the EU want the vaccine so badly that they forget that fact and so the vaccine is the facto approved regardless of the data. Notice, that the EU also placed pressure to get the Pfizer vaccine approved sooner or so the Le Monde reported. 

Similar things are happening with the J&J vaccine. Everybody acts like the vaccine is already approved.

I think Joanna is right here.

There are definitely indications that the EU wouldn't approve the Astrazeneca vaccine for over 65 year olds.  When you have the CEO of Astrazeneca say that is not a problem (see Guardian article that was linked earlier), that's a big red flag.

Now maybe the EMA will decide in the end that there is enough data but suboptimal.  I don't know.  But its disappointing news.

As for this whole "EU pressured the EMA" thing.  This is the problem with the age we live in.  Media must media.  What does "pressure" mean?  Ignore the science?  I very much doubt it.  Take short-cuts?  Doubt that too.  Approve as much overtime as you need?  Bring in contractors?  Work Christmas Day? Much more likely.

If something gets to the end of Phase 3 trials, it probably has a high probability of being approved.  People did get a little carried away and thought that was close to 100% but given the times, I can see why people would grasp onto any life vest they can.  They certainly need to prepare for approval, as if it will be approved.

Anyhow, if the approval is constrained, this will mess up plans.  I know Ireland was going to use this vaccine for older people that weren't in hospitals/care homes.  But there are plenty front line people that can use it.  And as mentioned, it probably will eventually get approved completely.

Roll on J&J.  The results next week are 1-dose, so let us see.

Edited to add:  This issue with lack of 65+ year olds clearly was known about months ago.  So I wonder what the logic was for the EU application.  Could they have waited for the US test data?  Did the EU encourage AstraZeneca to give it a shot?  Part approval was better than none.? Again, lots of questions.

[Padraig]

14 minutes ago, Fragile Bird said:

The idea that any company would go all out and produce a billion doses of a vaccine that might not work 6 months from now does not sound like a thing most companies would do.

My understanding of this is that once the vaccines are developed, they will be a lot easier to modify.  Like the flu vaccine every year.  The new mRNA vaccines are supposed to be even easier than the classic vaccines (IIRC)?

[ljkeane]

24 minutes ago, Fragile Bird said:

The idea that any company would go all out and produce a billion doses of a vaccine that might not work 6 months from now does not sound like a thing most companies would do.

I've got disagree on that one. From a purely mercenary point of view if your company makes vaccines the entire population of the world needing to get a new vaccine every year sounds pretty good.

[Fragile Bird]

I guess I wasn't clear enough about what I meant.

We're going to need well over a billion doses of vaccine just to cover North America and Europe. The vaccine rollout will take at least until September. Right now the vaccines seem to be effective against the UK, Brazilian and South African variants, but with the caveat that it's less effective against the South African variant. Next week another variant may pop up in the UK or the US or some other country that the vaccines will be dramatically less effective against. Actually, I saw a report two days ago that there appears to be a new California variant which accounts for the fast and massive spread in that state.

The next variant could be the one that makes the vaccines only 50% effective. Do you continue making hundreds of millions of doses, or do you do the gene map and create a new vaccine? Do you have to go through more trials? What if the new vaccine is effective against the new variant but not very effective against the old variant? The mRNA type apparently get made in batches that take a month to 'brew', for lack of a better term. Do you stop production of one and shift to the other?

Do you make your billion doses and give the shots and tell people they'll need a booster shot? But won't everyone need the booster shot? So you're back on the vaccine treadmill, going nowhere. That's why I think we will be in this Covid era for a long time.

I'm sure I'm not describing things well! But this is more complicated than the flu. Will it be easier to change production of the other, non-mRNA type vaccines?

[Wilbur]

Well, Chinese authorities are now indicating that anal swabs are the superior testing method compared to saliva or nasal swabs, and they are using it in Beijing and other major metro areas.

And I don't have anything further to say about that.

