Coronavirus Vaccines

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DAllen

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Good chance no vaccine will ever be found so...no big launches ever again?
 

cwbullet

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Good chance no vaccine will ever be found so...no big launches ever again?
They already 3 vaccines in testing. It will be found. It just may not be one shot-one kill.
 

DAllen

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Of course this could just be yet another fear mongering news article - but then news outlets never do that do they? They just report unbiased facts.

Maybe I shouldn't posted on this as its been hinted to me rather unsubtly elsewhere here on TRF in PMs and in other posts I am far too stupid to be commenting on this topic. :rolleyes:
 

Mike Haberer

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Of course this could just be yet another fear mongering news article - but then news outlets never do that do they? They just report unbiased facts.

Maybe I shouldn't posted on this as its been hinted to me rather unsubtly elsewhere here on TRF in PMs and in other posts I am far too stupid to be commenting on this topic. :rolleyes:
There are valid reasons to have a healthy skepticism that a vaccine will be found for Covid-19.

I suggest you read the Wikipedia entries on the common cold "virus" for general background and on cororonaviruses, specifically. What people need to understand is there are a couple of hundred different strain of viruses that cause the "common cold" and many that cause influenza. The common cold is cause by rhinoviruses about 50% of the time, by adenoviruses for some percentage I can't remember and by different strains of coronoaviruses about 15% of the time. We do not have any vaccines for any of these viruses, nor do we have vaccines for SARS and MERS, which are closely related to Covid-19. Another example: there is no vaccine for HIV after 30 years of research, only antiviral combinations that keep it at bay.

So, might they find a vaccine for it? Sure, there are 100+ different efforts underway. That includes new avenues that have not been used before. The trouble with that last statement is that the new methods have never been used to deliver a vaccine, so those methods are, basically, unproven. New vaccines can also be problematic; some have been developed and abandoned because they made the target illness WORSE. That is why you do four phase clinical studies and why it takes time. Cutting corners is risky. Plus there is the real possibility that they may not find a vaccine. At that point we live with it like the world lived with the Spanish flu for decades (it still reared its head regularly into the 1950's).

For me, if they do develop a vaccine in 18 months or less, I'll be at the back of the line to get it. Hand washing, social distancing and masks work and will continue to work. A bad vaccine could kill you; I'll let others be the guinea pigs. Another data point: when the new Shingrix shingles vaccine came out, I asked my doctor about getting it. He said to wait a year to make sure there were no issues with it. This is a vaccine that went threw the normal process and took years to develop. The same advice would apply here.
 

Ez2cDave

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I was just going to start a new thread on the subject of vaccines . . . Not necessary, now.

From Australia, yesterday :

We've never made a successful vaccine for a coronavirus before. This is why it's so difficult

By Jo Khan for the Health Report
Posted 16 April 2020, updated 16 April 2020

Developing a vaccine to target Sars-CoV-2 has a number of challenges.(National Institute of Allergy and Infectious Diseases, NIH)

For those pinning their hopes on a COVID-19 vaccine to return life to normal, an Australian expert in vaccine development has a reality check — it probably won't happen soon.

The reality is that this particular coronavirus is posing challenges that scientists haven't dealt with before, according to Ian Frazer from the University of Queensland.

Professor Frazer was involved in the successful development of the vaccine for the human papilloma virus which causes cervical cancer — a vaccine which took years of work to develop.
https://www.abc.net.au/radio/programs/coronacast/latest-segments/12025304
He said the challenge is that coronaviruses have historically been hard to make safe vaccines for, partly because the virus infects the upper respiratory tract, which our immune system isn't great at protecting.

And while we have vaccines for seasonal influenza, HPV and other diseases, creating a new vaccine isn't as simple as taking an existing one and swapping the viruses, said Larisa Labzin, an immunologist from the University of Queensland.

"For each virus or different bacterium that causes a disease, we need a different vaccine because the immune response that's mounted is different," Dr Labzin told ABC Science.
"Just because we've got a really good vaccine against polio doesn't mean the same thing will work with coronavirus, because it's so different."
The challenge of respiratory infections

There are several reasons why our upper respiratory tract is a hard area to target a vaccine.

