On the Agenus HerpV vaccine trials

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.


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


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.

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.


  1. 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. 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?

    • 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.

      • 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. 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

  4. 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 :)

    • 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.

  5. 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.

      • 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.

        • 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,

    • 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.

  6. 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 !

    • 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).

    • 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.

  7. 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:)

  8. My husband committed adultery. I found out in March 2013. The last time I was intimate with my husband was the following August. I was feeling inept, depressed, and lonely. The end of August, I met a new friend. We talked, had lunch together, went out a few times, then invited to his home. In November, more of an interest had developed and we became intimate partners. At which time, but after the fact, I scheduled a PAP smear and requested testing for everything. I tested twice unaware I had to request testing for herpes, Syphallys, and HIV. During the second test, I had an OB I assumed was a yeast infection but was found to be BV (due to stress, lack of sleep, and not eating properly). All other test came back negative both times. I was relieved to say the least. That was a short relief after being told a culture is not a valid test for herpes. That a blood test was the only way to know. As a result, I encouraged my husband to test as well. However he tested only for HSV 2 and the result was positive at 1.50, I think. I know it was low. Meanwhile, the diagnosed BV transitioned to and from a yeast infection with minimum relief between and continues today. Fearful of a positive outcome as well and my possibly exposing my new partner, I didn’t take/receive my lab result until a few weeks later (6 days ago) and it read >5.0. Needless to say, I was speechless, numb, shocked, and depression set in not too long after. To live with such a disease is a hopeless feeling. I was just getting back to being me. I had made the decision to end what I had developed with my new partner unhappy about my behavior as a married women. All to be the best I could as a mother for my daughter as we transitioned from a single family home with both parents to divorced parents and single parent home. With focus on rebuilding my life in a way that lessoned the negative effect of our divorce on her. Hopeful that my successes in 2013 would make for a brighter future for the both of us and one day I would find love again. What man would want me now? How could I even divulge such a thing. I would rather be single for the rest of my life than to put myself out their like that not knowing what the outcome would be OR possibly infecting others in-spite of them knowing. I feel like my life is completely over. To make matters worse, my husband decided NOT to pay the mortgage for the last 4 months in addition to a few other financial responsibilities without telling me. So we could be facing foreclosure and the other depts. reported as delinquent. As a result, my good credit I worked hard to maintain dropped. Putting me at a disadvantage to find appropriate housing in a appropriate area for my daughter. And I’m facing divorce. Can it get any worse. I feel no way out. I’m at my end. I have no more fight in me. I just want to be left alone. The only thing keeping me going is my daughter….thank GOD for her.

    I share this story so that you know your hard work and dedication to finding a vaccine is worth it. For people like me who has herpes and is having a very difficult time accepting my fate because it means possibility living without having a loving partner to share my life with because I have this stigma over my head. To know there is hope for a normal life exempt of a lifetime STD is reachable gives hope and something to look forward to.

    I have one question, please explain the value result I received of >5.0. And why is my percentage so much higher than my husbands. Could I have contracted herpes a long time ago and gave it to my husband? But that would have been months ago. So why isn’t his value the same or close. Perhaps he got his from a newer partner I’m not aware of? And, I got exposed by my new partner. Know, for 16yrs, I have only been with my husband. It wasn’t until November 2013 I obtained a new partner. I stop sleeping with my husband almost 4mths prior. With only my new partner as my only sexual contact since. Prior to meeting my husband, I have had 8 partner in my lifetime since the age of 19yr old. Who, when….is the question. Why aren’t there test that could determine how long. Better yet, why aren’t blood test for herpes 1 and 2 a standard test for PAP smears and/or Male and Female yearly physicals (including children). For better awareness and possibly better decision making.

    • 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.

