Therapeutic HSV-2 Vaccine: Critical Goal or Pipe Dream?

RML-Lost TrailTherapeutic HSV-2 Vaccine: Critical Goal or Pipe Dream?

To those who have followed my blog in the past, please accept my apology for about 7 months of radio silence. I took a Sabbatical Leave at the Rocky Mountain Laboratories ( from Dec 2013 to June 2014 to brush up on my techniques, and develop some new assays to measure the T-cell response to a live-attenuated HSV-2 vaccine. Dr. Kim Hasenkrug and the great people in his lab made this a fabulous 7 months ( I learned a ton, and this was time well spent. I am a skier, and I can also report that Lost Trail ski area (, which is 45 miles south of the lab, gets very high marks for tons of fresh powder in early 2014!

The last 2 months of my Sabbatical were ridiculously busy, and the 6 months since I returned to my home institution at SIU School of Medicine have been equally nuts. Very productive, but no time for a life and no time for the blog….hence the long silence.

So, without any more excuses, time to get down to business. I said in May 2014 that I would write three posts to address a reader’s questions, which went something like this: “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 would an arm shot benefit the genital area for protective or therapeutic purpose?”

There are three components to this question, and these are:

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?

3) What is the goal of a ‘preventative’ versus a ‘therapeutic’ HSV-2 vaccine, and are each of these goals equally feasible?”

I addressed the first two questions in earlier blog posts:


I address the third and final question below in this blog post. Way to be a slacker Halford… only took you 7 months!! Well, better late than never…here it goes.




The basic principles on which the natural world and biology operate are generally pretty straightforward. That said, human beings have an infinite capacity to screw things up and make something that should be simple seem far more complex than necessary. This is the situation with HSV-2 vaccines…..what should be a simple problem has become a quagmire of contradictory logic and bad ideas.

A preventative HSV-2 vaccine would be simple if we considered a live-attenuated HSV-2 virus as the means of vaccination. Worked for smallpox, measles, chickenpox, etc and would work for HSV-2, but we have not tested any live HSV-2 vaccines in the U.S. So where things have gotten complicated is that scientists hypothesized that a live-attenuated HSV-2 vaccine might be “too dangerous” to pursue (based on no compelling evidence to support the claim), and scientists started developing “safer alternatives.” The need for these “safer alternatives” has never been proven, but nonetheless HSV-2 vaccine researchers have spent >99% of their time and money studying vaccine approaches based on just a few bits or pieces (subunits) of HSV-2.

When I say subunit vaccines, I am specifically talking about approaches like…….(1) the Agenus HerpV vaccine, (2) the Genocea GEN-003 vaccine (i.e., Herpevac + ½ of another HSV-2 protein), (3) Vical’s HSV-2 vaccine, (4) the Corridon / Admedus HSV-2 vaccine fundraising effort. This general subunit vaccine concept has been failing in human clinical trials since the mid-1980s, and there is no compelling evidence that the newer versions of this old concept will be any better as preventative HSV-2 vaccines.

If one INCLUDES a live-attenuated HSV-2 vaccine as an option in our human clinical testing of HSV-2 vaccine candidates, then a preventative HSV-2 vaccine should be a no-brainer provided that the live HSV-2 vaccine in question elicits (1) at least 30% of the pan-HSV-2 IgG antibody response that is observed in asymptomatic carriers of wild-type HSV-2 and (2) that this vaccine-induced HSV-2 antibody response is durable and is maintained at a detectable level for at least 3 years post-vaccination.

In contrast, if one EXCLUDES a live-attenuated HSV-2 vaccine as an option for human clinical testing of HSV-2 vaccine candidates (which has been the case in the U.S. for the past 30 years), well that would make it damned near impossible to develop an effective HSV-2 vaccine.

So, a preventative HSV-2 vaccine is easy if one uses the right tool that nature has provided us for the job (a live-attenuated vaccine), but human beings have complicated the issue by creating a scientific culture is which most ‘experts’ have arrived at precisely the wrong conclusion that “We should test any and all HSV-2 vaccine concepts except for the ‘most dangerous approach’ of a live-attenuated HSV-2 vaccine.”

Call me crazy, but I am going to go out on a limb and suggest that human testing of a well-vetted live-attenuated HSV-2 vaccine in n=20 people is probably much safer than what we have been doing for the past 30 years……watching n=10 to 20 million people per year get newly infected with HSV-2 while scientists keep tinkering with HSV-2 subunit vaccines that don’t work.




Everything I write above may be distilled into one sentence: The likelihood that a live-attenuated HSV-2 virus would function as a very effective, preventative vaccine to prevent HSV-2 genital herpes is similar to the probability that the sun will rise tomorrow.

I will be the first to admit that I don’t have a crystal ball, and I really cannot see into the future. However, in both cases, experience tells me that it would be prudent to assume these two things are very, very, very likely to come to pass, and thus we should probably plan accordingly. I have no plans to hang myself or shoot myself tonight on the off-chance that the sun won’t rise tomorrow, and the world will suddenly become an uninhabitable rock. Likewise, there is no basis in logic or reason to assume that a live-attenuated HSV-2 vaccine should be any less likely to succeed than the live-attenuated viruses that have been successfully used to control smallpox, yellow fever, polio, mumps, measles, rubella, and chickenpox.

As certain as I am that a PREVENTATIVE HSV-2 VACCINE is infinitely feasible, I would put myself somewhere precisely in the middle when it comes to the feasibility of a THERAPEUTIC HSV-2 VACCINE.

Before proceeding, I offer my simple take-home message on therapeutic HSV-2 vaccines in the next two paragraphs.

The promise of a therapeutic HSV-2 vaccine lies in that, in theory, it might be (1) administered to a person with uncontrolled HSV-2 genital herpes outbreaks and (2) might re-program that person’s adaptive immune system to do a better job in the future of controlling their HSV-2 infection such that their outbreaks either stopped altogether, or occurred at a much lower frequency. The importance of this possibility for tens of millions of herpes sufferers cannot be overstated, and thus the possibility of a therapeutic HSV-2 vaccine deserves the scientific community’s full attention.

