One-year anniversary

one year anniversary One year anniversary

For those of you who follow this blog with some regularity, I thought a quick post was in order to acknowledge that this blog site is approaching its first anniversary; the first blog post was made on June 15, 2013.  By June 14, 2014, the Herpesvaccine Blog will have been visited over 116,000 times.  Thank you one and all for your support.

From my perspective, perhaps the most notable / important utility of the Herpesvaccine blog has been in providing me with an initial outlet to help identify gaps in my own thinking and in my field of study that are important, but which are often not discussed in a clear and transparent manner in the scientific literature.

A case in point is my first full-length post on this blog entitled “Why don’t we have a HSV-2 vaccine yet?”  I opened this post with the following statements:

“The true definition of madness is repeating the same action, over and over, hoping for a different result.” – Albert Einstein

A common problem in science is that the natural world does not always conform to our initial expectations about how things “should work.”  In a nutshell, this is the primary problem that has plagued herpes simplex virus 2 (HSV-2) vaccine research for the past 40 years.  I elaborate below.

In this initial post I made a case that the primary reason we still lack an effective HSV-2 vaccine in the clinics is that, in essence, we have only seriously considered a single approach; namely, vaccines based on HSV-2′s glycoprotein D protein plus an adjuvant.  In contrast, a live-attenuated (replication-competent) HSV-2 vaccine has never been tested despite the success and safety of similar live-attenuated vaccines used to prevent smallpox, yellow fever, polio, mumps, measles, rubella, chickenpox, shingles, and rotavirus-induced diarrhea in small children.

Fast forward nearly a year.  My laboratory has just published a full-length, peer-reviewed article that makes this same argument, but in a much more complete manner and which cites over 200 published studies, hence offering the reader with my opinion on the important question of why we still lack a HSV-2 vaccine, but against the backdrop of the past 40 years of research and clinical literature on the topic.

The link to this June 2014 review of the status of HSV-2 vaccine research may be found here:  http://informahealthcare.com/doi/abs/10.1586/14760584.2014.910121

I close with the following text from the Prologue of the review, which summarizes the intended purpose of this new review of the HSV-2 vaccine research literature:

—————————————————————

PROLOGUE

“Herpes simplex virus 2 (HSV-2) vaccine reviews often provide an overview of which vaccine approaches have been considered in recent years [1,2]. The current review focuses on what I believe is a more pressing question: Why do promising HSV-2 vaccines keep failing in clinical trials [3–9]?  What doctors and the general public desire is a HSV-2 vaccine that works. What scientists desire is a better understanding of how to separate the wheat from the chaff when it comes to HSV-2 vaccines. The intention of this review is to consider such matters.

I hope to make plain that ‘antigenic breadth’ is a critical concept in HSV-2 vaccine efficacy, but has slipped under scientists’ radars for too long. Although vaccine scientists have been testing HSV-2 vaccines for three decades [10,11], the spread of HSV-2 genital herpes has not been slowed. Millions of our children will suffer the same fate unless we advance an effective HSV-2 vaccine into clinical trials posthaste.  The key questions are, ‘Is HSV-2 genital herpes a vaccine-preventable disease?,’ and if so then ‘Which HSV-2 vaccine approaches are most likely to achieve this goal?’ Against this backdrop, I discuss what I believe has gone awry with past HSV-2 vaccine strategies and consider what we might do differently in the future to improve our odds of success.

——————————————————————

It is my sincere hope that this review may help remind one or more academic scientists and/or vaccine industry leaders that, for better or worse, we are the individuals responsible for choosing which HSV-2 vaccine approaches will, or will not, be explored in the future.  The past decade of HSV-2 vaccine research has been fraught with disappointments and failure as we have done little more than pursue the status quo.  I sincerely hope that we collectively make better, and braver, choices in the next decade.

- Bill H.

button print gry20 One year anniversary

17 Responses to “One-year anniversary”

  1. lion May 18, 2014 at 10:39 am #

    I have been suffering from herpes for about 3 years now. There are days I feel as if there is a dark cloud over me that will never vanish. A vaccine would literally be a dream come true. I will not rest until there is a cure. We CAN cure it and we WILL!!

