THE IMPORTANCE OF UNDERSTANDING HOW HSV-2 VACCINES WORK

When most people (laypeople or scientists) talk about “a vaccine,” they usually gloss over the details of (1) the active ingredients in the vaccine or (2) how it works.  This general level of unfamiliarity (ignorance) about how vaccines work explains why an unscrupulous scientist can still, in 2013, effectively put snake oil into a sexy package and sell it as the “next HSV-2 vaccine.”

Will snake oil ever yield an effective herpes simplex virus 2 (HSV-2) vaccine?  Obviously not.

However, the real question is, “Can someone sell the next promising HSV-2 vaccine (that will fail in 5 or 10 years) to the National Institutes of Health (NIH), companies, or biomedical investors for long enough to attract several million dollars of funding?”  The history of HSV-2 vaccine research suggests that if someone has enough political clout and academic titles behind their name, then it is possible that they can pretty much sell anything as a HSV-2 vaccine provided that it sounds sufficiently fancy that noone really understands what the hell they are talking about.

This is nothing new, and this general phenomenon of exploiting the gaps in people’s understanding as a way to make money is not unique to science. The quote that comes to mind is, “If you can’t dazzle them with brilliance, then baffle them with bullshit.”  True in science, but hardly unique to it.  Likewise, Hans Christian Anderson’s story of “The Emperor’s New Clothes” nicely illustrates that the group dynamic of dealing with the preferred interpretation of reality (i.e., favorite hypothesis) is nothing new….this story was published in 1837.    Just as the king was duped into walking around his kingdom naked until a young boy called it as he saw it, so too the most studied HSV-2 vaccine candidate in 2013 (the gD-2 subunit vaccine) is effectively a neat hypothesis from 1982 that we are still tiptoeing around in academic circles in 2013 and pretending still merits further testing.  As long as we continue on with this story, then scientists can (1) maintain the appearance that we are still trying to cure genital herpes, and avoid owning up to the fact that (2) we have squandered >20 years and several hundred million dollars chasing a red herring.

In the case of a HSV-2 vaccine, I would suggest that it is time to put the interests of the tens of millions of people who live with HSV-2 genital herpes first, own up to the error in our logic, and move on to testing a fundamentally new type of HSV-2 vaccine that might, unlike HSV-2 glycoprotein subunit vaccines, actually succeed in preventing HSV-2 genital herpes in human clinical trials.

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LIVE HSV-2 VACCINE VS HSV-2 GLYCOPROTEIN SUBUNIT VACCINE………WHAT’S THE DIFFERENCE?

This is too big of a question to tackle all at once.  In particular, the underlying biological theory of (1) how the adaptive immune system responds to foreign substances and (2) how vaccines work are big questions that will take some time to cover in any detail.  I think it is feasible to wittle away at the underlying immunology theory that explains why certain vaccines are better than others over the next 6 months through a series of posts.

However, for today, I want to start by simply summarizing one representative finding that illustrates the fact that a live-attenuated HSV-2 vaccine (named “0NLS”) elicits far better protection against HSV-2 genital herpes than a gD-2 subunit vaccine.  This is illustrated in the picture shown at the top of this post, and this picture comes straight out of Figure 4 in a paper that my lab recently published (http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0065523).  Below, I attempt to explain how this experiment was performed and what the photo illustrates.

Before diving into the vaccine-HSV-2 challenge experiment presented above (i.e, the photo at the top of the post), I need to provide a little biology background.

One of the properties of all mammalian animals (humans, cows, cats, mice, guinea pigs, etc.) is that we possess cells called lymphocytes (a type of white blood cell) that provide our bodies with the ability to (1) recognize anything foreign that differs from all the cells and proteins in our own bodies and (2) mount an “immune response” on a 2nd, 3rd, 4th, etc. exposure to that same foreign substance that results in a far more rapid removal / destruction / clearance of the foreign substance from our bodies.  This is in essence why most people only had the chickenpox once as a kid…..you were probably exposed 10 more times later in life, but your “immune response” to chickenpox was revved up the last 10 times, and so you cleared the chickenpox virus before you developed any symptoms.  This is precisely the biological process that we exploit with vaccines.

