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156085 tn?1204330585

Therapeutic Vaccine Targets HCV

This surely sounds like a promising new development for HCV. We can't deny the fact it is our own immune systems that need the right terrain to beat down the virus. Hopefully, the Intercell vaccine will be the ticket for those who currently have resistance to SOC tx.
It breaks my heart to read of those that fight so hard and endure treatment, then end up dealing with a relapse. Keep the faith. Something's bound to happen with all of the latest developments in the works.

Anyone have any thoughts or input on the vaccines? www.intercell.com is the one I have bets on... : )

31 Responses
156085 tn?1204330585
Smart Vaccines
Most of the content of a conventional vaccine is not needed to induce immune response. Intercell's smart vaccines consist only of the absolutely necessary components.

Behind Smart Vaccines
Many existing vaccines consist largely of inactivated organisms, like viruses and bacteria. Such vaccines contain, along with the protective antigens, numerous components that are unnecessary and cause side effects. We specialize in minimizing the set of components needed. In fact there are only two: the antigen(s), which gives the vaccine its specificity against a certain organism, and the Immunizer (adjuvant), which activates the immune system in a way that enables it to recognize the antigen and trigger a strong immune response. One of our programs deals with identifying novel adjuvants, and another with novel antigens. These are Intercell's core technologies. They result in innovative vaccines that contain only the essential components needed to activate the immune system.
Such a vaccine is easier to produce, and is safer because it does not contain living organisms, focuses better on the immune system, and is likely to have fewer side effects. That is what we call a "smart" vaccine.

Smart Vaccines Work
The starting point for the development of smart vaccines is the human immune system, and the way it tackles a given disease. The molecules detected with the help of the human immune system are the most effective. Our core technologies provide an outstanding source of our own products and give rise to lucrative partnerships. This is what makes our company competitive.
The information for identifying antigens is imprinted in antibodies from individuals who have had an encounter with a specific pathogen and have destroyed it through their inherent antibody response. By carefully analyzing a patient's response, it is possible to learn which antigens his/her immune system recognized and how it threw off the disease. These findings open the way for eradicating a pathogen and developing a vaccine.

Avatar universal
I know that this topic comes up time and again but please bear with me as I still don't understand.  We know that viral load does not equate to liver damage - counterintuitive but an established fact I believe.  We also know that liver damage is caused by the inflammation which occurs when the immune system fights the virus.  So if this vaccine is intended to ramp up the immune system but not eliminate the virus then isn't the result just going to be more inflammation -> more liver damage?

Now, I don't think that a lot of clever people would be developing the vaccine if my logic on this were actually correct, and it would be great to think that HCV could be controlled in a beneficial way with a vaccine.  So could somebody please explain where I'm going wrong in my figuring on this so that I can finally get it.

Avatar universal
Therapeutic vaccines for mainly HBV and HCV are indeed my special interest and i worked actively in several of these developments ( basic  and clinically)  and as a consultant/ advisor to the respective industry.

So I feel competent to answer these questions.

dointime: "We also know that liver damage is caused by the inflammation which occurs when the immune system fights the virus.  So if this vaccine is intended to ramp up the immune system but not eliminate the virus then isn't the result just going to be more inflammation -> more liver damage? "

This is a good question. To understand the answer some refinements in the understanding of the way the immune system reacts to the virus and how it targets the virus  and how it damages or protects the liver are needed.

The HCV virus/its "antigens'    activate the immune system in 3 fundamentally different ways: 1, 2a and 2b ddescribed below:

1. More primitive/ancient ways to react in nonspecific fashion to an intruder are activated: Unspecific figther cell - macrophages, "Kupfer cells", "Natural Killer cells (NK) - are secreting proinflammatory cytokines - like TNFalpha and Il-beta, Il-6 and ahost of other signaling molecules that participate in a self enhancing "cross talk' between immune cells and also directly activate the production of Hydrogen Peroxide, NO, Nuclear Factor Kappa B in themself and the cells surrounding them.

This often leads to the  partial destruction of invading microorganisms, but also produces a lot of damaging effects to the tissues in which this fighting occurs, in this case mainly the liver. This is also part of the old "innate immune response", that was in existence long before the more refined and effective ways to fight invading microorganisms was developed in our evolution. In summary: A lot of fighting with low efficacy and a lot of collateral damage.

2. Later, to defend us better with less self damage inflicted by "defending" , we invented the so called "adaptive immune response". Here highly specific aspects of the actual invading organism are used and recognized to concentrate and focus the defense with less collateral damage.