Despite the importance of this possibility, it is equally important for HSV-2 genital herpes sufferers to recognize that, unlike a preventative HSV-2 vaccine, there is simply no historical precedent that dictates that a therapeutic HSV-2 vaccine MUST be possible. A HSV-2 therapeutic vaccine is an important possibility, but it remains to be determined if the idea falls into the realm of “science” or “science fiction.” Maybe someone who has lived with symptoms of recurrent HSV-2 genital herpes that have been ongoing for years may be “dialed back” to zero symptoms, or close to zero symptoms, by immunizing them with a series of “therapeutic HSV-2 vaccine shots.” It is an appealing idea (or hypothesis), but it is a hypothesis that remains largely untested, and thus unknown.

Below I consider some of the theory that underlies (1) the counterargument why a therapeutic HSV-2 vaccine SHOULD NOT be possible and (2) the argument why a therapeutic HSV-2 vaccine MAY BE possible.




The against therapeutic HSV-2 vaccines that immunologists (including myself) have been trained to think in terms of is that…….”immunity to HSV-2″ is a binary variable (i.e., a 0 or a 1)……you either have it or you do not.

With this rationale in mind, the story goes something like this………….

After a person is infected with HSV-2, their body’s B- and T-lymphocytes mount a response to the HSV-2 virus. The activated B-lymphocytes produce HSV-2-specific antibodies that circulate through the blood and lymph. The activated T-lymphocytes enter the circulation and migrate into HSV-2-infected tissues. Collectively, the development of (1) HSV-2-specific antibodies and (2) HSV-2-specific T-cells constitutes “immunity to HSV-2,” and under this logic, a therapeutic HSV-2 vaccine should NOT be possible.

That is, if being infected with wild-type HSV-2 is sufficient, in and of itself, for a person to convert from being “naïve” (i.e., a 0) to “HSV-2-immune” (i.e., a 1), then how could a therapeutic HSV-2 vaccine possibly help?   Is the therapeutic HSV-2 vaccine going to make them a 1+?

There are at least two limitations in this logic.

First, in the natural world, complex biological processes like the development of an adaptive immune response to HSV-2 are rarely (if ever) describable in terms of a purely binary variable (i.e., black=0 or white=1). Hence, a more realistic (although still overly simplistic) way to think of “protective immunity to HSV-2” is to think of this immunity as lying on a scale of 0.0% to 100.0% possible protection against HSV-2.

Second, if we consider the actual basis of immunity to HSV-2, this relies on a diverse population of millions of B-lymphocytes, CD4 T-helper lymphocytes, CD8-lymphocytes, and likely some less studied CD4+CD25+ regulatory T-lymphocytes (which can dampen a protective immune response, and push the immune system towards “tolerance”). Aside from the sheer numbers of cells involved, these lymphocytes may recognize hundreds to thousands of different bits (epitopes) of HSV-2 distributed across 75 viral proteins. To help put this in perspective, it is useful to remember that a single B-cell or T-cell recognizes a very small piece of HSV-2 on the order of 6 to 25 amino-acids in length. In total, HSV-2 encodes 39,100 amino acids worth of protein. Given the reality of how the biological system operates, it is really not accurate to suggest that “immunity to HSV-2” may be described as a binary variable, and thus to think of human beings as either being HSV-2 seronegative (naïve) or HSV-2 seropositive (immune). Such descriptions are such gross oversimplifications of the truth that they are about 10% right and are about 90% wrong. Nonetheless, that is how most doctors and scientists have been trained to think of immunity to HSV-2 (+/-). This mindset (1) creates the illusion of understanding for doctors; (2) is based on ignorance of how the adaptive immune response to HSV-2 actually operates; and (3) creates no opportunity for people to rationally discuss and consider the possibility of a therapeutic HSV-2 vaccine, which requires a more accurate and nuanced understanding of HSV-2 immunity.

So, we return to the primary counterargument against a therapeutic HSV-2 vaccine. The suggestion that prevents most doctors and scientists from considering a therapeutic HSV-2 vaccine is that we have been trained to believe that infection with wild-type HSV-2 renders a person fully immune to HSV-2. I offer three scenarios below that suggest it is vanishingly unlikely that everyone who is infected with HSV-2 immediately acquires 100% of the protective immunity against HSV-2 that is possible.

1) 80% of people who are infected with HSV-2 mount an antibody response to the virus, but never experience any symptoms. Thus, it is a well known fact that 80% of HSV-2 infections are completely asymptomatic, and it would appear that in these individuals that the protective immune response might approach 100% of the protective immunity against HSV-2 that is possible.

2) People who develop symptomatic HSV-2 herpes often take 4 to 12 months to effectively control the primary infection. That is, they have HSV-2 outbreaks almost continually for the first 4 to 12 months of the infection. Likewise, these same individuals may not “seroconvert” and become clearly positive for HSV-2 antibodies in their blood until 4 months after the initial infection. In contrast, animals that are immunized with wild-type HSV-2 or a live-attenuated HSV-2 vaccine mount a very potent antibody response within the first 30 days after immunization. If the people whose primary HSV-2 infection (1) drags on for 4 to 12 months and (2) it takes 4 months for their antibody levels to HSV-2 to become detectable, is it really reasonable to assume that this represents “100% of the protective immunity to HSV-2” that is possible?

3)   A subset of HSV-2 infected people (~1 per 1,000 infected persons) develop recurrent HSV-2 genital herpes with outbreaks often occurring 6 to 12 times per year, and sometimes more often. This pattern may continue for over 20 years. Is this level of immune control of a HSV-2 infection really the best the adaptive immune system has to offer? It seems possible to me that some, or perhaps all, individuals who suffer with HSV-2 genital herpes may be stuck in a vicious cycle where their adaptive immune system is just not learning from their repeated encounters with HSV-2. If this is the case, then it is possible that some HSV-2 genital herpes sufferers may only possess 1 to 10% of the “protective immunity to HSV-2” that is possible.  If this were indeed the case, then it might explain why some people experience >4 outbreaks per year and why some have outbreaks that last on the order of 10 to 21 days at a time.

