Proper Vetting of HSV-2 Vaccines and its Importance

OVERVIEW

In an earlier post on June 30, I suggested that there are two steps that could be taken to expedite the rate of HSV-2 vaccine development, and these are:

Step 1.  Appropriate Use of Small Animal Models (i.e., De-Risking HSV-2 Vaccine Development)

Step 2.  Streamlining the Path to Phase I Human Clinical Testing of HSV-2 Vaccines

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In a subsequent post on July 17, I considered the latter issue of (Step 2) how we could (and should) streamline the path for HSV-2 vaccine candidates that look promising in animal models to advance to Phase I human clinical testing.   I argued that a far more sane approach to HSV-2 vaccine development would involve therapeutic vaccine testing of any reasonable HSV-2 vaccine in human patients who suffer from chronic outbreaks of HSV-2 genital herpes.  The basic rationale is that of a “Compassionate Use Trial,” where in essence the patient population in question have (1) nothing to lose from receiving an experimental HSV-2 vaccine and (2) everything to gain if the HSV-2 vaccine actually reduces their genital herpes symptoms.  Even in our current CYA-minded society, it is clear that it would be hard for a HSV-2 vaccine to be worse than the prospect of living with a chronic disease driven by wild-type HSV-1 or HSV-2 for which conventional medical drugs and therapies have failed.  If anyone questions how badly such chronic HSV-1 or HSV-2 infections may affect a person’s psyche, then I invite them to peruse the Comments posted by readers of this blog.

Today, after a 2-month hiatus from adding to the blog (i.e., my teaching responsibilities ramped up in August), I wish to finish up this discussion by considering the importance of the “Appropriate Use of Small Animal Models.”

The underlying issue of Phase I Clinical Testing boils down to “putting the ball across the goal line” and getting new HSV-2 vaccines into people where they can do some good.

The underlying issue of Appropriate Use of Small Animal Models boils down to promoting a common-sense understanding of the difference between (1) HSV-2 vaccines that should work well versus (2) sales pitches, which tout “a promising HSV-2 vaccine” but then offer little to no direct evidence to support the claim.

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THE “PROMISING VACCINE” SALES PITCH

HSV-2 plaques(and the millions to be gained regardless of whether or not it works)

To an expert who has been working with small animal models of HSV-1 and HSV-2 infection for more than 20 years, the difference between an “effective HSV-2 vaccine” and “a good sales pitch” is quite obvious.  Clearly, Herpevac and all of the related-gD subunit vaccines were the product of very good sales pitches.  Of all the HSV-2 vaccines that are currently being discussed in human clinical trials, Sanofi Pasteur’s ACAM-529 vaccine is the only one to have gone through proper pre-clinical animal testing in a manner that included publishing the data for all the world to see.  For this reason, I endorse the ACAM-529 vaccine as a HSV-2 vaccine that merits our support and consideration for testing in human clinical trials.  In contrast, the Genocea, Agenus, Corridon, and the Immunovex HSV-2 vaccines are / were all examples of HSV-2 vaccine approaches that were advanced to human clinical trials with little effort to publish animal-based research studies that are the conventional means by which new vaccine candidates are vetted (i.e., proof that the “new vaccine” is not just a sales pitch).  In particular, I would like to see the evidence for any and all of these approaches that (1) they should elicit protection against HSV-2 genital herpes that is superior to the Herpevac vaccine in animal models, or (2) they should elicit protection against exogenous HSV-2 infection that is on par with the type of protection that follows from a limited infection with wild-type HSV-2.

Now, the next question that should arise is……Why?  Why would a company not complete and publish pre-clinical animal studies (at a cost of $100,000) that could bolster their case for a HSV-2 vaccine rather than rushing straight to human clinical trials that could easily cost $20 million?

I do not have inside knowledge of what goes on inside these companies, but I suspect that money lies at the core of this disconnect in logic.  While I do not claim to be privvy to the specific details that led to the development of these vaccines, the typical sales pitch for a new HSV-2 vaccine might go something like this………..

1.  Important Scientist convinces his colleagues, “Well Herpevac failed despite what the animal models said should happen, so animal models of HSV-2 infection and challenge are useless as screening tools.”  In other words, the claim is made that you can protect mice and guinea pigs against HSV-2 by injecting them with anything including water, so why waste your time screening a new HSV-2 vaccine in animals when animal models tell you that all HSV-2 vaccines work?  Thus, let’s just jump straight into human testing of our new HSV-2 vaccine candidate and get some “good data” that will mean something.

2.  Company recruits, or is formed around, Important Scientist with new HSV-2 vaccine candidate in hand.

3.  This company recruits an elite Board of Scientific Directors, and they are sold to federal funding agencies as the “Rolex Watch” of up-and-coming HSV-2 vaccines that will deliver the long awaited miracle of a successful HSV-2 vaccine.  Yes, snob appeal is used that overtly as a common sales tactic in selling new technologies to other scientists and funding agencies.

4  A small amount of federal backing in terms of federal grant support (Important Scientist has many friends) is leveraged into the opportunity of a lifetime for biomedical investors to back the first successful HSV-2 vaccine.

5.  Company-supported HSV-2 vaccines are based on either the FDA’s favorite approach, the subunit vaccine, or some equally benign approach that poses no perceived risks so that approval for clinical testing will occur.  Biotech Company’s lawyers work on this while Important Scientist and others raise money.

6.  Only after millions of dollars have been raised from investors and governments do Phase I Clinical trials start.  Initial results of clinical trials (however cursory and speculative) are released as evidence that this new HSV-2 vaccine is really far more promising than past HSV-2 vaccines.  This data is not published but is announced as press releases, and is leveraged into (1) more biomedical investment and (2) more federal research funding for a promising new HSV-2 vaccine.