2a. By producing antibodies specific to the structure  of the outer shell of the invader we are able to inhibit, by simple binding and coating - without a lot of self damaging extra "activation" its entry inside our cells, threby no further spread of the infection occurs and everything fades to nothing without much illness at all. Thats how the HBV vaccine works ( the prophylactic one).

2b. In all body surfaces we have high numbers of highly specialized "sentinel" cells,  "dendritic cells" sitting and lurking for invaders.
When they locally encounter an HCV invader on its slow way in , eg at the mucosal entry site in the superficial tissue after sex, or in the skin after kittys infected claws have scatched, they engulf the invading virus - like in the old days, because their grandfathers were macrophages, predator cells, that know how to atttack and "eat and digest" and process its proteins/antigens  in a highly specific fashion, cutting them into short specific peptides either 10 or 20 amino acids long - these pieces are called epitopes.

The dendritic cells then actively move these pieces to their surface, bound to specific proteins called MHC class I and class II, that have well suited grooves on them, to which those viral protein pieces fit.

The whole thing ( MHCs with bound epitopes on them)  now  protrudes  to the outside of the dendritic cells. While doing the eating and processing, the dendritic cells have actively moved from their lurking position in the tissues (eg skin or vagina or oral cavity) to the local lymphnodes, where the real adaptive immune function drama will now start.
Up to now we are still in the "innate branch of the adaptive immune system. But now the superior technology of late evolution finally comes into play.

The human body has produced, by somatic mutation and complex recombination, a huge array of tens of thousands ENTIRELY DIFFERENT  types of T and B lymphocytes. Just a few dozen  of  the individual kind  are initially present. They are called naive lymphocytes  and most of them never do anything but wait for their time to function that never ever comes.

But now something happens that is close to a miracle: All these naive lymphocytes are constantly checking the incoming (into the lymphnodes where the action happens) dendritic cells, these are showing their cut up prey- the engulfed HCV virions -  like a butcher would show his pieces of meat prepared from an animal that he has carefully dismantled.
They are in a long long but very efficient line, to test one by one if these epitopes presented fit their individual surface recognition molecules - The Tcell receptor. The vast majority does not fit and simply moves one.

But if and when, in the rare rare instances where  there is a precise fit between the offered epitope and the T-cell receptor , - an extremely sensitive and specific interaction-  a truly dramatic chain of events is initiated.  
The one precisely fitting T cell is now positively selected to be the specific fighting machine against the very intruder ( HCV) on hand and will receive "a licence to kill", ( class I, or Cytotoxic T lymphocyte or Killer cell")  or a licence to make a ton of activation noise and signaling (class II "helper"Tcell) and most importantly a license to reproduce rapidly -  "proliferate" - so as to rapidly produce huge numbers out of a single naive lymphocyte. That could mean dozens  of billions of specific progeny for that very cell. How exiting for that lucky lymphocyte!

And more than that, it also gets endowed - all by the dendritic cells that is the "authority" that gives out these licenses- with extra weapons, like the capacity to exude antivirals like gamma and alpha interferon, surface power drill like weaponry enabling it to drill deadly holes in infected cells, furthermore the authority to issue suicide orders to the infected cells they encounter and furthermore the license to spray the whole neighborhood of infected cells with antivirals. Broad powers in a state of war indeed, but only to those highly trained and specifically qualified.
Avatar universal
Continued from above:

This immune response is "adaptive" becuse a huge number of defense cells is produced that are specifically adapted to only - with extreme precision!! - recognize pieces of that one invader - HCV - and nothing else! That specificity makes this type of defense so much more effective and less hurtful for the infected organism.

How do these "CTLs" lymphocytes, now swarming out and searching the whole body for HCV infected cells, recognice a cell that is infected?  Simple: Like an army of green barrets equipped with ultra high tech testing devices, they check the trash can of every house in the country ( cell) , to see if some tiny piece of trash from the harboring of these pesty Martians in the house can be found in the can.
They have no warrant to search the house, but their detection device for Martian body parts is so incredible sensitive and specific, that a single molecule on a hepatocyte can be enough to sound the alarm. Then the license to kill and also to spray the neighbors with antivirals is engaged.

The Tcell receptor is the recognition device on the CTL surface and the processed viral peptides - now called "epitopes" are transported to the cell surface with the usual protein trash chute of the cell - after shredding it into 10 aa pieces in the cells protein shredders - the proteasome-  it gets packed onto the hepatocytes trash conveyor belt - the MHC class I molecules and out it goes to the surface and bang it is now recognized by the Tcell receptor of the CTls patrolling by and the killing starts.

