Are vaccines the light at the end of the tunnel?

[markeb]

2 minutes ago, npcl said:

I think September my be a bit optimistic for trial completion.  If it is released by the end of the year I would expect it to be limited approval, such as for medical professionals, first responders, etc.

 

We still need to see what the efficacy is.  We also need to see how long the immunity remains. 

 

In additional we  should see what happens when someone gets infected, after they have had the vaccine, then have the immunity wear off. This is especially of concern if we see people tending to more severe symptoms the second time they are infected (as some cases have reported). Just to make sure we do not run into a situation like Sanofi did with their Dengue fever vaccine.  Now Dengue is pretty unique, but Corona viruses have some unique characteristics as well and so little is still known about COVID-19.

 

There are so many nuances here beyond the headlines. Booster schedule being a big one. The approach everyone's taking against the SPIKE makes the most sense from a public health standpoint, but I can definitely see work on another vaccine targeted further downrange in the disease process. But if the current candidates can block entry fast enough to stop both disease and transmission...

 

And I'll stay away from those fun Coronavirus characteristics. Those still scare me, and we may not see them until we're well into the Phase III, and if the Phase III gets truncated because it hits power on efficacy, we're into post marketing surveillance. Or it gets an EUA for special populations and the trial continues, which would be fine for truly assessing safety on repeat exposure, but the companies want an approved BLA to move into marketing. I do have a hard time seeing the BLA approved without some data on duration of immunity and an initial booster schedule.

 

I would like to say for the record for people on the board that I think all of us being cautious aren't so much pessimistic as just cautious because we've seen this movie from different viewpoints of vaccine development. Dustin Hoffman and Rene Russo don't actually save the world in 2 hours...

[UnorigionalName]

57 minutes ago, npcl said:

This is especially of concern if we see people tending to more severe symptoms the second time they are infected (as some cases have reported)

 

do you have a source for this?  Everything I have seen so far has not shown this to be the case, and possible reported reinfection cases have been mild:

https://link.springer.com/content/pdf/10.1007/s42399-020-00335-8.pdf

 

I know there was some animal models from SARS showing the possibility, and the fact that antibody production seems to be linked to disease severity, but so far I haven't seen anything showing that the feared pre-formed antibody forms severe reactions to be true.

[cscurlock]

36 minutes ago, UnorigionalName said:

 

do you have a source for this?  Everything I have seen so far has not shown this to be the case, and possible reported reinfection cases have been mild:

https://link.springer.com/content/pdf/10.1007/s42399-020-00335-8.pdf

 

I know there was some animal models from SARS showing the possibility, and the fact that antibody production seems to be linked to disease severity, but so far I haven't seen anything showing that the feared pre-formed antibody forms severe reactions to be true.

Here is one.  But there are a lot. 

https://www.newsweek.com/texas-woman-diagnosed-coronavirus-twice-four-months-1511197

A lot of them show around 2-4 month span.  Which seems to correspond to the Spain study saying that antibodies don't last long.  

[UnorigionalName]

38 minutes ago, cscurlock said:

Here is one.  But there are a lot. 

https://www.newsweek.com/texas-woman-diagnosed-coronavirus-twice-four-months-1511197

A lot of them show around 2-4 month span.  Which seems to correspond to the Spain study saying that antibodies don't last long.  

 

right, i'm not asking about if reinfection occurs, but that the reinfections can be worse. all the published cases most likely to be reinfection have shown the second go around to be mild with no real lung damage findings.

[cscurlock]

2 minutes ago, UnorigionalName said:

 

right, i'm not asking about if reinfection occurs, but that the reinfections can be worse. all the published cases most likely to be reinfection have shown the second go around to be mild with no real lung damage findings.

"TON OF BRICKS" 

[npcl]

1 hour ago, UnorigionalName said:

 

do you have a source for this?  Everything I have seen so far has not shown this to be the case, and possible reported reinfection cases have been mild:

https://link.springer.com/content/pdf/10.1007/s42399-020-00335-8.pdf

 

I know there was some animal models from SARS showing the possibility, and the fact that antibody production seems to be linked to disease severity, but so far I haven't seen anything showing that the feared pre-formed antibody forms severe reactions to be true.