7.  Somewhere in Phase 2 or Phase 3 Clinical Trials, it turns out that the HSV-2 vaccine does not really work as well as the initial data suggested it might 5 to 10 years earlier.  However, during the years it took to “figure this out,” Biotech Company got lots of publicity and millions of dollars in federal research support as well as investments from biomedical investors whose return on investment is contingent upon the success of the vaccine.

Yes, it is the Emperor’s New Clothes.  Biotech companies want enough data to back a sexy idea, but they deliberately delay the collection of data that might cut into the viability of the story so long as federal governments or private investors are willing to keep spending money on yet more testing.  The ugly little secret is that an unscrupulous person can base a Biotech Company on an “invention of the future” that has no real hope of success so long as there exists an audience who wants to buy / support the hypothetical product.  In vaccine circles, the FDA and NIH have both promoted a pro-subunit vaccine culture and keep throwing money at HSV-2 vaccines that conform to their mental model of what an ideal HSV-2 vaccine “should look like.”  The trouble is that these “ivory tower” HSV-2 vaccine approaches keep falling flat on their face.

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PROPER VETTING OF HSV-2 VACCINES

To an expert who has been working with small animal models of HSV-1 and HSV-2 infection for more than 20 years, the difference between an “effective HSV-2 vaccine” and “a good sales pitch” is quite obvious.

I have heard many of our current scientific leaders espouse the idea that “(1) Herpevac failed despite what the animal models said should happen, and thus (2) we should abandon animal models of HSV-2 infection as this is not a useful screening tool.”  I am here to say that this notion is patently false, and is a misnomer that needs to be critically re-evaluated.  The mindless repetition of this soundbyte at vaccine meetings needs to end.

When a trained expert runs a rigorous HSV-2 vaccine-challenge study in mice with all of the appropriate controls (including a positive control), it turns out that Herpevac is a lousy HSV-2 vaccine in mice (http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017748).  Likewise, when similar tests are run using guinea pigs, it turns out that Herpevac is a lousy HSV-2 vaccine in guinea pigs (http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0065523).  If Herpevac (a gD-2 based subunit vaccine) is a lousy vaccine in mice and guinea pigs, then why should it be any better in humans?

Oh, that’s right…Herpevac failed in humans too (http://www.nejm.org/doi/full/10.1056/NEJMoa1103151); it just took 20+ years of testing the idea over and over in humans to eventually arrive at the correct conclusion that we could have deduced in mice had the experiments been performed in a rigorous and appropriately controlled manner the first time when this line of investigation was started in the 1980s.  In fairness to investigators who came before me, I have the benefit of hindsight and hindsight is 20/20.  Nonetheless, we should not pretend that HSV-2 vaccine-challenge models cannot differentiate a lousy HSV-2 vaccine from a good HSV-2 vaccine; they most certainly can.  However, the experiments (1) need to performed rigorously with an overwhelming dose of HSV-2 challenge virus and (2) both negative and positive controls need to be included in the experiment.  None of the failed HSV-2 vaccines were ever compared to a positive control in an animal model.

The simple reality is that human beings (not nature) chose this circuitous path that we have been following for 30 years, which leads in circles around a HSV-2 vaccine but never seems to get us to the destination we keep blathering on about.  Today,  30 years later, what we have to show for our efforts is the simple realization that Herpevac and other gD-subunit vaccine-based approaches are unlikely to represent a final solution in efforts to vaccinate against HSV-2 genital herpes.

Moving forward, I would propose that we could, and should, (1) man up, (2) admit our past mistakes, and (3) move on to some new and better choices that will actually lead to the deployment of a safe and effective HSV-2 vaccine.

Vaccines are just not that complicated, and the reason that a live-attenuated HSV-2 vaccine would work better than all of the “ivory tower HSV-2 vaccines” we keep pinning our hopes on may be summarized, as follows:

(1) a live-attenuated HSV-2 vaccine can expose the vertebrate immune system to ~40,000 amino acids of HSV-2’s proteome (nearly 100% of the viral antigens are there; we don’t have to worry about choosing the “right stretch” of amino acids);

(2) all of these HSV-2 antigens are presented in their natural context to B-cells, CD4+ T-cells, and CD8+ T-cells (i.e., we don’t have to guess whether or not our antigens will be presented in a way that faithfully mimics a real HSV-2 infection); and

(3) all of these HSV-2 antigens may be presented in their proper immunological context over a period of days to weeks; in other words, the duration of time the immune cells are exposed to HSV-2 antigen should be proportional to the resulting degree of protection.

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WHERE’S THE BEEF?

From the reader’s perspective, you may agree that the three ideas I lay out above might give you a better HSV-2 vaccine, but where is the proof?

If animal models are useful tools for screening HSV-2 vaccine potential, what piece of data can I show you that suggests that a live HSV-2 vaccine does a better job engaging the immune system of a mouse (or a guinea pig) relative to a Herpevac-like vaccine?

Vaccine-induced protection is mediated by lymphocytes, which come in three flavors…..B-cells, CD4+ T-cells, and CD8+ T-cells.  An effective HSV-2 vaccine will engage both B-cells and T-cells.  While I cannot yet offer formal evidence from the T-cell side of the equation, my lab has investigated the B-cell response to HSV-2 vaccines for several years now and the evidence is clear.  A live-attenuated HSV-2 vaccine elicits a much broader (more polyclonal) and quantitatively greater B-cell response than a Herpevac-like vaccine.  At the top of this post, I provide one type of visual evidence of this principle.