[williamjm]

8 hours ago, JoannaL said:

now The Guardian also has this story about the AstraZeneca vaccine and age groups:

https://www.theguardian.com/world/2021/jan/26/astrazeneca-vaccine-may-not-be-given-to-older-people-says-eu-medicines-chief

Even if the EMA gets now pressured into also authorizing for this group (which will not be clear either way before  Friday) these articles more or less destroyed the confidence in this vaccine here in Germany . We have a very vaccine critical population and if there are rumors that a vaccine isnt working thats very damaging. It should be noted that the EMA is not saying it doesnt work, only that there are not enough data. So at a later point in time an authorization may be possible still. But would that help? I think the best way forward regardless of the EMA decision on Friday is to only administer this vaccine to the younger than 65 old . Everything else will met with protests and endless discussions in the media.  The AstraZeneca vaccine can still be useful, e.g. for physicians, teachers and so on...

I don't know if there's more context in the full transcript of what the EMA boss said but from what's quoted in that story it sounds like they were very non-committal about whether there would be any age restriction in their approval. I think it's inevitable that it would be left open as a possibility in comments made before the official announcement.

8 hours ago, Consigliere said:

J&J initiated a second phase 3 trial in November to determine the efficacy of a two dose regimen. So we'll have to wait and see what dosing regimen they recommend. Hopefully there's no significant difference between the two - a single jab vaccine would make things much easier for everyone especially the developing world.

https://www.jnj.com/johnson-johnson-initiates-second-global-phase-3-clinical-trial-of-its-janssen-covid-19-vaccine-candidate

Thanks, I hadn't seen that story. The one dose would be nice but even if it's the two dose that gets approved it's still good to have another vaccine.

I suppose there could be a difficult decision if they both have good efficacy but the two dose regime is noticeably better.

7 hours ago, rotting sea cow said:

I don't know about you, but with the later polemics en relation to the Oxford/AZ vaccine and statements regarding the J&J, I get the feeling that the Phase 3 process has just become moot as these vaccines will be approved regardless of the data. Don't get me wrong, I do think they are effective and sorely needed but by getting political it's undermining the whole process. I think it would have been better and saving everybody precious time to approve the vaccine for emergency use after Phase 1 & 2 and do Phase 3 & 4 in parallel too.

I think the mass safety testing element of Phase 3 was important as well and I wouldn't want that to be skipped, fortunately it doesn't seem to have generated as much controversy as the efficacy data. An earlier approval might have some benefits but there would have been even fewer doses manufactured to go around at that time so it perhaps isn't making a big difference in the long term.

It does feel like there could be more transparency in the process, that might avoid things like the German news report allegedly misinterpreting numbers if they had all been published somewhere they could be reviewed.

3 hours ago, Padraig said:

My understanding of this is that once the vaccines are developed, they will be a lot easier to modify.  Like the flu vaccine every year.  The new mRNA vaccines are supposed to be even easier than the classic vaccines (IIRC)?

I think there was a quote from the German company behind the Pfizer vaccine that a modified vaccine could be ready in about 6 weeks - although I'm not sure if that would take into account how long it would take to mass produce it.

[Mudguard]

3 hours ago, Fragile Bird said:

I guess I wasn't clear enough about what I meant.

We're going to need well over a billion doses of vaccine just to cover North America and Europe. The vaccine rollout will take at least until September. Right now the vaccines seem to be effective against the UK, Brazilian and South African variants, but with the caveat that it's less effective against the South African variant. Next week another variant may pop up in the UK or the US or some other country that the vaccines will be dramatically less effective against. Actually, I saw a report two days ago that there appears to be a new California variant which accounts for the fast and massive spread in that state.

The next variant could be the one that makes the vaccines only 50% effective. Do you continue making hundreds of millions of doses, or do you do the gene map and create a new vaccine? Do you have to go through more trials? What if the new vaccine is effective against the new variant but not very effective against the old variant? The mRNA type apparently get made in batches that take a month to 'brew', for lack of a better term. Do you stop production of one and shift to the other?

Do you make your billion doses and give the shots and tell people they'll need a booster shot? But won't everyone need the booster shot? So you're back on the vaccine treadmill, going nowhere. That's why I think we will be in this Covid era for a long time.