The photo shown at the top of the post is of 4 female guinea pigs that were (1) first immunized with 4 different potential vaccines and (2) were later challenged with 1,000,000 infectious units of wild-type (disease-causing) HSV-2, which was instilled into the vaginal vault of these guinea pigs.  The photos were taken 7 days after HSV-2 inoculation of the vagina, and the disease you see is a direct result of the HSV-2 challenge virus’s replication in the tissues at the opening of the vagina.

The timeline of the experiment is, as follows.  The guinea pigs were immunized (injected) with 1 of 4 different HSV-2 vaccines or a negative control on Days 0 and 30.

On Day 90, a HSV-2 vaginal challenge (inoculation) was performed.  Between Days 90 and 97, the virus replicated in the vaginas of 2 of the 4 guinea pigs in an uncontrolled fashion.  The photo was taken on Day 97, and is simply a convenient readout for showing how well the different HSV-2 vaccines worked.

The guinea pig on the upper-left that is labeled “naive” was given a mock immunization on Day 0 in the right rear footpad, and was given a 2nd mock booster shot on Day 30 in the left rear footpad.  That is, the guinea pig was injected with the same liquid (carrier) used in the other vaccines, but there was no active ingredient (no foreign substance), and so the mock immunization did nothing to prime the adaptive immune system of the animal.

The guinea pig on the upper-right that is labeled “gD-2″ was given an immunization with the same type of glycoprotein subunit vaccine that we were testing in human clinical trials from 2003 – 2009 (Belshe, et al., 2012, New Engl J Med).  Specifically, this guinea pig was given a gD-2 immunization on Day 0 in the right rear footpad, and was given a 2nd gD-2 booster shot on Day 30 in the left rear footpad.  Consistent with many other results from my lab, guinea pigs immunized with a gD-2 subunit vaccine possessed only very limited (incomplete) protection against genital herpes disease.

The guinea pig on the lower-left that is labeled “0NLS” was given an immunization with a live-attenuated HSV-2 0NLS virus developed in my lab in 2009 (Halford, et al., 2010, PLoS ONE).  Specifically, this guinea pig was given a 0NLS immunization on Day 0 in the right rear footpad, and was given a 2nd 0NLS booster shot on Day 30 in the left rear footpad.  Consistent with many other results from my lab, guinea pigs immunized with a live-attenuated HSV-2 0NLS vaccine were completely resistant to HSV-2 vaginal challenge, and so did not develop genital herpes.

The guinea pig on the lower-right that is labeled “MS + ACV” was immunized on Days 0 and 30 with an acyclovir (ACV)-restrained wild-type HSV-2 infection on Day 0 in the right rear footpad and on Day 30 in the left rear footpad.  This is simply an experimental trick to allow the guinea pigs to be exposed to a low-level infection with wild-type HSV-2 that won’t make them sick (because acyclovir restrains the replication and spread of wild-type HSV-2).  Consistent with many other results from my lab, guinea pigs immunized with an ACV-restrained wild-type HSV-2 MS immunization were completely resistant to HSV-2 vaginal challenge when challenged on Day 90, and so did not show and symptoms of genital herpes when photographed on Day 97 (guinea pig in lower-right photo at top of post).

WHY SO DIFFERENT?

Again, this is too big of a question to tackle all at once?  However, I think that I can convey the essence of the basic principle in the few paragraphs that follow.

If one wishes to appreciate what your immune system does for you, just think about (1) what your body will look like two weeks from now versus (2) what your body would like two weeks after you die in the absence of any specific funeral preparations.

Our intestines are loaded with bacteria that help us digest and obtain nutrition from the food we eat.  There is a very active war going on in your body right now that is actively beating back intestinal bacteria that are in the process of trying to invade your bloodstream and tissues, but are failing because of your body’s “adaptive immune response” to the foreign signatures present on these bacteria.

If you want to be a large animal (human, cat, cow, mouse, guinea pig, etc), then part of the gig is that you need an immune system (white blood cells) that can quickly find and destroy all the microbes that may enter your body.