Each of the pictures contains a photograph of a single HSV-2 plaque.  This is a round cluster of many cells that are in the process of supporting HSV-2 replication in cell culture, and each of these cells is loaded with tens of thousands of HSV-2 proteins.  Surrounding each plaque is a monolayer of cells that have not yet been infected with HSV-2.   A HSV-2 plaque starts as a single, virus-infected cell and the viral infection spread like a ripple in a pond (after you throw in a pebble) with the advancing concentric circle of infection spreading outward from the first HSV-2-infected cell.  Each of the plaques in the photos above were fixed with formaldehyde and methanol at 36 hours post-infection (by which time ~200 cells were virus-infected), and now I am going to use these plaques loaded with HSV-2 proteins to ask how much anti-HSV-2 antibody is present in three groups of mice.

The first group of mice are immunologically naïve (photo on left).  They have never seen HSV-2, and so they possess no antibodies against HSV-2 and likewise have no protection against HSV-2.  The degree of redness bound to the plaque is an index that these naïve mice have no antibody that specifically binds HSV-2 protein.

The second group of mice were immunized twice with Herpevac (photo in middle).  These mice have a ton of anti-gD antibody, but gD is only 1 of 75 proteins found in HSV-2 infected cells.  Thus, you only see a light red color where anti-gD antibody has found the gD protein in a plaque of HSV-2+ cells.  Likewise, I find that this low level of antibody against total HSV-2 protein (pan-HSV-2 IgG antibody) correlates with only very limited protection against HSV-2 in Herpevac-immunized animals.

The third group of mice were immunized twice with a live-attenuated HSV-2 vaccine (photo on right).  There is a lot more red color bound to the plaque, which is an index that live HSV-2 vaccine-immunized mice have a lot more IgG antibody against total HSV-2 protein (pan-HSV-2 IgG) than mice immunized with a Herpevac-like vaccine.  As reported in the following publication, http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0065523, my lab found that (1) on average a live HSV-2 vaccine elicits about 40 times more pan-HSV-2 IgG antibody than a Herpevac vaccine in mice and guinea pigs, and likewise (2) this heightened antibody / B-cell response correlates with a 40-fold increase in functional protection against HSV-2 challenge.

Again, this should not be complicated to people who study infectious disease.  Like most things in the natural world, the correct answer proves to be the obvious one:  A live HSV-2 vaccine that (1) contains more antigens (2) expressed in their natural context and (3) expressed for longer periods of time works a lot better than a monovalent gD-2 vaccine that elicits an antibody response that only poorly cross-reacts with the biologically relevant target, HSV-2 virions and HSV-2 infected cells (as illustrated in the Figure above).

The underlying issue of Appropriate Use of Small Animal Models boils down to promoting a common-sense understanding of the difference between HSV-2 vaccines that work versus everything else.  Perhaps it is time that we consider (for the first time) placing more faith in HSV-2 vaccines that have been vetted in properly controlled animal experiments as opposed to being duped by HSV-2 vaccine sales pitches that proceed straight to fundraising efforts without a shred of evidence that the putative vaccine may elicit at least 10% of the protection against HSV-2 genital herpes that is possible.

– Bill H.

 

25 thoughts on “Proper Vetting of HSV-2 Vaccines and its Importance

  1. God bless you abundantly Doctor
    What about Russian drug called “profetal” ….A myth or it really can cure?
    There is the possibility of healing or should wait for treatment only ?
    And about the virus is not resistant against oxygen? That’s true ?

  2. It is so reassuring to see someone taking the time to research and combat this disease. I’m currently awaiting the results of my Hsv 1 and 2 test since I’ve had symptoms for the past month. I’ve been lucky not to have any rashes or multiple external sores thus far. I guess my question is which anti-viral drug would be a good for someone with predominantly internal symptoms? Or would it be better to get a vaccine you recommended first, then go towards the anti-viral drug route?

  3. Dr. Halford,
    Agenus released their initial phase 2 results: http://www.antigenics.com/docs/press-releases/2013/herpv-vaccine-for-genital-herpes-meets-primary-endpoint.php . I’m trying to appreciate why a 15% reduction in viral shedding would be clinically significant since, if I understand the explanation of the Genocea results, it is barely statistically Significant. Am I misunderstanding the significance of the results? It seems like this trial was a flop.

    Also, assuming they weren’t grinding the participants up and measuring viral protein, is the viral load reduction estimate simply a measure of how much virus was being picked up by the culture swabs?

    • Hi Staying Upbeat,

      I am afraid that I have to agree with your interpretation that if Agenus is reporting a “15% reduction in viral shedding,” then that is the scientific equivalent of putting lipstick on a pig. Prettier lips…..but still not a supermodel.

      Before I make any judgments about whether or not this trial was a flop, or warrants further study, I will really need to analyze the results which I have not done yet. I will come back and amend my response once I have had a chance to take a look at Agenus’s press release.

      In this day and age, the simplest way to estimate the frequency, magnitude, and duration of HSV-2 reactivation in placebo- or vaccine-treated patients would be to collect genital swabs of known outbreak sites, but it is unlikely that the test was looking for infectious virus (i.e., a cell culture-based test). Rather, PCR (polymerase chain reaction) detection of HSV-2 DNA is on the order of 10 to 100 times more sensitive, and thus I suspect that the average level of genital HSV-2 DNA (as detected by swabs) would have been compared in placebo- versus vaccinated-patients.

      Why would a company report these results? Probably because biomedical investors and the NIH paid this company to run this trial and collect this data, and they were probably contractually obligated to make the data publicly available regardless of whether it helps or hurts their cause.