None of the points I bring up above prove that a therapeutic HSV-2 vaccine is possible. However, I note that there is no hard evidence that supports the prevailing belief that recurrent HSV-2 genital herpes “just happens” in the face of “100% of the protective immunity to HSV-2” that is possible. I would suggest that if a person’s immunity to HSV-2 was really all that, then logically they should either be (1) asymptomatic or (2) should only get very occasional and very brief outbreaks of HSV-2 genital herpes. It is hard to reconcile how someone may possess “100% of the protective immunity to HSV-2” that is possible, and yet still experience 4 or more recurrences of HSV-2 genital herpes each year where each outbreak may last for 7 to 21 days. Sounds like pretty lousy “immunity” to me.




If we are willing to consider the possibility that a subset of people who live with >4 outbreaks per year of HSV-2 genital herpes may possess less than optimal protective immunity to HSV-2, then it may be possible to improve (or re-program) such an individual’s adaptive immune response to better recongnize HSV-2 via a therapeutic HSV-2 vaccine. Again, I ask the reader to please bear in mind that everything that follows is simply theoretical (speculative), and is nothing more than a tour of the hypothetical. Therefore, the reader should not arrive at the end of this post with the certainty that a therapeutic HSV-2 vaccine must be feasible. No such certainty exists. Rather, what I outline below simply represents a possibility that merits more careful examination by the scientific community.


1.   Therapeutic HSV-2 vaccines in current clinical trials.

I note that several therapeutic HSV-2 vaccines are being tested in human clinical trials (e.g., GEN-003, HerpV), but I think these approaches represent pretty lame ideas. The HerpV vaccine is a T-cell only vaccine. Newsflash…..antibodies are important too. A “T-cell only” vaccine is about as good as the left half of a condom or half of a bicycle helmet. Call me a perfectionist, but I generally find that half-protection is little more than the illusion of protection with all of the dangers of no protection at all. GEN-003 is just Herpevac-plus, and the Herpevac-approach has already failed in six human clinical trials. So, brace yourself, but it is just a matter of time until GEN-003 (Herpevac-plus) is shown to be as lame as all of the Herpevac-like predecessors that came before it.  Tweaking the same bad idea (gD-subunit) by adding half a protein (half of ICP4) and changing the name to “GEN-003,” does not alter the fact that it is still an approach that is eerily similar to a bad idea that failed in human clinical trials in 1990, 1994, 1997, 1999, 2002, and 2012.

When I talk below about the “potential of a therapeutic HSV-2 vaccine to reduce herpes symptoms,” I am talking about a real, honest-to-God live HSV-2 vaccine that is 99% similar to wild-type HSV-2. I am not talking about GEN-003, HerpV, Vical, or Admedus or whatever permutation of the subunit vaccine approach (based on <3% of HSV-2’s proteome) is supposedly going to elicit 100% of the protective immunity against HSV-2 that is possible. Just like it is a bad idea to enter a boxing ring with both of your arms tied behind your back, I think it is a bad idea to show the human body a wimpy “<3% of HSV-2” subunit vaccine and hope it will elicit 100% of the protective immunity against HSV-2 that is possible.


2.   Therapeutic HSV-2 vaccines that might have a better chance of working

Even with the best possible HSV-2 vaccine imaginable, a therapeutic HSV-2 vaccine that prevents or reduces the symptoms of HSV-2 genital herpes is going to be a heavy lift. Thus, no matter how well a therapeutic HSV-2 vaccine is designed, there can be no assurances that it will work.

If one wanted to stack the deck in favor of a therapeutic HSV-2 vaccine, a few of the essential features of the best possible therapeutic HSV-2 vaccine would be that:

(1) It would be a good B-cell antigen that engages the broadest repertoire of HSV-2-specific B-cells found in the body;

(2) It would be a good T-cell immunogen that engages the broadest repertoire of HSV-2-specific T-cells found in the body;

(3) It would achieve the broadest possible breadth of B- and T-cell stimulation possible by carrying or encoding >95% of HSV-2’s antigens; and

(4) All of these properties defined above would elicit the broadest possible HSV-2-specific antibody response, HSV-2-specific CD4+ T-cell response, and HSV-2-specific CD8+ T-cell response.

In light of these desired properties of a therapeutic HSV-2 vaccine, I would suggest that my laboratory’s live-attenuated HSV-2 0DNLS vaccine strain would be a far better candidate for a therapeutic HSV-2 vaccine because (1) it encodes 99.3% of HSV-2’s foreign proteins and (2) it establishes a short-lived infection (~3 days) at the site of immunization. While some might claim a live-attenuated HSV-2 vaccine would be “too dangerous,” I would remind everyone that this attenuated virus is ~10,000-fold less virulent than the wild-type HSV-2 that herpes sufferers already carry, so the “too dangerous” argument is largely irrelevant in the context of a therapeutic HSV-2 vaccine.


3.   How would a therapeutic HSV-2 vaccine work?

Assuming one starts with a reasonably designed therapeutic HSV-2 vaccine, below I outline how it might work to reduce the symptoms of HSV-2 genital herpes.

The immune system must, at all times, make a decision about what substances it deems “foreign” and decides to attack versus substances that it deems “self” (or close enough to self) that it decides it should not attack. In the context of HSV-2, I am sure many are thinking, “What is the point of this decision….attack that little son of a bitch that is HSV-2!!!” Well, the downside of having an overzealous immune response that spills over from things that are foreign to things that are you (self) is called “autoimmune disease.” Examples include lupus, Sjögren’s syndrome, and Grave’s disease…..very real problems that our bodies try to avoid by making very judicious decisions about what precisely the immune system chooses to attack.

In the case of chronic infections, like HSV-2 genital herpes, it seems that these infectious agents have developed an array of tricks to fool the immune system into becoming tolerant to many of their foreign proteins (i.e., tricking the immune system into seeing a microbial protein as “self” that should not be attacked). So, even though your bone marrow makes a truckload of HSV-2-specific B- and T-cells, it is unclear, even in people who have been infected with HSV-2 for years to decades, that the full repertoire of HSV-2-specific B- and T-cells (and the antibodies made by B-cells) have been fully enlisted to help combat these infections. Thus, it is possible that someone with HSV-2 recurrent genital herpes may only possess 1 to 10% of the protective immunity against HSV-2 genital herpes that is possible, because most of your B- and T-cells have been tricked into seeing HSV-2 as self and entering a state of anergy (i.e., non-responsiveness).