The way your adaptive immune system works is that it starts off (just after you are born) being “naive” and unable to recognize the foreign signature of molecules when a bacteria or virus enters your body.  However, the adaptive immune system (lymphocytes) has the power to “learn” through exposure to something foreign, and this learning improves over time and through repeated exposures to the same foreign substance.  After 2 or 3 exposures, the body becomes quite adept at recognizing a microbe with a specific foreign signature, and rapidly beating it back / destroying it / clearing it from the human body.

This is precisely the basic biology that we are exploiting to develop any vaccine including a HSV-2 vaccine.  Specifically, the active ingredients in the vaccine are pieces of the foreign signature of the HSV-2 virus.  The more of the foreign signature we can present to the adaptive immune system, the better the immune protection against HSV-2 genital herpes that will follow.

The problem with a gD-2 glycoprotein subunit vaccine is that while this is undoubtedly a component (subunit) of HSV-2′s foreign signature, it only represents about 1% of HSV-2′s foreign protein signature.  The question we should be asking is, “Is it realistic that such a small snippet of HSV-2′s foreign signature should fully prepare the adaptive immune system to elicit 100% of the protection against genital herpes that is possible?”  The photos at the top of this post (and a lot of published data) raise serious questions about the feasibility of this proposal.

In contrast, a live-attenuated HSV-2 0NLS vaccine retains the capacity to present ~99% of HSV-2′s foreign protein signature to the adaptive immune system, and thus has a much higher probability of eliciting something closer to 100% of the protection against genital herpes that is possible.  The photos at the top of this post (and a lot of published data) suggests that a live HSV-2 vaccine can, in fact, elicit complete protection against HSV-2 genital herpes.

To put a number on it, the available evidence indicates that a live-attenuated HSV-2 0NLS vaccine elicits 10- to 100-fold better protection against HSV-2 genital herpes than a gD-2 subunit vaccine (http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017748).

WHAT SHOULD BE NEXT FOR CLINICAL TRIALS?

I would suggest that it is time to test a different HSV-2 vaccine approach in human clinical trials that is more effective in animal models than a gD-2 subunit vaccine, and will likely be more effective in human clinical trials.

I would advocate that we begin by testing Sanofi Pasteur’s (David Knipe’s) ACAM-529 vaccine, which represents a replication-defective HSV-2 virus.  This is very similar to the approach I am taking, but the nature of the attenuating mutations in the HSV-2 vaccine strain (ACAM-529) are more severe and prevent the vaccine strain from replicating in human recipients.  While this approach may not be as effective as possible, I suspect that it will represent a radical improvement over the glycoprotein subunit vaccines that we have been testing since the late 1980s.

The research leading to the development of the HSV-2 ACAM-529 vaccine candidate dates back to the mid-1990s, and it is the best developed HSV-2 vaccine alternative to a gD-2 subunit vaccine.  It is time to really start advancing knowledge once again of how each of our different HSV-2 vaccine options performs in a clinical setting.  A clinical trial of the ACAM-529 vaccine is the next logical step.

- Bill Halford

“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.

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ORIGIN OF THE GLYCOPROTEIN SUBUNIT VACCINE APPROACH

The problems can be traced back to the 1970s when researchers thought (mistakenly) that HSV-2 might be a cause of cervical cancer in women……turns out human papillomavirus (e.g., Pap smears/ the recent Gardasil vaccine) was the real culprit.  Nonetheless, a belief system was created that a live-attenuated HSV-2 virus would be “too dangerous” to use as a human vaccine and so a search was begun for “safer” alternatives.  A major fear was that that a live HSV-2 vaccine (which would contain the virus’s DNA [genetic material]) could cause cancer in vaccine recipients.  In addition, the specter of a live HSV-2 vaccine that established a latent infection in vaccine recipients was another hypothetical concern although there is no scientific evidence to support the idea that a latent (silent) HSV-2 infection poses, in and of itself, a significant health risk to a human carrier.  Rather, all of the medical issues associated with wild-type HSV-1 or HSV-2 relate to the fact that these viruses can periodically re-awaken and cause new rounds of disease (e.g., recurrent cold sores or recurrent genital herpes).  By definition, a viable live-attenuated HSV-2 vaccine would be rendered incapable of causing either primary or recurrent herpetic disease.