      I don’t blame companies like Agenus for taking the government’s money to run clinical trials of a vaccine based on snippets of HSV-2 peptides embedded in heat shock proteins. Scientifically, I think that this is a stupid approach to a HSV-2 vaccine for a myriad of reasons. However, from a business point of view, this is what the NIH and biomedical investors want in 2013……HSV-2 vaccines that sound more like science fiction than science. If the NIH offers a company tens of millions of dollars to test an uber-molecular / sci-fi HSV-2 vaccine, then I don’t blame Agenus for taking the NIH’s money. If Agenus had not been awarded million of dollars to test this latest science-fiction HSV-2 vaccine, then the NIH would have awarded the money to another company for a different HSV-2 vaccine approach that was even less likely to succeed.

      So long as the “leaders” at the NIH fail to lead by virtue of continuing to only fund HSV-2 vaccine ideas that are scientifically ridiculous……like heat shock proteins that contain small snippets of HSV-2 peptide, well we are going to continue to see stupid HSV-2 vaccine ideas advanced, trumpeted about, and then fail when they are tested because they are just stupid ideas that don’t mesh with the rules by which nature operates.

      In religious terms, it is as though the leaders at the NIH want to tell God how vaccines “should work” despite the fact that the universe was not the NIH’s creation. A humbler group of individuals might acknowledge that a better approach would be to ask God how the universe works, and then make a HSV-2 vaccine that is consistent with those rules.

      In scientific terms, this means that scientists should (1) try to learn how HSV-2 vaccines actually work first and then (2) devise HSV-2 vaccines that are consistent with the principles by which immune responses are mounted to viruses and control those viral infections. I approach vaccines from this latter perspective, and in terms of that perspective, the Agenus heat shock protein-HSV-2 peptide is even stupider than Herpevac.

      Perhaps one day the NIH will take their putative leadership role more seriously, and re-evaluate if their current policies are leading HSV-2 vaccine science (and biomedical science in general) in the best long-term direction.

      Will take a look at the specifics of what was posted online, and amend my comments accordingly next week.

      – Bill H.

  4. Dr. Halford,

    Thanks for everything that you do. You have made all of us so much more informed. What is your take on today’s news from Agenus’ Phase 2 results on HerpV?

    Thanks,

    Chas

  5. Dr. Halford,
    I wish you the best of luck on your sabbatical and, to parrot what Lauren has said, it is heartwarming and encouraging to see a principal investigator who is as passionate and responsive about this work as you.

    • Hi Staying Upbeat,

      Thanks for the words of encouragement. I hope that I can eventually do something a bit more concrete for people with HSV-2 genital herpes…either in terms of reducing their symptoms (a therapeutic vaccine) or eliminating the risk of spreading HSV-2 to a sexual partner (preventative vaccine). However, I am glad to know that the blog discussions are helpful in their own right, regardless of where things stand with my efforts to bend the ear of pharmaceutical companies or the FDA. As my Mom used to always say……Rome was not built in a day. Glad to hear the blog offers some encouragement while we are waiting for the Coliseum to be completed.

      – Bill H.

  6. I’d just like to say that, as a new follower of your research and current sufferer of genital HSV-1, your work is encouraging to say the least. I was in no way included in the decision-making process for receiving HSV-1. My ex-husband gave it to me without consulting me in the least after testing positive for it months before meeting me. So, even though I have only ever suffered 4 outbreaks in total since contracting it in 2009, the stigma associated with having HSV-1 makes dating (and life in general) very, very hard. Not only that, but self-esteem issues are now entering the picture after never having suffered them before. For me, knowing that someone out there is dedicating their research to finding a vaccine is comforting. I am still young. I could see a vaccine and maybe even a CURE in my lifetime! While I am not able to participate in scientific gander as to why a live-attenuated HSV-2 vaccine works to invoke a natural response by the body to eradicate the chances of disease setting in, I can say that I enjoy seeing your passion come out in your writing. I like to see that you, as the principle investigator, care enough to get angry. That alone keeps gals like me hoping for the future. Still lonely and somewhat afraid to kiss my baby girl on the face, but nonetheless…hopeful.

  7. I received the following e-mail from a reader, and post it here as it is a question about content on the blog that others may question.
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    Bill,

    You mentioned that ACAM-529 was the only vaccine which published the animal tests. Do you know if ACAM-529 used a positive control like you advocate so much?

    I also noticed you said your vaccine has not tested for T-cell response, but on wikipedia it says that ACAM-529 has T-Cell response and cross protection against HSV-1. I know you say that your vaccine replicates a little so it should produce a stronger immune protection. Since ACAM529 was allowed to trials it would be nice if their vaccine was effective enough. It would be nice if it could get to market in two years or less, but I think I heard it takes about 5 years, which is really long, especially if we don’t know if it works or would have to start over and wait another 5 years for your vaccine trial. 5 or 10 years more after so many years already is a crazy amount of time to go through the process.

    Do you know around what year the technology was available that could develop your vaccine or ACAM-529?

    It looks like the safety trial started in July: http://clinicaltrials.gov/ct2/show/NCT01915212
    It says completion date 2016? That is just for phase 1 of one vaccine?

    Thanks,

    • Dear Blog Reader,

      I answer your questions, as follows:

      Question 1. You mentioned that ACAM-529 was the only vaccine which published the animal tests. Do you know if ACAM-529 used a positive control like you advocate so much?