  9. Well, Bill, yours is what I call an expert opinion,clearly delineating the nuances of the cell-mediated and humoral immunity needed to combat HSV-2. The idea of a live HSV-2 vaccine is plausible, especially in the case that it has been genetically modified to prevent replication, and hence latency. If I understand you, the idea here is to elicit a robust immune response that not only deals with the current exposure, but leaves enough memory cells that would react faster, more efficiently, and more intensely next time the latent viruses attempt to activate.
    Presumably, asymptomatic carriers of the virus are able to elicit such an adequate immune response, which is able to keep the virus in a perpetual latent state. It goes without saying that our God-given immune system, when in optimum shape, remains our best defense against any microbe. Most of the people that I’ve heard have been able to go from symptomatic to asymptomatic are people who made very drastic lifestyle changes. People have identified food items, stress and many other factors that trigger their symptoms. All these factors have one thing in common : they have a deleterious effect on the immune system.
    Getting depressed over HSV-2 would only make one’s symptoms worse, simply because depression suppresses the immune system(probably through production of immuno-suppresive actors such as IL-10, TGF-B, corticosteroids etc). Some food products, and environmental factors could be doing the same as quite a few people have escaped symptomatic HSV by making drastic changes to their diet and lifestyle. My advice is for people to adapt healthier lifestyles, and to use the antiviral drugs on the market, some of which are very effective at killing activated viruses that cause the symptoms.

    The other alternative to keeping the viruses in a latent state would be to somehow elicit activation, such that systematically all the viruses are activated at once. Then, it could all be killed and eradicated with the available antivirals we have. I believe some researchers have been pursuing this approach, having developed a way to target the viral genome within a cell and activate it. This is probably a long way from clinical trials, but the idea is brilliant if it can be replicated in vivo with human subjects.

  10. Thank you so much for that detailed response, Bill, it really cleared up a lot of the questions and concerns that have been bouncing around in my head.

    So now – is it just a matter of waiting until scientists realise that these other approaches do not work, before they will try testing with the live attenuated vaccine?

    Why is it that Coridon and Sanofi Pasteur can test their vaccine but you cannot test yours? Is it a matter of funding, silly safety concerns, or simply that other scientists believe this approach will not be effective?

    I’m sorry if I seem ignorant – I’m just trying to fully understand why something is being held back from millions of people who are suffering from the physical/psychological effects that can come with living with HSV2.

    I realise it is the purpose of this blog to get that word out there – and I am so, so grateful for all of your efforts. I just wonder if there is anything else that can be done, perhaps anything readers of this blog can do at an individual level to help get things moving?

    Thanks again,


  11. Hi Bill,

    I’ve read the theories posted about how potential therapeutic/prophylactic HSV2 vaccines should work, but I am still left with one question that I would like to get your personal opinion on.

    Do you think it is possible that a therapeutic vaccine can be developed that is so effective that it completely eliminates the moral/ethical obligation to inform potential partners of your previous exposure to HSV2? I think if something of that calibre were to be created, then it could be considered a cure for all intents and purposes.

    I’m just wondering if it is realistic to expect that such a vaccine could be developed.



    • Hi Susan,

      Your central question is, “Do you think it is possible that a therapeutic vaccine can be developed that is so effective that it completely eliminates the moral/ethical obligation to inform potential partners of your previous exposure to HSV2?”

      I will answer this in 3 parts.

      First, I think that GEN-003 and HerpV are pretty ridiculous approaches to a therapeutic HSV-2 vaccine. If the approach is possible, it will only be possible with the most conceivably effective HSV-2 vaccine; namely, a live-attenuated HSV-2 vaccine. If the concern is, “Well would a live HSV-2 vaccine be too dangerous for these patients?”, I would respond “They are already infected with millions of copies of wild-type HSV-2 which is obviously one hell of a lot more dangerous than a live HSV-2 vaccine that cannot cause disease in severely immmunocompromised hosts (i.e., SCID mice).” I think therapeutic HSV-2 vaccines can be vastly improved by using live HSV-2 vaccines that deliver the other 99% of HSV-2’s antigens that are missing from the GEN-003 and Herp V vaccines currently in human clinical testing.