 

Here is one case.  Will see if I can find the source on a couple of others.  Too early to see any kind of trend.

 

https://www.vox.com/2020/7/12/21321653/getting-covid-19-twice-reinfection-antibody-herd-immunity

 

My patient caught Covid-19 twice. So long to herd immunity hopes?

 

 

Covid-19 may also be much worse the second time around. During his first infection, my patient experienced a mild cough and sore throat. His second infection, in contrast, was marked by a high fever, shortness of breath, and hypoxia, resulting in multiple trips to the hospital.

[npcl]

1 hour ago, UnorigionalName said:

 

do you have a source for this?  Everything I have seen so far has not shown this to be the case, and possible reported reinfection cases have been mild:

https://link.springer.com/content/pdf/10.1007/s42399-020-00335-8.pdf

 

I know there was some animal models from SARS showing the possibility, and the fact that antibody production seems to be linked to disease severity, but so far I haven't seen anything showing that the feared pre-formed antibody forms severe reactions to be true.

Yes my concern does relate to the potential for ADE as seen in the SARS research and has popped up in some other research of Corona Virus Class.  Especially considering the inflammation and cytokine storms seen in severe cases.  I cetainly hope we do not see it, but we still know so little about COVID-19.

 

This is from a paper of the status of SAR vaccines from 2006

 

Antibody-dependent enhancement (ADE) has been observed in vaccinated and wild-type infections of FIP. ADE is thought to potentiate viral infection through the infection of macrophages. Viral entry into macrophages occurs when antibodies bind the virus and attach to macrophages via the Fc region of the antibody and its interaction with cell surface expressed Fc receptors ^[46]. Neutralizing antibodies can also be enhancing antibodies if antibody titer is low or is of the IgG class ^[47], [48]. Because macrophages increase with viral disease, this cell type may provide an abundant reservoir for the virus and thus expansion of the virus in the host. Some similarities between FIP and SARS exist. First, in both cases macrophages can be infected with the virus ^[9], [49], and in the case of SARS, the etiology of disease is contributed by infiltrating alveolar macrophages leading to pneumonitis ^[8]. Second, the treatment with corticosteroids and/or interferon alpha ameliorates SARS disease ^[50], suggesting an inflammatory, immune-mediated disease. While there has been no observation of ADE during SARS infection, it is worth noting that one coronavirus, FIPV, is capable of eliciting ADE and in the evaluation of vaccines, we may want to consider this possible outcome. However, the difficulty in testing animal models for ADE bears the caveat that if ADE is not observed; it has not proved that vaccines are safe with regard to ADE in humans. In contrast, if an animal model for ADE is developed, we may learn more about the mechanism of SARS-induced ADE, which may help form the basis for developing guidelines for safe vaccine development.

[chipmaster]

20 hours ago, cscurlock said:

The last trials will probably be into 2021.   The vaccine might only make you immune for a short period of time if its based on antibodies.   So will take multiple doses over a period of time.

 

You mean we all need to take a does every couple months, hmm that is 300 Million - the vaccine non-believers.

 

So for fall we are looking at 1/2 billion during flu season for the US, then another 1.2 billion doses a year just for the US, good god the US drug companies are seeing $ and the US for health care will really be laid bare.  Then with that many people/doses I'm sure we'll find some surprises adding to the drama for the non-vaccine believers as we rush these trials, LOL

Edited July 16, 2020 by chipmaster

[cscurlock]

10 minutes ago, chipmaster said:

 

You mean we all need to take a does every couple months, hmm that is 300 Million - the vaccine non-believers.