      As far as I am aware, the protective immunity elicited by ACAM-529 in animal models has not been compared to the relevant positive control group (i.e., animals that survive a sub-lethal exposure to wild-type HSV-2).
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      Question 2. I also noticed you said your vaccine has not tested for T-cell response, but on wikipedia it says that ACAM-529 has T-Cell response and cross protection against HSV-1.
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      I will be spending 7 months on Sabbatical Leave at the Rocky Mountain Laboratories for the express purpose of working side-by-side with immunologists who routinely study T cell-responses to viruses. I am confident that my live-attenuated HSV-2 vaccine elicits a T-cell response, and have pilot data that incontrovertibly proves this. Once I have the methodologies down, it will be interesting to quantify the relative efficacy with which a live, replicating HSV-2 vaccine elicits a T-cell response against HSV-2 antigens relative to a non-replicating HSV-2 vaccine. So, just to be clear, I have not published on the T-cell response to my live HSV-2 vaccine yet, but the approach was only fully introduced into the published literature in March 2011. In contrast, the ACAM-529 HSV-2 vaccine approach originated in the mid-1990s. Due to this >10-year head start, the HSV-2 ACAM-529 vaccine is further along in the vaccine development pipeline.

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      Question 3. I know you say that your vaccine replicates a little so it should produce a stronger immune protection. Since ACAM529 was allowed to trials it would be nice if their vaccine was effective enough. It would be nice if it could get to market in two years or less, but I think I heard it takes about 5 years, which is really long, especially if we don’t know if it works or would have to start over and wait another 5 years for your vaccine trial. 5 or 10 years more after so many years already is a crazy amount of time to go through the process.

      Do you know around what year the technology was available that could develop your vaccine or ACAM-529?
      ——-
      The technology already exists to put ACAM-529 into human subjects. The only “questions” are whether or not it (1) ACAM-529 is safe and well tolerated by test subjects in a Phase I clinical trial and (2) ACAM-529 is effective enough in Phase 2 and 3 clinical trials before proceeding to actual deployment in a clinical setting. You have to remember that it costs Sanofi Pasteur money to test ACAM-529 even on a small scale, and hence the clinical trials is a means to make sure that their product is going to have a viable market (i.e., can they recoup their investment?). And yes, it will take at least 5 years for ACAM-529 to clear all of the hurdles of trials and be scaled up in production for full-fledged clinical deployment. Of course, all of that is assuming that all phases of clinical trial reveal that ACAM-529 is a full-blown, slam dunk success……..which remains to be proven in humans. So, I would advise against putting the cart before the horse.

      With my HSV-2 0deltaNLS vaccine strain, it is at least 3 years behind ACAM-529 (which is an incredibly optimistic timeline) because it still lacks a corporate sponsor, has not been looked at by the FDA, and has not even been turned into a “GMP-grade stock” which is essential just to start the Investigational New Drug (IND) application with the FDA. Again, a more realistic estimate is that the 0deltaNLS vaccine is at least 5 years behind ACAM-529 and entry into a human clinical trial…..at least this is the case in the United States. Given this ludicrous system of ours (i.e., millions of people will contract HSV-2 genital herpes over the next 5 years), this is why I am suggesting that an overseas venue in a less bureaucratic country might be the best route for my lab’s live HSV-2 vaccine.

      I don’t need a bureaucrat in the FDA to tell me the score here. My live HSV-2 0deltaNLS vaccine would be a huge improvement over our current situation in which wild-type HSV-2 continues to spread unchecked in the human population, in much the same way that it did 2,000 years ago in Ancient Rome. Transportation and communication have improved a lot over the past 2,000 years, but sadly our capacity to disrupt the HSV-2 life cycle in people has not really changed that much. This is why I suggest that we should “Just Do It,” and follow what common sense, the available evidence, and history tells us should happen…..a live HSV-2 vaccine will end genital herpes as soon as it is deployed on a large scale, and common sense tells us it will be safe because my lab’s HSV-2 ICP0- mutant vaccine strains is barely able to cause disease in animals with no lymphocytes (i.e., “boy-in-the-bubble” mice with SCID).

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      Question 4. It looks like the safety trial started in July: http://clinicaltrials.gov/ct2/show/NCT01915212
      It says completion date 2016? That is just for phase 1 of one vaccine?

      I am not sure about that. My impression from speaking with Dr. Knipe in May 2013 (at a scientific conference) was that the Phase I clinical trial of the ACAM-529 vaccine would be completed by Summer 2014. However, this is not my study, and I do not have regular conversations with Dr. Knipe, Sanofi Pasteur, or any of their colleagues who are pushing ACAM-529 forward. Thus, I would expect that the clinical evaluation of ACAM-529 should be well beyond Phase I by 2016. This is my best guess, and I think it is important for me to acknowledge that the actual investigators (Drs. Knipe and Cohen) would be in a much stronger position to address a question about the timeline of clinical testing of the ACAM-529 vaccine.

      – Bill H.

  8. I am very scientifically ignorant so don’t understand the mechanics of your vaccine but maybe it is the idea of being injected with a “live” virus that sounds scary

    I think all vaccines are therapeutic only to individuals who are already infected possibly reducing the number and severity of outbreaks. Is there any possibility that the virus could be completely eradicated?

    I wish science wasn’t so commercial with “patents” etc. I wish it was all about scientists worldwide working together to try and find solutions rather than a big moneymaking exercise :-(

    • Hi Ben,

      The process is not perfect, but the fact is that science has over the past 200 years resulted in your life expectancy increasing by 20 – 30 years.

      A vaccine cannot eradicate a pre-existing HSV-2 infection, but it might be able to reduce the symptoms of the infection if the immune system’s response to HSV-2 infected cells could be “ratcheted up” a few notches.