      Second, no matter how good a therapeutic HSV-2 vaccine is, the risk of transmission will always be there, and so likewise the moral/ethical obligation to inform potential partners of your HSV-2 history will always be there.

      Susan, the third point is the most important point, so please read and re-read this as needed until it fully sinks in.

      Third, a therapeutic HSV-2 vaccine is a high bar to clear, but a prophylactic HSV-2 vaccine should be much easier once we quit wasting our time on Herpevac, GEN-003, HerpV and all the other failed HSV-2 vaccine approaches that promise 100% protection against HSV-2 by immunizing with 1% of HSV-2’s antigens. As soon as scientists in my field wake up to the simple truth that (1) the past HSV-2 vaccines that failed were lame ideas from the word go and (2) the solution to the genital herpes problem is as plain as day…..a live-attenuated HSV-2 vaccine. Once scientists put on their big boy pants (i.e., admit the error in logic that has held us back for 30 years), then the scenario that HSV-2 discordant couples face will be a non-issue.

      Any live HSV-2 vaccine that would work as a therapeutic HSV-2 vaccine that reduces or eliminates the symptoms of genital herpes in someone already infected with HSV-2 (i.e., the hard task), then a lower dose of THE EXACT SAME VACCINE should certainly work quite easily as a preventative vaccine.

      Bottom line: If we can ever get live HSV-2 vaccines out of the shadows and into human clinical trials, then (1) this will be your best shot at a good therapeutic HSV-2 vaccine and (2) will solve the problem faced by discordant couples, because the seronegative partner can get immunized with a highly effective, live HSV-2 vaccine. Once a seronegative person has been immunized twice (4 to 6 weeks apart), then they will no longer be susceptible (immune) to developing a full-blown HSV-2 infection that results in symptomatic genital herpes. This is why we say that effective vaccines induce “immunity” to a disease. The only reason that we don’t have such a HSV-2 vaccine is because scientists have become so pre-occupied with proving that HSV-2 subunit vaccines (Herpevac, GEN-003, HerpV) “should” work, that they have lost sight of the big picture……the data says otherwise.

      Thus, yes, it is realistic to expect that an effective HSV-2 vaccine is highly feasible, and I would suggest that live HSV-2 vaccines such as the one developed by my laboratory would fulfill precisely the role you suggest. However, I am currently delayed by the fact that the majority of HSV-2 vaccine scientists are years behind in coming to the realization that (1) subunit HSV-2 vaccines have failed and (2) live HSV-2 vaccines are the solution that everyone is waiting for. The Nike slogan goes “Just Do It.” Likewise, I am waiting for a critical mass of scientists to be persuaded that it is time to just do it and test live-attenuated HSV-2 vaccines, and start making genital herpes a vaccine-preventable disease of the past.

      – Bill H.

  12. Hello Bill

    iv´e been visiting your blog for some months and i have a question about the Gen-003, theres a forum i also visit and theres a girl involved in the Clinical trial of GEN-003 who has been OB free for 10 months now, What do you Think about that?
    Becouse i have read about what you think about GEN, Coridon and Agenus

  13. Hi Bill.

    I have a general question about vaccines. If the herpes virus hides within neurons, how will antibodies be able to find the virus in order to kill it? Also, wouldn’t antibodies or killer cells have to destroy the nerve cells harboring the virus in order to eradicate the virus? Since the virus lives in sensory neurons, would those nerves die? Does that mean that patients would lose sensation in the dermatomes supplied by those nerves? It just seems that after a long time of working for a cure, very little real progress has been made toward finding a cure for HSV 1/2, and I’m starting to question the feasibility of the whole concept. I guess I am skeptical that anything will truly work.

    Thanks for all your efforts.


    • Dear Suffering,

      All of the HSV-2 vaccines advanced to human clinical trials over the past 30 years present a whopping 0.5 to 1% of HSV-2’s antigens to the immune system. Yes, these approaches have not worked. However, I hate to be nit-picky and bring science into the discussion, but I would argue that the 99.0 – 99.5% of HSV-2 antigens missing from those vaccines likely limited their ability to “teach the immune system” how to better recognize HSV-2.

