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    DNA Vaccines: The Future Of Disease Control
    By News Staff | July 29th 2012 06:00 AM | 17 comments | Print | E-mail | Track Comments
    Right now, we protect people and animals against diseases by inoculating them with vaccines based on real infectious agents - but that brings risk of reinfection and the expense of cultivating and handling deadly viruses and bacteria.

    The future may mean DNA vaccines, basically cutting out the biological middleman. 

    DNA vaccines are not new but they haven't taken off - an entire anti-science political sphere rejects both vaccines and genetic modifications so combining both is not making them feel better.  Plus, existing vaccine technologies work;  they are the most effective defense ever deployed to fight disease. Along with access to clean water and the development of drugs to fight infections, vaccination strategies have saved billions from death and illness.

    But using vaccines is not without problems. Deploying live (but weakened 'attenuated') viruses can sometimes result in the virus mutating and reverting back to its harmful ways, spreading a new strain of the disease.

    However, in animals DNA vaccines may make a lot of sense.  DNA vaccines can circumvent the general reinfection danger because they contain only DNA and not infectious agents. So rather than introducing a virus or bacteria (antigen, or part of) to provoke a protective immune response in the form of host antibodies, DNA vaccines only carry the agent's genetic code. The result is the same – antibodies are produced that remain in the body to guard against infection; the middleman infectious agent remains in a test tube out of harm's way.

    This approach offers other advantages: DNA vaccines are stable at a wider range of temperatures, reducing the need for costly and logistically challenging cold-delivery chains that can prevent treatments getting to where they are most needed, particularly in the developing world. DNA vaccines are easier to manipulate than many conventional vaccine elements, and genomic technology can make bespoke sequences (which are delivered as DNA loops called plasmids) quickly to tackle rapidly emerging threats, such as food poisoning outbreaks, or local variants of established diseases.

    And culturing infectious agents for vaccines requires expensive quarantine facilities that can never be 100% failsafe – accidental (or even malicious) release into the environment is always a possibility.

    Since the 1990s, DNA vaccines have been aimed at more than 30 animal diseases, yet despite more than two decades of research there are only three licensed vaccines – for West Nile virus in horses, haematopoietic necrosis virus in salmon, and melanoma in dogs. 

    This is because DNA vaccines lead to a wider array of immune responses than conventional immunization techniques because the precise metabolic machinery that leads to a favorable immune response is not fully understood. Hence, researchers have grappled with various factors such as site and method of injection to improve host immunity, coupled with a repertoire of chemical extras (adjuvants) that are used with vaccines of all types to elicit more favorable cell responses.



    Making a DNA vaccine. Credit: National Institute of Allergy and Infectious Diseases

    For instance, there are three main methods of applying DNA vaccines: needle inoculation; electroporation, which is using a current to create pores in cell membranes for DNA to pass through; and use of a 'gene gun', a device that propels DNA-coated gold particles directly into live cells. All three methods elicit different cellular reactions because they may stimulate, or bypass, important immunological pathways that lead to immunity.

    Then there is the site of injection: what's good on one animal, such as the ears of a pig, doesn't work for other livestock such as sheep or cows.

    And yet another way to tinker with the efficacy of the DNA vaccine is to add other biological ingredients into the mix. These take the form of short sequences of DNA or protein (peptides) called prime boosts which can increase antibody numbers, as well as their activity and persistence. Recombinant (from engineered bacteria) proteins or viruses can also induce better immune responses when used in conjunction with DNA vaccines, activating new classes of immune cells into the fight. To tackle foot-and-mouth disease virus (FMDV), Barnet used a prime-protein boost strategy. The prime is DNA coding for the full capsid (protein shell) structure of the virus. The protein boost is essentially the same antigen component used in the traditional FMD vaccine – chemically inactivated FMD virus.

    So aren't the benefits lost if the conventional vaccine is also used? Not so, says
    Dr. Paul Barnett of the Institute for Animal Health (IAH) in Pirbright, UK, who demonstrated for the first time that cattle can be clinically protected against FMD virus by tactical delivery of a DNA vaccine, albeit with the right accompaniments.(1) "There are reasons why we went for this approach. Firstly, in pigs it was shown that this prime-protein boost regime gave a considerably higher antibody response than is normally seen by conventional vaccine. Moreover, the response was more cross-reactive across different serotypes [strains of virus]."