So, finally….after explaining a lot of immunology background, we come to the reason that a therapeutic HSV-2 vaccine might work. Wild-type HSV-2 can slink around in your body and hide relatively well from detection by the host immune system…..this is a known quantity. HSV-2 encodes at least 4 proteins that trick the immune system and delay recognition of the infection; namely, ICP47 which delays CD8 T-cell recognition, gE-gI, which dampens the useful effects of antibody; gC, which dampens the activation of the complement cascade; and ICP34.5, which antagonizes PKR / interferon-induced shutoff of viral protein translation (particularly in neurons). So, it should not be news to anyone that HSV-2 messes with the immune system pretty hard. The new wrinkle I am suggesting here is that it is possible (but absolutely unproven) that as small quantities of HSV-2 (100s to 1000s of infectious virus) are slinking around a person’s body and delaying recognition and control by the host immune defenses, this process could be the very thing that tricks their B- and T-cells into becoming complacent (anergic) and not responding efficiently to suppress HSV-2 reactivation events as soon as they flare up. So, instead of having a 2-day subclinical outbreak that is controlled before you ever see a lesion, because the adaptive immune response to HSV-2 is on permanent holiday (i.e., a weak antibody response and an inadequate T-cell response), HSV-2 reactivation events are allowed to slink along and cause 2 to 3 weeks of disease in a subset of ~1 per 1,000 HSV-2 infected persons who, for whatever reason, have simply failed to stitch together 100% of the protective immunity against HSV-2 that is possible.

If this hypothetical scenario is true, then a live-attenuated HSV-2 vaccine could work as a therapeutic HSV-2 vaccine by delivering a 5,000- to 10,000-fold higher dose of a live-attenuated HSV-2 virus into the epithelium (skin) than a herpes sufferer would ever produce during an outbreak.  That live-attenuated virus could replicate and spread in the skin around the injection site for 2 to 4 days, and teach (re-program) the immune system to better recognize HSV-2’s foreign proteins.

Let us hypothetically say that the dose of live-attenuated HSV-2 vaccine delivered in the skin was 40 million infectious units. That would represent about a 20-fold increase relative to what I have given 30 g mice. A relatively small human weighs at least 40,000 g, and so on a mg / kg basis, 40 million infectious units of a live-attenuated HSV-2 vaccine would be a reasonable guesstimate of how to appropriately scale a live-attenuated HSV-2 vaccination of mice up to a scale appropriate for an animal the size of a human.

Unlike wild-type HSV-2 which is good at hiding its protein antigens and flying below the radar of the immune system as it slinks along based on a few thousand infectious units of virus (i.e., smaller than the population of South Lake Tahoe), a single shot of a therapeutic HSV-2 vaccine containing 40 million infectious units of a live-attenuated virus would be like introducing the immune system to the entire population of California. Such a large dose of infectious virus negates any possibility that HSV-2, however devious and clever, may hide its proteins from the immune system when delivered in such a large bolus dose.  This would introduce the possibility of bringing together all of the necessary ingredients to elicit a far more protective immune response against HSV-2; namely, (1) inflammation, (2) appropriate danger signals, and (3) nearly all 75 of HSV-2’s foreign proteins being expressed in their native context of (i) virus-infected cells that serve as HSV-2 virion factories and (ii) the infectious HSV-2 virions that are released from those virus-infected cells.

Whether or not 2 or 3 shots of such a therapeutic HSV-2 vaccine would be sufficient to alter the duration or frequency of HSV-2 genital herpes outbreaks in sufferers remains to be determined. However, I believe that it is an obvious enough possibility that it deserves the scientific community’s attention.

We could try and achieve the potential benefits of a therapeutic HSV-2 vaccine with the Agenus HerpV vaccine (T-cell only vaccine), Genocea GEN-003 (<2% of HSV-2), or U.V.-inactivated HSV-2 (not a live virus) as was advocated by Dr. Gordon Skinner (  I think there are a lot of simple and valid immunological reasons that each of the these approaches should be less effective than a live-attenuated HSV-2 vaccine, and all of those detailed immunological consideration(s) effectively reduce to the same reason that one does not enter a boxing ring with their arms tied behind their back……most of us don’t like getting our butts kicked the way HSV-2 vaccines based on <3% of HSV-2’s proteome have been getting their asses handed to them for the past 30 years.

If the world wishes to test a therapeutic HSV-2 vaccine with any hope of success, I would suggest that a live, replication-competent, but appropriately attenuated HSV-2 virus would be the right tool for the job, and my lab’s live-attenuated HSV-2 ICP0- mutant viruses represent just one of many possible approaches that could be taken (

Whether or not a therapeutic HSV-2 vaccine is even possible remains an open question. If my laboratory is able to acquire the financial means to test such a concept with our live HSV-2 ICP0- mutant viruses, then I would enlist the help of herpes sufferers around the world to volunteer for such clinical trials.

If you have HSV-2 genital herpes and would like to be added to such a list, in the event a therapeutic HSV-2 vaccine trial of my lab’s live-attenuated HSV-2 vaccine comes to pass, then please let me know by e-mailing [email protected]

As I said at the beginning of this post….. I meant to write this blog post back in June 2014…. better late than never.

– Bill H.


Where to vaccinate: arm or the bum?



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


Dear Curing,

I responded to your first question last week, which was “1) How does the human immune system respond to a HSV-2 vaccine?”

I now respond to the 2nd question, 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?”


In my previous post addressing this question, I reviewed and highlighted why all vaccine-induced protection against infectious disease effectively reduces to vaccine-induced (1) activation and (2) clonal expansion of microbe-specific B-cells and T-cells.

