On the Agenus HerpV vaccine trials


November 12, 2013 |

Two readers recently asked me about the Agenus HerpV trials.  Given that this is a topic of broad concern to genital herpes sufferers, I have converted the original query and my response to a blog post as follows.

– Bill H.

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November 8, 2013

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?

– Staying Upbeat

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November 12, 2013

Hi Staying Upbeat,

I have read the link to the press release you cite and I am deeply troubled. I am not sure who I am more upset with…..the scientists who are willing to distort the truth and say that these results are “exciting,” or the biomedical investors and NIH reviewers who will likely continue to support this folly. The “statistically significant” 15% reduction in HSV-2 shedding they report is a non-event. What is the cutoff for a non-result here? What % reduction in HSV-2 shedding does valtrex achieve? Probably well above a 200% reduction if I had to guess. The goal of a therapeutic HSV-2 vaccine should be to do better than valtrex……not worse.

If I had 6 genital herpes outbreaks in 2012 that lasted for an average of 10 days, and then I enrolled in the Agenus trial in 2013 and experienced 6 genital herpes outbreaks that “only lasted” for 8 days, that would be a 20% reduction in genital herpes symptoms and this might be accompanied by a 40 – 60% reduction in HSV-2 shedding. This type of response for a herpes therapeutic would seem pretty weak to me, but in the bizarro world that “herpes vaccinologists” have entered, apparently as long as you can clear the bar of p < 0.05, then apparently your herpes vaccine is a home run and the results should be trumpeted from the highest tower.

I suspect that there is a single motivation for this press release………the only logical reason for putting lipstick on this pig is if Agenus hopes to ask (1) NIH reviewers and/or (2) biomedical investors to support the continued folly of testing the HerpV vaccine in human clinical trials.

I would hope that any science-minded person would recognize that a “15% reduction” is an average across a group, and that in the real world a 15% reduction in HSV-2 shedding would have a standard error on the order of +/- 50%.

In the world of science, the way we formally state such a result is…….”This HSV-2 vaccine produces a 15 +/- 50% reduction in HSV-2 shedding from the genital tract.” What most scientists would conclude from this result is……”This HSV-2 vaccine is a waste of time, since what I was looking for was a vaccine that elicited at 1000 +/- 300% reduction in HSV-2 shedding (i.e., a 10-fold reduction in HSV-2 shedding).”

For me, the take-home message is simple from the Herpevac trial, the Genocea (GEN-003) trial, and now the Agenus HerpV Trial……..It is time for scientists to put on their big boy pants, and admit that the molecular reductionist approach to HSV-2 vaccines has simply not panned out. It is time to move on and test some fundamentally new ideas like a live-attenuated HSV-2 vaccine that elicits 100 times greater protection in animal models.

Titanic

Millions of lives continue to be destroyed each year by the vaccine-preventable disease that is HSV-2 genital herpes. People deserve better than the continued folly of HerpV and all of the other HSV-2 vaccine approaches that continue to ignore the obvious………..when you immunize people with 0.2% of HSV-2’s antigens, you tend to harvest only 0.2% of the protection against HSV-2 that is possible.

Dear Staying Upbeat, thank you for your query. I am, of course, not in the least upset with you. Rather, I am upset with people who continue to occupy “leadership positions” in the HSV-2 vaccine world despite their chronic inability to differentiate promising HSV-2 vaccines from hollow promises like HerpV.

The reason I find the claims that “the HerpV 15% reduction is exciting” so troubling is that a scientist either has to be (1) ignorant of what a real HSV-2 vaccine-induced change would look like or (2) willing to distort the truth and pretend like a vaccine that induces a 15% reduction in HSV-2 shedding is anything other than an abject failure. I note that all of my colleagues who study herpesviruses or herpes vaccines tend to be exceedingly smart people, and thus I don’t really question their intelligence; by-and-large, these are people who I consider much smarter than myself and certainly better able to navigate the NIH funding system. However, intelligent or not, I fear that these individuals may be selling out their integrity to support a flavor-of-the-day herpes vaccine (i.e., the HerpV vaccine) that the objective measurements indicate is in the process of sinking, much like the Titanic after it hit that iceberg in the North Atlantic. The only question left in my mind is how much more time and money are we going to waste on the HerpV vaccine before a critical mass of scientists agree that this is not a viable herpes vaccine candidate.