      – Bill H.

  9. Dr. Halford,
    I’m curious what your take is on the most recent press on Genocea: http://www.pharmabiz.com/NewsDetails.aspx?aid=77650&sid=2 ?
    I agree that there is way too little critical skepticism of these products and far too much press release style hype but, as a sufferer, it’s tough to look a gift horse in the mouth if this therapeutic vaccine can actually reduce disease burden by 51% (I realize that’s not exactly the translation of the results).
    Is this a smoke and mirrors game with investors as dupes? Have they created measures of performance that are positive feedback on process noise? Did the team happen upon a transient statistical anomaly?
    If I’ve read the headlines correctly, Anna Wald was at least in the room if not a presenter. It seems unlikely she would tweak results.
    The CEO of Genocea (or so he claims to be) posts frequently to this site: http://www.herpes-coldsores.com/messageforum/showthread.php?58269-For-those-who-haven-t-seen-update-of-Genocea-s-Gen-003-on-website&p=328288#post328288 .
    If you’re willing it seems like asking him some critical technical questions would be reasonable.
    Genocea has “prophylactic HSV-2 development” on their pipeline page. Maybe they would be open to backing an ICP0 deletion mutant to compete with Dr. Knipe’s or make ATLAS available to your efforts (if that would even be at all helpful).

    • Hi Staying Upbeat,

      Thanks for your question.

      Dr. Wald and all of her colleagues in Seattle have done fantastic work over the years, and no I certainly am not suggesting that they would fabricate any data with regard to their testing of HSV-2 vaccine approaches.

      What I am saying is that the GEN-003 vaccine consists of approximately 380 amino acids of glycoprotein D-2 (the active ingredient in Herpevac) and approximately 300 amino acids of HSV-2’s ICP4 protein (per this Abstract in Pubmed… http://www.ncbi.nlm.nih.gov/pubmed/?term=gen-003). By my calculations, the GEN-003 vaccine contains ~700 of HSV-2’s 40,000 amino acids (~2% of HSV-2’s proteome). The assumption in such “subunit vaccine” approaches is that the other 98% of the foreign amino acids encoded by HSV-2 are (1) not relevant antigens and thus (2) would not contribute to the effectiveness of a HSV-2 vaccine. This defies common sense, and is inconsistent with the data my lab has been collecting for years now. Also, I note that ICP4 is not a particularly dominant antigen. Thus, what I am trying to say / draw attention to is……….since all of the failed HSV-2 vaccines are based on glycoprotein D-2, does it really make sense that adding 300 amino acids from ICP4 is going to be a complete game-changer with regards to the effectiveness of a HSV-2 vaccine? Possible, but not self-evident to me that the “Gen-003” vaccine is anything other than “Herpevac-plus.”

      Regarding the 51% reduction in HSV-2 shedding that was recently reported, let me put that number in perspective. A 51% reduction in HSV-2 shedding equals a 2.0-fold decrease. A 1.0-fold decrease is “no change whatsoever,” and even with the best of statistics a 1.5-fold change is the absolute bare-minimum for a “significant difference.” Therefore, a 2-fold decrease is a definite sign of progress in the right direction, but is what would generally be described in science as a “modest, but reproducible effect.” That is of course assuming that this 2-fold difference would be reproduced if the study were repeated.

      Finally, in my own animal experiments, when I compare acute HSV-2 shedding from the vaginas of naive (no immunization) versus vaccinated animals, I generally observe about a 50,000 per cent reduction in HSV-2 shedding from the vaccinated animals (i.e., a 500-fold reduction in HSV-2 shedding) relative to naive animals. In contrast, what you are describing / relaying to me is a 2-fold reduction in HSV-2 shedding in those who received the GEN-003 vaccine (where a 1.5-fold reduction is about the bare minimum for a measurable reduction). Now, the types of experiments I am running are apples versus oranges relative to the GEN-003 experiments in human clinical trials of a potential therapeutic vaccine. So, I don’t want to imply that a 50% reduction in HSV-2 shedding does not mean anything. However, what I do wish to convey is that I don’t know that a 2.0-fold reduction in HSV-2 shedding shortly after receiving a vaccine (i.e., when the vaccine’s effects are greatest) will correlate into a clinically meaningful result. Likewise, I do not think that anyone can really claim that a 2.0-fold reduction in HSV-2 shedding will necessarily translate to a slam-dunk success for a therapeutic HSV-2 vaccine.

      I agree that it is a positive sign, but I think that only time will tell if this is simply a blip on the radar of scientific press releases, or if this is the beginnings of a clinically meaningful cure for HSV-2 genital herpes.

      – Bill H.

        • Hi Jonas,

          I have now had a chance to look through the data. My overall impressions are that this is a proof-of-principle study, which has yielded some interesting suggestions for the future about HSV-2 therapeutic vaccines.

          The two most important slides to note are Slides 8 and 17.

          Slide 8 is the study design, and indicates that test subjects were immunized at Days 0, 21, and 42. From Days 42 – 70, test subjects collected vaginal swabs twice per day that were analyzed for HSV-2 DNA by polymerase chain reaction (PCR). Importantly, these same test subjects collected baseline swabs to monitor their HSV-2 DNA shedding by PCR from Day -28 to 0 (one month prior to receiving the GEN-003 vaccine).

          Once you know the study design, Slide 17 presents the primary metric of the effect of the GEN-003 vaccine; namely, the range of “percent change in HSV-2 shedding” after GEN-003 or placebo vaccination. What I observe is a relatively subtle shift towards a reduction in HSV-2 shedding in subjects receiving the GEN-003 vaccine.

