Jump to content
Sign in to follow this  
mooeypoo

A "One-Time" Flu Vaccine might be found..

Recommended Posts

Team finds secret that could stem flu viruses

 

Scientists led by a team from Dana-Farber Cancer Institute have discovered what they describe as the Achilles' heel of the influenza virus, a finding that suggests it might be possible to end the ritual of the annual flu shot.

(source: http://www.boston.com/news/health/articles/2009/02/23/team_finds_secret_that_could_stem_flu_viruses/)

I read this in BadAstronomy (here's the post http://blogs.discovermagazine.com/badastronomy/2009/03/29/is-a-one-time-flu-shot-on-the-horizon/) which links to a Boston Globe report.

 

I'm not very well versed in immunology, but it was my understanding that the major problem of vaccination (and specifically the flu vaccine) is that the virus adapts and therefore a new vaccine is needed each season.

 

In fact, I always understood that the flu is one of those viruses that adapts *so quickly*, that it's hard to really produce a good vaccine; it's as "good as we can" thing each season.

 

So.. seeing this news report - how viable is this, really? Can a one-time vaccine really be made for such a quickly evolving virus??

Share this post


Link to post
Share on other sites

The basic point is that they change their cell surface so rapidly that they do not present the same epitopes, the areas where antibodies will bind, all the time. So in theory, if there are non-changing surface properties that could be exploited to create a vaccine (that is, it makes you create antibodies against those areas) then yes, it may be feasible. In the end it is not that straightforward, of course. First, there is the technical problem of creating a suitable vaccine, and the second one is hoping that this conserved area is really conserved due to certain constraints that the virus cannot overcome.

One should probably add that for HIV quite a while a go conserved areas have been reported but for various reasons no viable vaccine has been formulated yet.

Edited by CharonY

Share this post


Link to post
Share on other sites

Can this new discovery be used on other viruses? that is -- is this an old property that was recently found specifically for the flu, or is this an entirely new technique we can also use on different viruses as well?

Share this post


Link to post
Share on other sites

Actually this is what you always try to find in a virus (or anything that you want to vaccinate against), a conserved area. If you ask whether it is always the same structure, then the answer is no. Viruses (except very closely related ones) are structurally distinct so that it is unlikely to find a single epitope that is common to all (or even most) viruses.

Share this post


Link to post
Share on other sites

how could some one get the antibodies for something that mutates so fast? is there just like a discovered kill all vaccine? all shapes in one?

Share this post


Link to post
Share on other sites

The reverse. One shape found in all.

Share this post


Link to post
Share on other sites
The reverse. One shape found in all.

Yes, but then eventually those will mutate and appear with other "shapes" no? Isn't that the fate of all viruses/vaccines?

Share this post


Link to post
Share on other sites

Seems unlikely. It might make a big dent for a while, but I doubt that it can get every single strain.

Share this post


Link to post
Share on other sites

Good find! That was an interesting article indeed.

I agree with Mr. Skeptic. It seems too perfect that they found a part of the virus that never changes. Sure, it'll work for a while, but there'll be a few strains that it won't be able to combat. I don't know that much about Immunology myself, but I'm willing to bet that the part that they think is stable might end up changing because of this. Who knows?

Share this post


Link to post
Share on other sites
Yes, but then eventually those will mutate and appear with other "shapes" no? Isn't that the fate of all viruses/vaccines?

 

For most it is. The idea behind it, however, is that even virus only has a limited degree of freedom when it comes to building up its capsule. Of course this still leaves a large space of epitopes to explore. And it is quite possible that change in one region allows an otherwise non-feasible change in another.

However a blanket statement that mutations will always change everything is not taking in the restriction of these self-assembled structures. In fact this is a problem that now physicists start to probe (as they apparently either ran out or are bored with non-biological samples ;)).