In the case of B-cells, the effector mechanisms by which vaccine-induced B-cells would contribute to host control of HSV-2 infection would be exclusively mediated by the antibodies that some of their progeny cells (plasma cells) secrete.  Because of their antibody-mediated mechanism of contributing to a host immune response, an effector B-cell may contribute to the host response of HSV-2 infection without being even remotely close to the site of HSV-2 replication / infection.

In the case of CD4+ T-cells and CD8+ T-cells, the effector mechanisms by which vaccine-induced T-cells would contribute to host control of HSV-2 infection would be exclusively mediated by the T-cells themselves either through serving as (1) cytokine-secreting cells or by serving as (2) cytolytic killers of virus-infected cells.  Importantly, cytokines (unlike antibodies) cannot act at a distance, and thus T-cells can only influence events in their local environment (e.g., a draining lymph node or a virus-infected tissue.

The primary point of this background is to reiterate there is a very good reason that we refer to lymphocytes, neutrophils, macrophage, and dendritic cells as white blood cells (as opposed to red blood cells).   White blood cells primarily inhabit our bone marrow, bloodstream circulation, lymphatic circulation, and the lymphoid organs that filter the bloodstream (e.g., the spleen) and the lymphatics (i.e., lymph nodes).  Against this background, it is obvious that our immune systems are a system, or network, of cells that is spread throughout all the blood and lymph that carries oxygen and nutrients to (and CO2 and waste away from) all the cells in our body.  Thus, the immune system courses throughout your entire body, and in general effective immune responses tend to be systemic in nature.

Given the systemic nature of the host immune response, I would suggest than an effective HSV-2 vaccine should be able to provide robust protection against HSV-2 genital herpes regardless of whether the shot is administered in the arm, the leg, the buttocks, the back, or the stomach.  A HSV-2 genital herpes vaccine might be slightly more effective if delivered in the buttocks simply because the draining lymph nodes (where much of the immune response to the vaccine occurs) for this anatomic region are largely overlapping with the lymphatics that drain the genital region with several major lymph nodes occurring in the groin (which explains why some people with severe genital infections could potentially feel a generalized ache in their groin as the local lymph nodes swell in size, as the lymphocytes inhabiting those nodes respond to a microbe’s antigens).

In my own studies in mice, I find that an effective live HSV-2 vaccine fully protects mice against HSV-2 genital herpes regardless of the anatomic location of where the vaccine is administered to mice (i.e., nostrils, eyes, vagina, or rear footpads;  However, as I indicate above, a more careful analysis does support the interpretation that vaginal immunization with the live HSV-2 vaccine offers slightly (subtly) better protection against HSV-2 vaginal challenge relative to, say, mice that receive a nasal immunization with the live HSV-2 vaccine.  If this seems counterintuitive, just remember that no matter where a mouse is immunized, the predominant route by which HSV-2-specific antibodies and HSV-2-specific T-cells arrive at the scene of the crime (site of HSV-2 invading the vaginal mucosa) is via the bloodstream, and movement / leakage through the blood vessel walls at the site of infection (i.e., site of inflammation).  It is important to remember that inflammation is not an accident, but is a feat of nature / highly orchestrated process by which our bodies get immune components (including antibodies and T-cells) out of our bloodstreams and to locations where a potential infection is in progress.

Bottom line:  I don’t think the anatomic location of a HSV-2 vaccine relative to which limb is injected is super-critical.  In contrast, I believe that the precise collection of antigens / formulation of a HSV-2 vaccine will be critically important in differentiating effective versus ineffectual vaccines.  Likewise, for whole HSV-2 viral vaccines such as ACAM-529, it may be very relevant to inject the vaccine into the skin where HSV-2-susceptible cells clearly reside.  While an intramuscular injection of ACAM-529 may be equally effective, it would be relevant to explicitly test this in people immunized with ACAM-529 by the intramuscular route versus the more certain intradermal route (where HSV-2-susceptible cells clearly reside).

– Bill H.


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:

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:



“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.

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.



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


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.




Innate-Adaptive-2At 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.


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.



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.

On the upcoming ACAM-529 vaccine trial

David Knipe, Lynda Morrison, and Jeffrey Cohen are three of the principal scientists who have been involved in research over the past 15 years that has brought the HSV-2 ACAM-529 vaccine to a Phase I Clinical Trial.  Sanofi Pasteur is the company that has backed / sponsored the ACAM-529 vaccine, and Sanofi Pasteur will presumably be bringing the HSV-2 ACAM-529 vaccine to market if it succeeds in all phases of human clinical trials.

Dr. Knipe was kind enough to share the following information with me earlier today, which I pass along for those who may be interested in enrolling in the ACAM-529 vaccine clinical trial.


Hsomething completely differenti Bill,

Here are the links for the start of the HSV5-29 trial for your blog.

If people want to write to me about the trial (I am not conducting it though), they can write to me at this address:  [email protected]



David, I believe that I speak for millions of genital herpes sufferers worldwide when I say thank you for your dedication and perseverance over the past 15 years, which has brought ACAM-529 from a HSV-2 vaccine concept to the first human clinical trial of a HSV-2 viral vaccine that has real potential to be a game-changer.

You have my best wishes and hopes that the trials of the HSV-2 ACAM-529 vaccine represent a turning point in the development of a HSV-2 genital herpes vaccine that is both safe and effective.

– Bill H.

On the Agenus HerpV vaccine trials

TitanicTwo 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: . 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 (, 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 (, 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.

Proper Vetting of HSV-2 Vaccines and its Importance

 HSV-2 plaques


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

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

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


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

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

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

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


(and the millions to be gained regardless of whether or not it works)

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

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

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

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

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

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

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

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

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

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

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


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

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

When a trained expert runs a rigorous HSV-2 vaccine-challenge study in mice with all of the appropriate controls (including a positive control), it turns out that Herpevac is a lousy HSV-2 vaccine in mice (  Likewise, when similar tests are run using guinea pigs, it turns out that Herpevac is a lousy HSV-2 vaccine in guinea pigs (  If Herpevac (a gD-2 based subunit vaccine) is a lousy vaccine in mice and guinea pigs, then why should it be any better in humans?