I'm sure I'm not describing things well! But this is more complicated than the flu. Will it be easier to change production of the other, non-mRNA type vaccines?

You should be able to administer the vaccine as a cocktail like we do for the influenza vaccine.  If there are 2 or 3 coronavirus strains out there, you can make all 2 or 3 vaccines and mix them together into a cocktail.  For at least the mRNA and adenovirus based vaccines, it should be relatively trivial to update the vaccine now that the new vaccine platform has been validated.  It's a matter of swapping out the RNA or DNA sequence that encodes for the spike protein, which is not difficult to do, and everything else can be left the same.  Instead of having to run a full phase III clinical trial for a new vaccine to one of the variants, you can probably just do a quick trial to see if the vaccine can generate neutralizing antibodies.

[Impmk2]

3 hours ago, Fragile Bird said:

The mRNA type apparently get made in batches that take a month to 'brew', for lack of a better term. Do you stop production of one and shift to the other?

 

This simply cannot be true, naked mRNA has a half-life of minutes, hence the extreme storage and shipping requirements. Pretty sure you're getting confused with adenovirus vector vaccines, which are typically produced in batches on a infect, lyse, harvest workflow. Though a month seems long to me. Approx a week is more regular in my experience, but not sure about the various attenuated strains and how these things scale.

Either should be extremely quick and easy to change. Far easier than a traditional subunit vaccine. No messing about looking at protein folding / stability and reoptimising large scale purification.

[rotting sea cow]

4 hours ago, Padraig said:

I think Joanna is right here.

There are definitely indications that the EU wouldn't approve the Astrazeneca vaccine for over 65 year olds.  When you have the CEO of Astrazeneca say that is not a problem (see Guardian article that was linked earlier), that's a big red flag.

Now maybe the EMA will decide in the end that there is enough data but suboptimal.  I don't know.  But its disappointing news.

As for this whole "EU pressured the EMA" thing.  This is the problem with the age we live in.  Media must media.  What does "pressure" mean?  Ignore the science?  I very much doubt it.  Take short-cuts?  Doubt that too.  Approve as much overtime as you need?  Bring in contractors?  Work Christmas Day? Much more likely.

If something gets to the end of Phase 3 trials, it probably has a high probability of being approved.  People did get a little carried away and thought that was close to 100% but given the times, I can see why people would grasp onto any life vest they can.  They certainly need to prepare for approval, as if it will be approved.

Anyhow, if the approval is constrained, this will mess up plans.  I know Ireland was going to use this vaccine for older people that weren't in hospitals/care homes.  But there are plenty front line people that can use it.  And as mentioned, it probably will eventually get approved completely.

Roll on J&J.  The results next week are 1-dose, so let us see.

Edited to add:  This issue with lack of 65+ year olds clearly was known about months ago.  So I wonder what the logic was for the EU application.  Could they have waited for the US test data?  Did the EU encourage AstraZeneca to give it a shot?  Part approval was better than none.? Again, lots of questions.

 

18 minutes ago, williamjm said:

think the mass safety testing element of Phase 3 was important as well and I wouldn't want that to be skipped, fortunately it doesn't seem to have generated as much controversy as the efficacy data. An earlier approval might have some benefits but there would have been even fewer doses manufactured to go around at that time so it perhaps isn't making a big difference in the long term.

It does feel like there could be more transparency in the process, that might avoid things like the German news report allegedly misinterpreting numbers if they had all been published somewhere they could be reviewed.

Just to make clear. I'm not criticizing the Phase 3 process which I find of course necessary. I'm criticizing the attitude of some companies, politicians and administrative bodies that are acting as the vaccine is approved. Comparing to Pfizer and Moderna, the data from AstraZeneca looks subpar, but it will be nevertheless approved, because hey we need a vaccine, undermining the credibility of the process. People who know a little bit more are going to try hard to get the Pfizer/Moderna vaccines instead of the Oxford/AZ one. People who know less are going to try to avoid all vaccines because they are now all muddled together.  This is my point. 