"It's a separate immune system, if you like, which isn't easily accessible by vaccine technology," Professor Frazer told the Health Report.

Despite your upper respiratory tract feeling very much like it's inside your body, it's effectively considered an external surface for the purposes of immunisation.

"It's a bit like trying to get a vaccine to kill a virus on the surface of your skin."

Your skin, and the outer layer of cells in your upper respiratory tract act as a barrier to viruses, stopping them getting into the body.

And finding a way to neutralise the virus "outside" of the body is very difficult.

This is partly because only the outer layer of cells (the epthelial cells) get infected, which, compared to a severe infection of internal organs doesn't produce the same immune response, so is harder to target.

It's hard to produce a successful vaccine if the virus isn't activating a strong immune response.

And if a vaccine elicits an immune response that misses the target cells, the result could potentially be worse than if no vaccine was given.

"One of the problems with corona vaccines in the past has been that when the immune response does cross over to where the virus-infected cells are it actually increases the pathology rather than reducing it," Professor Frazer said.

"So that immunisation with SARS corona vaccine caused, in animals, inflammation in the lungs which wouldn't otherwise have been there if the vaccine hadn't been given."

What's the story with antibodies?

Antibodies are proteins that are released by the immune system to neutralise a threat, like a virus.

Stay up-to-date on the coronavirus outbreak

We've so far found with coronavirus that those infected have had different antibody responses, some weak, some strong.

The ABC has received many questions around how long immunity lasts and whether someone can be reinfected.

So is antibody response critical to whether or not a vaccine is going to work?

To answer this we have to go back to what we know about coronaviruses that cause the common cold, according to Professor Frazer.

"Yes, you get antibodies after a [cold] infection, and yes it lasts for a while, but it's not lifelong... sort of months rather than years," he said.

"I think it would be fair to say that the natural immunity that you get after infection from this coronavirus is probably going to turn out like the coronaviruses we've seen in the past.

"There will be some natural protection over a period of months, maybe even years, but it won't be lifelong.
"The good news is that if you get reinfected with the virus a second time some months down the track, there will probably be enough immunity there to stop you becoming seriously ill."

What are the vaccine options?
At the moment, teams around the world are deploying different technologies in vaccine development, from killing the virus and using it in the vaccine like we do with influenza, to using messenger RNA to prompt the infected cells to produce antibodies.

But the reality of vaccine development is that many fail before a successful one is developed.

The 'spike' protein sticks out of the coronavirus shell, and could be used in some vaccines to trick the body into shutting out the virus.(NIH)

Professor Frazer's prediction is that the most likely candidate will be a vaccine that uses a part of the virus attached to a chemical to induce an immune response, or "subunit" vaccine.

"That [vaccine type] has been successful in animal models for coronaviruses in the past and that is of course where the money is being put in large measure at the moment," he said.

"Another sort of vaccine would be just antibody transferred from somebody who had been infected already and had got rid of the infection.

"Which would be an immunological means of preventing infection, and could probably be more quickly developed than an actual vaccine."

This sort of vaccine was tested with SARS in 2003 and resulted in reinfected lab monkeys having a nasty immune response, which is why many groups working on a vaccine for Sars-CoV-2 are going for a very specific antibody response.


Professor Frazer said the narrow, targeted approach is fine, unless you pick the wrong specific antigen — the substance that stimulates an immune response which antibodies bind to — in which case you could end up with the same problem.

Will we ever get a vaccine?

We don't yet have vaccines against any coronaviruses in humans, in part due to the challenges of developing vaccines for viruses that infect the upper respiratory tract.

There are a lot of vaccine experiments going on around the world at the moment trying to change that though, including some in human trials.

While this gives us the best possible chance of getting a successful vaccine, it also highlights that there isn't an obvious winner yet, said Professor Frazer.

"I think it would be fair to say even if we get something which looked quite encouraging in animals, the safety trials in humans will have to be fairly extensive before we would think about vaccinating a group of people who have not yet been exposed to the virus.

"They might hope to get protection but certainly wouldn't be keen to accept a possibility of really serious side effects if they actually caught the virus."
 