    Obtaining a one-size fits all vaccine that works against serotypes is, as Barnett puts it, "a holy grail in FMD vaccine research." He adds that if the immunity was enhanced by a DNA prime-protein boost to the extent that you stopped cattle getting persistently infected this approach was even more valuable. "However, unfortunately it seems the merits of this approach in pigs were not substantiated in cattle."

    Barnett also experimented with various adjuvants to make his DNA vaccines work against FMDV. One of the most effective is an extra DNA plasmid that codes for the cytokine, bovine granulocyte-macrophage colony-stimulating factor, or GM-CSF. This is useful because cytokines are a large class of protein molecules used extensively in intercellular communication, and four of six previous studies using cytokines with DNA vaccines have reported full protection in pigs (ref 1).

    "GM-CSF is a cytokine and is a key part of the immune-inflammatory cascade, by which activation of a small number of macrophages can rapidly lead to an increase in their numbers, a process crucial for fighting infection," says Barnett. "This function we think helps to enhance the vaccine's ability."

    In addition, Barnett found that electroporation was the best delivery strategy, protecting 75% of animals after 91 days, compared to only 25% of animals where electroporation was not used
    .

    DNA vaccines for cows and chickens may be some way from commercial reality, but their potential benefits – ease of making DNA, reactivity, thermostability, theoretical low cost, and proven effectiveness in other animals – means that further research will continue.

    And there are other benefits, specific to certain animals and diseases. For instance, limitations of the current FMD vaccine include a lack of induction of sterile immunity; this is where in persistently infected animals, replicating FMD virus can be found in the samples of oropharyngeal fluid taken from the back of the throat, in either vaccinated or non-vaccinated animals, that have been exposed to the virus.


    "The current FMD vaccine prevents clinical signs of the disease but doesn't stop this sub-clinical replication going on in this area," says Barnett. "The fact that replicating virus can be isolated from these animals has always been a cause of concern, particularly to other countries which want to trade in animals and animal products."

    This means that vaccinated and non-vaccinated animals cannot be distinguished, which can hamper control strategies. It also restricts the movement of animals, which is a major economic consideration at local, regional and global levels. DNA vaccines could, in theory, see an end to this problem.

    Development of DNA vaccines is still a relatively young field, compared to the first FMD vaccine which was developed in Germany in 1937 for example. But in the age of genomics where DNA can be sequenced and created more quickly, accurately, and cheaper than ever before, and where safety and handling live pathogens will always be fraught with risk and difficulty, further research on DNA vaccines is surely a worthwhile pursuit when addressing modern food security, animal health and perhaps even human healthcare challenges.


    REFERENCES:

    (1) V. Fowler, L. Robinson, B. Bankowski, S. Cox, S. Parida, C. Lawlor, D. Gibson, F. O’Brien, B. Ellefsen, D. Hannaman, H.-H. Takamatsu, P.V. Barnett, 'A DNA vaccination regime including protein boost and electroporation protects cattle against foot-and-mouth disease', Antiviral Research, Volume 94, Issue 1, April 2012, Pages 25-34, ISSN 0166-3542, 10.1016/j.antiviral.2012.02.002.

    Comments

    Frank Parks
    I think this is showing the future of virus treatments for humans.  Of course, there are many hurdles to overcome.  Not least of which is the monumental task of convincing the general public that DNA manipulation is a safe, and more effective, alternate to standard immunizations.  If indeed it is so.

     We are standing on the threshold of advanced human immunology.  Whether we actually enter that realm remains to be seen.
    Gerhard Adam
    We are standing on the threshold of advanced human immunology.
    My concern is that most of this will prove to be irrelevant, because the technology will become too economically constrained to be meaningful to the majority of people.  We are already seeing the first indications of this regarding the issues about biosimilars in new treatments.

    No one wants to admit that there is really no such thing as a biosimilar, so we are going to go through the motions of having the FDA and other organizations attempt to set standards and guidelines regarding patient safety and establish equivalencies, but in truth, it comes down to the fact that the "innovator" becomes a monopoly holder of the technology.  As a result, we will see little or nothing to improve the situation for the majority of people without fortunes being exchanged. 

    The public is justifiably concerned, because regardless of whether their view is "anti-science" or "anti-corporate" or whatever, there is a growing sense that none of this is being done for their benefit, as much as it is being done to enrich others.  With such motives, there should be a great deal of public skepticism.


    Mundus vult decipi
    Frank Parks
    Ah. I had forgotten the profit motive and the wonders of patents. So, you're right, even if the procedures work out nicely, it is not likely that the new items will be widely available at a reasonable price. I agree completely with your last paragraph. I am beginning to see my first question (about a product announcement) along the lines of 'Who is going to be enriched at my expense?'. That is a rather sad commentary on my outlook.
    Gerhard Adam
    BTW, I wish that it weren't true, but to get a sense of how this works, just have anyone look up the Makena incident for a perspective (Feb. 2011). 