          What I think is the coolest thing about this study is the experimental design; an important step forward in science is figuring out how to properly execute an experiment such that you measure the variable of interest. In this case, I believe Anna Wald and colleagues show that they have established a solid experimental design for objectively evaluating a therapeutic HSV-2 vaccine. However, I suspect that there are other HSV-2 vaccine formulations that might give a more obvious therapeutic effect. Statistically significant results are a good start, but I would hope for at least a 10-fold reduction in HSV-2 shedding from a useful therapeutic HSV-2 vaccine; the current study shows a 2-fold reduction.

          The GEN-003 vaccine contains 2 of HSV-2’s 75 proteins (most of gD and one-third of ICP4), which represents about 800 amino acids of the more than 40,000 foreign amino acids encoded by HSV-2. I note that a live-attenuated HSV-2 vaccine that encodes 99.5% of HSV-2’s proteome might be more effective as a therapeutic vaccine whose primary purpose should be to give the human body’s lymphocytes a better look at HSV-2 antigens that they either (1) did not “see” during the original wild-type HSV-2 infection and outbreaks, or alternatively (2) human lymphocytes may under the right conditions of anergy or suppression choose not to respond to an antigen. For a therapeutic HSV-2 vaccine, I would assume that we should start broad and re-expose the immune system to as many HSV-2 antigens as possible in attempts to (1) expand the numbers and (2) broaden the repertoire of HSV-2 specific lymphocytes that are “actively engaging the enemy,” and thus could reduce the frequency and duration of HSV-2 genital herpes outbreaks. GEN-003 is a good start, but I suspect a live-attenuated HSV-2 vaccine would be a lot more effective if a therapeutic HSV-2 vaccine is really possible (as Dr. Wald’s data suggests is the case).

          Very cool study design from Wald and colleagues. I just hope that one day they will consider testing some other HSV-2 vaccines that contain a 10- to 50-fold greater array of HSV-2 antigens, and thus contain a 10- to 50-fold greater potential to re-educate the human immune system about HSV-2 in the form of a therapeutic vaccine.

          – Bill H.

          • Thanks for the response, I am glad to get an expert eye to look things over.

            I came to the same conclusion: statistically significant but clinically underwhelming. Still, early days, perhaps some messing about with dosages in future trials will produce more impressive results.

            With that said, I would love to see the results of a study like this with ACAM529, which had some promising animal data. But it’s going to be a slow road for that, seeing as how their Phase 1 trial is scheduled for a Sept. 2016 completion date.

            Something I’m wondering about is that the subjects for this trial are rather frequent sufferers of HSV-2, with 3-9 recurrent episodes per year. Would you expect any better results with those who have much more infrequent episodes, or perhaps for those who are seropositive but display no overt symptoms but may be asymptotically shedding?

          • Hi Jonas,

            I believe that Wald and colleagues have chosen the logical patient population to target in a therapeutic HSV-2 vaccine trial. Remember that one of the big issues in science is making sure that whatever you are measuring is above the lower limit of detection of your measurement. If Wald and colleagues chose people who were asymptomatically infected with HSV-2, then there is a good chance that asymptomatic individuals would shed only vanishingly small quantities of HSV-2; maybe 1-10% of the levels of the high HSV-2 reactivator population they chose just to put a ballpark number on it. Now, if the test population receiving the HSV-2 vaccine barely ever shed HSV-2 DNA PRIOR TO VACCINATION, this would make it really hard to convincingly see an effect of the HSV-2 vaccine. To look for vaccine-induced reductions in HSV-2 DNA shedding in a population of low reactivators or HSV-2 asymptomatically infected persons, you would probably need about 100 – 200 patients per group and you would have to follow them for 4 months pre-vaccination and 4 months post-vaccination. More patients and more time = more expense.

            I concur with Dr. Wald and colleagues that high reactivators are the right patient group for testing a therapeutic HSV-2 vaccine.

            – Bill H.

          • Certainly for purposes of testing, I agree that highly symptomatic patients are the logical choice. And in this case, it certainly seems as though the vaccine’s effects are fairly marginal with respect to those types of patients.

            I am just wondering if it would be possible for the increase in HSV immune response from this vaccine to be strong enough to completely control the virus in those patients whose immune systems already do a decent job (infrequent outbreaks). Obviously, it would be difficult to test as you’ve mentioned, just curious I suppose.

          • Hi Jonas,

            I would assume that a HSV-2 vaccine that is therapeutic would have the most potential to succeed in people who suffer from frequent recurrences of HSV-2. In those who are asymptomatically infected with HSV-2 or suffer only rare outbreaks, their immune system generally is doing the job so I suspect it would be harder to improve upon that which already exists. All that said, the concept of a therapeutic HSV-2 vaccine is uncharted territory, so I don’t think anyone (including myself) can really predict much……just a matter of testing and seeing what works.

            In contrast, a preventative HSV-2 vaccine is a much simpler proposition, and it is quite clear how a preventative HSV-2 vaccine would work (i.e., the same as all of other successful viral vaccines…..smallpox, oral polio, MMR, chickenpox, etc).

            – Bill H.

    • Dear Suffering,

      Thank you for posting this important piece of information. You are absolutely correct that these are the relevant people to contact, and I have yet to reach out to this group. My concern as a Principal Investigator (i..e., the guy who developed a live HSV-2 vaccine), as that any inquiry I make will be viewed as self-serving. Also, speaking in generalities, my discussions with other scientists are always immediately followed within minutes by the question, “Which company are you partnering with?” When I provide the answer……”I have talked to a half dozen, but none of them seem overly eager to invest into a live-attenuated HSV-2 vaccine,”…..then the conversation seems to grind to an abrupt halt.

