How does the immune system respond to a HSV-2 vaccine?

Innate Adaptive 2 How does the immune system respond to a HSV 2 vaccine?It has been over 6 months since I made a new post on the blog.  Sorry about the hiatus…..the laboratory has been occupying all of my time, but I managed to carve out some time to work on the following post.   Someone sent me a query / comment on this blog last month that I thought might be of general interest to many readers. The blog post below is my response.

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QUESTION:

Dear Dr. Bill,

Let’s discuss the therapeutic effect of a future vaccine. So basically the patient gets a vaccine shot in his arm, just like all other vaccines are given. How does the human immune system respond next in the case of Acam-529 as an example?  Antibodies and T-Cells get generated. Would an arm shot be enough or yet better a shot in the behind area / under the belt? How would an arm shot benefit the genital area for protective or therapeutic purpose?

– Curing

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Dear Curing,

There are a few different questions here, and so I will break them apart and tackle them one by one in a series of blog posts. Specifically, your questions are “Let’s discuss the therapeutic effect of a future HSV-2 vaccine.

1) How does the human immune system respond to a HSV-2 vaccine?

2) Would a shot of HSV-2 vaccine in the arm be enough or would a shot in the behind provide better protection against genital herpes? How would an arm shot benefit the genital area for protective or therapeutic purpose?”

3) In addition, I will add the following question into the mix here that I believe is relevant:  “What is the goal of a “preventative” versus a “therapeutic” HSV-2 vaccine, and are each of these goals equally feasible?”

 

For today, I focus on addressing the first question.

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HOW DOES THE HUMAN IMMUNE SYSTEM RESPOND TO A HSV-2 VACCINE?

At a minimum, there are two essential ingredients in any vaccine and these are (A) an irritant that establishes a pro-inflammatory response at the site of injection and (B) one or more foreign components that significantly differ from the molecular complexes and/or cells that are part of “self” (i.e., that which is normally present in the human body).

A. The first ingredient in any vaccine is an “irritant activity,” which is commonly introduced into a vaccine in the form of an adjuvant. The word adjuvant effectively means a “helper” or “facilitator.” The purpose of the irritant activity in a vaccine adjuvant is to help elicit “danger signals” (pathogen-associated molecular patterns) that activate cells of the immune system and induce them to turn on, or upregulate, molecules and machinery that render the body’s B- and T-lymphocytes competent to respond to the foreign components in a vaccine. Specific examples of the types of molecules that are up-regulated by the irritant activity in adjuvants include co-stimulatory molecules such as CD28, B7, CTLA4, and antigen-presentation molecules such as MHC class I and II.

The key concept here is that the optimal / most productive immune response to the foreign components of a viral vaccine cannot be mounted by any one cell of the immune system. Rather, productive immune responses to a viral vaccine are essentially a decision that will optimally involve a “committee” of at least five different cell types, and these cell types are: (1) virus-infected structural cells in the case of a live viral vaccine, such as ACAM-529 (e.g., epithelial cells of the skin); (2) professional antigen-presenting cells such as dendritic cells or macrophage; (3) B-lymphocytes (which give rise to antibody-producing cells); (4) CD4+ T-helper cells; and (5) CD8+ T-cells, which can directly interact with virus-infected cells by (a) killing virus-infected cells or (b) secreting cytokines that directly suppress virus replication.  The picture at the top of this post illustrates most of the members of the cellular committee that respond to a vaccine.

These five different populations of cells only become fully competent to “act as a committee” (talk to one another) in response to a viral vaccine if they receive adequate danger signals, and this is one of the major functions of adjuvants such as alum (aluminum salts) and/or monophosphoryl lipid A (MPL). This combination adjuvant is used in the Gardasil vaccine and was used in the Herpevac vaccine (i.e., a failed HSV-2 vaccine). So, when considering vaccines, it is critical that there is either an adjuvant or some other, comparable, pro-inflammatory activity.

A second, critical aspect of this pro-inflammatory activity is that it actively recruits immune cells (white blood cells) to the site where the vaccine is injected, and thus ensures that the foreign components in the vaccine are seen (encountered by) large numbers of white blood cells. In the case of HSV-2 ACAM-529, this is actually a genetically modified version of the HSV-2 virus, and thus ACAM-529 actually infects cells in the human body, but is unable to spread / propagate the infection (and thus is unable to cause disease). In the case of a whole HSV-2 vaccine, the virus has its own pathogen-associated molecular patterns that provide the “danger signals.” Thus, whole HSV-2 viral vaccines generate their own pro-inflammatory / immune-activating signals, and do not require additional adjuvants such as alum or MPL.

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B. The second ingredient in any vaccine is one or more foreign components, which are generally referred to as “antigens” or “immunogens.” This portion of vaccines is the most complex part of a HSV-2 vaccine and is, in my opinion, where the difference lies between (1) robust HSV-2 vaccines that offer complete protection against HSV-2 genital herpes versus (2) HSV-2 vaccines that are ineffective in animal models and in clinical trials (e.g., Herpevac).

The logic behind the terms “antigens” and “immunogens” is circular in nature, and so I will restrict my discussion of these terms to their functional significance.  Fortunately, the formal nomenclature of immunology is not necessary to explain the general concept that (1) the foreign components in a HSV-2 vaccine serve as activators of those B- and T-lymphocytes that happen to be HSV-2-specific; and (2) vaccine-induced expansion of these HSV-2-specific B- and T-lymphocytes radically increases the rate with which the immune system may recognize and suppress HSV-2 replication (before disease occurs). Hence, we say that an effective HSV-2 vaccine should confer upon the vaccine recipient the property of “immunity” to ever contracting the disease of HSV-2 genital herpes.