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

– Bill H.


Halford HSV-2 Vaccine Research Highlights

lab geek

Since setting up this blog in June 2013, I have received several inquiries about how my research fits into the broader topic of the field of HSV-2 vaccine research.  To address such questions in advance, I provide a brief summary below.

For anyone interested in all the details, a quick visit to PubMed ( followed by entry of the search term “Halford W” will pull up everything I have published on the topic.

For anyone who wishes to donate to my lab’s research efforts to find a HSV-2 vaccine, I provide the relevant information at the bottom.

– Bill H.


1.  Bill Halford’s 2007 Future Virology Editorial on HSV-2 vaccines:


2.  Karen Carlson’s 2010 Aspects magazine article:


3.  Lachlan Whatmore’s 2010 Diffusion Science radio show interview:


4.  Dean Olsen’s 2010 State Journal Register newspaper article:


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.

The Phase I Clinical Testing Bottleneck


In an earlier post, I suggested that an important step that could be taken to expedite herpes simplex virus 2 (HSV-2) Vaccine Development would be to “Streamline the Path to Phase I Human Clinical Testing of HSV-2 Vaccines.”

In today’s post, I wish to expand upon this point, and suggest that a “Compassionate Use Trial” of a HSV-2 vaccine might be one means to achieve a better balance between (1) the need to ensure the safety of all HSV-2 vaccine candidates tested in human clinical trials versus (2) the need for TIMELY TESTING of new HSV-2 vaccine candidates.

Over the past 25 years, a single HSV-2 vaccine approach (glycoprotein subunits) has advanced to human clinical testing, and has failed in 6 trials.  Recently, a new and completely different type of HSV-2 vaccine (Sanofi Pasteur’s ACAM-529 vaccine) was approved for Phase I Clinical Tests, which are to begin in late 2013 or early 2014.   At this rate of testing (i.e., 1 new HSV-2 vaccine strategy every 25 years), it could take us another 25 to 75 years to identify an effective HSV-2 vaccine if the ACAM-529 vaccine does not succeed.

In contrast, if we change the rules such that any and all reasonable HSV-2 vaccine approaches may be advanced to Phase I Human Clinical Trials as soon as they become available (i.e., as opposed to languishing on the sidelines for 10 years as ACAM-529 has), then it is likely that we could identify a safe and effective HSV-2 vaccine in a fraction of the time (i.e., 10 years or less).

This ridiculously long lag time between identification of a viable HSV-2 vaccine candidate and its advancement to a Phase I Human Clinical Trial is the key rate-limiting factor that explains why efforts to identify a clinically viable HSV-2 vaccine are proceeding at a snail’s pace.

Below, I offer one suggestion for what we might do differently in the future to streamline the path to Phase I Clinical Testing of all new HSV-2 vaccine candidates for which there is credible evidence that the approach is both safe and effective in animal models.



When it comes to HSV-2 vaccines, I would suggest that the current FDA regulatory system lies somewhere between cumbersome and dysfunctional.  In particular, I refer to the process by which HSV-2 vaccine candidates progress from animal-based studies to human clinical trials in the United States.

At issue is the fact that by the time a scientist has worked out how to elicit robust vaccine-induced protection against HSV-2 in two species such as mice and guinea pigs, scientifically much of the “heavy lifting” is done, and it is simply time to “put up or shut up.”  Sure, some refinements will have to be made in terms of (1) cleaning up the HSV-2 vaccine formulation and removing impurities (i.e., producing a GMP, pharmaceutical-grade product) and (2) optimizing the vaccine dosage and route of delivery for humans.  At the end of the day, however, the primary thing that needs to happen is simply to immunize a small group of human subjects, and determine if a dose of the HSV-2 vaccine candidate in question (1) elicits a respectable immune response and (2) is well tolerated by human subjects.  This is effectively what a “Phase I Human Clinical Trial” of any HSV-2 vaccine would involve.

Such cursory tests do not address how effective a HSV-2 vaccine will be in the long term in a larger population of patients, but proceeding from Phase I Clinical Trials to test these larger questions in Phase 2 and 3 Clinical Trials has been less of a bottleneck in the past.

History informs us that in the United States, a single HSV-2 vaccine approach has made it to such Phase I Clinical Tests in the past 25 years.  Just like its close relative, varicella-zoster virus (VZV; which causes chickenpox and shingles), a live-attenuated HSV-2 vaccine would crush the genital herpes epidemic and bring this chapter of history to a close just as the live-attenuated VZV Oka vaccine has vastly reduced the burden of human disease caused by VZV.

Against this background (i.e., HSV-2 genital herpes should be vaccine-preventable), I find the current rate of HSV-2 vaccine development to be unacceptably slow.  I would vastly prefer the low and manageable risk of a well-designed, live-attenuated HSV-2 vaccine to the certainty that at least another 500 million people will contract new infections with wild-type HSV-2 and/or genital herpes if we continue our current pace of HSV-2 vaccine testing.



There is no mystery, scientifically, regarding how to execute a Phase I Clinical Trial, and in principle such a trial could be planned and executed in less than 6 months, as they typically involve a small number of human subjects (i.e., 10 to 20).  In principle, a Phase I Clinical Trial is the equivalent of putting your toe in the water of a lake to figure out how cold it is before you jump in.  If something is really off with an Investigational New Drug, such as a new HSV-2 vaccine candidate, a Phase I Clinical Trial is your first look and opportunity to figure out if the drug is safe and/or well tolerated.  You may garner a little more information, but safety and tolerability are the primary focus of such trials.

Everyone can agree that it is imperative that a treating physician should disclose any and all potential risks of administering an investigational new drug to a human subject in a Phase I Clinical Trial.  Typically, this is done both verbally and via a 20- to 40-page disclosure form that (1) each patient signs to acknowledge the risks of being enrolled in a human clinical trial of an investigational new drug whose potential risks and complications are not fully vetted, and (2) this document spells out in no uncertain terms ALL of the potential adverse consequences that a patient might conceivably suffer as a result of being treated with an investigational new drug.  Moreover, each and every patient must be monitored closely after treatment to assure that adverse events do not occur, are recorded and documented if they do occur, and all of the resulting data is reported to a Data Safety Monitoring Board that oversees the Clinical Trial, and ensures that the trial is proceeding in a manner that is both safe and fully transparent.