DAllen

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Ok I get why this has been moved to a new thread...whatever. But as such I am not going down this road again only to get my head caved in with walls of texts filled with ridicule and pissy pms from mods. I learned my lesson about expressing my opinion on this topic on TRF.
 

NateB

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I don't think we should put all of our hope into a vaccine. One may work to where this can be practically eradicated like some other viruses, may only be partially effective, or one may never be found. In all cases, it will be a while before any vaccine would be proven safe and effective, and ready for mass production. We will need to learn better methods of testing and treating this disease in the meantime, which we are doing. As a society, we need better ways to deal with this and still function.

One advantage we have to developing a vaccine is the amount of attention this virus is getting. There is a lot of research being done all over the world which greatly increases the odds that something will work.
 

Ez2cDave

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Ok I get why this has been moved to a new thread...whatever. But as such I am not going down this road again only to get my head caved in with walls of texts filled with ridicule and pissy pms from mods. I learned my lesson about expressing my opinion on this topic on TRF.
The "bottom line", based on fact, not opinion, is that there has never been a successful vaccine against any Coronavirus . . .

From my research, there are 7 known Coronaviruses that can infect Humans and they come from 1 of 4 sub-groups, Alpha, Beta, Gamma, & Delta.

SARS-coV2 / Covid-19 is in the Beta group . . .

Dave F.

SUBGROUPS-1.JPG

SUBGROUPS-2.JPG
 
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cwbullet

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I will be blunt: This garbage is meant to sell papers, panic, and clicks. We have not really tried to complete a vaccine for a Coronavirus. All prior infections have been such short-lived. This is the first pandemic that was this widespread. We already have vaccines very far forward in testing. In fact, a few are in human trials.

One even has been shown to help monkeys. https://www.sciencemag.org/news/202...nkeys-new-coronavirus-chinese-biotech-reports

We will know soon how protective (3-6 months) it is and then move will be to mass-produce it. I would be shocked if we are not on the receiving end of a shot by January - March or sooner.
 

Ez2cDave

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Chuck,

Sorry for the long list of questions . . .

What about the different strains of Covid-19 ?

Would there have to be a separate vaccine for each one ?

If the virus mutates, would that nullify a vaccine ?

Is there any immunity from having had Covid-19, permanent or otherwise ?

Would the FDA have to approve a vaccine ? The reason I ask is that 12-18 months of human testing is required for that, isn't it ?

Dave F.
 
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cwbullet

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Chuck,

Sorry for the long list of questions . . .

What about the different strains of Covid-19 ?

Would there have to be a separate vaccine for each one ?

If the virus mutates, would that nullify a vaccine ?

Is there any immunity from having had Covid-19, permanent or otherwise ?

Would the FDA have to approve a vaccine ? The reason I ask is that 12-18 months of human testing is required for that, isn't it ?

Dave F.
What about the different strains of Covid-19 ?
What about the different strains? Most cause a less serious infection such as a cold. Could they cause a more serious infection? Yes, but is unlikely.

Would there have to be a separate vaccine for each one ?
Yes, most likely. They might be able to combo vaccines but they will probably not.

If the virus mutates, would that nullify a vaccine?
It depends on the mutation. Hard to discuss "what ifs".

Is there any immunity from having had Covid-19, permanent or otherwise ?
No immunity is permanent. It all fades with time.

Would the FDA have to approve a vaccine ?
They will probably do a EUA or Emergency Use Authorization to allow it to be used. Human testing is required , but it can be less rigorous in an emergency.
 
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Marc_G

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Also rememBet, necessity is the mother of invention and profit is the father.

The amount of effort going in this thing is astounding.
 

Bat-mite

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The amount of effort going in this thing is astounding.
Exactly. Never before has there been such a push to develop a coronavirus vaccine. We can't use the past as a gauge of the future, because we have never poured these kinds of resources into a coronavirus vaccine before.

Wouldn't it be funny if, while developing a COVID-19 vaccine, they also manage to cure the common cold? :D
 

Steve Shannon

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Exactly. Never before has there been such a push to develop a coronavirus vaccine. We can't use the past as a gauge of the future, because we have never poured these kinds of resources into a coronavirus vaccine before.