I think of the formal definition of “antigens” and “immunogens” as being analogous to road signs in Philadelphia. They make perfect sense once you have lived there for 2 years and know exactly where you are going, but are generally more confusing than helpful to newcomers. Specifically, the term “antigen” means any foreign component that stimulates antibody-generation when introduced into the human body, and the term “antibody” means a protein-based product of B-lymphocytes that binds tightly to the specific antigen that stimulated its generation. Like road signs in Philly, this should make perfect sense to anyone who has already studied immunology, and will probably sound like Greek to everyone else. For the purposes of this discussion, it will suffice to say that “antigens” are activators of the body’s B-lymphocytes and “immunogens” are activators of the body’s T-lymphocytes.

 

B-1. Background information. Before proceeding into a discussion of how a vaccine engages the human immune system, there are three pieces of background information that a reader must appreciate to fully appreciate how a specific vaccine may reduce the incidence of an infectious disease, such as genital herpes, that is caused by a specific microbial pathogen, such as HSV-2. These three pieces of information are:

(1) In the absence of vaccination, less than 20% of microbial infections of humans result in overt disease. Even in people who are immunologically naïve (i.e., who have not previously been exposed), most microbial infections don’t spread far enough or last long enough in the human body to produce the visible symptoms of infectious disease. This is certainly true for HSV-2, but is true for many other infectious agents as well.

(2) The difference between an asymptomatic HSV-2 infection versus a disease-causing HSV-2 infection largely reduces to the duration of HSV-2 replication and/or spread following a primary infection. Asymptomatic HSV-2 infections may be thought of as lasting for 2 – 4 days, and may lead to seeding of <100 peripheral nerve fibers with 1 to 50 copies of HSV-2 DNA per latently infected neuron. While this is still a “life-long, latent HSV-2 infection,” in quantitative terms this might represent less than 1% of the latent HSV-2 DNA load that exists in persons who experience disease-causing, primary HSV-2 infections that progress to recurrent genital herpes. By contrast, a disease-causing, primary HSV-2 infection might last 7 – 21 days, thus allowing far greater HSV-2 viral amplification and seeding of the peripheral nervous system. Such a latent HSV-2 infection might seed 1000s of peripheral nerve fibers (coming off the lower backbone) with 100s of copies of HSV-2 DNA per latently infected neuron. This >100-fold increase in the size of the reservoir of latent HSV-2 DNA is what places who people who experience symptomatic, primary HSV-2 infections at a >100-fold higher risk for a lifetime of recurrences of genital herpes relative to people whose first encounter with HSV-2 causes only an asymptomatic infection.

(3) The idea of a preventative HSV-2 vaccine is simple. In an unvaccinated population, 80% of people infected with wild-type HSV-2 will have no symptoms, whereas 5% of HSV-2 infected persons will fail to initially control the primary infection, and thus will be placed at risk for a lifetime of episodic recurrences of HSV-2 genital herpes. In contrast, in a population of individuals vaccinated with an effective HSV-2 vaccine (vaccinated before onset of sexual activity), essentially 100% of people would experience only asymptomatic infections, which last for 2 – 4 days, if exposed to wild-type HSV-2 later in life; this would be insufficient to produce the symptoms of genital herpes. Importantly, the load of latent, wild-type HSV-2 DNA in such persons would be too low to support recurrent genital herpes. Thus, an effective HSV-2 vaccine would prevent both primary and recurrent genital herpes caused by HSV-2, and would likewise prevent the downstream consequences of neonatal herpes and enhanced risk of HIV infection.

 

B-2. Why do less than 20% of infections produce visible disease in an unvaccinated population?

Our immune systems are critical to our survival, and constantly beat back microbes from the skin, mouth, and intestines. If this seems like an abstract idea, compare the human body in life and death. In life, you will look nearly the same four weeks from now. What would your body look like 4 weeks from now if your heart stopped beating? The human immune system is the difference. As long as your blood is flowing (and is loaded with antibodies and T-cells), then the microbial flora of your skin and intestines is kept in check. When a person passes away, and the blood quits flowing, the immune system stops functioning and our bodies are consumed by microbes in a matter of days to weeks.

Likewise, our immune systems gives us an innate ability to repel invading microbes such as HSV-2 (i.e., even in an unvaccinated population). By the numbers, this “innate immune response” is adequate 80% of the time to keep a primary HSV-2 infection from spreading in an uncontrolled fashion and causing symptomatic disease. However, 15% of the time, primary HSV-2 infections get far enough ahead of the innate immune system to produce some symptoms of herpetic disease. About 5% of the time, primary HSV-2 infections get completely beyond the control of our innate immune defenses, and these infections may last for 2 or 3 weeks and may set the infected person up for a lifetime of recurrences of HSV-2 genital herpes disease.

Once you appreciate that our “innate immune systems” (a few key cells are shown in the picture at the top of the post) reduce the burden of HSV-2 genital herpes in the world by about 10- to 20-fold, then the question becomes, “Why doesn’t our innate immune system do the job 100% of the time?” Our immune systems are a double-edged sword; they keep microbial invaders out of our bodies, but if our immune systems are overactive, then they may cause diseases in their own right such as Crohn’s disease, Grave’s disease, lupus, rheumatoid arthritis, and a myriad of other conditions where the immune system’s killing potential is turned against components of self (i.e., against tissues and cells of our own bodies).

Given that the human immune system is like a huge army with a tremendous killing potential, it is essential that our bodies tightly regulate this killing potential and selectively focus the ATTACK on only those things that enter our body that are foreign, such as microbial invaders like HSV-2. The way in which the human immune system achieves this delicate balance is that it has created a subset of cells, lymphocytes, whose sole function lies in enhancing the rate of RECOGNITION of that which is foreign. This is the primary function of our body’s B- and T-lymphocytes. Much of the potential of the immune system to ATTACK that which is foreign is embedded in the “innate immune system,” however the weakness of the innate immune system is that it is clunky, or inefficient, in its capacity to RECOGNIZE that which is foreign. Thus, left to its own devices, our innate immune system is slow to recognize and attack a primary HSV-2 infection; 80% of the time this innate immune response is adequate to control a primary HSV-2 infection, but 20% of the time HSV-2 wins the battle and spreads enough to cause some symptoms of herpetic disease.