I don’t think anyone questions the wisdom of all of these important safeguards in the structure of a Phase I Human Clinical Trial of a new drug or vaccine.

The problem lies in the many layers of bureaucracy that separate (1) a research team asking the FDA for permission to initiate a Phase I Human Clinical Trial and (2) the actual execution of the Phase I Clinical Trial.

I have spoken about this process with representatives of three major pharmaceutical companies (Merck, Sanofi Pasteur, and Crucell).  Each of them has offered a ballpark figure of 5 years and $20 million to satisfy the FDA evaluation requirements for a new HSV-2 vaccine, and each has questioned whether or not the FDA would ultimately be willing to allow a live-attenuated HSV-2 vaccine to advance to Phase I Human Clinical Trials.  Given these lingering doubts (“What if the FDA says no?”), none of these 3 companies expressed eagerness to shell out $20 million or walk uphill into machine gun fire as they sought to buck the prevailing wisdom that a live-attenuated HSV-2 vaccine would be “too dangerous,” and seek FDA approval for a Phase I Clinical Trial of this new vaccine approach.  Intriguingly, this reticence to pursue a live-attenuated HSV-2 vaccine as a pharmaceutical product is in spite of overwhelming scientific evidence that the approach I am proposing is (1) very safe in animal models, and is (2) 100 times more protective than the FDA-sanctioned HSV-2 subunit vaccines of the past 20 years.




I don’t pretend to understand which specific facets of FDA rules, regulations, and procedures have every company with whom I have spoken unwilling to “go to bat” for a live-attenuated HSV-2 vaccine regardless of the proof that this HSV-2 vaccine would work 100 times better than what we have been doing.   However, common sense tells me that something is wrong when the prevailing belief system of FDA regulators trumps scientific observations and facts, to the point that 99% of scientists and companies are unwilling to act upon experimental evidence that, in no uncertain terms, indicates that a live-attenuated HSV-2 vaccine would serve as an effective genital herpes vaccine.

Regardless of the whys and wherefores, what is apparent is that the FDA has fostered a culture in which the pharmaceutical industry and business-minded scientists only consider “FDA friendly” HSV-2 vaccines that will get the green light to proceed to Phase I Human Clinical Trials.  This is why HSV-2 subunit vaccines are so prevalent today…..not because they work well, but because the FDA will approve their advancement to Phase I Human Clinical Trials.

The downside of allowing the FDA to effectively dictate HSV-2 vaccine development policy in the United States is simple; the FDA is not well versed in the rules of herpes immunology (which I have been studying for 20 years), which suggest that a live-attenuated HSV-2 vaccine may be the only approach that can yield a sustainable victory over HSV-2 genital herpes.  If this interpretation of the available evidence is correct (which I believe to be the case), then current FDA policies and procedures are effectively blocking human testing of the one class of HSV-2 vaccine that is actually capable of stopping the spread of HSV-2 genital herpes.



I expect and respect the fact that other scientists and regulators will not necessarily agree with the premise I propose above, that a live-attenuated HSV-2 vaccine is the only feasible approach to devise a clinically viable genital herpes vaccine.  Such discourse, disagreements, and debates are as fundamentally important to the advancement of science as good experiments.

Likewise, I would suggest that other scientists and regulators should respect the reciprocal possibility that a live-attenuated HSV-2 vaccine may indeed, as I propose, be the only approach that will work.

A good scientist knows that going into a problem from the front end, it is not possible to know what will happen.  Thus, good science boils down to (1) defining / considering all of the possibilities and then (2) figuring out which possibility is actually correct.

This has, and always will be, the landscape on which science is conducted.  We can pretend that HSV-2 vaccine research is different and that we “know” the next HSV-2 vaccine candidate will work.  However, I note that such claims date back to the 1980s, and yet we still lack an effective HSV-2 vaccine.

The simple reality is that, as in all other areas of scientific inquiry, we cannot know which HSV-2 vaccines will achieve a desirable balance between safety and effectiveness in preventing HSV-2 genital herpes in a clinical setting until we positively identify such an entity in a Human Clinical Trial…..period…..end of sentence.

For this reason, I would suggest that it is imperative that we devise a new paradigm that allows any and all HSV-2 vaccines that have proven, beyond a reasonable doubt, to be safe and effective in animal-based studies to advance in A TIMELY MANNER to Phase I Human Clinical Testing (i.e., in 10 – 20 human subjects).  There is no legitimate reason that the process of asking for permission to run such a small scale, Phase I Clinical Trial should require millions of dollars and 5 years of paperwork filings with the FDA.  Again, each year that we tarry and fill out FDA paperwork ensures that ANOTHER 20 MILLION PEOPLE WILL BE NEWLY INFECTED WITH HSV-2.   This is bad policy, plain and simple.  Stated another way, this is the scientific equivalent of sticking our heads in the sand and ignoring the available mountain of evidence that we are in the middle of a HSV-2 genital herpes epidemic.  The danger is not the HSV-2 vaccine candidates that have been proposed; the danger is our ongoing failure to develop a meaningful countermeasure to slow the spread of the HSV-2 epidemic.

It is time to change the system by which HSV-2 vaccines are allowed to advance to Phase I Clinical Trials so that we may, for the first time, honestly assess our available options for identifying a clinically viable HSV-2 vaccine today (i.e., not 50 years from today).



I would suggest that people who live with frequent recurrences of HSV-2 genital herpes represent a group of patients who have not been adequately considered as a target population for Phase I Human Clinical Testing of new HSV-2 vaccine candidates.  First, I describe this patient population, and second I consider why this patient population should be granted immediate access to any HSV-2 vaccine that offers the hope of improving their condition.