    • Bill Halford May 18, 2014 at 10:52 am #

      Thanks Lion,
      It is hard to overemphasize the importance of patient advocacy for their own cause. It reminds both scientists and those who fund science why a vaccine for HSV-2 genital herpes is important if they can hear such words that put a human voice and/or a human face behind the disease. Genital herpes is “no big deal” to people in the world who don’t realize that 1 of 6 of their friends are carriers of the HSV-2 virus. In contrast, people who know the score and understand how HSV-2 genital herpes can send their friends into a downward spiral of negative thoughts realize that this is potentially a big deal to people (millions of people), and it deserves our attention.

      Breast cancer and AIDS have rightly been pushed to the forefront of lawmakers and scientists’ minds by patient advocacy groups. Brief statements such as you offer above could help a larger percentage of lawmakers and scientists realize two important facts: (1) HSV-2 genital herpes is a big deal when it derails the life of someone you love like your son or your daughter; and (2) this is a vaccine-preventable disease. With just a little bit more attention and support from groups such as the Gates Foundation, we could solve this problem sooner rather than later and end this needless source of human suffering.

      - Bill H.

  2. Dante May 21, 2014 at 8:11 am #

    Hello Dr Bill.

    First of all congratulations about your website. You way of thinking truly should be heard by “the mans on the big chairs” and i’m certanly that your effort will really lead us, hsv sufferes, to beat this disease that some say “it’s no big deal”.

    About hsv, why some people have outbreaks all the time and some other folks dont feel a thing at all and spend even years without feeling an outbreak or experience mild simptons.
    It’ about the immunologic sistem or differents strains of the virus?

    Thanks’s Dr

    • Bill Halford May 24, 2014 at 1:29 pm #

      Hi Dante,

      Your question is basically “Why do some people who are HSV-2 infected have outbreaks all the time, whereas other HSV-2 infected individuals have no symptoms at all?”

      The simple answer is noone knows for sure, and thus what I write hereafter is speculative.

      I would guess that one major variable is the specific conditions of the primary infection. Some people may get infected with a large dose of HSV-2 that they are exposed to over the course of hours of sex (i.e., new couples often go at it several times in one night). Other people may be exposed to a lower dose of virus over a shorter period of time, so the efficiency of inoculating the cells in the epithelium of the vagina or the penis may be much lower. No two HSV-2 infections are exactly the same when you think through the details of how the virus is transmitted / contracted, and this variability in infection creates a lot of variability in how far the virus will spread before the immune system controls it. Moreover, if the person who contracts HSV-2 is anemic, run down through sleep deprivation, or on immunosuppressive medications, all of those factors will slow the immune response to the virus down…..hence allowing for more primary HSV-2 spread. The bottom line is that the extent of primary HSV-2 spread is a very important variable in dictating how heavily HSV-2 will seed the peripheral nerve fibers, and thus in dictating the “size of the reservoir latent HSV-2 DNA available” to support subsequent reactivation events.

      The second, less well understood variable is the “adaptive immune response to HSV-2.” This is a virus that encodes 75 HSV-2 proteins. There is nothing saying that the immune system of every single person who is HSV-2 infected responds to the virus with precisely the same populations of B-cells, CD4+ T-helper cells, CD8+ T-killer cells, and CD4+CD25+ T-regulatory cells. The simple reality is that the adaptive immune response to HSV-2 is very complex, and within this complexity may lie the answer of why some people mount an adaptive immune response to HSV-2 that is only “pseudo-protective.” That is, it “sees” and can eventually control HSV-2, but a pseudo-protective immune response to HSV-2 may be inefficient and days longer to intercept a HSV-2 reactivation event; that difference / delay of several days (relative to an efficient immune response) is enough to allow a HSV-2 reactivation event (a microscopic, single-cell event) to progress to a full-blown outbreak of genital herpes. In contrast, the adaptive immune response of an asymptomatic carrier of HSV-2 may have done a better job “learning” how to quickly recognize HSV-2 reactivation events (single-cell event) and thus “may head the virus off at the pass” and prevent reactivated HSV-2 from spreading to the point where an outbreak becomes visible (which typically takes 4 to 5 days after the initial reactivation event).

      There are other potential variables such as (3) virus strain variation and (4) host genetic variation. I cannot formally exclude these possibilities, but I will simply say that I find the evidence for these latter possibilities to be weak.