These CTL actions and the local interferon gamma prooduction are only mildy proinflammatory. And they tend to reduce viral production quite effectively, thereby overall reducing and curbing tissue damage and ideally limiting and terminating the disease. This is the "good" immune response - highly efficient, little damage.

THE THERAPEUTIC VACCINES as tested/developed  by Intercell in Austria and Innogenetics in Belgium are basically  strings/ mixtures of HCV peptides/epitopes, selected for effectiveness and combined with a critically important second aspect : A local adjuvant, a substance that activates /alerts the denditic cells - see above- to be even more active in processing, instructing and endowing the specific figthers (CTLs) and also the  class II "helper cells" that further help in the activation and training process for the CTLs, enhancing their numbers and giving them wild "peptalks', riling them up, sharpening their weapons and helping them to reproduce even faster., so they basically get a license to help the above licensing process to maximum efficacy.

In the end therefore we "enjoy" a huge double amplification process in the adaptive arm of the immune system.

The vaccine provides in concentrated form  the most effective epitopes in the context of ancient "danger recognition signals " ( the "adjuvants"), that gets the licensing authority ( the dendritic cells)  itself up to maximum speed.

So these vaccines work by driving the anti HCV Tcell response to maximum efficiency, to fight the virus in a more effective, less proinflammatory way and to get the infection to a low or no level.

Unfortunately, thus far, they do not work very well as hoped. This is partly, because HCV has learned to strip itself of all or most of  these fancy recognition epitopes, so the trash can looks perfectly clean and the CTL moves on, with no antiviral action...

Avatar universal
this is the most excellent explanation...reads like a true war story i very much enjoyed.

"HCV has learned to strip itself of all or most of these fancy recognition epitopes"
would you please continue on how it does this. i might be confused in thinking it is because of the hypervariable surface proteins on the hcv molecule, but now i am wondering if you mean something else. and please in the fascinating style as above.
Avatar universal
The above was just a very crude introduction in the adaptive cellular immune events - to explain how these therapeutic vaccines work without introducing more harm than good as dointime wondered.

The failure of this excellent adaptive defense system is at the very heart of the fact that HCV is a chronic disease, why IFN and/or riba work or not work.

The virions are produced inside the hepatocytes and some of their proteins, structural and nonstructural,  are cleaved to small peptides  and processed as described above and transported to the surface together with other cell "trash peptides".
In the evolution of HCV it invents ( for each of its components)  a functionally ( for its own purposes= max survival) optimized protein.

These  proteins ( a certain portion of them)  will, upon been cleaved/split up in the above described proteasome contain some peptide pieces (now at the hepatocyte surface laying in the described groove of the MHCclass I molecule) that have the inherent capacity to bind very well to the incoming CTLs. Other pieces do not bind at all. Not enough sticky amino acids are contained within them.

Thus there are good and bad epitopes ( from the human perspective).

There are quite a few restrictions on being a "good"epitope ( peptide fragment). It must be cleaved properly, fit the trash can ( the class I MHC molecule on the surface in which groove it must be well stuck and fitting).
It also must have "sticky and outreaching"' amino acids in its middle portion, so as to atttach firmly to the CTL detection device ( the "Tcell receptor")

Therefore in the end only a few good epitopes exist in small viruses like HBV and HCV, that will do the trick for presenting to /binding/exiting our adaptive immune system.

The virus needs these peptide stretches inside its proteins like  eg you need the handle on your vaccum cleaner for optimum functionality.

But when special forces are around that destroy your house if they find a vacuum cleaner with a handle ( they only can see the handle with their special devices) , you might want to sacrifice the good handle for a lousy one, like made of tape, to escape destruction, and if push comes to shuff you might sacrifice even more functionality in the items that end up in the trash, just not to be seen. Better half or 99% crippled than dead.

Thus HCV with its incredible evolutionary power finds a way to change literally most all the important ( for presentation and recognition) amino acids needed in those critical epitopes.  It is called epitope mutation and "epitope escape mutations". So it is less fit ( only one leg now, two fingers and no more tongue) but so what if you can have a trillion kids a day, you can settle for less offspring for a while, even when you are down to only 30000 a day, under IFN and riba - HCV often prevails in the end, after month of incredible hardship existence and crippled beyond recognition - literally. Pun fully  intended.

When the army is called back to regular medium duty - after IFN has stopped - HCV can return to a more comfortable lifestyle, regain a leg and a lousy tongue.

It is just that this pesty ribavirin is causing so much frantic adaption, that the beleagered HCV might overadapt and oops, creates a recognizable epitope again - on comes the merciless CTL - and the neighbors HCVs , despite  being much more careful, die also, because of the widespread spraying with local antivirals...
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