One of the quotes I learned as a junior scientist that deeply resonated with me was that of Charles Sanders Pierce (http://todayinsci.com/P/Peirce_Charles/PeirceCharles-Quotations.htm), and the quote is as follows: “There is one thing even more vital to science than intelligent methods; and that is, the sincere desire to find out the truth, whatever it may be.”

The truth is that the concept of “antigenic breadth” explains both why HSV-2 subunit vaccines like HerpV keep failing (i.e., because 0.2% of HSV-2’s foreign peptides is too little to make for a good HSV-2 vaccine), and the concept of “antigenic breadth” explains why whole HSV-2 viral vaccines are far superior…..because they present 50 to 99% of HSV-2’s peptides to the vertebrate immune system in the proper context of virus-infected cells.

Perhaps it is time to consider some new ideas that might actually lead us to the important goal of making a HSV-2 genital herpes a vaccine-preventable disease of the past, and sparing tens of millions of our children from the needless suffering caused by this disease. For this reason, I look forward to the results of the HSV-2 ACAM-529 whole virus vaccine trial (http://www.niaid.nih.gov/news/newsreleases/2013/Pages/HSV11-8-13.aspx), as this is the only new HSV-2 vaccine idea of any scientific substance that has advanced to human clinical trials in the past 10 years. ACAM-529 truly offers a new and real hope of eliciting some type of real protection against HSV-2 genital herpes, and I hope that my colleagues in the vaccine industry and the NIH will support its rapid advancement through human clinical trials. ACAM-529 may not be the final solution to our HSV-2 vaccine needs, but at least it is the first concrete step that we have made in the right direction in the 21st century.

– Bill H.


38 Responses to On the Agenus HerpV vaccine trials

  1. faith in god November 11, 2014 at 11:32 pm #

    Please Dr. Halford, just.do it!! You seem confident in ur vaccine, so the faster it gets tested the sooner you get to test ur hypothesis. If the vaccine is effective you will change the world for so many!! Blacks, Latinos, Asians, Europeans You will be in the history books. Most people affected will donate for the cause. Please find a way!!

  2. Kevin November 7, 2014 at 5:02 pm #

    Well said Bill. Thanks again for all your work in this area. I am an American through and through but I am convinced that this country’s best days are behind us, at least in the short term. Meanwhile, time waits for no man. I do hope you find support for your research abroad and I hope your success vindicates your pragmatic approach and hard-data-based convictions.

    – Kevin

  3. Bill Halford November 7, 2014 at 4:55 pm #

    Hi Kevin,

    Thanks for the comments. My basic thought process is that the FDA has, in the space of vaccine development, largely proven itself to be out of touch and irrelevant. There is a memorable scene in the movie “Johnny English” where an individual has tattooed across their back end the words, “Jesus is coming. Look busy.” I think the FDA operates on a similar principle. For a decade, they have had numerous Ebola virus vaccine candidates on their desk that could have been in useful in preventing an all-out epidemic in Africa. This time last year they were doing nothing to move these applications forward, but now that there is a hue & cry, all of a sudden treatments that languished in stacks of paperwork are getting approved.