 

[Fragile Bird]

1 hour ago, Impmk2 said:

This simply cannot be true, naked mRNA has a half-life of minutes, hence the extreme storage and shipping requirements. Pretty sure you're getting confused with adenovirus vector vaccines, which are typically produced in batches on a infect, lyse, harvest workflow. Though a month seems long to me. Approx a week is more regular in my experience, but not sure about the various attenuated strains and how these things scale.

Either should be extremely quick and easy to change. Far easier than a traditional subunit vaccine. No messing about looking at protein folding / stability and reoptimising large scale purification.

The information about the one month period came from a news report I saw about manufacturing the covid vaccines, so I have no link. A quick look on the internet shows estimates of two to six weeks, the issue being since no mRNA vaccine has been previously manufactured in quantity people were guessing, but one bottleneck is the supply chain. I also saw that a 2 litre reactor will manufacture enough to create a million doses. 

https://news.ncsu.edu/2020/12/vaccine-manufacturing-q-and-a/

 

[Padraig]

2 hours ago, rotting sea cow said:

Comparing to Pfizer and Moderna, the data from AstraZeneca looks subpar, but it will be nevertheless approved, because hey we need a vaccine, undermining the credibility of the process.

Is that definitely true?  Isn't the AstraZeneca data fine for those between 18-65?  Or have you heard that there is something lacking in that data too?

I do agree that, if the EU only approves it for those aged less than 65, it will set off some alarms.  If you are 64, what are you going to think?

But I would interpret it differently.  It is an excess of caution rather than being soft on approval.  It was always going to be a little challenging to convey this story.  There is no real upside in approving something that doesn't work.

6 hours ago, Fragile Bird said:

Do you make your billion doses and give the shots and tell people they'll need a booster shot? But won't everyone need the booster shot? So you're back on the vaccine treadmill, going nowhere. That's why I think we will be in this Covid era for a long time.

I'm sure I'm not describing things well! But this is more complicated than the flu.

Its more complicated than the flu because its more deadly, so more people may have to take the vaccine.  So I agree there.  But what you are otherwise describing seems to be the challenge of making the flu vaccine every year?  People were worried about from that start.  In fact, people were worried about ever finding a vaccine originally, so hopefully this fear wouldn't come to fruition either.

2 hours ago, williamjm said:

I think it's inevitable that it would be left open as a possibility in comments made before the official announcement.

lt's the AstraZeneca CEO's comments that worried me more.  But hopefully it wouldn't lead to anything.

[Mudguard]

2 hours ago, Impmk2 said:

This simply cannot be true, naked mRNA has a half-life of minutes, hence the extreme storage and shipping requirements. Pretty sure you're getting confused with adenovirus vector vaccines, which are typically produced in batches on a infect, lyse, harvest workflow. Though a month seems long to me. Approx a week is more regular in my experience, but not sure about the various attenuated strains and how these things scale.

Either should be extremely quick and easy to change. Far easier than a traditional subunit vaccine. No messing about looking at protein folding / stability and reoptimising large scale purification.

I think the half-life in minutes for mRNA that you are referring to is the half life in cells.  In the vaccine preparation, it should be much longer.  The Pfizer mRNA vaccine can be stored in the fridge for up to 5 days.

Scale up is one of the big issues for both types of vaccines.  Also, production of drugs/vaccines for human use is much more stringent than product of materials for research use.  There are likely many testing and validation steps throughout the manufacturing process.  So depending on how large the lot size is, I could see it taking about a month to manufacture.

I believe the mRNA vaccines are made through a synthetic process.  Synthesizing enough mRNA, which uses modified nucleosides, for a millions doses requires extremely specialized manufacturing processes that will take time to scale up.  And for both types of vaccines, they are relying on third party suppliers for many raw materials, such as the modified nucleosides for the mRNA vaccine, and cell culture media for adenovirus vaccines.  How fast their suppliers can ramp up production will affect how fast Pfizer, Moderna, and Astrazeneca can scale up their own processes.  It's not all in their control.  Kind of like how shortage of basic reagents were holding up coronavirus testing early on.  I assume similar supply chain problems are occurring with the unprecedented amount of vaccine production that is going on right now.  People shouldn't be surprised about 3 to 6 month delays as these issues are worked out.