Wouldn't it be funny if, while developing a COVID-19 vaccine, they also manage to cure the common cold? :D
Given that the infected person’s immune system plays a huge role also and experimental combinations of drugs used for treating Covid-19 include immunomodulators, I’m hoping that insights into immune systems will help with autoimmune diseases also.
 

boatgeek

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Exactly. Never before has there been such a push to develop a coronavirus vaccine. We can't use the past as a gauge of the future, because we have never poured these kinds of resources into a coronavirus vaccine before.

Wouldn't it be funny if, while developing a COVID-19 vaccine, they also manage to cure the common cold? :D
As always, there's an XKCD for that. https://xkcd.com/2306/
 

Marc_G

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Will read the rest later, but right up front there seems to be a misunderstanding about how RNA vaccines work:

This is an experimental technology that has never been done before in history. What is does, it injects a snippet of the virus that carries a genetic code in its RNA that is designed to alter the DNA, the code in every cell in your body to get your body to naturally start producing those antigens.

“It is a form of genetic engineering. It is genetic engineering. It has been condemned by the Geneva Statement because those genetic changes will survive in your sperm and they will live in your children or in your ovaries.


RNA vaccines don't change your DNA or impart germ line mutations.

Perhaps they change their tune later. Will read rest after work.
 

Ez2cDave

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Excerpt from that link :

16:43 Kennedy: “Bill Gates said from the beginning he was not going to allow any of his vaccines to be used unless he got full immunity from all from all the governments in all the countries that use his vaccine because he knows he’s going to kill a lot of people. He himself said this vaccine is only going to be tested on at most only a thousand people.”

“What if there’s an injury rate of one in 10,000? You won’t see that if you test a thousand people. You will never see it.

“Let’s say it’s a death rate of one in 10,000. Very, very possible, and you will never see it. If you give that vaccine to seven billion people, which is what he’s intending, that means the 700,000 people are going to die from it.

“Ultimately you will get to a level where with other injuries etc. that you’re causing more problems than you’re averting. It’s very, very possible.

“If you don’t test it on animals, you go right to humans and you test a thousand humans, plus there’s no placebo, but they don’t care. They’re under the Prep Act, complete, blanket immunity from liability.

“They could end up killing every person they give this to in Seattle. What do they care? It’s a gamble for them because if that Moderna vaccine works Gates is going to make a billion dollars. And if it doesn’t work, he’s got eight others in the pipeline. He’ll just say that was a bad experiment.

“The reason they’re going forward so quickly with that is because there’s no biological material. You don’t have to manufacture anything. With other vaccines you have to start a factory, you have to grow the vaccine… It’s a long process, but with the Moderna vaccine your body becomes the factory because you’re altering the human DNA so that it will produce the antibody.

“They don’t have to build any factory. They just have to take little snippets of the RNA and inject them into human beings and let you do all the work. They can fast track it overnight. They can literally get it to market within months, and that’s what they did. Within weeks, all they needed was that genetic code from the Chinese and they can make this RNA virus.

“It’s never proven in any model, and the company that’s making it has never brought a product to market. They’ve never been through phrase three trials and they were on the edge of bankruptcy.

“It is really, really, really crazy. How willing they are to play God. …Gates…believes is up there and he can experiment with lesser human beings. If there’s collateral damage, then so be it. He’s well-intentioned, and he’s going to save the world….”


20:48 Dr. Buttar:”When you introduce RNA into the body, the implications aren’t something that will be necessarily seen in a week or in a month. It could be a year or two years and then the generational component, because now it’s actually changing the genetic code, and it’s going to be something that’s going to stay consistent and continue to propagate generation to generation. …”

21:18 Bigtree; “One of the studies we were looking at, I believe it was the Moderna study, they are forbidding sexual intercourse without full protection, meaning they are so concerned. There can be no pregnancy allowed by anybody involved in this study, meaning they are so concerned that they may have a generational problem…

“I think one of my biggest concerns when I talk about this, I think Bobby, you put it perfectly, I believe this is the God vaccine. We’re talking about no longer letting the body react… We’re talking about messaging RNA. We’re talking about putting in manmade messages that go to all of your cells to make the cell think it’s getting information from the DNA…

“ Here’s my biggest concern. We do know that they are all focused on this antibody immune enhancement issue that you very well described. The animals all died in the trials and now we’re going on to human beings.