      Regarding possibility 3 (difference in HSV-2 strains), if there were certain “high reactivator” strains of HSV-2 circulating in the human population, then we should be able to find cohorts of people in certain towns or cities who all experience high levels of visible HSV-2 reactivation events (outbreaks) because these hypothetical “high reactivator” HSV-2 strains would be passed from person-to-person within a given town or city. However, the epidemiological data does not support / fit this hypothesis. Thus, I do not believe that differences in HSV-2 strain are a huge variable in controlling who gets frequent outbreaks of HSV-2.

      Regarding possibility 4 (difference in host susceptibility to HSV-2), differences in host genetic susceptibility have been hypothesized for the past century as explaining why some people get sick and others do not. However, after a century of investigating this hypothesis, there is no clear-cut evidence that this is a major factor in the human population. Certainly, there are serious genetic immunodeficiencies (scid, agammaglobunemia, stat1-deficiency, congenital neutropenia) that render people highly susceptible to infection to the point where their expected life span may drop from 75 years to less than 2 years. However, such immunodeficiencies are exceedingly rare (1 per million births?), and thus do not explain why some people get HSV-2 outbreaks and other carriers do not. I note that for almost ever infectious agent studies, there are a significant number of people who get asymptomatically infected whereas others experience disease. So, overall, I do not find the “host genetic susceptibility” hypothesis to be particularly compelling.

      So, I believe that the difference in HSV-2 infected people who experience asymptomatic infections versus those who have frequent outbreaks is largely controlled by the variables of (1) severity of primary infection / seeding of peripheral nervous system with latent HSV-2 during the first two weeks post-infection, and (2) the efficiency with which the adaptive immune response controls HSV-2 over the following years to decades. For reasons we do not completely understand, some carriers of HSV-2 mount adaptive immune responses (i.e., diverse populations of antibodies and T-cells that help the body “find” cells in which HSV-2 is actively replicating) that are very efficient at controlling HSV-2 reactivation events (single cell event) such that they never cause disease. For reasons that escape me (and apparently most investigators in my field of study), some individuals who carry HSV-2 seem to get stuck in a vicious cycle where there adaptive immune response to HSV-2 is only “pseudo-protective” and requires days to weeks to control a HSV-2 reactivation event…..hence allowing time for visible outbreaks of genital herpes to occur.

      - Bill H.

  3. John Raibley May 22, 2014 at 10:12 pm #

    Happy Anniversary Dr. Bill and a thousand thanks for all you do! JP

  4. Jonathan May 28, 2014 at 11:26 pm #

    Dr. Halford:

    Thank you so much for all of your work and the time you take to give such comprehensive answers tat are understood by the layman.

    Just one question related to your previous reply regarding severity of recurringHSV-2 infections:

    If lower recurrence (if there is any at all) or lesser severity of recurrances is dependent on the amount of latent reservoir initially established, do you believe that means that asymptomatic HSV-2 positive persons are -less- likely to transmit it to others? Obviously, asymptomatic persons can and do transmit the virus, but do you believe there may be a linear relationship between the frequency and severity of subsequent outbreaks (after the initial) by a seropositive individual and the level of virus that is shed by the them and hence, their propensity to infect an “average” person?

    Do you think that seropositives that exhibit no symptoms, take something like Valtrex daily, and always have protected sex, are extremely unlikely to transmit the virus? Like at the <1% annual level or even better? (I have heard that Valtrex+protection = 3/4 reduction in transmission propensity but nothing ever mentions how recurrence frequency or severity influences transmission risk)

    Thank you,

    Jon

    • Bill Halford May 29, 2014 at 7:43 pm #

      Hi Jon,

      At the end of the day, I am a science geek and not a real doctor. Hence, bear in mind that my answer really reflects my understanding of how HSV-1 and HSV-2 behave in animal models, and how I believe these findings translate to the human condition. Disclaimer, caveat, this is not medical advice, etc., etc.