 

B-3. Why does the human immune response to HSV-2 get more efficient over time?

In an unvaccinated population, people who contract a primary HSV-2 infection develop an improved capacity to RECOGNIZE and control the HSV-2 infection over time. This change (increase) in the efficiency of immune recognition of HSV-2 is due to an ~100- to 1,000-fold expansion in the numbers of initially rare HSV-2-specific B- and T-lymphocytes in the bloodstream and lymphoid organs.

When the body’s numbers of “HSV-2-specific lymphocytes” are small (1 per million lymphocytes), then these cells are too rare in number to initially contribute to the fight, and so your “innate immune response” does the best it can in the relative absence of  HSV-2-specific B- and T-lymphocytes.  As a person’s lymphocytes see (RECOGNIZE) the antigens and immunogens of the HSV-2 virus, two changes occur: 1. the RECOGNITION event is a growth stimulus that activates the sleeping lymphocyte out of its coma, and drives it to start proliferating giving rise to greater numbers of HSV-2-specific B- and T-cells; and 2. the RECOGNITION event activates a subset of HSV-2-specific B- and T-cells to become effector (fighter) cells that actively engage the enemy. B-cells contribute to the fight by by differentiating into antibody-secreting cells; antibodies are simply a soluble form of the “B-cell receptor” by which the B-cell RECOGNIZES foreign HSV-2 antigen. T-cells contribute to the fight in a variety of ways, but one of the more graphic is that some HSV-2-specific T-cells become killer cells (cytotoxic T-lymphocytes) that can deliver a death blow to any virus-infected cell that presents the RECOGNIZED component of HSV-2 to the T-cell, which it “sees” via its “T-cell receptor” .

Pulling back from these mechanistic details, the broad concept is that regardless of whether or not we have been infected with HSV-2, we all possess at least a small number of B- and T-lymphocytes that are specific for HSV-2, and in an uninfected person I would put that number at ~1 HSV-2-specific lymphocyte per million lymphocytes; the other 99.9999% of lymphocytes are specific for the myriad of other microbes that might enter your body.  Lymphocytes give your body’s immune system the capacity to adapt to (learn how to deal with) any infection you may experience; this is why lymphocytes are described as the body’s “adaptive immune system.”   The weakness of the adaptive immune system is that the handful of HSV-2-specific lymphocytes in an uninfected person are (1) metabolically asleep and need to be jarred out of their slumber to be useful, and (2) these rare HSV-2-specific lymphocytes are just too few in number to initially contribute to the fight during a primary HSV-2 infection.  As illustrated in the picture at the top of this post, the critical cells of our adaptive immune systems are specifically B-cells, CD4+ T-cells (helper T-lymphocytes), and CD8+ T-cells (cytotoxic T-lymphocytes).

When a person is infected with HSV-2, the antigens and immunogens in the HSV-2 virus engage the body’s B- and T-lymphocytes, and thus (1) wake them from hibernation and (2) drive the clonal expansion of rare HSV-2 specific T- and B-cells until they are no longer that rare (e.g., from ~1 per million to ~1 per thousand). That level of clonal expansion of HSV-2-specific lymphocytes requires at least 4-weeks because it takes 24 hours to one activated lymphocyte to give rise to 2 daughter cells, and another 24 hours for 2 cells to become 4 cells, etc, etc). At the end of that expansion of HSV-2-specific B- and T-lymphocytes, the body is 100- to 1,000-fold more efficient in its capacity to RECOGNIZE a HSV-2 infection, and so a person with pre-existing “acquired immunity” to HSV-2 is highly resistant to exogenous infection with a 2nd, outside strain of HSV-2.  The bottom line here is that more HSV-2-specific lymphocytes = far more rapid RECOGNITION of HSV-2 infection, and more rapid ATTACK of HSV-2 infected cells by all components of the innate and adaptive immune systems (which work together in our bodies).  When it comes to fighting the enemy, lymphocytes may be thought of as the directors / managers and the components of the “innate immune system” may be thought of as the worker bees that provide the brute force to ATTACK and get the job done.

 

B-4. What do the foreign components in a HSV-2 vaccine do for the human body?

As discussed above, the foreign components in a HSV-2 vaccine consist of 1. “HSV-2 antigens” (activators of the body’s HSV-2-specific B-lymphocytes) and 2. “HSV-2 immunogens” (activators of the body’s HSV-2-specific T-lymphocytes).

The purpose of a HSV-2 vaccine is simple. If the “innate immune response” is inefficient in its capacity to RECOGNIZE a HSV-2 infection (and thus the ATTACK is slow to develop), then the purpose of a HSV-2 vaccine is to bridge the gap. In an unvaccinated population, 20% of HSV-2 infected people will develop some symptoms of herpetic disease because the infection is essentially a race between (1) HSV-2 replication and spread versus (2) clonal expansion of initially rare HSV-2-specific B- and T-cells (which can stop HSV-2 replication and spread). An effective HSV-2 vaccine bridges this gap by artificially introducing a wide variety of HSV-2 antigens (B-cell activators) and HSV-2 immunogens (T-cell activators) into the human body, such that we may artificially increase our “adaptive immune response” to HSV-2 before it is actually required to combat the wild-type HSV-2 virus. In other words, by delivering all of the components of the HSV-2 virus (less the disease-causing potential) into a vaccine recipient, we may thus prime, boost, and increase the vaccine recipients’ number of circulating HSV-2-specific lymphocytes from very rare (1 per million) to very frequent (1 per thousand), such that their “adaptive immune response to HSV-2″ can be pre-established prior to an actual  exposure to the disease-causing virus. In addition to the (1) vaccine-induced clonal expansion of HSV-2-specific B- and T-lymphocytes, another critical activity of HSV-2 vaccines is that they (2) establish large numbers of HSV-2-specific antibodies in the circulating blood and lymph, which may directly and immediately contribute to the ATTACK should a vaccine recipient contract an HSV-2 infection.