“This is what Hotez sat before Congress and talked about. Even Tony Fauci said on television there is a concern that this vaccine could make people more sick. We don’t want to do that. But the most troubling thing about it that most people don’t understand is how little these virologists know about how a vaccine works, and even more so, what Dr. Peter Hotez said. We don’t know why antibody immune enhancement happens. We don’t know what’s causing it.

“So my concern is that in these small test groups that they’re doing… what happens if let’s say … one of these vaccines gets to one of these small trials and for some reason antibody immune enhancement doesn’t happen. What I want to say is that since the beginning of mankind there’s never been a bacteria or a virus outbreak that took out the species.

“There’s something about nature and our relationship to it that we survive. We even get stronger as we go along. We’re talking about a vaccine that’s being discussed by world leaders, being driven by Bill Gates saying everyone in the world is going to get this vaccine.

“Can you imagine a vaccine that gets to the trials, looks like it’s safe…? Their dream is to vaccinate everyone in the world. And then all of a sudden, maybe the strain that they design the vaccine around avoid that problem, but all of a sudden there’s a mutation …gets out and starts triggering antibody immune enhancement.

“Now all of a sudden, we’re not watching .1 percent of the people die, .3 percent or 10 percent. You could talk about a scenario with 30 percent of those coming in contact with what would have been a cold, like those ferrets, their bodies are over reacting to this and they’re having complete organ failure and shutdown.


“You could honestly be looking at a vaccine for the first time that has the potential to eradicate our species. That is how dangerous this vaccine is.

End Excerpt :
 

Ez2cDave

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Thanks for taking the time to read it all first !
 

Marc_G

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Ok I made my way through it, to some detriment to my work day.

I will state at the outset that I have some significant concerns about the RNA vaccine approach in particular in a context where usual safety protocols may take a back seat to expediency. So I support critical review of the program.

But this hysterical anti-vaxxer screed doesn't help things. In typical children's health defense style it blends facts, misinterpretation, and bald fabrication into a rambling story that suits their agenda.

For example:

21:18 Bigtree; “One of the studies we were looking at, I believe it was the Moderna study, they are forbidding sexual intercourse without full protection, meaning they are so concerned. There can be no pregnancy allowed by anybody involved in this study, meaning they are so concerned that they may have a generational problem…

This is a common practice in clinical trials for any biological therapy and many routine small molecule trials. It's not a proactive indictment of the vaccine.

And from ~49 minutes:

You don’t build a movement starting from a position, I hate all vaccines; all vaccines are bad. I always start by telling audiences I’m for vaccines, never for mandatory vaccines.

“If there’s a vaccine that’s good for me, it has no bad side effects, and does everything that it’s advertised to do. …I would of course take that vaccine. I just haven’t seen it happen.


Well, most vaccines in common use today even if they aren't perfect have such amazingly strong value propositions that his statement makes me sick.

Along the way they even indict 5G technology which is a dog whistle for these anti-vaxxer conspiracy type folks.

While plenty of good points are found in the article, on the whole I consider it anti-vaxxer claptrap. Sorry!
 

FMarvinS

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Until a potential vaccine is made, there has been progress in the use of convalescent plasma and initial studies in the development of molecularly produced humanized monoclonal anti-COVID-19 IgG and in a similar fashion polyclonal anti-COVID-19 therapeutic antibodies. In essence, early studies demonstrate that if patients are treated relatively early in the disease course good outcomes occur. Thus, other therapeutic modalities are developing to decrease morbidity and mortality as vaccine development progresses.

Fred, L2
ICBM, Camden, SC
KG4YGP
 

Ez2cDave

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Leave that anti vax bullshit somewhere else. There's no place for that here.
Nate,

On what authority do you speak ?