Share this post


Link to post
Share on other sites

With the flu virus, the two most antigenic proteins are neuraminidase ("N") and hemagglutinin ("H"), which are found on the outside of the virion. Each comes in several varieties, which virologists have numbered, hence subtypes like H5N1, H2N2, etc. All of the 16 H and 9 N varieties exist in natural reservoirs (mainly birds), and the viruses readily "mix and match" their antigen types to generate all possible combinations.

 

We develop immunity to each of the antigens to which we are exposed, thus if you were exposed to a flu strain having H3N3 last year, you're likely not susceptible to any strain this year having either H3 or N3. And since your immunity lasts for more than a year, only a few combinations of H&N are likely to slip past your immune system and cause illness. These, of course, are the strains that become pandemic. This also explains why you need a new flu vaccine formulation each year: if the virus was the same as one a few years ago, most people would be immune, and the virus would not be able to spread.

 

Closing in on the point: within each variety of antigen (the 16 Hs and 9 Ns), mutations occur. Thus, the (e.g.) H12 you encounter this year might be a bit different from the H12 that popped up several years ago. Mutations happen most readily in the part of the protein that is not essential for activity (each of these proteins has a function), because a sufficiently large mutation renders the antigen "new" to your immune system. Stated another way, there is a selection pressure against the old, unmutated antigens.

 

The antibodies discussed in the article bind to a highly conserved region on the antigen. At some point, if use of the antibody becomes widespread, there will be selection pressure against that conserved region as well. We can then expect to start seeing flu virions having a mutation at or near the antibody binding site.

Share this post


Link to post
Share on other sites

The antibodies discussed in the article bind to a highly conserved region on the antigen. At some point, if use of the antibody becomes widespread, there will be selection pressure against that conserved region as well. We can then expect to start seeing flu virions having a mutation at or near the antibody binding site.

 

I don't quite get what you're saying when you wrote that we can expect to see a mutation at or near the antibody binding site. Is it that because of the constant mutations, this new vaccine will cease to be effective at a certain point?

Share this post


Link to post
Share on other sites
I don't quite get what you're saying when you wrote that we can expect to see a mutation at or near the antibody binding site. Is it that because of the constant mutations, this new vaccine will cease to be effective at a certain point?

 

If I recall correctly, the product in question was a monoclonal antibody that specifically binds a portion of the antigen close to the membrane (as opposed to the more distal part, where most antibodies bind to this antigen). Not a vaccine, which would be a chunk of the antigen itself.

 

When there is no selection pressure, there will not be many mutations. Or rather, the mutations that occur will typically not be competitive with the original sequence, and will die out. If mutations decrease the fitness of the organism, then you'll get those mutations only if the environment changes so that selection pressure favors them. That a sequence is "highly conserved" is our hint that that part of the sequence serves a vital function.

 

Now, we change the virus's environment. Suddenly, that particular sequence (or that epitope of the antigen) is selected against. In this environment, the mutated sequences (which arise spontaneously all the time, although not necessarily at a high frequency) suddenly have an advantage. Then, the viruses with the mutation will proliferate, and possibly out-compete the original version. You end up with a shift in the antigen sequence, and eventually the antibody stops working.

Share this post


Link to post
Share on other sites

Why don't we flood the body with artificial virus receptors We can then make antibodies against the virus receptors and so the antibodies would block the virus from getting into the cell - like locking a door and breaking the key off in the door so that no one can get in? I am not a virologist.

Share this post


Link to post
Share on other sites

There are some efforts in that direction. The main problem is that the cell surface receptor that the virus uses typically has a function (although sometimes this function is unknown), and blocking that function may not be the healthiest thing to do. This is especially a problem when you don't know what the receptor protein does.

Share this post


Link to post
Share on other sites

In addition, if we raise antibodies to do the blocking (instead of using an analogon that binds the receptor) chances are high that we create an autoimmune disease. In fact a number of them (including e.g. Grave's disease) are the result of the immune system raising antibodies against a receptor with regulatory functions.