      Having satisfied my legal / liability obligations, yes, I generally agree with the interpretation you offer. I believe that the words “asymptomatic carriers” are thrown around loosely in discussing patients and patient concerns, and I believe this creates needless confusion and an excessive amount of worry about the risks of asymptomatic HSV-2 shedding. My interpretation of what I have seen HSV-1 and HSV-2 do in the laboratory in animals, and what I have read in the literature about HSV-1 and HSV-2 in people, all seems highly consistent with the notion that (1) the severity of an individuals’ first exposure (primary infection) with HSV-1 or HSV-2 does indeed set the stage for (2) that person’s relative risk of experiencing a lifetime of episodic and symptomatic HSV-1 or HSV-2 recurrences. One of the logical reasons that this is the case (which is supported by extensive data in animal models) is that the severity of the primary infection is one of the main variables that influences how much latent HSV-1 or HSV-2 DNA will be seeded into neurons of the peripheral nervous system. So, simplistically speaking……..(1) severe primary HSV infection translates into huge reservoir of latent HSV DNA available to reactivate and drive recurrences later in life, whereas (2) an asymptomatic HSV infection that causes a person to become HSV-2-antibody positive but is too low level to produce symptoms of disease (i.e., 80% of HSV-2-infected people fall into this latter category) is probably going to be associated with a reservoir of latent HSV-2 DNA that is 10 to 100 times smaller (i.e., 1 to 10% of the latent HSV-2 DNA load of someone with recurrent genital herpes).

      The reason I re-visit these definitions is so that I may, in this paragraph, call attention to the problem with lumping all “asymptomatic HSV-2 shedding” together into one kettle. Let’s call the first group of HSV-2 infected persons who experience frequent recurrences of HSV-2 genital herpes “high reactivators.” These “high reactivators” may experience weeks to months of asymptomatic periods in between visible outbreaks. I believe what the literature clearly shows is that patients who are “high reactivators” always pose a risk to sexual partners regardless of their disease status, because they frequently shed infectious HSV-2 virus at their genital epithelium even when they are not having a visible outbreak.

      In contrast, I am unaware of any literature that meaningfully documents that people who are “HSV-2 antibody positive” but have never once had an outbreak of genital herpes disease pose the same risk to prospective sexual partners when they are also “asymptomatic.” Therefore, I believe that discussions of the relative risks of “asymptomatic shedding of HSV-2″ should be qualified to indicate whether we are talking about (1) high reactivator patients who (a) experience at least 2 outbreaks per year and (b) are in between outbreaks versus (2) persons who have serum antibodies against HSV-2 (i.e., are seropositive), but who have never had an outbreak of what they recognize as HSV-2 genital herpes. I don’t know what the relative levels of HSV-2 shedding would be from these two populations of patients, but everything I have seen in animal models would suggest that people who are HSV-2 seropositive but are fully asymptomatic likely shed 10- to 100-fold less HSV-2 than “high reactivators” during their asymptomatic periods between outbreaks.

      So, Jon, we come to your main question……..
      “Do you think that seropositives that exhibit no symptoms, take something like Valtrex daily, and always have protected sex, are extremely unlikely to transmit the virus?”

      My answer is yes, I think that such fully asymptomatic carriers of HSV-2 pose a low risk for HSV-2 transmission relative to persons who are in between outbreaks of HSV-2 genital herpes. However, unfortunately, I cannot quantify the relative risk and have not done the necessary studies to provide a real answer. Investigators at the University of Washington have done a lot of studies of asymptomatic HSV-2 shedding, but to the best of my knowledge most of this work focuses on patients with symptoms of HSV-2 genital herpes. Thus, I am not aware of any studies that quantify the relative risk for HSV-2 transmission that fully asymptomatic carriers of HSV-2 pose to their sexual contacts.

      If someone else knows more, please feel free to chime in as I have no doubt that there are others in this particular arena who are more knowledgeable than myself.

      - Bill H.

  5. yoshida June 7, 2014 at 11:50 pm #

    Hi Dr.
    Is is possible to locate the the reservoir of latent HSV DNA seeded in the neurons and surgically removed it?
    Thanks -

    • Bill Halford June 8, 2014 at 1:32 am #

      Hi Yoshida,

      That is a nice idea, but no it is not feasible. HSV-infected neurons look to our eye (even with a microscope) like any other neuron, so it would not be obvious which neurons are infected. Moreover, it is likely that in an average person with genital herpes, tens of thousands of neurons distributed through a variety of ganglia are latently infected, so this is not like removing a wart. Finally, the function of the peripheral nerves is pretty critical to your ability to feel and sense your surroundings. While I don’t think surgery could be used to cure herpes, the attempt to do so could leave a patient with chronic sensations of tingling and nerve pain due to tissue damage from the surgery. So, for a variety of reasons, surgery is not a viable solution to cure herpes.