If one accepts the 1970s-derived premise that a live HSV-2 vaccine would be “too dangerous,” then the early to mid-1980s saw the emergence of a solution to this potential problem.  Several high profile Science and Nature papers heralded the beginnings of the “HSV-2 glycoprotein subunit vaccine” approach.  In particular, scientists cloned one of HSV-2′s genes that encoded a target of the host immune response to HSV-2 named “glycoprotein D” (References 1-4 below).

With this new gene in hand, the belief was that scientists could artificially synthesize HSV-2 glycoprotein D (gD) in the laboratory in fabulously large quantities and this one piece, or subunit, of HSV-2 would be the basis of a HSV-2 vaccine that would be very safe and effective at preventing HSV-2 genital herpes.  For good measure, scientists also cloned a 2nd HSV-2 gene that encoded glycoprotein B (gB) with the idea that a combination of gB and gD might make an even better HSV-2 vaccine (Reference 5).

Thus, by the mid-1980s, it appeared that scientist had solved the potential safety problems surrounding HSV-2 vaccines, and could move forward with a new and improved approach……the HSV-2 glycoprotein subunit vaccine.  Unlike a live HSV-2 vaccine, purified gB and/or gD proteins contained no HSV-2 DNA, and thus could not cause cancer or establish a life-long, latent HSV-2 infection.  It is the promise and potential of these approaches to safely cure HSV-2 genital herpes that yielded several Science and Nature papers in the mid-1980s.  The next steps seemed simple…..just a matter of determining the optimal formulation of gB and/or gD that elicited a strong immune response when injected into vaccine recipients, and then we would have a safe and effective HSV-2 vaccine.

REFERENCES

1. Vaccinia virus recombinant expressing herpes simplex virus type 1 glycoprotein D prevents latent herpes in mice. Cremer KJ, Mackett M, Wohlenberg C, Notkins AL, Moss B.  Science. 1985 May 10;228(4700):737-40.

2.  Protection from genital herpes simplex virus type 2 infection by vaccination with cloned type 1 glycoprotein D.  Berman PW, Gregory T, Crase D, Lasky LA. Science. 1985 Mar 22;227(4693):1490-2.

3.  An immunologically active chimaeric protein containing herpes simplex virus type 1 glycoprotein D.  Weis JH, Enquist LW, Salstrom JS, Watson RJ.  Nature. 1983 Mar 3;302(5903):72-4.

4.  Herpes simplex virus type-1 glycoprotein D gene: nucleotide sequence and expression in Escherichia coli.  Watson RJ, Weis JH, Salstrom JS, Enquist LW. Science. 1982 Oct 22;218(4570):381-4.

5.  Expression in bacteria of gB-glycoprotein-coding sequences of Herpes simplex virus type 2.  Person S, Warner SC, Bzik DJ, Debroy C, Fox BA. Gene. 1985;35(3):279-87.

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ONE SMALL PROBLEM (1990s)

The glycoprotein subunit vaccine approach of the mid-1980s finally made its way to efficacy (effectiveness) trials in the 1990s, and now it was time to find out if immunization with gB- and/or gD-based vaccines either (1) reduced the symptoms of genital herpes in those already infected with HSV-2 or (2) protected naive individuals from acquiring HSV-2 genital herpes for a period of 2 to 5 years after vaccination.  On both counts, gB- and/or gD-based subunit vaccines were a disappointment.

Vaccination with gB- and/or gD-vaccines elicited a strong antibody (immune) response against the HSV-2 proteins contained in the vaccine itself, but this immune response did not render vaccine recipients any better off in their ability to fight off infection with the actual HSV-2 virus.  In particular, the gB- and/or gD-based vaccine failures of the 1990s may be found in the following four research publications:

1990.  Double-blind, placebo-controlled trial of a herpes simplex virus type 2 glycoprotein vaccine in persons at high risk for genital herpes infection.  Mertz GJ, Ashley R, Burke RL, Benedetti J, Critchlow C, Jones CC, Corey L.  J Infect Dis. 1990 Apr;161(4):653-60.