 

So for fall we are looking at 1/2 billion during flu season for the US, then another 1.2 billion doses a year just for the US, good god the US drug companies are seeing $ and the US for health care will really be laid bare.  Then with that many people/doses I'm sure we'll find some surprises adding to the drama for the non-vaccine believers as we rush these trials, LOL

Yeah, why do you think so many jumped on the vaccine bandwagon.  Its all about the benjamins.

[npcl]

1 hour ago, cscurlock said:

Yeah, why do you think so many jumped on the vaccine bandwagon.  Its all about the benjamins.

Not really.  Vaccines are not a high revenue area.  I expect the price for these vaccines to be similar to other older vaccines, which pretty inexpensive.  In many cases the companies may not even make back what they spent on their candidates.

 

From talking with some of my previous co-workers, and others with contacts in the field have also confirmed the companies are focused on solving the problem of COVID as urgently as possible and not really concerned about costs or profits.  While they would like to recover costs, I expect the pricing to be more in cost recovery range, not lets make a lot of profit range.

[Shadow9612]

13 hours ago, TeeRick said:

Ok some thoughts only for what they are worth (but if too much for this board just feel free to go to the links or just move to the next post.   I will try to put this in context of this current thread on vaccines for cruising.

@TeeRickThank you so much for a wonderful post!

[Shadow9612]

12 hours ago, TeeRick said:

Over the last 30 years if I have not been cruising then I have spent a lot of time in R&D on a number of different vaccines

The million $ question..... which do you enjoy more 😉

[Shadow9612]

8 hours ago, UnorigionalName said:

 

I feel like people are being overly pessimistic about the vaccine.  I think people want it to fail so that the US won't look as stupid as it is.

 

The antibody response does potentially go away, but what does that mean?

 

- reinfection by COVID that causes a severe disease the second go around has not been yet described, and this far into the pandemic that is a very good sign

- It seems that those that get severe lung infections, get higher levels of titers that so far persist longer, possibly for years, so those people are probably somewhat safe

- We lose antibody titers for all other coronaviruses in a similar fashion to those with maybe weak covid infections

-  usually in other coronaviruses, there is limited data suggesting that future infections produce less severe symptoms, and higher antibody responses

-  probably after repeated responses, older people have more antibodies to other common-cold coronaviruses and you get less active infections as you get older

-  The titers produced so far by the current front runner vaccines are high and more similar in amount to those with deep lung infections, but unknown if it will persist

-  Unknown how effective the antibodies from the vaccine are compared with antibodies from a real deep lung infection

 

So you have to realize the number one goal is preventing mortality and permanent morbidity.  Maybe if you get the vaccine, and then lose the antibody titers, it turns out when you get covid, it turns into more of a normal common cold, with no mortality risk and no permanent damage to the body.  That would be a win, even if it means we can't monitor the antibodies.  Maybe it will turn out that with the correct dosing and the correct timing of multiple administrations, we can devise a vaccination strategy that will produce effective antibodies that least years.  And maybe that's all we need.  Maybe we can get rid of this thing for good if all countries try and like sars we won't have to worry about the same strain again.

 

or maybe the worst case scenario is you have to get the vaccine every few months for a few years till you get more durable antibodies.  I mean, that's not too horrible of a worst case scenario.

 

The real real worst case scenario of never being able to make a vaccine, like in HIV, does not seem like it is going to be true. Or the other real possible worst case scenario of vaccine worsening the disease (like some SARS models suggest) does not seem to be overly happening so far.

To clarify, I wasn't intending to be pessimistic by posing my question. The responses received from @TeeRick and yourself were exactly what I was looking/hoping for.

 

I'm looking for positive light at the end of the tunnel because the news articles are sometimes negative....

 

Thank you for your insight. 

[chipmaster]

1 hour ago, npcl said:

Not really.  Vaccines are not a high revenue area.  I expect the price for these vaccines to be similar to other older vaccines, which pretty inexpensive.  In many cases the companies may not even make back what they spent on their candidates.

 

From talking with some of my previous co-workers, and others with contacts in the field have also confirmed the companies are focused on solving the problem of COVID as urgently as possible and not really concerned about costs or profits.  While they would like to recover costs, I expect the pricing to be more in cost recovery range, not lets make a lot of profit range.