For these reasons, an effective HSV-2 vaccine delivered in a preventative manner to adolescent children (prior to the onset of sexual activity) would reduce these individuals’ risk of contracting HSV-2 genital herpes disease by several thousand-fold relative to their risk if left unvaccinated.  If an effective HSV-2 vaccine were delivered into a population of human beings, it would remain possible that these people could be infected with wild-type HSV-2 (an invisible, molecular event), but the incidence of such HSV-2 infections progressing beyond an “asymptomatic infection” to the symptoms of genital herpes would effectively drop to 0%.   This possibility of effective vaccine-induced control of HSV-2 genital herpes in the human population stands in stark contrast to the current situation in which 500 million to 1 billion people serve as carriers of latent HSV-2 infections, ~20 million people are newly infected with HSV-2 each year, and 5% of HSV-2 infected persons [~20 to 40 million people] suffer through a lifetime of recurrent genital herpes disease.

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IF HSV-2 VACCINES ARE SIMPLE, THEN WHY DO THEY KEEP FAILING IN HUMAN TRIALS?

The explanation offered above for how HSV-2 vaccines is relatively simple.  If HSV-2 vaccines are so simple, then why do our efforts to advance a HSV-2 vaccine keep missing the mark?  I think there is a simple and plausible answer to this question, and I offer it below.

A narrative emerged amongst immunologists and vaccinologists over 30 years ago that suggested that any infectious agent, such as HSV-2, could be thought of as a collection of “antigens” and “immunogens.”  While the concept of antigens and immunogens certainly explains how lymphocytes “see” (RECOGNIZE) an infectious agent, it is in my opinion that it is nothing short of a “leap of faith” to cross your fingers and believe that a single antigen (a single protein) may be extracted from HSV-2, and will be sufficient to serve as an effective HSV-2 vaccine.  In my book, this idea is up there with the tooth fairy and Santa Claus.

One of the many problems with this theory is that HSV-2 encodes at least 75 proteins, and thus the “antigen” in the failed Herpevac vaccine (a truncated form of gD) represents only 0.8% of the proteins that HSV-2 may encode. While gD may be an important antigen, I find it incredibly naïve to suggest that the other 99.2% of HSV-2’s proteins have absolutely nothing to contribute to an effective HSV-2 vaccine. Aside from my internal belief system, the available evidence supports this interpretation. Thus, a like contributor to the failure of past HSV-2 vaccines is that they present too few of HSV-2’s foreign antigens / immunogens to the B- and T-lymphocytes. Hence, HSV-2 vaccines such as Herpevac may only drive the activation and clonal expansion of ~3% of the body’s total repertoire of HSV-2-specific B- and T-lymphocytes that are available to contribute to vaccine-induced protection against HSV-2.

button print gry20 How does the immune system respond to a HSV 2 vaccine?

28 Responses to “How does the immune system respond to a HSV-2 vaccine?”

  1. Curing May 11, 2014 at 8:39 am #

    Thank you for this post.
    Hope you can continue giving further insight in in the form of a new post on your blog soon.

  2. Tom May 14, 2014 at 2:30 pm #

    Hi Bill, Checking back. We communicated last year. I had a few questions from easy to more complex..

    Have you given up or delayed pursuit on your vaccine given ACAM-529 has movement?

    I recall yours appeared to offer the maximal immune response to many antigens as well as secondary products later in the infection process. It seemed to offer not only the best vaccine probability of success but also had merit as a recurrence reduction medicine which move sit away from the difficult “near-live” vaccine trial and FDA environment? What are your current thoughts on trialing it for this in a less difficult environment?

    Have you seen any more evidence that using your vaccine on an already infected person would boost even their immune response such that recurrence is either reduced or shifted to asymptomatic? This is very valuable and might be an early first step given ACAM-529 has taken the stage.

    Given HSV-2 is considered a major factor in HIV transmission especially in Africa and presumably due to sores and immune system effects, hasn’t interest in this by folks like the Gates foundation led to interest in your vaccine given it potential for better efficacy and reduction of recurrence should help HIV transmigration. It would seem the barriers to entry and the dire situation for HIV in Africa a would help your vaccine there.

    Does ACAM-529 help with recurrences?

    How does the innate immune system discriminate between self and non-self – The adaptive has learned to recognize amino acid sequences or epitopes which are typically unique to a particular microbe due to DNA variations that cause coding different sequences of Amino Acids for similar immune system visible molecules/peptides/proteins etc…

    Do you have any comments on why Arginine seems to aggravate recurrence wile Lysine seems to reduce them?

    Is there any hope of using a strategy like the one Kim Lewis from Northwestern used on MRSA pesisters with HSV? he used a drug to activate latent persisters which brought them all out so an antibiotic and immune system could clean them up. If there was a drug that caused full activation of all hiding HSV so they came out, then wouldn’t a combination of antivirals plus your vaccine boosting the immune response might cure HSV? Similar in strategy as Kim Lewis used but obviously an HSV awakening drug. Is such a thing possible?

    When a recurrence pops up in a new location, is that because it moved on top of the skin and re-entered or because it found a new nerve fiber path to take?

    Where exactly do the latent HSV hide?

    • Bill Halford May 14, 2014 at 5:30 pm #

      Dear Tom,

      Thanks for your comment / note. I most definitely remember our interactions last year. I am pretty busy at the moment, and thus must keep my response short. That said, I will get back to you with a more appropriate / comprehensive response when time permits.