There is no place for your bullshit here.

Dave F.
 
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Ez2cDave

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That organization and its predecessor, World Mercury Project, is responsible for most of the misinformation spread about vaccines. This type of junk science costs lives.
I believe that a rushed vaccine, produced by a company that has never produced a vaccine before ( certainly not an RNA vaccine ), without long-term and thorough testing, could do more harm than good.

Just because an "EUA" is authorized does not mean that the vaccine is as safe as possible, only that it can be used as rapidly as possible.

I would take accuracy & safety, over speed, every time !
 
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NateB

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Just because an "EUA" is authorized does not mean that the vaccine is as safe as possible, only that it can be used as rapidly as possible.

I would take accuracy over speed, every time !
That part, I agree with. I would prefer the normal trial process to determine safety and efficacy for something put in my body.

I will wait, if I can. If the vaccine is mandatory per my employer, I'll get it.
 

Ez2cDave

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This is "above my pay grade" . . . But, some things in it, "caught my eye".

DNA and RNA-based vaccines: principles, progress and prospects

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1986720/

Excerpt :

7. Self-replicating genetic vaccines have some clear advantages over conventional vectors

‘Self-replicating’ genetic vaccines are designed to overcome the poor efficacy of some current DNA-based and RNA-based genetic vaccines. The idea and the elements for this new generation of vaccines come from members of the Alphavirus genus, which includes Sindbis virus, Semliki Forest virus (SFV) and Venezuelan equine encephalitis (VEE) virus. These RNA viruses contain a single copy of positive-stranded RNA encapsidated by a protein/lipid envelope. The viral RNA encodes its own RNA replicase, an autoproteolytic polyprotein that cleaves itself into four non-structural protein components (nsP1-4) [111,112]. Upon infecting a cell, the viral RNA first translates the replicase complex, which in turn drives its own RNA replication. The replicase complex then synthesizes a genomic negative-strand (anti-sense RNA), which is used as a template for the synthesis of the genomic positive-stand RNA as well as a subgenomic RNA encoding the structural viral proteins (Fig. 3). The genes for structural proteins can be replaced with the gene for the antigen of interest to construct powerful replicase-based vaccines [113].
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Fig. 3

Self-replicating genetic vaccines

The first product of the self-replicating RNA is a four-subunit-replicase which uses the (+) strand RNA as a template to make (−) strand RNA and more copies of full length (+) strand ‘genomic’ RNA and (+) strand ‘subgenomic’ mRNA for the encoded antigen. Due to the high number of RNA-copies, the main product of the transfected cells becomes the encoded antigen. The host cell eventually undergoes apoptosis.

Theoretically up to 200,000 copies of RNA can be produced in a single cell within 4 h and expression of the encoded antigen can be as much as 25% of total cell protein [114].
The alphavirus replicase functions in a broad range of host cells (mammalian, avian, reptilian, amphibian and insect cells) [115]. Replication takes place in the cytoplasm of the host cell and, therefore, is independent of the host’s replication system. All the above features, i.e. high level expression, broad host range and cytoplasmic replication, are useful features in genetic vaccine development.

To facilitate vaccine production, genomic alphavirus RNA alone can be used as a vaccine vehicle. The in vitro transcribed self-replicating RNA contains sequences coding for the SFV replicase and a model antigen. A single intramuscular injection of a self-replicating RNA elicited antigen-specific antibody and CD8+ T cell responses and was shown to be significantly more effective than non-replicating RNA [115,116]. DNA-based vaccines can also be constructed by inserting a strong promoter like the human CMV immediate promoter/enhancer element to initiate the transcription of the full length ‘genomic’ RNA in the nucleus [112,117-119]. Replicase-based DNA vaccines may be significantly more immunogenic and efficacious than conventional DNA-plasmid vaccines when low doses of the vaccine are given. Indeed, nanogram amounts of replicase-based vaccine can induce antigen-specific antibody and CD8+ T cell responses [118-120] (and Leitner WW et al., in preparation).