 

A counterpoint, sorry I have no faith in the pharm companies, they aren't in it for the greater good of the human condition, they will leverage it for all they can get, and in the US they will extract a lot.   

 

Love at the end the differential for Britain and US, hmmmm

 

https://khn.org/news/analysis-how-a-covid-19-vaccine-could-cost-americans-dearly/

[TeeRick]

13 hours ago, npcl said:

Yes my concern does relate to the potential for ADE as seen in the SARS research and has popped up in some other research of Corona Virus Class.  Especially considering the inflammation and cytokine storms seen in severe cases.  I cetainly hope we do not see it, but we still know so little about COVID-19.

 

This is from a paper of the status of SAR vaccines from 2006

 

Antibody-dependent enhancement (ADE) has been observed in vaccinated and wild-type infections of FIP. ADE is thought to potentiate viral infection through the infection of macrophages. Viral entry into macrophages occurs when antibodies bind the virus and attach to macrophages via the Fc region of the antibody and its interaction with cell surface expressed Fc receptors ^[46]. Neutralizing antibodies can also be enhancing antibodies if antibody titer is low or is of the IgG class ^[47], [48]. Because macrophages increase with viral disease, this cell type may provide an abundant reservoir for the virus and thus expansion of the virus in the host. Some similarities between FIP and SARS exist. First, in both cases macrophages can be infected with the virus ^[9], [49], and in the case of SARS, the etiology of disease is contributed by infiltrating alveolar macrophages leading to pneumonitis ^[8]. Second, the treatment with corticosteroids and/or interferon alpha ameliorates SARS disease ^[50], suggesting an inflammatory, immune-mediated disease. While there has been no observation of ADE during SARS infection, it is worth noting that one coronavirus, FIPV, is capable of eliciting ADE and in the evaluation of vaccines, we may want to consider this possible outcome. However, the difficulty in testing animal models for ADE bears the caveat that if ADE is not observed; it has not proved that vaccines are safe with regard to ADE in humans. In contrast, if an animal model for ADE is developed, we may learn more about the mechanism of SARS-induced ADE, which may help form the basis for developing guidelines for safe vaccine development.

npcl thank you but please note the rules here so this helpful thread does not get closed.  On CC we cannot cut and paste text from published materials.  Copyrights.  You can however post a link to the material or publication and try to offer a summary in your own words.

[TeeRick]

9 hours ago, Shadow9612 said:

@TeeRickThank you so much for a wonderful post!

You are most welcome!

[TeeRick]

9 hours ago, Shadow9612 said:

The million $ question..... which do you enjoy more 😉

Cruising is easy and relaxing.  I really cannot say the same for vaccine development!😀

[TeeRick]

8 hours ago, chipmaster said:

 

A counterpoint, sorry I have no faith in the pharm companies, they aren't in it for the greater good of the human condition, they will leverage it for all they can get, and in the US they will extract a lot.   

 

Love at the end the differential for Britain and US, hmmmm

 

https://khn.org/news/analysis-how-a-covid-19-vaccine-could-cost-americans-dearly/

I can only tell you my perspective here and sure I will not change your mind.  But I know from personal experience that a very large number of people working in every aspect of drug and vaccine development, manufacturing, distribution, etc. at Pharmaceutical companies enjoy what they do and think they have a noble profession contributing to the betterment of the human condition.  These folks have no control on pricing and many do not make a huge amount of money.  But they are dedicated.  If they develop a COVID vaccine in record time they will be extremely proud to have done it.  Maybe you can object to very senior management making enormous salaries but that happens in most large public companies too.