    So, yes, I am over the FDA and their ridiculous, self-important “process” for bringing a vaccine to market that starts with: “Step 1- Raise $200 million and hire an army of attorneys.”
    Last time I checked 96% of the world’s population lives outside of the U.S. I don’t discriminate….black, white, Latino, Jewish, Chinese, Indian……herpes is a universal problem, and I will head to whichever jurisdiction and government is willing to consider the underlying science, and safety data, that says a live-attenuated HSV-2 vaccine is sufficient to stop the genital herpes epidemic. I note that the U.S. is currently about 30th or 40th in the world in math and science. I am from the U.S., and am American through and through, but I also have no problem saying that we are becoming a country of idiots, run by idiots. Nothing special about the U.S. when it comes to advancing a HSV-2 vaccine that works. So, yes, my sights are firmly set beyond the boundaries of FDA-sanctioned stupidity that (1) advocates saving everyone from the dangers of a live HSV-2 vaccine (that is much safer than the live VZV Oka vaccine we use in the U.S.) while simultaneously (2) ignoring that 1 million Americans contract real (wild-type) HSV-2 each year.

    Stupid people get to vote too. As a scientist, I retain the right to ignore them, and do what needs to be done to advance a HSV-2 vaccine that actually works into clinical usage where it can actually help those who need it.

    – Bill H.

  4. Kevin Peters November 7, 2014 at 4:26 pm #

    Dear Dr. Halford, first of all I applaud your work and your blog is the single most sober fact-based source of information on HSV I have been able to find on the Internet. To start, let me say thank you! I’ve been reading through your blog for some time now. I have also researched the various efforts (and failures) in the space of HSV vaccine development. Given the “titanic” repeated failures of the subunit vaccine route, it seems obvious to me that a live attenuated virus is absolutely the way to go. There is a safe and proven attenuated live vaccine (VZV Oka) already in use for varicella, about as similar to HSV as you can get. If your hurdle in progressing forward is that the FDA’s concern for “liability” prevents them from performing a simple risk/reward calculation (i.e. the potential risk from broadly administering an attenuated vaccine vs. the almost certain reward of stamping out a viral epidemic), why not consider other jurisdictions for making progress with this important work? Even though our country seems to be progressing backwards when it comes to data / science / logic informing our decisions and priorities, other countries (notably Western Europe and Australia) do not appear afflicted with our particular brand of madness (yet). Have you given any consideration for applying for grants in other jurisdictions?

  5. poe huang July 23, 2014 at 3:54 am #

    Dear Bill Halford,I am a SHV-2 patients to China. I hope you can give me help. Let me know the current vaccine development. To help me and my family to regain the joy.thanks

  6. Bill Halford July 18, 2014 at 12:22 pm #

    Dear Moazam,

    I am not a stickler for formalities, and certainly don’t expect to be addressed as “Dr. Halford” in the setting of a blog. However, “Billy” just seems like a bit much to swallow, and so I respond as a long-standing Seinfeld fan, “No soup for you!”

    – Bill H.

  7. Moazam July 13, 2014 at 9:02 pm #

    Dear Bill Halford, its always a treat to read your input on any advancement made to find a cure or vaccine, my question is slightly different. I think i was infected with Hsv2 three months back The Dr in UAE looked at my thing there were few pimple like bumps he declared it genital herpes which was also confirmed recently by my blood test of IGg , in about 4 months post GH exposure, i had i think 2 recurrence once on genital the other time on my back same 2 pimples, both time it was not much of any worry. only reading about it has got me really worried. my question is would it get worse than this, if not i think i can handle it. reading the post of most people with genital herpes makes me think its really a nightmare which i havent faced it yet, do u think the worse is yet to come? lastly which therapeutic vaccine result should we wait for as there are many in the pipeline, to me IAN frazer looks like the man to come with a break through . thanks Billy :)

  8. Bill Halford June 16, 2014 at 6:10 pm #

    Dear T. Pealer,

    I am unaware of a centralized website that discusses ongoing HSV-2 vaccine clinical trials. Sorry I cannot help more with this question.

    – Bill H.

  9. Bill Halford June 16, 2014 at 5:54 pm #

    Dear Bukx,

    Vitaherpavac, Panavair, and Lupidon……..sounds like snake oil if I had to guess…….that is, “solutions” that are made available to people for a price, but which probably have as much of an effect on HSV-2 genital herpes as a good diet, exercise, and a positive attitude. All of these things cannot hurt, but are not exactly a “cure” for genital herpes.