      The Genocea GEN-003 vaccine and Agenus HerpV vaccine suffer from the same limitations.

      The fact remains that noone has ever asked the question, “What if we vaccinated people with a HSV-2 vaccine that could encode 99.3% of HSV-2’s antigens?” with the goal of driving clonal expansion of all of the B- and T-cells that could conceivably contribute to protection.

      If you choose to be skeptical, then so be it. As a scientist, I am here to say that your skepticism is not warranted. The reason the chickenpox vaccine works is because it is a whole, live-attenuated VZV virus. HSV-2 and VZV are kissing cousins. Scientifically, there is no good reason that a live-attenuated HSV-2 would not generate the exact same outcome.

      However, I note that it is very difficult to discover the true potential of a live-attenuated HSV-2 vaccine to prevent genital herpes when 0 PEOPLE IN THE UNITED STATES HAVE BEEN ENROLLED IN SUCH A CLINICAL TRIAL IN THE PAST 25 YEARS. In that same period of time, more than 14,000 people have been enrolled in clinical trials of HSV-2 subunit vaccines that contained an average of 0.8% of HSV-2’s antigens.

      I cannot prevent the U.S. government from continuing to back stupid HSV-2 vaccine approaches that have no real hope of success. However, I note that the U.S. government cannot re-write the playbook that God provided us. That is, we were born into a world where the rules of nature were established and in place before we got here. Those rules say that a HSV-2 vaccine that contains 99% of HSV-2’s antigens will work, and likewise those same rules that HSV-2 vaccines that contain 0.8% of HSV-2’s antigens will not work.

      HSV-2 genital herpes is a vaccine-preventable disease, but the human beings in charge of deciding which approaches we are going to test need to quit choosing stupid HSV-2 vaccines that are inconsistent with nature’s rules.

      – Bill H.

      • Thanks for your response, Dr. Halford. I can certainly appreciate the idea that a vaccine with a much larger percentage of viral antigens than what has been used thus far would likely be more successful. I guess I just don’t understand enough about how vaccines work. How can you kill the virus if it hides away from circulation inside a neuron? And if you kill the neuron that harbors the virus, how does the individual not lose the function of those sensory neurons?

        And if you’ll indulge me, I have another general question. Do our immune systems generally get better at containing HSV over time, or does the immune system start to tire from keeping the virus at bay and thus become less effective over time?

        Thanks again for all your hard work and dedication to helping people like me.


        • Hi Suffering,

          Will respond in a few days…..I am going on Sabbatical Leave for 7 months at the Rocky Mountain Laboratories (a division of NIH). In transit at the moment. Will respond once I settle into my home away from home in Hamilton, Montana.

          – Bill H.

        • Hi Suffering,

          All good questions, which I can answer to some extent but not completely, as the answers are not all known at the moment. I will do my best.

          Your first question was “I guess I just don’t understand enough about how vaccines work. How can you kill the virus if it hides away from circulation inside a neuron?”

          The key here is that the immune system does not need to “kill the virus” (i.e., or the cells it infects) in order to contain HSV-2 infection. Indeed, I would suggest that, by definition, any virus that routinely persists in the human body for decades has evolved a trick or two to avoid having its home (virus-infected cells) uniformly nuked by cells of the immune system. Herpes simplex virus 2 (HSV-2) is one example of a virus that persists in the human body. Likewise, hepatitis B virus (HBV) is another virus that routinely establishes a persistent infection, but at a different anatomic site; namely, HBV establishes a persistent infection in the liver.

          There is ample evidence that for HSV-1 (and by extension HSV-2) and HBV, the host immune response that controls these infections is predominantly non-cytolytic in nature. That is, T-cells are essential to get full protection against these viruses, but the predominant controlling mechanism that shuts down viral infection does not involve the typical CD8 T-cell mediated destruction (cytolysis) of virus-infected cells. Rather, activated CD8 T cells (and CD4 T cells) secrete cytokines such as interferon-gamma which can synergistically stop HSV or HBV replication when combined with cytokines of the innate immune response like interferon-alpha/beta or tumor necrosis factor-alpha.