    A drug which had been in-use for more than 50 years [off-label by pharmacists compounding the agent for about $15-20] was suddenly granted protection status by the FDA as an "orphan drug".  This allowed KV Pharmaceuticals to enjoy the patent protection of a drug that had already been around for 50 years.

    What did the company do with this new found protection?  They immediately raised the price per dose from $15-20 to $1500.  After all, I guess that was justified after all the research and "investment" they had to make.  Oooh .. my mistake.  They didn't actually invent the drug.
    http://www.dailymail.co.uk/news/article-1364747/Preemie-outrage-Cost-makena-drug-prevents-premature-birth-rise-10-1500-KV-Pharmaceuticals.html

    http://www.stltoday.com/business/local/article_bda7ebe9-ee6c-5d8b-b4e8-09daf6399ede.html

    Fortunately the FDA indicated that pharmacies that continued to compound the drug for $15-20 would not be legally prosecuted, so that KV finally dropped their price ... to $690 per dose [which also illustrates why I think corporations are the problem].

    http://www.boston.com/news/nation/washington/articles/2011/04/02/price_of_preterm_birth_medicine_cut/

    So, when people ask why insurance rates are high, and why medical expenses keep going up ... well, at least we know what part of the answer is.
    Mundus vult decipi
    Frank Parks
    Yes. About the only humor in that horror story is how quickly the March of Dimes back pedaled.

    As a general comment on the state of health costs: I have many friends who make regular trips to Mexico for medical and dental treatments. The savings are substantial.

    Who do we really need to blame for the escalating health care costs? Ultimately, we must blame ourselves. The very wealthy and the very poor are not much affected by the spiraling costs. Those of us in the murky middle bear the true costs. Whether it’s because we made spurious malpractice claims, or lobbied for better (costlier) insurance coverage at our workplace, or demanded increased dividends at the shareholders meeting, we are to blame.

    Gerhard Adam
    I have many friends who make regular trips to Mexico for medical and dental treatments. The savings are substantial.
    Yes, I know about that and it's an interesting comment regarding the U.S. system.
    Who do we really need to blame for the escalating health care costs? Ultimately, we must blame ourselves.
    Perhaps that's true, but I simply have  a problem with the entire "business model" of health care and health insurance.  After all, it is impossible to make a profit in any business that collects less in premiums that it must ultimately pay out.  Yet, that's the entire basis for health insurance [unless they can deny coverage or have pre-existing conditions].  The only way health insurance can make money is to insure the healthy.

    In the second instance, they've acted to guarantee whatever the medical profession wishes to charge.  As a result, we have absurdities like $18 aspirins.  Again, the point is that few are interested in providing services as much as they are in maximizing profits.  We are a country run by accountants and lawyers.

    So despite all the rhetoric about "free markets", we want a health care system that is based on middle-men and fixed prices.  An insurance company does not represent the "market" and yet this is the entire basis for determining what the price being set is.  Similarly, an insurance company will determine what is covered rather than what is needed, so in effect, we have the insurance companies and health insurance industry determining what health care is available to the patient.  The patient has no input unless they also have the financial means by which to express their opinion.  Without that, their opinion doesn't count.

    While it it tempting to look for blame, I really believe that we have done far too much to protect large businesses, as a result we are now paying higher and higher prices for their intrinsic inefficiencies and bureaucracies.  Instead of encouraging smaller companies and more opportunities for entrepreneurs, we are now paying for the sins of allowing entrenched interests to dictate the terms of how our society operates.


    Mundus vult decipi
    Hank
    I have many friends who make regular trips to Mexico for medical and dental treatments. The savings are substantial.
    Their poorest people come to the US because it's free.  So Mexican dentists undercutting American ones in return for cash is not really an indictment of the US.  
    Gerhard Adam
    We're not just talking about dentists.  This is especially true with plastic surgery and other options that are simply too expensive in the states.

    Also, we're not talking about back-alley, "cash under the table" type of transactions.  These are fully staffed hospitals and facilities that perform these services. 

    The fact is that we would be able to enjoy a more competitive environment if we could take advantage of foreign resources [like our corporations can] except the government restricts U.S. citizen's ability to purchase foreign goods [like prescription drugs]. 
    Mundus vult decipi
    Frank Parks
    First, I should apologize for helping to derail this article.