      For now, I will simply say that my plans are unaltered by the launch of the HSV-2 ACAM-529 vaccine trial. While I wish these investigators the best, and hope that their vaccine renders my own efforts redundant, the past 30 years of HSV-2 vaccine research history offer quite the cautionary tale against (1) putting all your eggs in one basket and (2) assuming that the latest approach to advance to human clinical trials negates the need to pursue other, alternative HSV-2 vaccine approaches.

      I will respond to the remainder of your comment when I have a bit more time.

      – Bill H.

  3. cts May 14, 2014 at 5:12 pm #

    Dr. H,

    Another subunit vaccine bites the dust.
    http://jvi.asm.org/content/early/2014/05/08/JVI.01130-14.abstract

    It seems increasingly clear that your approach is the way to go. Wishing you the best of luck — as do we all.

    • Bill Halford May 14, 2014 at 5:22 pm #

      Dear cts,

      You wrote: “Another subunit vaccine bites the dust.
      http://jvi.asm.org/content/early/2014/05/08/JVI.01130-14.abstract
      It seems increasingly clear that your approach is the way to go. Wishing you the best of luck — as do we all.

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      I have yet to read the article, so I cannot say at this point if I agree or disagree with your conclusion. I will take a look as soon as time permits.

      – Bill H.

  4. Tony Stark May 15, 2014 at 3:37 am #

    Hi Bill,

    Thank you for your direct and clear explanation on the mechanisms by which the body mounts an immune response and the extent of the “playing field” by which a successful vaccine will have to function within. I am eagerly awaiting your follow up responses on the remaining points.

    Also fyi it looks like we may have to bring you here to Australia as we have just commenced the development and implementation of what we hope to be the largest Medical research fund operated by a government in history.

    http://www.skynews.com.au/news/national/2014/05/14/medical-research-fund-in-budget.html

    Thanks again

    Tony Stark

    • Bill Halford May 15, 2014 at 9:36 am #

      Hi Tony,

      I lived in Sydney for a year (1989) while attending Sydney University as an exchange student. Regarding a potential return to Australia, if there was a clearer opportunity to advance my vaccine research than exists in the United States, I could happily re-adapt to driving on the “wrong side” of the road.

      – Bill H.

  5. Michael May 16, 2014 at 1:10 pm #

    Given what you have written above, why not simply inject people with the blood of an HSV-2 infected person which already contains a large amount of HSV-2-specific B- and T-lymphocytes, rather than injecting an altered form of the virus to induce growth of the very same cells? It’s almost the same theory as developing an anti-venom from horse blood. I assume your answer will be because the body sees them as foreign cells and will try to destroy them.
    Following up, a logical conclusion from what you have wrote is that a high IGG antibody result should come from a person with light symptoms as opposed to someone with a low positive result. However, I am being told that there is really no correlation between antibody count and symptoms.

    • Bill Halford May 16, 2014 at 2:30 pm #

      Hi Michael,

      Perhaps you are not thinking this through. I would suggest that a transfusion of someone else’s blood is inherently far riskier than a live-attenuated viral vaccine. Blood transfusions account for how many people acquire HIV, hepatitis B virus, and hepatitis C virus. So, if someone is risk-adverse, a blood transfusion would not help.

      Antibodies may be adoptively transferred from one animal to another and this is done in certain clinical situations to (1) provide someone with immediate protection against tetanus if there is a potential exposure and they have not been immunized or (2) as you suggest to deal with / provide immediate immunity to snake venom. In the case of horse serum, one adoptive transfer is OK, but two or three horse serum transfers can be quite deadly as our bodies see horse proteins as foreign and thus mount an immune response against the horse proteins. Hence, multiple serum (i.e., serum = the non-cellular portion of blood) transfers can produce serum sickness which is effectively a form of anaphylactic shock that can kill you within 1 – 2 hours post-transfer. So, again, transferring blood products is far more perilous than a live-attenuated viral vaccine.

      Regarding the immunology of the situation, a person who is vaccinated is said to be “actively immunized” against disease because their own immune system mounts the response, and this protection has the potential to last for life. What you are suggesting, transfer of blood products, is considered “passive immunization” and is only used in lieu of vaccination as a stopgap measure when there is inadequate time to let the body respond to a vaccine. There are two very good reasons for this. First, my T-cells learn to respond to intracellular-antigens or presented-antigens exclusively as presented by my cells. If I possessed HSV-2-specific T-cells and tried to transfer them to another person, they would be unable to contribute to protection against HSV-2 in another person. More importantly, they would see the other person as foreign and would attempt to attack them. When a T-cell graft succeeds in attacking a foreign host and causing autoimmune-like symptoms, this is called graft-versus-host disease (GVHD), which is particularly a problem in the realm of certain organ transplant situations. Second, although my antibodies can potentially help another person deal with an infectious disease (e.g., tetanus), they have a half-life of 3 weeks and so dissipate over time. The most obvious example of how antibody-mediated passive immunity wanes over time is observed in newborn babies. While they are in utero, they acquire a large subset of mom’s IgG antibodies, and are born with that passive protection in place. Hence, newborns don’t tend to get sick for the first 3 to 4 months of life. However, once newborns hit 6 months and Mom’s pre-formed IgG antibodies are largely gone, all hell breaks loose as any parent may attest.

      So, long story short, active immunization (vaccines) are far more effective than passive immunization in protecting people against infectious disease, and are far safer than passive immunization as may be observed by looking at the laundry list of potential medical complications that hemophiliacs and other users of blood products may suffer as downstream consequences of their treatments.

      Finally, you write…..”Following up, a logical conclusion from what you have wrote is that a high IgG antibody result should come from a person with light symptoms as opposed to someone with a low positive result. However, I am being told that there is really no correlation between antibody count and symptoms.”