          I appreciate that this is getting a little technical, so let me distill the important message: (1) the immune response that controls HSV-2 replication appears to be highly dependent on getting HSV-2-specific T cells to find, or recognize, HSV-2 infected cells and (2) the control mechanism is based on T cell-secretion of cytokines, not T cell-mediated destruction of virus-infected cells.

          Against that background, I return to your question………”I guess I just don’t understand enough about how vaccines work. How can you kill the virus if it hides away from circulation inside a neuron?”

          The answer is that an effective HSV-2 vaccine will not kill the virus, and it will almost certainly not kill all of the cells that HSV-2 infects. However, what an effective HSV-2 vaccine will do is (1) drive clonal expansion of HSV-2-specific T-cells which will directly improve immune control / suppression of HSV-2 replication in host cells and (2) drive clonal expansion of HSV-2-specific B-cells which will produce HSV-2-specific antibodies that can help “tag” HSV-2-infected cells as foreign and set up pro-inflammatory signals that call HSV-2-specific T-cells to sites of viral replication. So, in short, antibodies are the molecular beacons (1/100 billionth the size of a T-cell) that can diffuse into tissues and quickly find HSV-2 infected cells, and these molecular beacons (antibodies) can set up the pro-inflammatory environment that calls in the T-cells to sites of HSV-2 infection where they can suppress HSV-2 replication.

          Whether or not you understand exactly how immune effector mechanisms (the controlling mechanisms) work is less critical. What is critical is to understand that T cells and B cells essentially do one thing for the immune system…..they mediate recognition of that which is foreign, but they only recognize that which is foreign in very small snippets of 6- to 30-amino acids at a time (HSV-2 encodes 39,100 amino acids). HSV-2 vaccines do one thing, and one thing only……they drive clonal expansion of those rare B- and T-cells in your blood, spleen, and lymph nodes that happen to recognize HSV-2. The more HSV-2-specific B- and T-cells you have at the end of being vaccinated against HSV-2, the better equipped your immune system will be to QUICKLY RECOGNIZE cells in which HSV-2 is actively replicating. Between RECOGNITION and suppression of HSV-2 replication are the effector mechanisms, which are still not completely agreed upon by herpes immunologists, but which as I indicated appear to be highly dependent on T-cell secretion of cytokines such as interferon-gamma, which do not kill virus-infected cells, but which do convince HSV-2 that it has a choice to make: (1) stop replicating now! or (2) I am a CD8+ T cell and about 5 minutes away from nuking your home (virus-infected cell) with granzyme and perforin which collectively cause cells to commit suicide (undergo apoptosis).

          BOTTOM LINE: The most effective HSV-2 vaccines will likely be those that stimulate clonal expansion of the greatest number of HSV-2-specific B-cells (antibody producers) and T-cells.

          Your second question is “And if you kill the neuron that harbors the virus, how does the individual not lose the function of those sensory neurons?”

          More importantly, if cytolytic CD8+ T cells killed every last HSV-2 infected neuron, then herpes would be the equivalent of influenza virus, and would cause an acute infection for 1 to 3 weeks and would then disappear. However, the CD8+ T cells don’t kill every last HSV-2 infected neuron, and in reality kill surprisingly few HSV-infected neurons in experimental models of HSV-1 infection. Thus, as one might expect from the course of disease, HSV-1 and HSV-2 have acquired a neat set of tricks to prevent the immune system from doing its job and delivering the death blow to HSV-infected neurons. Rather, the immune cells settle for “containment” and suppression of active replication. An important thing to remember is that during its latent state, HSV-infected neurons do not synthesize high levels of viral protein……in fact, it is unclear that they synthesize any viral protein. Immune recognition and destruction of HSV-infected cells can only occur when viral proteins are present. Thus, during latency, HSV-infected neurons are largely invisible to T-cells and thus during latency it is easy to understand why HSV-specific T-cells don’t destroy HSV-2 infected neurons…..because there are no viral proteins available to trigger the T cells to attack.