[Mudguard]

5 minutes ago, Padraig said:

lt's the AstraZeneca CEO's comments that worried me more.  But hopefully it wouldn't lead to anything.

To be fair, many of the CEO's and/or lead scientists have been extremely aggressive with their vaccine promises.  There was a mad rush to make big promises to secure all these billion dollar grants and contracts.  I remember one of Trump's earliest meeting with a bunch of pharma CEO's, and they all kept trying to one up each of other with their promises and claims.  Predictably, the ones that made the biggest and boldest claims got the most funding.  We were in a desperate position, so I'm actually OK with this in this situation.

I get a used car salesman vibe from the AstraZeneca CEO.  Just ignore all the marketing BS and focus on the data from the clinical trials.  I agree with a lot of criticisms made in this thread of AstraZeneca.  Many missteps compared to how Pfizer and Moderna have rolled out their vaccines.

[Mlle. Zabzie]

6 hours ago, Fragile Bird said:

I guess I wasn't clear enough about what I meant.

We're going to need well over a billion doses of vaccine just to cover North America and Europe. The vaccine rollout will take at least until September. Right now the vaccines seem to be effective against the UK, Brazilian and South African variants, but with the caveat that it's less effective against the South African variant. Next week another variant may pop up in the UK or the US or some other country that the vaccines will be dramatically less effective against. Actually, I saw a report two days ago that there appears to be a new California variant which accounts for the fast and massive spread in that state.

The next variant could be the one that makes the vaccines only 50% effective. Do you continue making hundreds of millions of doses, or do you do the gene map and create a new vaccine? Do you have to go through more trials? What if the new vaccine is effective against the new variant but not very effective against the old variant? The mRNA type apparently get made in batches that take a month to 'brew', for lack of a better term. Do you stop production of one and shift to the other?

Do you make your billion doses and give the shots and tell people they'll need a booster shot? But won't everyone need the booster shot? So you're back on the vaccine treadmill, going nowhere. That's why I think we will be in this Covid era for a long time.

I'm sure I'm not describing things well! But this is more complicated than the flu. Will it be easier to change production of the other, non-mRNA type vaccines?

 

3 hours ago, Mudguard said:

You should be able to administer the vaccine as a cocktail like we do for the influenza vaccine.  If there are 2 or 3 coronavirus strains out there, you can make all 2 or 3 vaccines and mix them together into a cocktail.  For at least the mRNA and adenovirus based vaccines, it should be relatively trivial to update the vaccine now that the new vaccine platform has been validated.  It's a matter of swapping out the RNA or DNA sequence that encodes for the spike protein, which is not difficult to do, and everything else can be left the same.  Instead of having to run a full phase III clinical trial for a new vaccine to one of the variants, you can probably just do a quick trial to see if the vaccine can generate neutralizing antibodies.

Right - my understanding is that this is EXACTLY how the flu vaccine is done in terms of trials.  And, I feel relatively ok that the Moderna and Pfizer vaccines at least can be very easily tweaked from what I understand.  I’m a bit more optimistic that this is actually relatively manageable.  

BUT I’ve decided I need to go back to my 2 week rule.  It’s really impossible to make broad predictions of any kind more than two weeks out.  MAYBE a month. MAYBE.

15 minutes ago, Mudguard said:

To be fair, many of the CEO's and/or lead scientists have been extremely aggressive with their vaccine promises.  There was a mad rush to make big promises to secure all these billion dollar grants and contracts.  I remember one of Trump's earliest meeting with a bunch of pharma CEO's, and they all kept trying to one up each of other with their promises and claims.  Predictably, the ones that made the biggest and boldest claims got the most funding.  We were in a desperate position, so I'm actually OK with this in this situation.

I get a used car salesman vibe from the AstraZeneca CEO.  Just ignore all the marketing BS and focus on the data from the clinical trials.  I agree with a lot of criticisms made in this thread of AstraZeneca.  Many missteps compared to how Pfizer and Moderna have rolled out their vaccines.

Agree.  And I guess we will all see how we feel about J&J next week?