    Next, of course the poor people would come to the US for ‘free’ health care. If my friends were in the ‘poor’ category, they wouldn’t be going elsewhere for health care.

    I didn’t intend to indict us. It is simply a matter of personal finances. If the insurance company denies treatment, or if the co-pay and deductible are very large portions of the final costs, then it makes financial sense for my friends to make the trip to Mexico City for the equivalent - or more often better – treatments.

    As for the rest, Gerhard makes the point with far less gibberish and more logic than I.

    Frank Parks
    Yes. And it isn’t just in the health care industry either. The concept that ‘money is power’ carries over very nicely for lobbyists of every persuasion.
    randallmayes
    It's too bad this great article was reduced to bitching about patents. There are significant scientific hurdles such as highly evolved pathogens with lipid membranes that are a nightmare to DNA vaccine resesrchers. If a biotech company ever solves this problem, they deserve financial rewards.
    Randall Mayes
    Frank Parks
    I absolutely agree with those statements. I suppose the question would become how much financial rewards. And further, how restrictive would the price be?

    Still, this is likely many years in the future.

    Gerhard Adam
    If a biotech company ever solves this problem, they deserve financial rewards.
    ... and this is how the myth persists.  The reality is that the people that actually solve the problem will be unlikely recipients of the rewards.  They won't become wealthy.  They won't become superstars.  Instead another excuse will be foisted on us, which is that ... well .. the people that put up the money deserve a return on their investment ... etc... etc.   ... etc.

    So, the lie is that the problem-solvers will be the ones rewarded.  I'll bet that if I were to compare the bank statements of the scientists that make these discoveries and the CEO's of the companies ... we'll be able to quickly see how this concept of rewards actually works. 

    It's interesting that it's always the "biotech company" that solves the problem, rather than an individual that deserves the praise and the rewards.  We all know how this game is played, so the self-righteous indignation doesn't work.


    Mundus vult decipi
    Frank Parks
    Well, I sorta agree with that.  Except that it's unlikely that a scientist without the funding provided by a big company would be able to afford the equipment and personnel required.

    (Yeah.  I read his profile too.)
    Gerhard Adam
    I agree that that's how the economics works out.  My problem is that people are quick to point out how such "innovations" are to be rewarded, and yet they generally fail to reward the actual people that did the work.

    So, if the purpose is simply return on investment, then we know how to deal with that.  However, let's not pretend that it's for some stroke of genius, or problem solving skill, or contribution to mankind.  It is nothing of the sort.  It is simple economics and we can dispense with the other rationalizations.

    However, that changes the argument, because we already know about recovering costs and the costs of manufacturing, so it becomes much easier to analyze the numbers and determine what is a reasonable profit, versus what is price gouging.  This is important because the pharmaceuticals are being specifically protected from competition and consequently have a monopoly, bypassing the free market.

    Interestingly enough it's another "adjustment" to the "free market" because it obviously doesn't work in this situation, so the objective is to provide a protected period whereby a company can recover it's investment and make a profit.  Of course, to look at the actual numbers indicates that nothing short of robbery is actually occurring.  You have companies that aren't simply recovering their investment and making a profit.  They are recovering 1000's of times their investment.

    Now, this is where the real question comes in.  If you're already protected in recovering your investment, then what is the basis for being "rewarded" on top of that?  You see ... that's where I have the problem, because "reward" should only be a term used for those individuals that actually did the work.  Businesses don't get rewarded.  They are afforded opportunities to recover their investments or they make a profit, but they are incapable of doing anything for which they should be rewarded.   Only individuals can do that, and, as I indicated, it is highly unlikely that they are being rewarded in that fashion.
    Mundus vult decipi
    very pessamistic comments for technology that has the potential to redirect our entire approach to such an established field of biological sciecnce.west nile, melanomas, fmd, and hematopoetic necrosis in fish, sound to me like their covering a pretty diverse spectrum of pathology and doing their due dilligence on the science. let's not worry about the theoretical potential monetary issues just yet. a. sounds like they deserve to get paid b. when the technology gets bought by pfizer or merck and applied to the horses and not just the zebras, the cost will fraction and of course c.what say we just do our jobs and supprt our colleages that have devoted their lives to beak fresh ground, and are apparently rocking it.

    Frank Parks
    Well, like I said upstream, I'm in favor of the research.  One thing for sure, articles like the one quoted by the original poster will stimulate further ideas.  It may be that this particular technique doesn't work out, but it might spur some lonely bio chemist to develop something even better.