          And your third question was…..”And if you’ll indulge me, I have another general question. Do our immune systems generally get better at containing HSV over time, or does the immune system start to tire from keeping the virus at bay and thus become less effective over time?”

          Great question….and like most great questions, I cannot answer it because the answer in unknown. Thus, what follows is little more than my own musings and speculations on the matter.

          I think it is important to remember that 75% of HSV-2 infections are completely asymptomatic, whereas most people who are sufficiently motivated to learn more about HSV-2 and genital herpes (e.g., visitors to this blog) represent the outliers who are in the top 1% of disease sufferers. In people whose HSV-2 infections are completely asymptomatic, it seems that their immunity to HSV-2 generally remains very stable and very good over time provided that they are not severely immunosuppressed. For example, (1) AIDS, (2) organ transplant recipients, (3) patients who take immunosuppressive medications to combat an autoimmune disease, (4) cancer patients on chemo drugs, or (5) people who become severely malnourished / anemic may have been “HSV-2 asymptomatic” for years, but then when their health declines may suddenly experience greater problems with HSV-2 due to the sudden loss of the immune system’s function which kept HSV-2 at bay for years or decades.

          So, in people who are asymptomatic and remain immune competent (i.e., most people), I am unaware of any evidence that these people’s immunity to HSV-2 wanes over time or becomes exhausted. Exhaustion of T-cells is relevant to many chronic viral infections, but is not the norm in thinking about HSV latency and the virus’s interaction with the immune system.

          That said, when we focus on the 1% who get chronic herpes (e.g., 6 or more outbreaks per year), I believe that the concepts of T-cell exhaustion, anergy, or a dysregulation of a potentially productive / effective immune response against HSV-2 become very relevant. I have heard far too many individuals describe symptoms that are essentially chronic in nature, and if you try to pin them down and find out how many outbreaks the answers range from “More than 24 outbreaks per year” to “How can tell you how many outbreaks I have had when the symptoms have been constant for the past 5 years?”

          In individuals where HSV-2 genital herpes is no longer an episodic disease, but is more chronic in nature, then my gut feeling is that something is specifically going awry with their immune response to HSV-2. These are people that appear healthy by all conventional measures, but their adaptive immune response fails to, well, adapt to HSV-2’s antigens and thus fails to get better at holding the HSV-2 virus in check. This sounds like T regulatory cells to me and some bizarre vicious cycle where the T cells are failing to improve their response to HSV-2 over time, but at this point in time I do not know that I or anyone else has a concrete answer as to how this occurs.

          Importantly, I believe that a real therapeutic HSV-2 vaccine (i.e., a live-attenuated HSV-2 virus) might be able to break this vicious cycle by delivering (1) a truckload of HSV-2 antigens and (2) a truckload of inflammatory signals to a vaccine recipient all at once, and thus awakening these T-cells from their stupor of anergy or antigen-unresponsiveness.

          Like a said, just a theory, but one that I think will be important to test in the near future!

          – Bill H.

          • Dr. Halford,

            As always, your thoughtful and thorough response is greatly appreciated. It really does seem like our best hope is a live-attenuated HSV vaccine. But real questions remain as to both if, and when, such a vaccine might ever be a reality. In thinking about your explanation, new questions also come to mind. I was hoping you could tackle them for me when you have get a chance.

            Regarding the importance of T-cell secreted cytokines in controlling viral infections such as HBV and HSV, and the suggested roles of downstream proteins in that response, I was wondering why one couldn’t simply bypass the immune system and administer those proteins exogenously. Have INF, TNF, or other proteins shown any efficacy in treating herpes? What about in combination with anti-virals? Is that something worth looking at further?