      I think the interpretation you offer is overly simplistic. In the context of people who already have HSV-2 genital herpes disease, I agree that they possess a specific collection of antibodies and T-cells that is inadequate to prevent recurrent herpetic disease, and noone knows precisely why. There are many possibilities including anergic-T-cell responses, T-regulatory cells, or lymphocyte responses against the “wrong subset” of HSV-2’s 75 different proteins. Such complexities of the immune response to HSV-2 and HSV-2 vaccines go well beyond the intended scope and purpose of this blog, and are really more appropriate for the primary research literature. However, at the end of the day, all this speculation reduces down to “Nobody knows exactly why a subset of HSV-2-infected people get stuck with the outcome of a lifetime of recurrences of genital herpes despite the presence of T-cells and IgG antibodies against a subset of HSV-2’s 75 proteins.”

      However, I note that the number of persons who are asymptomatically infected with HSV-2 is ~20 times greater than the much smaller sub-population who suffer with frequent recurrent outbreaks of HSV-2 genital herpes, and which you are effectively suggesting represent the “norm” or the average. There is simply not a shred of evidence to support this assumption. In the vast majority of HSV-2-infected individuals, the immune system does its job, they mount a high IgG antibody response, and the immune response is so effective that they walk through life completely unaware that they are infected with HSV-2 (i.e., 80% of HSV-2-infected persons are seropositive but are unaware of any active disease). In these people (the majority of HSV-2-infected persons), it is reasonable to expect that their IgG antibody and T-cell response to HSV-2 is critically important in keeping the virus in check, and does a remarkably good job at doing precisely this. Therefore, I believe your error in logic is that you are focusing on the exception (i.e., 2-4% of HSV-2-infected persons with recurrent disease) rather than focusing on the most common outcome of (1) HSV-2 infection and (2) the host immune response to HSV-2, and hence are arriving at an erroneous conclusion that IgG antibodies play no role whatsoever in immune-mediated protection against HSV-2.

      Stepping away from the equivocal (debatable) points above, if one actually reads the literature on the topic, then there is clear evidence that in the context of a preventative HSV-2 vaccine, vaccine-induced antibodies both (1) correlate with and (2) functionally contribute to vaccine-induced protection against HSV-2. Here are two citations (among many others) that support these two points: (1) http://www.ncbi.nlm.nih.gov/pubmed/23755244 and (2) http://www.ncbi.nlm.nih.gov/pubmed/11152492. I am currently doing a 7-month sabbatical comparing vaccine-induced protection in normal mice versus those who cannot make IgG antibodies (or any other isotype of antibody). The simple fact is that in the context of mice, there can be no question that IgG antibodies functionally contribute to vaccine-induced protection against HSV-2.

      – Bill H.

  6. Michael May 22, 2014 at 1:05 pm #

    Hi Bill,

    I am wondering if newborns, born of an HSV-2 positive mother without complications, will develop antibodies, either as a result of a natural birth, or as a result of acquiring them in the womb? In other words, is it possible for a birth, as described above, to act as almost a natural vaccination? Would you guess that babies of positive mothers would have, on average, an elevated immunity to the disease? If so, would you expect it to wane over time? It seems like most vaccines are recommended periodically, and not good for life (Rabies, Yellow Fever). Therefore, would it really matter if said immunity did not last until the age of expected commencement of sexual activity? Regardless, do you think studying such subjects would be a productive endeavor?
    I guess my other inquiry regarding this scenario is more sociological. In the above scenario, lets say the baby’s blood was drawn at 1 year and tested >1.1 for antibodies. The baby would be considered “positive” and because there is no cure, would that baby/person always legally “have herpes” even if subsequent yearly tests consistently went down and tested negatively? I guess what I am really getting at is where does the magic number of 1.1 come from? Do you ever see people that test consistently negative, yet have more than trace readings, say in the .5-.75 range?

    Thanks,

    Michael

    • Madscientist May 24, 2014 at 9:03 am #

      The baby would loose the antibody level, usually after a couple of months, because the antibodies are the mother’s and not the baby’s, but are still in the blood of the baby. The baby could get infected with herpes virus even more, after these couple of months when the antibodies of the mom cease to exist, so it’s left totally unprotected against herpes (more vulnerable after then before).

      Also, the “legal” status of a baby would not interest anyone I think. Basically it’s just herpes, people do not even standardly get tested on herpes, even after when they grow up. Also these antibody titers etc. do not show much, they are different in every human and depend on their immune system and also the ammount of the herpes infection they’ve caught.

    • Bill Halford May 24, 2014 at 12:45 pm #

      Dear Michael,

      The short answer is I concur with MadScientist.

      The longer answer is that (1) IgG antibodies do not confer complete protection against HSV-2 genital herpes in and of themselves (i.e., antibodies and T-cells together are the winning formula) and (2) IgG antibodies are protein-based molecules that have a half-life of 21 days and thus decay over time unless the body also has the B-cells/plasma cells that are producing the HSV-2-specific antibodies. Hence, for all intents and purposes, a baby born to a HSV-2 seropositive mother would be seronegative by 3 – 4 months after birth.

      Given this simple reality that all IgG antibodies transferred from Mom to a newborn decay in abundance rather quickly, the rest of your questions are a moot point.

      – Bill H.

  7. Madscientist June 1, 2014 at 7:35 am #

    Dr. Bill,
    do you have an opinion on the following quote by Admedus (Company affiliated with Ian Frazer):

    “Traditional vaccines differ from DNA vaccines as they stimulate immunity by injecting a part of the virus (either live, weakened or killed forms) for the immune system to fight off thus creating immunity to future exposure. The type of immune response typically generated in this way is more suited to protection from infection rather than treatment if the patient is already infected.”

    Thanks.

  8. Andi June 1, 2014 at 8:36 pm #

    Dr. Bill,

    Allow me first of all to add my small voice to the many who have expressed their gratitude for your unflinching efforts on so many fronts.