      So, I could talk to FDA regulators myself, but without a product development plan / corporate support (a source of bucks), it seems like putting the cart before the horse to me.

      However, I don’t see any reason why people who suffer from oral or genital herpes should not ask “What’s the deal with herpes vaccines?” There are dozens described in the published literature that might work, but then only a select few are cherry-picked to advance to human clinical trials? What could the FDA possibly have to lose by testing ALL OF THE POTENTIAL HSV-2 VACCINE approaches rather than continuing their current policy of “only subunit vaccine approaches are safe enough to put into human clinical trials.”

      Humans have been around for well over 100,000 years, and herpes simplex virus has been infecting us since we first became a species (chimpanzees, apes, etc. have their own equivalent of herpes simplex virus). If the WILD-TYPE herpes simplex virus has been circulating for all that time without wiping out the human race, I have a really hard time believing that even a live-attenuated HSV-2 vaccine could possibly pose any real danger.

      Dear Suffering, thank you for posting this link. I hope that a few people who visit this site will contact members of the FDA and apply some pressure as a person who LIVES WITH CHRONIC HERPETIC DISEASE THAT IS UNRELIEVED AND WANTS SOME ANSWERS REGARDING THE “LOGIC” BEHIND NOT TESTING ANY HSV-2 VACCINES IN HUMANS OTHER THAN SUBUNIT VACCINES, WHICH ARE GENERALLY ONLY ABOUT 1-2% AS EFFECTIVE AS LIVE-ATTENUATED VACCINES.

      I can beat on this drum, and other scientists will think I am just being self-serving and trying to sell a story. (1) Barack Obama, (2) members of Congress, and (3) the federal agencies under them use your tax dollars for EVERYTHING EXCEPT developing effective HSV-1 and HSV-2 vaccines. To put this into perspective, the annual budget of the National Institutes of Health (NIH) is about 30,000 million dollars per year. In my experience, it has been like pulling teeth to get a NIH study section to award my lab a grand total of $0.3 million dollars over the past 6 years that I have been asking……that represents $50,000 per year and an investment of 0.0002% of the NIH budget in my HSV-2 vaccine research to date. I am simply not convinced that the NIH has invested in HSV-2 genital herpes vaccines to a degree that is commensurate with the size of the problem. I know for a fact that the NIH invests between 1,000 and 2,000 million dollars per year on preventing “bioterrorism.”

      When is the last time that you knew of a friend who suffered the ill-effects of bioterrorism? So, apparently if a few Congressmen receive anthrax in the mail, that warrants spending 2 billion per year for more than 10 years (i.e., >$20 billion dollars). In contrast, the NIH “cannot afford” to support small labs such as my own who are asking for about 0.0002 billion dollars per year to develop a vaccine that could spare tens of millions of people from genital herpes.

      Aside from the disconnect in logic, my overly angry tone and frustration with this stems from the fact that I have easily invested 6 – 12 months of my time over the past 6 years trying to re-formulate new ways to explain to NIH reviewers in multiple grant applications (about 10 in total) why this research is important. I have not seen any change in the frank negativity of NIH reviewers towards my grant applications requesting support for research to develop a live-attenuated HSV-2 vaccine that is about 100 times more effective than Herpevac. Thus, that 6 to 12 months of grant writing has garnered me a grand total of $0 in NIH support where reviewers said, “Yes, absolutely, this is important to develop a better HSV-2 vaccine because what we have done in the past has not worked.” Rather, I only received $0.3 million in funding from the NIH in Summer 2009 on accident because of ARRA federal stimulus funds that coincided with the review of an R21 grant application from my lab that was reviewed in Jan 2009 (i.e., when the fiscal dung was hitting the fan, as Pres Obama was coming into office). In short, the HSV-2 vaccine work I have been able to publish was based on an accidental quirk of the NIH system, and was not because I convinced a panel of NIH reviewers that were as any value in developing a HSV-2 vaccines that was 100 times better than “the gold standard” of Herpevac. Ironically, most of the NIH reviewers who reviewed my multiple NIH grant applications for funding in 2007, 2008, and 2009 cited the ongoing Herpevac vaccine trial (described by Belshe, et al, 2012) as evidence that (1) we already possessed a HSV-2 subunit vaccine that worked, so (2) why would want to investigate an old-fashioned, live HSV-2 vaccine that would be “too dangerous” to use clinically.

      If people who suffer from HSV-1 or HSV-2 herpes voice their discontent to people in positions of power, then that might help lawmakers and people within the FDA recognize that genital herpes is an infinitely solvable problem with a simple and not terribly expensive solution. This is common sense and good business from a health care delivery point of view. Prevention of oral and genital herpes with effective HSV-1 and HSV-2 vaccines would cost less than 1% of what insurance companies, medicare, etc are currently spending treating the symptoms of a chronic disease that AFFLICTS MILLIONS OF AMERICAN TAXPAYERS. Also, in the positive column, alleviating human suffering is not an entirely bad thing either.

      The squeaky wheel gets the grease, or as I have heard from Chinese friends “The crying baby gets the candy.”

      My advice is to give people in positions of power an earful until it is obvious to them that it would be a lot easier and cheaper to address your concerns (and make you go away) rather than have to read another letter or respond to another phone call from a person who is sick and tired of genital herpes taking a back seat to every other conceivable topic-du-jour that Washington D.C. chooses to focus on…..like bioterrorism that continues to waste about $1.7 billion per year of the NIH’s ~$30 billion per year budget.

      Sincerely yours,
      Bill Halford

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