Share this post


Link to post
Share on other sites

OK guys and I don't know if I am making much sense here, why can't we flood the body with 'self' viral receptors which are engineered to bind irreversibly to the viruses. During an infection so that there is no antibody response against 'self' but virus particles who leave a cell to invade others become 'distracted' by the receptors around them and the scope of the infection is localised and mitigated.

Share this post


Link to post
Share on other sites
OK guys and I don't know if I am making much sense here, why can't we flood the body with 'self' viral receptors which are engineered to bind irreversibly to the viruses. During an infection so that there is no antibody response against 'self' but virus particles who leave a cell to invade others become 'distracted' by the receptors around them and the scope of the infection is localised and mitigated.

 

Unfortunately, this is a little more complicated than it sounds. Suppose you have identified the human receptor that the virus uses to gain entry into the cell. It is sometimes possible to clone the receptor and truncate the part that binds it to the membrane (this does not work for all receptors), and make what is called a "soluble" receptor. ("Soluble" because you have eliminated the hydrophobic anchor that would otherwise keep it bound to the cell membrane.) I think this is basically what you are proposing.

 

The first problem is that by truncating the protein, one often disturbs the structure of the receptor protein. It may be a subtle change, but often this is enough to change the binding affinity for the virus by a factor of 10 (or more). Of course, it is also possible that the binding would increase (but this is less likely). So the decoy protein will still bind the virus, but you'll need a higher concentration in order to shift the equilibrium away from binding the native receptor.

 

OK, let's assume that you've solved the first problem, and can make decoy protein that binds the virus just as well as the native form of the receptor. The second problem is that the decoy protein is now unfamiliar to your body, and you will develop an immune response to it. Just by truncating the end, you expose a part of the protein that was previously inaccessible to the immune system, which will treat it as foreign. Sometimes this can spill over into an immune reaction against the native receptor, in which case you have a nasty autoimmune problem (e.g., myasthenia gravis), the symptoms of which may be disabling or deadly, depending on the receptor and the strength of the response.

 

OK, let's assume you've solved the first two problems. Perhaps you got lucky, and there is already a native soluble receptor (there are such things, although I have not heard of one serving as a viral entry). You still have the problem (#3) of flooding the body with something which binds not only the virus, but whatever the receptor's natural ligand is. If that ligand is important, you may not have improved the patient's health. Suppose the target receptor binds insulin: by administering a lot of insulin receptor decoy proteins, you might mop up all of the patient's insulin along with the virus, thus giving the patient immediate iatrogenic diabetes. Sure, you can modify the decoy so that it no longer binds to the natural ligand, but then you are back at problem #2, with a foreign protein.

 

OK, let's assume that you've managed to solve or ignore problems 1-3: the final problem is that protein drugs tend to be more expensive than the regular chemical type (what we call "small molecules"). The economics of health insurance basically dictate that this drug would be used only for really serious/lethal infections.

 

Actually, let's go back and check one of our assumptions: not all receptors can be truncated (let's call this problem #0). Some receptors are integrally a part of the cell membrane (e.g., 7TM-GPCRs, 7-transmembrane G-protein-coupled receptors, which cross the cell membrane 7 times), and cannot be truncated without completely falling apart.

 

Having said all that, sometimes you will find a receptor that you can work with, and develop a drug that may be immunogenic, but would not have to be administered for long enough that it would be cleared out by your immune system. If you're lucky, disrupting homeostasis by mopping up some of the natural ligand doesn't unduly perturb the patient. And perhaps the disease is lethal enough, or terrifying enough, that patients will pay for it. Your final problem is mutation. All pathogens mutate at some rate (retroviruses tend to be the fastest). If your new drug stops all of the viruses that have the "original sequence", you will find that some small fraction of the viruses have already mutated such that either (a) they now bind to the original receptor better than your decoy (this can happen if your decoy is not identical to the original receptor), or (b) they now bind a related but different receptor (your body is full of receptors that resemble each other structurally).