    If someone has more information (that I am missing), please chime in. All I can say is that although I consider herpes simplex virus research my full-time job, Vitaherpavac, Panavair, or Lupidon are certainly not mainstream treatments that scientists spend a lot of time to discussing / studying…….and thus, I have never heard of them as treatments for genital herpes.

    – Bill H.

    P.S. Pubmed citations on Panavir are enough, in and of themselves, to convince me this is little more than thinly disguised snake oil: http://www.ncbi.nlm.nih.gov/pubmed/19227121

    P.P.S. Pubmed citation on Lupidon from 1975: http://www.ncbi.nlm.nih.gov/pubmed/179231; I would suggest that if Lupidon were an effective anti-herpes medicine, then it probably would have caught on at some point in the last 40 years (I was 7 years old when this paper was published).

  10. JohnDJoe June 16, 2014 at 4:34 pm #

    I think that Nobsterbot was referring to T. Pealer, because he was asking of a place to start looking out for recent clinical trials in progress.

    Kind regards,
    Joe

  11. Bill Halford June 14, 2014 at 11:41 am #

    Dear Nobsterbot,

    I appreciate the thought, but I will stick to my less obvious website for now. As expected, the Wikipedia entry includes a lot of discussion of other HSV-2 vaccine approaches with which I do not necessarily agree. While dispersion of information is important, my survival as a scientist requires that I avoid stepping on the toes of my colleagues as much as possible. On the Herpesvaccine Blog, I can offer my unadulterated views on where the field of HSV-2 vaccine research stands, and at this politically correct point in time, I think that this is actually the most important service I can offer……to just say what most scientists are thinking, but are understandably hesitant to say. Every time a scientist offers a strong opinion, they jeopardize their political future which means that they are rolling the dice with their odds of garnering future funding for their laboratories in what are incredibly uncertain times (i.e., the NIH funding rate for scientists at the moment is at a historical low point, and thus scientists are bailing out and/or retiring in droves).

    The difference between myself and most scientists is that I think speaking the truth, and getting down to the heart of why HSV-2 vaccines have been failing for 30 years, is a lot more important than whether or not my scientific colleagues think I am a nice guy…..even if that means that every one of my NIH grant applications is triaged moving forward.

    Given the political landscape / reality of how science-funding works, I think it best if I stay away from Wikipedia and hope that most of my scientific colleagues will forgive me for expressing my unfiltered views on this blog.

    – Bill H.

  12. Nobsterbot June 14, 2014 at 11:04 am #

    The best website to start featuring an overview is always Wikipedia:
    http://en.wikipedia.org/wiki/Herpes_simplex_research

    Kind regards
    Nobsterbot

  13. T. Pealer June 13, 2014 at 3:08 pm #

    Dr. Halford,

    I have was diagnosed with Herpes Simplex I & II back in the mid ’80’s. I have been taking Acyclovir and now Valtrex to ease the breakouts, which if I do not take my meds, happen quite frequently.

    Is there a website somewhere that I can keep informed on any HERPV clinical trials that may begin again? I like so many others am willing to participate. Last I read, the Agenus trials for HERPV were at a standstill. Is this still the Case? Are there any websites I can monitor to keep me informed of future clinical trials that may arise?

    Thank you.

  14. Bukx June 12, 2014 at 8:47 pm #

    Dr. Halford, have you heard of Vitaherpavac, Panavair or Lupidon, supposed therapeutic vaccines used in Russia and Europe? I heard of them in hsv blogs and forums but don´t know if are real and if they work. I would appreciate to hear your thoughts on it…
    thanks a lot !

  15. Bill Halford March 26, 2014 at 1:38 pm #

    Hi JohnC,

    Promising results are always good. What it all means for the long haul……I have no idea. I guess we will see how Genocea’s therapeutic HSV-2 vaccine pans out. It is certainly an underexplored opportunity that Genocea is looking to tackle, and thus it is great that they are running these studies. However, I think it is too early to know whether or not these results will translate into an everyday clinical cure for genital herpes. Always good to remain hopeful, but at the same time not to count your chickens before they hatch.