Regarding the patient population in question, a significant fraction of patients infected with HSV-2 suffer from recurrent HSV-2 genital herpes disease that recurs so often that these patients essentially live with a CHRONIC VIRAL DISEASE.  Nearly all such patients are aware of the available antiviral drugs (e.g., acyclovir, famvir, valtrex), but these drugs are insufficient to control their chronic HSV-2 genital herpes symptoms.  Such patients may experience HSV-2 outbreaks that recur 10 to 20 times per year, and each outbreak may last for 7 – 14 days in duration.  Such patients describe only brief respites from active disease, and thus are best described as living with a chronic viral disease.  Aside from the visible symptoms of HSV-2 genital herpes, many of these patients also describe an episodic neuralgia (nerve pain) in the tailbone area, which is where HSV-2 permanently resides in the sensory ganglia that innervate the genital area.

One can imagine that such a chronic viral disease might take a tremendous toll on a patient’s psyche over a single year.  However, in some patients, this unaddressed condition of chronic HSV-2 genital herpes outbreaks lasts for periods of 5 years or more.

Some women report the onset of such symptoms associated with and on the heels of menopause.  For other patients, medical management of organ transplants or autoimmune diseases may require that a patient chronically take immunosuppressive drugs.  Chronic immunosuppression can compromise the body’s ability to keep the HSV-2 virus in check, and thus chronic outbreaks may become the norm.  In short, for a variety of reasons, some patients live with chronic HSV-2 genital herpes outbreaks.

For such patients, I would suggest that the FDA’s guidelines for a “Compassionate Use Trial” exemption could be modified to include tests of new HSV-2 vaccine candidates that have the potential to serve as “a therapeutic HSV-2 vaccine,” and reduce the symptoms of HSV-2 genital herpes in patients who live with a chronic disease.  The following is one website that discusses the FDA’s Compassionate Use Trial guidelines:

The idea of a “Compassionate Use Trial” is that it provides a formal mechanism to request an exemption from the normal FDA policies and procedures to streamline delivery of an Investigational New Drug (IND) to a patient population who (1) could immediately benefit from the new treatment; (2) lack an available medical option to alleviate their symptoms;  and who (3) suffer from a chronic and/or progressive medical condition that is so miserable that they have nothing to lose (and a lot to gain) by enrolling in a clinical trial of a new treatment that may offer some relief.

As I read the current FDA rules and regulations, it appears that “Compassionate Use Trials” only appear to apply to medical conditions that are life-threatening.  I would suggest that the law could (and should) be changed to include any disease that is “chronically and physically debilitating” and for which patients lack any satisfactory treatment options.

I would suggest that many of the HSV-2 vaccines that have been proposed have the potential to serve as “therapeutic vaccines,” which have the potential to re-educate the host immune response to HSV-2 such that it becomes more efficient in its recognition of sites of HSV-2 infection.   In particular, it is well known that the human immune system may, through a variety of mechanisms, become tolerant of foreign antigens.  Thus, it is conceivable that the immune systems of individuals who live with chronic HSV-2 outbreaks may have become “tolerant” of HSV-2’s foreign proteins, and thus it is a selective (HSV-2-specific) defect in their immune response to HSV-2 that explains why they live with chronic herpetic disease.

I cannot offer any proof in support of this hypothesis, but I note that it is an obvious potential explanation for the pattern of infection in people who live with chronic HSV-2 herpes outbreaks, and this possibility could be very simply tested in a “Compassionate Use Trial” in a patient population who have nothing to lose, and a great deal to gain if this hypothesis is correct.


This post has grown far too long, and so I will stop and leave it here.  The topic of “Compassionate Use Trials” and streamlined delivery of HSV-2 vaccines into Phase I Human Clinical Trials will be a topic that I re-visit in the future.  The bottom line is that I don’t know where the answer lies, but I believe that scientists, regulators, and members of the U.S. Congress need to come together on this issue and figure out a more efficient system for bringing the power of an effective HSV-2 vaccine to bear in a timely manner, so that we may end the HSV-2 genital herpes epidemic sooner rather than later.

– Bill Halford

Thoughts of one of the millions of genital herpes sufferers….


In my line of work, every now and then, I receive e-mails and letters from people with genital herpes.  This is the primary means by which I have come to gain some small,  limited appreciation of how HSV-2 infection and genital herpes affect people in ways that simply cannot be measured with an antibody titer, a PCR, or any other calipers that a scientist may have in their toolbox.

Below, I have copied (word-for-word) an e-mail I received from an anonymous individual seven years ago.  It forever changed how I looked at the problem of HSV-2 genital herpes, and made me realize that you have to think about this disease through the eyes of the individual to see its impact.  Looking at the HSV-2 genital herpes epidemic from 40,000 feet, as scientists are prone to do, is fine for understanding the epidemiology of HSV-2 spread.  However, such detached, sterile descriptions of the frequency of HSV-2 seropositive carriers simply does not lend itself to understanding why HSV-2 genital herpes is a big deal to people who carry the virus.

We possess the requisite knowledge and systems to deliver an effective HSV-2 vaccine to the human population.  E-mails such as the one below lead me to believe that it is time we did so.

– Bill Halford


I recently read an online article about your research into a potential vaccine against the herpes virus.  I wanted to thank you for your efforts in this field and, beg you to continue.  Society seems to reflexively associate the virus with promiscuity.  But, as I am sure you are already aware, this is not always true.  Some, after their marriage ended as a result of the rigors of graduate school, find out that their wife carried the virus, but never told them.  Such news can be paralyzing.  And it’s not just the fear that no one will ever want them.  That is a selfish fear. It is the fear that one could inflict that same feeling of shame and anger in another; which, in turn, prevents them from entertaining the notion of dating and possibly marrying again.

The virus may not be life threatening, but the emotional effects are nevertheless malignant.  It is not always secreted away in some back alley or brothel.  Sometimes it teaches Sunday school and gives money to charities.  Sometimes it practices a profession and leads a very healthy lifestyle.  And while its host participates in these activities, it authors silent words of despair and loneliness.  It wages war against the best days and amplifies the worst.  I ask of you two things: first, that you would keep the origin of this email absolutely confidential; and secondly, that you not give up in your pursuit for a vaccine.  It does matter.  It is important.  And it could very well save lives, in every possible sense of the word.