8. Mechanisms that could account for the high efficacy of self-replicating genetic vaccines

A major rationale for putting antigen-coding genes under the control of the alphaviral RNA replicase was to enhance antigen expression and presentation. Unexpectedly, the level of antigen expression of replicase-based constructs in vitro was not necessarily higher than that obtained with conventional DNA or RNA-vectors [118,120] (and Leitner WW et al., manuscript in preparation). The discordance between antigen expression level and the increase in immunogenicity suggests that other mechanisms are involved such as those illustrated in Fig. 4. A fundamental difference between replicase-based DNA vaccines and conventional DNA vaccines is the virus-like RNA-replication inside transfected host. Transfection of host cells with replicase-based genetic vaccines could trigger a series of ‘danger signals’[121].
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Fig. 4

Potential factors contributing to the high immunogenicity of self-replicating genetic vaccines

(Starting in the upper centre and moving clockwise): Accumulation of antigen in the transfected cell can result in highly efficient MHC-I-loading. A number of ‘danger signals’ may be generated such as interferon production and interferon release from infected cells resulting from the presence of dsRNA. Interferon may also be produced by bystander cells in response to dsRNA released from dead and lysed transfected cells. Heat shock proteins (HSP) have also been shown to be produced in response to the presence of dsRNA in the cells. Ingestion of antigen-loaded apoptotic cells by APCs can also result in the elicitation of powerful immune responses. Finally, the local release of large amounts of antigen at the site of injection by transfected cells may be fed into resident APC.


Continued . . .
 

Ez2cDave

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Replicase-based DNA or RNA induce apoptotic death of the host cell in vitro just as alphaviral infection induces apoptosis in host cells [116,122]. These apoptotic cells may be picked up by dendritic cells for presentation to the immune system [123]. Transfection with self-replicating genetic vaccines may also cause the production of heat shock proteins in transfected or bystander cells [124]. The activity of the viral replicase may provide a powerful adjuvant-effect because of the requisite production of double stranded RNA (dsRNA) intermediates (Fig. 5). dsRNA itself is a potent inducer of the interferons and virus-derived dsRNA can function as a strong adjuvant for cellular and humoral immune responses [125]. Several molecules are known to bind to and can be activated by dsRNA. The best characterized are 2′–5′ oligoadeny-late (2-5A) synthetase and protein kinase-RNA activated (PKR). The 2-5A system contributes to the antiviral effect of the interferons through the synthesis of 2-5A and its activation of RNAse, which degrades both viral and cellular RNA. PKR-expression both induces and is induced by the interferons. PKR is then activated by dsRNA to phosphorylate its substrates, including eIF2. This results in the inhibition of translation, further diminishing viral replication. The cellular death observed in response to dsRNA is likely to be mediated by both the 2-5A system-induced RNAse as well as some substrates of PKR [126,127]. INF-γ potentiates the apoptotic effects of dsRNA [128].
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Fig. 5

dsRNA might be a central element in the immunogenicity of replicase-based genetic vaccines

dsRNA is produced in cells infected with RNA-viruses, but is also expected to be an intermediate in the replicase-mediated duplication of mRNA after delivery of ‘self-replicating’ genetic vaccines. dsRNA is a potent inducer of interferon, which in turn induces the expression of PKR and 2-5A synthetase. These enzymes are activated by dsRNA and mediate at least some of the cellular effects associated with viral infection, including apoptotic cell death, aimed at preventing viral spread. The ‘danger signals’ resulting from the activation of these two enzymes could account for the increased immunogenicity of replicase-based genetic vaccines, providing an adjuvant-effect.

The mediators involved in the apoptosis of virally infected cells are subject to viral and cellular inhibitors, like vaccinia E3L [127], HIV-1 Tat protein [129] or the cellular P85IPK [130]. Inhibitors encoded by viruses allow efficient viral replication despite the host cells defense mechanisms. Although apoptosis of cells transfected with self-replicating genetic vaccines might contribute to their enhanced immunogenicity, their efficacy might be limited by the rapid death of host cells due to the absence of vaccine encoded apoptosis-inhibitors that delay the apoptotic death. The manipulation of apoptosis is likely to be a rich area of exploration for vaccinologists.

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Dave F.
 
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