    You may wish to have a look at your policy regarding the adverts which appear on your site. New visitors may possibly infer your endorsement of these products.

    Andi

    • Bill Halford June 2, 2014 at 7:49 am #

      Hi Andi,

      Thanks for your comment. Regarding the advertisements, all I can say is the ads that are posted in association with my blog purely reflect the choices of the administrators of Science Blog (http://scienceblog.com/). It is unfortunate if any of the advertisements reflect herpes treatments that do not represent the cutting edge in the available standard of care. However, all in all, the folks at Science Blog have been tremendously supportive of the Herpes Vaccine Blog, and have made it possible for me to maintain a blog whose visual appearance and organization far exceeds anything I could do on my own. Therefore, although I am not endorsing the ads that appear on this blog site, Science Blog is my partner in this endeavor, and I support their decision to recruit whatever source of advertising dollars they believe will make their website sustainable over time.

      – Bill H.

  9. Mohammed June 11, 2014 at 10:52 am #

    Dear Bill

    I appreciate your great efforts.
    and i would like to know from you,when do think HSV -2 vaccine would be available to patients?

    • Bill Halford June 11, 2014 at 6:57 pm #

      Dear Mohammed,

      I wish I could tell you when a HSV-2 vaccine will be available to patients, but I cannot. I think we possess the requisite technology to make it happen today, and that should be the source of some encouragement, as I think that 5 years this was not the case. The HSV-2 vaccine field in 2009 had deluded itself into believing that Herpevac was the answer despite the failure of similar, glycoprotein D-based vaccines in 1990, 1994, 1997, 1999, and 2002. In 2014, for those scientists whose minds are able to tune out the hollow promises of vaccine companies (who have been failing in this arena for >15 years) and focus on the published data, it is clear that we now understand why Herpevac failed, and what we need to do differently in the future. This is an important, and essential step forward.
      However, I still observe a lot of HSV-2 vaccine approaches being offered that strike me as yet more flawed concepts that, to anyone who understands how vaccines work, are obviously only capable of eliciting a fraction of the protection against HSV-2 genital herpes that is possible. So, the question becomes, when will a critical mass of scientists be willing to stand up to the FDA and say “Enough of the subunit vaccine stupidity. Yes, it is a fabulously safe approach, but it is immunologically an overly simplistic and naive approach (1) whose failure rate over the past 25 year is ~99%; (2) has set us back billions of dollars and years of time proving it is inadequate for many diseases such as HIV, tuberculosis, malaria, and genital herpes; and I note that (3) over 50 million people have died or suffered from these diseases while scientists have been absent-mindedly tinkering with their theories of why subunit vaccines should work and ignoring the mounting pile of carcasses of failed clinical trials of AIDS, TB, malaria, and herpes vaccines.
      Clearly, I am sick of the rhetoric, B.S., and ability of vaccine manufacturers and the FDA to ignore the price of their “safe” subunit vaccines that have been failing for the past 25 years…..people are dying or suffering from real human diseases while they test the next iteration of an approach that has failed 5 times before. So, Mohammed, your question boils down to, “How long will it take the FDA and scientific community to change their opinion and (1) admit the limitations of subunit vaccines and (2) acknowledge that maybe we made a mistake when we began to systematically discourage and dissuade researchers from developing new live-attenuated vaccines that are less sexy than subunit vaccines, but which have a >100 times better track record than subunit vaccines.
      My mind works on the principles of logic, which is great for figuring stuff out, and which is the worst thing in the world for operating in political circles and estimating what a group of people (i.e., the scientific community) is likely to do next.

      What I have written above is the long answer. The short answer to your question is……your guess is as good as mine. I have no idea what compels the FDA and scientific community to cling to outdated ideas about subunit vaccine approaches that seemed reasonable when they were first proposed (in the late 1970s), but which have simply not panned out to be the ultimate solution that was originally envisioned.

      – Bill H.

  10. Dant June 12, 2014 at 8:38 am #

    Dear Dr Bill

    I found this information on the Science Dayli website and want to know if it you already saw it or these news have any “good news” implicit.

    The title says “Herpesviruses undercover: How the virus goes undetected by body’s immune system”

    http://www.sciencedaily.com/releases/2014/06/140606102045.htm

    And about your research? found any sponsors?

    God Bless Dr.
    – Dant

    • Bill Halford June 13, 2014 at 11:54 pm #

      Hi Dant,

      The search for sponsors and funding for scientific research is never ending. So, about my research, I see small signs of progress, but the search to gain a broader base of support, and more sponsors, for the live-attenuated HSV-2 vaccine concept goes on.

      – Bill H.

  11. Clarke June 12, 2014 at 3:50 pm #

    Hello Dr. Bill,

    it is sad, that the government officials and all the people who are getting directly or indirectly payed using our taxes do not move a finger for the benefit of us, sufferers. Plainly speaking, the sores hurt. They itch, they make people uncomfortable, especially down there.. and the infectivity.. it’s like a cherry on the top of the cake (extra perk).
    – Can you spread a reccurent genital sore by applying antiviral acyclovir lips-creme ?

    – What about the Bill & Melinda Gates Foundation, any inquiry there (HSV falls under their HIV prevention programme 100%) ?

  12. Lynnlee June 13, 2014 at 2:41 pm #

    1. Would the new vaccine for herpes also be of help to individuals who have adult HSV2 encephalitis and/or HSV2 ascending myelitis?

    2. Have you heard of anyone having HSV2 infection affecting the heart? Shortly after a diagnosis of HSV2 on the inside of my arm, I was diagnosed with PCD (primary conduction disorder of the heart). In my case, I had a Right Bundle Branch Block, and a left anterior block. Crushing chest pain occurred at the time of my initial HSV2 infection. PCD is irreversible, but a latent herpes infection may pose additional threats (Joseph Berger, MD, Sidney Houff, MD, PhD., NEUROL/VOL 65 (nO.5) MAY 2008.
    3. Concerning the above herpes complications, would a herpes vaccine be given in one standard dose, or would there be different amounts given depending individual cases?
    4. Thank you for your tremendous contribution to helping people like myself whose lives are affected daily by the challenges of living with HSV2.