            And one more thought… Your theory, which sounds better than anything else I’ve heard so far, is that exposure to a hypothetical live-attenuated HSV virus would drive clonal expansion of HSV-specific T-cells and B-cells to get the immune system to better control viral activity and replication. It certainly makes sense that a live-attenuated virus would have a much better chance of succeeding in that regard than a subunit vaccine that has only a fraction of the viral proteins in it, but my question is why wouldn’t exposure to the real, non-attenuated wild virus do the same? In other words, if the immune system needs to see more of the entire virus to generate a therapeutic response, why doesn’t repeated exposure to the wild-type virus generate a robust response? Carrying it one step further, if the body doesn’t respond to the wild-type virus in such a way that viral activity is suppressed, why would an attenuated virus work?

            My questions are clearly a manifestation of the fact that I don’t have a clear understanding of the functioning our immune system, and I apologize for asking you to explain these things, but I greatly appreciate your indulgence.

            Once again I thank you for all you hard work and dedication.


          • Dear Suffering,

            I will start with the short answer…….live viral vaccines have been preventing human disease since 1798. I think there is a certain simple wisdom in recognizing that if it worked for our forefathers, and our grandparents, and our parents, and for us, then it is highly likely that live viral vaccines will work for our kids. Thus, I would say that, in no uncertain terms, your opening thought was the most on target; namely “It really does seem like our best hope is a live-attenuated HSV vaccine.” Yes, I most definitely concur with this sentiment.

            From there, you start to make logical inferences about derivative approaches that might work on paper, but would be pretty dicey propositions in clinical practice. Regarding flooding the body with exogenous interferon…..we have done this for years in treating chronic hepatitis C virus infections. It is effectively like 9 months of chemotherapy where the overriding thought that patients have is……God, I would rather be dead. Flooding the body with interferon to prevent herpes is a better idea than stepping in front of a bus (which also stops herpes), but this would be a pretty radical therapy. Likewise, flooding the body with the pro-inflammatory mediator tumor necrosis factor-alpha would be a radical therapy, and probably not a good idea….elevated bloodstream levels of TNF-alpha are the molecular basis of septic shock, a clinical presentation that ends about 50% of the time in death.

            Long story short…….local immune responses at the site of HSV-2 latent infection (an area that may be as small as the head of a pin) involving interferon-gamma, innate interferons, and pro-inflammatory molecules explain how the local immune response controls HSV-2. The thought of taking the molecular effectors (cytokines) and flooding the body with them is a scary proposition, and is the molecular basis of death in several infectious diseases.

            The general rule of thumb in immunology is “Small, local immune response is good.” “Large, systemic over-reactions of the immune system are bad, ranging from severe flu-like symptoms to life-threatening conditions like sepsis and toxic shock syndrome.”

            Regarding your second query, you should try to remember that for 80% of people, their natural immune response to HSV-2 WORKS PRECISELY AS YOU SUGGEST…..that is why they are completely asymptomatic. What nobody understands (including myself) is why 1 to 2% of HSV-2 infected people get stuck in a vicious cycle of reactivating / having recurrences all the time. It is possible that the wild-type HSV-2 virus tricks the immune system of these people through the tricks that many chronic viral infections use (e.g., HIV, HCV, etc.). If this hypothesis is true, then it is possible that a live-attenuated HSV-2 vaccine could break this vicious cycle by delivering (1) a lot of HSV-2 proteins and (2) the correct pro-inflammatory signals all at once to re-awaken / re-engage the body’s HSV-2-specific lymphocytes that have been “sleeping on the job” for years and failing to control HSV-2 outbreaks.

            Dear Suffering, it is important at this phase to remind you that the scientific method proceeds in the following steps:
            Step 1. Recognition of that which is possible;
            Step 2. Developing an experimental system to test the new possibility / hypothesis;
            Step 3. Acceptance or rejection of the basic possibility / hypothesis.
            Step 4. If the hypothesis is not rejected outright, then numerous cycles of refinement and retesting until we understand the underlying principles that explain why the hypothesis is true.