[TeeRick]

I think we need to also consider on this thread that we are all talking about the COVID vaccine as a one and done.  There might be multiple vaccines approved (in a rosy scenario).  And there might be multiple manufacturers worldwide.  Individual governments in most countries usually bid for doses of a vaccine and set the price.  They even manufacture their own doses. This is a process called Tendering (different from waiting for a trip to shore!).  So I think it might be worrisome to some about access to a COVID vaccine in their part of the world but I am pretty confident that their governments will be much involved representing their citizens.  It has always worked this way.  In small poorer countries, orginizations get involved too like WHO, Unicef, Gates etc.  So let's just get a vaccine for COVID first!

[chipmaster]

16 hours ago, UnorigionalName said:

 

right, i'm not asking about if reinfection occurs, but that the reinfections can be worse. all the published cases most likely to be reinfection have shown the second go around to be mild with no real lung damage findings.

 

We have yet to infect and get statistics for even the 1st and second wave.  What is clear who are highest risk and who are dying. 

 

There is the notable press about Tom Hanks who got COVID and is watching his anti-body counts decline suggesting ability to have a body ready to fight a re-infection may be foolish hopeful belief.

 

We will have to see what happens in North East, as it is clear other places like HK, China, Taiwan and most of Europe have leaders and policies that won't allow the opportunity to gather data like the US will, how sad, the richest country becomes the research ground for the world.

Edited July 16, 2020 by chipmaster

[cangelmd]

15 hours ago, npcl said:

Not really.  Vaccines are not a high revenue area.  I expect the price for these vaccines to be similar to other older vaccines, which pretty inexpensive.  In many cases the companies may not even make back what they spent on their candidates.

 

From talking with some of my previous co-workers, and others with contacts in the field have also confirmed the companies are focused on solving the problem of COVID as urgently as possible and not really concerned about costs or profits.  While they would like to recover costs, I expect the pricing to be more in cost recovery range, not lets make a lot of profit range.

Npcl, my question is related to your longer post about ADE (Sorry, everyone for getting so far into the weeds!). I know about ADE in conjunction with dengue fever vaccine development, but has ADE been shown to occur with any naturally acquired infections that a person might be expected to get more than once? Is it a putative mechanism for severe cases of influenza for example? Isn't part of the assumed mechanism of ADE that the person has already been exposed to the antigens and for some reason has an "overblown" reaction the second time?

My immunology is pretty ancient. and I've only kept up with where it intersects with cancer and other clinical testing.

[npcl]

14 minutes ago, cangelmd said:

Npcl, my question is related to your longer post about ADE (Sorry, everyone for getting so far into the weeds!). I know about ADE in conjunction with dengue fever vaccine development, but has ADE been shown to occur with any naturally acquired infections that a person might be expected to get more than once? Is it a putative mechanism for severe cases of influenza for example? Isn't part of the assumed mechanism of ADE that the person has already been exposed to the antigens and for some reason has an "overblown" reaction the second time?

My immunology is pretty ancient. and I've only kept up with where it intersects with cancer and other clinical testing.

Unfortunately I do not have the expertise to answer your question, though others here might.  My background comes from the data, development, regulatory and senior management side of things.

 

I just found in doing some literature searches the potential concerns related to SARS and the virus class. As such I have been looking for any signs that it might be an area of concern.

[npcl]

5 hours ago, TeeRick said:

npcl thank you but please note the rules here so this helpful thread does not get closed.  On CC we cannot cut and paste text from published materials.  Copyrights.  You can however post a link to the material or publication and try to offer a summary in your own words.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115537/

 

 I have not run into an issue here as long as I have included the link.  Missed it in this case.

[markeb]

31 minutes ago, cangelmd said:

Npcl, my question is related to your longer post about ADE (Sorry, everyone for getting so far into the weeds!). I know about ADE in conjunction with dengue fever vaccine development, but has ADE been shown to occur with any naturally acquired infections that a person might be expected to get more than once? Is it a putative mechanism for severe cases of influenza for example? Isn't part of the assumed mechanism of ADE that the person has already been exposed to the antigens and for some reason has an "overblown" reaction the second time?

My immunology is pretty ancient. and I've only kept up with where it intersects with cancer and other clinical testing.