    – Bill H.

  16. JohnC March 25, 2014 at 1:11 pm #

    http://www.businesswire.com/news/home/20140324006002/en/Genocea%E2%80%99s-Therapeutic-Vaccine-Herpes%C2%A0Simplex-2-Infection-Shows-Highly#.UzG39fl5MsZ

    Genocea’s Therapeutic Vaccine for Herpes Simplex-2 Infection Shows Highly Significant Reductions in Clinical Symptoms at 6 Months. Is this an end to the ongoing herpes-vaccine research, or does the battle just begin ?

  17. Omne vivum ex vivo February 4, 2014 at 11:59 pm #

    Dear Dr Halford, thank you for posting so much information and answering so many questions. By doing so you have taught me and I’m sure many others much . From all my extensive readings, I believe your icpo…. Vaccine is the best way forward in defeating HSV. I believe your work will prevail. It must! All the best to you:)

  18. Bill Halford January 15, 2014 at 2:15 am #

    Dear Karen,

    Sorry to hear about all of the emotional upheaval and turmoil in your life.

    I believe that you are a good example of why HSV-1 and HSV-2 serological tests are not routinely run; because most people who are infected with HSV-1 and HSV-2 are asymptomatically infected, and most asymptomatic carriers don’t know how to use this information in a productive way. In your case, you are only aware of your HSV-2 infection status because of an antibody test, not because you ever had any symptoms of genital herpes. Ignorance is bliss.

    With knowledge of your HSV-2 infection comes a whole slough of information, much of which may not really apply to you. Most of what we know about the “risk of HSV-2 transmission by those who are asymptomatically infected” pertains to people who are frequent HSV-2 reactivators (i.e., have frequent genital herpes outbreaks), and what is meant is that even during asymptomatic periods (i.e., in between visible outbreaks), these individuals still shed infectious virus in the absence of symptoms…..hence they always pose a transmission risk to any potential sexual partner.

    Now, Karen, we come to you. If it took an antibody test for you to figure out you carry the HSV-2 virus, then you clearly do not have what an OB/GYN would consider “recurrent genital herpes disease.” This is in stark contrast to “high reactivators” who may have more than 12 outbreaks of genital herpes lesions per year; I guarantee you that these people do not need an antibody test to let them know there is a problem. I am not personally convinced that people such as yourself who have (1) HSV-2 antibodies but (2) are blissfully unaware of their uber low-grade HSV-2 infection really pose the same level of HSV-2 transmission risk as “high reactivators” who are in between genital herpes outbreaks.

    If I had to guess, statistically speaking you probably were asymptomatically infected with HSV-2 by one of the people you were sexually involved with before you met your husband. His HSV-2 antibody titers strike me as low, so he either does not have the HSV-2 virus or has a low-level, asymptomatic HSV-2 infection that is just barely keeping his HSV-specific B-cells awake and in the game.

    Assuming your husband does carry the HSV-2 virus, it is not possible through conventional tests to figure out if you and your husband share the exact same strain of HSV-2 (i.e. if you gave HSV-2 to your husband, or if your husband transmitted HSV-2 to you…..either is possible, but it is also possible you independently contracted HSV-2 from your other sexual contacts).

    Moving forward, my advice would be that entering into a new relationship, full disclosure of your HSV-2 serological status would be appropriate. However, I think it is reasonable to point out that (1) you are either completely or nearly completely asymptomatic and (2) your husband of 16 years never contracted genital herpes disease and also never had any symptoms of which you were aware; this suggests that neither of you is a “high reactivator.” If I had to rate HSV-2 carriers for their relative risk of transmission to a sexual partner, your history says that you are a relatively low-risk. So long as you disclose your HSV-2 serological status to any future love interests, then I think you will have done your “due diligence” and you and your partner can decide what level of precautions (e.g., condoms) you wish to take if he is HSV-2 seronegative.

    – Bill H.