            In your query above, you are trying to jump straight to “How would a therapeutic HSV-2 vaccine work?”, which is Step 4.

            What I am saying in this and my earlier post is that the whole concept of a therapeutic HSV-2 vaccine is currently in Steps 1 and 2, and in the case of my live-attenuated HSV-2 vaccine is in Step 1. I am stating the possibility, and saying that this is a very important possibility that needs to be tested (Step 2) so that we can reject or accept the idea based on the resulting data (Step 3).

            How a therapeutic HSV-2 vaccine works is a downstream question. The relevant question today is, Is a therapeutic HSV-2 vaccine a pipedream or an attainable reality? I suspect that the latter is true, and would love to test this hypothesis ASAP. Until I can run the tests and obtain the data, it is nothing more than “That which is possible, but unproven.”

            – Bill H.

  14. Hi Bill,

    Can you tell me your thoughts on the Coridon vaccine? Many of the press releases have stated that it intends to be a cure as well as prevention. It seems to me to be one of the more promising ones simply because I’ve read the word ‘cure’ in so many of their articles, but haven’t Found much discussion on what this could mean. My question is – have you any idea if it is even possible to ‘cure’ the virus using such technology, or could it be referring to a clinical cure/treatment of symptoms?


    • Hi Susan,

      Personally, I am not impressed with Corridon / Dr. Frazier’s efforts in the realm of HSV-2 vaccines.

      What I have seen to date is a lot of hype, press releases, and all the standard vague talk of raising money for Corridon’s efforts.

      Dr Frazier’s group could easily change my opinion by publishing some results, and telling me about the science behind what they are trying to achieve. However, when all I hear are lots of press releases, and these are not balanced by scientific publications, then I start to have doubts. That is where I am with Dr. Frazier’s work.

      A scientific publication on the topic should (1) introduce what has previously been done with HSV-2 vaccines, (2) offer an alternative solution, (3) offer proof that the alternative solution works, and (4) describe the detailed methods regarding how the alternative solution works.

      To date, Dr. Frazier’s group has not addressed these questions in a detailed and substantive manner that convinces me that there is some real science behind their money-raising efforts. Hopefully they will prove me wrong soon.

      – Bill H.

      • Thank you for that detailed response. I too hope they have something that works to eradicate this virus in humans. It’s really taking its toll on my heart, soul and body, and I can’t imagine living with it forever. Which is why I genuinely appreciate the work that you are doing and the effort you are putting forth.

        I also have another question – I stumbled upon this article recently:


        Could it be possible that the anti-VZV vaccine can treat the symptoms of HSV2? If so, how have I not heard of this before, anywhere?

        Thanks again!

        • Hi Susan,

          I have heard back from at least 4 people with HSV-2 genital herpes who tried the chickenpox or shingles vaccines (live VZV vaccine), but who unfortunately did not derive any benefit. I am hopeful that other therapeutic vaccine options (e.g., a live-attenuated HSV-2 vaccine) will be far more effective. Just have to get it out there into clinical trials to test this hypothesis!

          – Bill H.

  15. Dear Dr. Halford, I, like more others russian exactly know about you research.
    More people interested in donating with follow comments “Is it possible to donate for example 1000$ and be sure that i will be in involved in trial at phase1”. Sometimes i understand their questions, people are afraid to donate money and doesn’t get this ivestement back in some period of time. Second side for this type of donation is that if 1000 people will donate 1000$ – it gives you $1mln. And i think that all these people can donate such amount if they be sure that get your vaccine.
    2) I read somethere in you blog that you are contacting with Dr. Knipe which developing ACAM-529 vaccine and they started trial few weeks ago. Great news that it’s first live-attendant vaccine for last 10 years, but may i ask you to ask Dr. Knipe why phase1 takes 3 years? I think that’s too long. Doest it mean that each phase takes 3 years?
    About how many russian are infected with H, you can see chat-history at follow links:

    p.s. sorry for my english
    BR from Russia

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