 

The poster child on this subject is Feline Infectious Peritonitis, another Coronavirus. Little or no disease on first exposure, but a devastating disease on some subsequent exposures, with a significant immune mediated component. At least some of that is mediated by the FIP SPIKE. 

 

If you do a quick Google Scholar on antibody dependent enhancement you'll find pages of articles on flu, FIP, RSV, and others, including SARS and MERS. Haven't read the entire paper, but there's a Lancet pre-publication paper here on SARS-CoV-2.

 

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3546070

 

Pulling out of the weeds now!

[npcl]

5 hours ago, TeeRick said:

I can only tell you my perspective here and sure I will not change your mind.  But I know from personal experience that a very large number of people working in every aspect of drug and vaccine development, manufacturing, distribution, etc. at Pharmaceutical companies enjoy what they do and think they have a noble profession contributing to the betterment of the human condition.  These folks have no control on pricing and many do not make a huge amount of money.  But they are dedicated.  If they develop a COVID vaccine in record time they will be extremely proud to have done it.  Maybe you can object to very senior management making enormous salaries but that happens in most large public companies too.

As one that has had the function of drug pricing, as well as contracting reporting,  to me in a company I will point out there are some very unique characteristics of drug pricing in the US.  The most destructive is that we have a system where decisions if drugs get added to formularies are often driven by the amount of discounts  given to the PBM's and other groups that control the formularies.  Not only does a lot of money gets siphoned off by these organizations that sit between the company and the consumer, but it creates a system where list prices are set high, and then very large discounts are given.  So you have the list price, the wholesale price, the actual price (which depends upon the contract developed) and the government best price calculations.  All results in a fairly complex mess.  Combine this with the fact that one can think of the set of pricing as being a big balloon. The total volume remains pretty much the same, but when you press in one one spot, it will bulge out in another.

 

If the US wanted to impact drug pricing and for that matter medical costs in general, without negatively impacting future drug development and medical access it could be done with a very simple process.  

 

1. Require that for any given drug or medical procedure that the same price must be changed to everyone.  Walk in, insurance company, government, etc.  Get the complexity out of the medical area.  Make it very clear exactly what is being charged. The provider can set the price, but must change everyone the same price (with the only exception being zero price donations)

This will make costs clear and visible and then the buyers can make decisions on the actual medical benefit in making decisions if to cover a drug or not.

 

2. Go to MAC level pricing for reimbursement by insurance companies and government programs when multiple drugs exist for treating a condition.  This will reduce pricing power by pharmaceutical companies for me too drugs while still preserving pricing power for truly innovative products to meet true medical needs. 

 

3. Make all prices public for both drugs and medical procedures.  Billing is done by linking to ICD9/ICD10 codes so any provider could easily publish their price for any procedure by code. Similarly insurance companies could publicly list what they will pay by ICD9/ICD10 code.  Reguire that any increase in price would need to have atleast 6 month advance notice.  Price could be dropped at anytime, but increases would require advance notice.

 

4. By making drug and medical pricing transparent you could go to the next step and have the provider provide to a patient the expected cost, reimbursement from their insurance company and exactly what out of pocket expenses (both in and out of network.  You can get this in the dental office, you can get this when you take your car in for repair.  No reason why you should not be able to get this for medical treatment (Yes I do know there are surprises and emergencies, but this be be done for the majority)

 

If you were to do these things you would find a lot of the money currently going to middlemen being removed from the systems, allow the public to know exactly what the cost would be, and make all pricing visible allowing decisions to be made based upon medical need.

 

No more hiding behind obscure prices with the resulting surprises anytime medical treatment is necessary.

 

Once you do this and improve the over all efficiency, all without controls.  At that point you can look at the system and see if any more controls might be necessary.  You can also at that point make informed decisions upon total costs and where assistance is needed for the poor.

 

I will now get off of my pricing soap box (wrote a white paper on this subject before I retired.  Would make the US system look more like the Japanese or Swiss systems).

Edited July 16, 2020 by npcl