 

Start over :doh:

Share this post


Link to post
Share on other sites

Excellent and detailed answer. Just what I wanted. Thanks for that. OK, next step, the virus needs enzymes, I presume to assemble the protein coat or to prepare its genetic material. How would it sound to flood the body with enzyme inhibitors which are inside liposomes (membrane bubbles) which are specific to virally infected cells. The enzyme inhibitors are attached to a cyanide or poisonous chemical which is only activated when the attachment to the enzyme occurs. The virally infected cells are destroyed specifically. I realise there are extra problems here but I am just starting again.

Share this post


Link to post
Share on other sites

Yes, interfering with viral enzymes is a very good method. For example, inhibitors for reverse transcriptase will prevent any retroviruses (such as HIV) that use the inhibited enzyme from infecting new cells. Of course, this might not work if the virus changes their enzyme. However, for reverse transcriptase it would be possible to target the active site since the protein is useless to us.

Share this post


Link to post
Share on other sites
Excellent and detailed answer. Just what I wanted. Thanks for that. OK, next step, the virus needs enzymes, I presume to assemble the protein coat or to prepare its genetic material. How would it sound to flood the body with enzyme inhibitors which are inside liposomes (membrane bubbles) which are specific to virally infected cells. The enzyme inhibitors are attached to a cyanide or poisonous chemical which is only activated when the attachment to the enzyme occurs. The virally infected cells are destroyed specifically. I realise there are extra problems here but I am just starting again.

 

Yes, viruses need enzymes: typically, their genomes encode only one or two structural proteins (and even these may also have an enzymatic activity), and everything else is an enzyme of some sort. Common types are polymerases (to replicate the viral genome), proteases (some viruses express their genome as one long "poly-protein", which is then cut into individual proteins: typically, the protease is at the end, and first cleaves itself from the rest of the polyprotein), and enzymes that modulate the cell's defenses. Viruses are so stripped-down that inhibiting any of its enzymes usually helps. (The exception is proteins like HIV's nef (IIRC), which keeps virus replication suppressed most of the time.) Generally, just inhibiting the enzyme is sufficient, without also attaching the "magic bullet."

 

Targetted liposomes have been tried for things like delivering chemotherapeutics to cancer cells, or antifungals to pathogenic fungi. It is difficult to target to a cell infected with a virus, because for the most part it looks like any healthy cell. If everything is operating properly, the infected cell will cleave some of the viral proteins and present the resulting peptides on its surface, bound to the cell's MHC proteins. This, of course, is why successful viruses inhibit MHC expression.

 

The real problem with cytotoxic liposomes, though, is selectivity. Nothing is 100%. Even if you had an antibody that was really, really specific for the target cell, some of the liposomes are going to stick, non-specifically, to innocent bystanders. Blam, they're dead. The reason this is tolerated in cancer treatment and combatting fungal infections is that the diseases are so serious that collateral damage is acceptable. Wouldn't do to give the patient chemo-like side effects when treating the flu.

 

The idea of administering compounds that inhibit the viral enzymes is good, though. This is the approach that most pharma companies use when developing antiviral drugs. It still isn't simple, though, as the compound still has to make it into the cells without being metabolized, and without unduly interacting with any of the patient's thousands of other enzymes. At least most small molecule drugs are small enough that the patient does not develop antibodies against them (although this can still happen if the drug happens to bind to a human protein, like serum albumin).

Share this post


Link to post
Share on other sites

Create an account or sign in to comment

You need to be a member in order to leave a comment

Create an account

Sign up for a new account in our community. It's easy!

Register a new account

Sign in

Already have an account? Sign in here.

Sign In Now
Sign in to follow this  

×
×
  • Create New...

Important Information

We have placed cookies on your device to help make this website better. You can adjust your cookie settings, otherwise we'll assume you're okay to continue.