      - Bill H.

  6. donaldo June 10, 2014 at 2:29 pm #

    Hi Dr Bill
    I know you have been asked this plenty of times but still, about the latest news on admedus or the corridon vaccine. I looked up the net and they said phase 1 is was completed and the vaccine seems to work. After phase 2 and 3 hopefully it will be in the market by 2015. Have they still produced any results or they are still yet to show anything. Don’t want to hear what the media says, i’d rather be informed by you as you are qualified. But being someone who is infected i hope they produce some remedy. As a matter of fact I hope any of them work.

    And about these vaccines, will they will stop the out breaks completely or will they just reduce the number outbreaks people have. I know it wont kill the virus but out of optimism and hope are there any vaccine that can kill it or at least stop it completely.

  7. vaccineistheonlyhope June 12, 2014 at 8:43 pm #

    donaldo, I do not think that the vaccine will come out that quick…2015 is way too soon, realistically maybe 2018-2020

  8. Needserenity June 16, 2014 at 2:38 pm #

    Dr. Halford,

    I am very interested in your research. I have just been diagnosed with HSV2. I would at the very least like to make a donation. Is this only possible by mail?

    Also, is there anything else that can be done volunteer wise to further your efforts?

    Thank you.

    • Bill Halford June 16, 2014 at 3:48 pm #

      Dear Needserenity,

      My university does have a mechanism to allow for online donations to the SIU Foundation, which represents the entire University (i.e., more than 25,000 students, staff, and faculty). To date, my experience tells me that while the SIU Foundation is very competent at taking people’s money, their track record at successfully identifying donations for the “Halford Vaccine Fund” is less than stellar.

      Thus, I can only assure that donations will successfully arrive in the Halford Vaccine Fund if they are addressed to my department’s business administrator, Risa Kirkpatrick, who is a consummate professional and makes sure that the donation arrives at the intended destination. The directions are below, and yes I am afraid the U.S. mail is the only option at this point in time.

      Many thanks in advance for supporting the cause!

      - Bill H.

      “Anyone interested in making a tax-deductible donation to the Halford Vaccine Research Program may do so by mail, as follows:

      Write a check payable to “SIU Foundation” and either in a letter or on the Memo line of the check write “Halford Vaccine Fund,” and mail the check to the following address:
      Mrs. Risa Kirkpatrick, Business Administrator
      Dept of Microbiology and Immunology
      Southern Illinois University School of Medicine
      P.O. Box 19626
      Springfield, IL 62794-9626

      These funds will be used solely for the purposes of HSV-2 vaccine research.

      Please note that while Online Donations to the SIU Foundation are technically possible, I can only personally assure that donations to the SIU Foundation are properly allocated into the Halford Vaccine Fund if they are mailed directly to my Departmental Business Administrator per the instructions above.”

      • JohnDJoe June 16, 2014 at 4:29 pm #

        Dr. Halford,

        you should maybe contact the SIU Foundation stuff, to enable the listing of your “Halford Vaccine Fund” under the priority School of Medicine.. so one can pick out School of Medicine > Halford Vaccine Fund as a donation priority.

        This would be much clearer then typing the same into Other Designations field.

        SIU-Foundation-Link:
        https://www.siuf.org/making-a-gift/give-online/

        • Bill Halford June 16, 2014 at 5:40 pm #

          Dear Joe,

          Great suggestion….thank you. I will look into this upon my return to Illinois next month.

          - Bill H.

  9. Michael June 18, 2014 at 8:59 pm #

    How about using an animal strain of herpes to vaccinate people, much like cow pox/small box. Many animals are also infected with herpes such as: dogs, horses, elephants, nonhuman primates, guinea pigs, tortoises, cattle, and cats.

  10. Mingyu June 22, 2014 at 12:46 pm #

    Congratulations, Bill!

    Great to see the blog has been doing so well, this blog has definitely an important venue to learn the herpes vaccine knowledge.

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