    • Bill Halford June 16, 2014 at 6:23 pm #

      Dear Lynnlee,

      I doubt that a HSV-2 vaccine could be used to reverse the symptoms you describe (HSV-2 encephalitis, ascending myelitis, or primary conduction disorder) regardless of how effective the vaccine was. I could be wrong, but these symptoms, once established and in place, do not strike me as vaccine-reversible.

      I would suggest that the highest and best use for a HSV-2 vaccine would be to protect those who are uninfected from the risk of acquiring HSV-1 or HSV-2 genital herpes (or oral herpes, ocular herpes, or herpetic whitlow, as well as encephalitis and all downstream complications). Vaccine-induced prevention of all herpetic diseases by vaccination of the uninfected strikes me as an eminently feasible and medically important goal.

      I am simply waiting for my colleagues in HSV-2 vaccine science to recognize that just because we all have 101 gee-whiz theories about a “neat” HSV-2 vaccine idea that might work, we are in 2014 faced with a very real and important choice, which is: (1) science geeks like myself can keep tinkering with “neat” HSV-2 vaccine ideas (that generally don’t work) for the next 100 years or (2) we can remember that HSV-1 and HSV-2 viruses are real pathogens that destroy millions of people’s lives while science geeks continue to play with their intellectual tinker toys and theories.

      I will be the first to admit that a live-attenuated HSV-2 vaccine is boring, and is definitely not a “gee-whiz” idea……it’s quite obvious that it will work and will crush / prevent all forms of herpetic disease caused by HSV-2. I note that a live-attenuated HSV-1 vaccine would do the same for all forms of herpetic disease caused by HSV-1. I would suggest that it is time for vaccine scientists to set aside their intellectual curiosity and questions, and just produce a f—ing herpes vaccine that works already. We have been talking about doing this since 1980….it is time to deliver the goods, and a live-attenuated HSV-2 vaccine (like the live VZV Oka / chickenpox vaccine) is the most sensible way to achieve this goal.

      So, Lynnlee, I doubt that a HSV-2 vaccine could help someone with the symptoms you describe, but it could prevent any of our kids from ever having to deal with these and other downstream consequences of HSV-2 infection (e.g., like being 3-fold more susceptible to HIV infection).

      – Bill H.

  13. Dant June 24, 2014 at 4:32 pm #

    Dr Bill!

    I was tracking some news about HSV and some new approaches of a possible cure and found this one that seems like a real deal.

    http://www.fhcrc.org/en/news/spotlight/imports/targeted-dna-cleavage-can-inactivate-latent-virus.html

    I dont know if you Dr have heard of it
    If you have the time to read it and maybe send us an opinion about it would be very great.

    Thanks Dr!

    • Sweet July 15, 2014 at 10:38 pm #

      I am aware of the research by the Keith Jerome lab. They have actually got over some major humps. It’s good news but a product of this type will not be available for several years. In the meantime this virus is still spreading and causing disease. It’s extremely important to have a real effective vaccine to prevent these infections. Hopefully it can help with existing infection as well.

  14. SN-AU August 1, 2014 at 8:18 am #

    That was the most positive, informative and interesting thing i have read about HSV-2 in a long time. This give me hope as after reading your blog and seeing Anon’s quote ‘It wages war against the best days and amplifies the worst.’ i cannot emphasize enough how true this is. Thank you, sincerely from deep in my heart for dedicating so much of your life to this. Keep up the exciting work and hopefully we can see some real results in the near future.

  15. libramale29 August 1, 2014 at 2:41 pm #

    Any news on pritelivir trials?

  16. litzler August 11, 2014 at 1:53 pm #

    Dear Mr. Halford,

    Could you shed some light on your herpes vaccine. Please give me your honest and most realistic opinion. No hype or hope but just plain brutal honesty. Is your vaccine going to stop outbreaks forever or is it going to require yearly booster shots much like the sub units in order to keep our immune systems ramped up? I know you havent tested it yet but surely you have some thought on it. If the body doesnt want to stay ramped up then how is a vaccine going to force it to?

    • Bill Halford August 11, 2014 at 2:05 pm #

      Dear Litzler,

      Here is my no-hype answer. For 200 years, viral vaccines have spared the human race from a lot of viral disease by being administered before infection with a disease-causing virus. Thus, there is a clear precedent that preventative vaccines work. I have made this point at least a half-dozen times on this blog, and there are millions of vaccinated people over >200 years that demonstrate the viability of this approach.

      You are asking about a therapeutic HSV vaccine, and you are saying “Is your vaccine going to stop outbreaks forever?” As I have said many times on this blog, what you are proposing is an experiment for which there is no supporting evidence. Have you heard of a therapeutic HIV vaccine that prevents people with HIV infection from progressing to AIDS? Personally, I have not, nor have I heard of a therapeutic hepatitis C vaccine. Likewise, for all the talk of a therapeutic HSV-2 vaccine and clinical trials to match, I am unaware of a single publication that unequivocally answers your question.

      So, I give you my clear and unequivocal opinion on therapeutic HSV-2 vaccines………it is an experiment worth conducting, but anyone who has been in science as long as I have knows that you run the experiment first, and then you offer a clear and unequivocal interpretation of the data collected. There is no crystal ball that allows a scientist to forego data collection. So, my thought on the matter is that……if we tested the potential of a live-attenuated HSV-2 vaccine to serve as a therapeutic vaccine, then we would have some data available to address your question (which I believe is a fascinating question). Until then, I am unwilling to offer you an interpretation of data that does not exist.

      – Bill H.

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