1994.  Placebo-controlled trial of vaccination with recombinant glycoprotein D of herpes simplex virus type 2 for immunotherapy of genital herpes.  Straus SE, Corey L, Burke RL, Savarese B, Barnum G, Krause PR, Kost RG, Meier JL, Sekulovich R, Adair SF, et al.  Lancet. 1994 Jun 11;343(8911):1460-3.

1997.  Immunotherapy of recurrent genital herpes with recombinant herpes simplex virus type 2 glycoproteins D and B: results of a placebo-controlled vaccine trial.  Straus SE, Wald A, Kost RG, McKenzie R, Langenberg AG, Hohman P, Lekstrom J, Cox E, Nakamura M, Sekulovich R, Izu A, Dekker C, Corey L.  J Infect Dis. 1997 Nov;176(5):1129-34.

1999.  Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection: two randomized controlled trials. Chiron HSV Vaccine Study Group.  Corey L, Langenberg AG, Ashley R, Sekulovich RE, Izu AE, Douglas JM Jr, Handsfield HH, Warren T, Marr L, Tyring S, DiCarlo R, Adimora AA, Leone P, Dekker CL, Burke RL, Leong WP, Straus SE.  JAMA. 1999 Jul 28;282(4):331-40.

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PROBLEM COMPOUNDED (2000-present)

In the 1990s, it was perfectly reasonable for scientists to focus on testing the new glycoprotein subunit approach as a potential means to cure and/or prevent HSV-2 genital herpes.  However, on the heels of 4 failures between 1990 – 1999, one might think that at the very least this would have served as a cue that scientists should consider a 2nd approach.  To put this in very simple terms, if I were trying to find a date for the prom, and had asked the same girl out 4 times, and all 4 times had been rejected and/or kicked in the groin, I would hope that on my 5th and 6th attempts at finding a date, it might occur to me ask a 2nd girl.  However, in the HSV-2 vaccine research sphere, this has not been the case…..the vast majority of money for HSV-2 vaccine research between 2000 and 2013 was still put toward determining if gB- and/or gD-based subunit vaccines could be used to prevent HSV-2 genital herpes.

Specifically, two more U.S. clinical trials were run to evaluate the efficacy of a gD-based vaccine in preventing HSV-2 genital herpes, and both trials failed to reveal any clear-cut evidence of protection.  These two failed clinical trials may be found in the following research publications:

2002.  Glycoprotein-D-adjuvant vaccine to prevent genital herpes.  Stanberry LR, Spruance SL, Cunningham AL, Bernstein DI, Mindel A, Sacks S, Tyring S, Aoki FY, Slaoui M, Denis M, Vandepapeliere P, Dubin G; GlaxoSmithKline Herpes Vaccine Efficacy Study Group.  N Engl J Med. 2002 Nov 21;347(21):1652-61.

2012.  Efficacy results of a trial of a herpes simplex vaccine.  Belshe RB, Leone PA, Bernstein DI, Wald A, Levin MJ, Stapleton JT, Gorfinkel I, Morrow RL, Ewell MG, Stokes-Riner A, Dubin G, Heineman TC, Schulte JM, Deal CD; Herpevac Trial for Women.  N Engl J Med. 2012 Jan 5;366(1):34-43.

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WHY DON’T WE HAVE AN EFFECTIVE HSV-2 VACCINE?

The answer to this question is actually relatively simple.  If one considers the total number of man-hours and financial resources dedicated to trying to find a genital herpes vaccine, we keep investing >99% of those resources into retesting new iterations of the same glycoprotein subunit vaccine approach that has been failing for >20 years.  In contrast, a concerted effort has not been made to support other, alternative HSV-2 vaccine approaches that might be far more effective.

The fact that the gB- and/or gD-based vaccines have failed in six clinical trials spanning 22 years and involving nearly 15,000 human participants does not seem to have dampened the enthusiasm of scientists for continuing to take this same basic approach, repackaging it, renaming it, and trying it yet again.

I would suggest that the key to developing an effective HSV-2 vaccine lies in acknowledging the possibility that a glycoprotein subunit may not represent the ideal HSV-2 vaccine approach, and thus considering (for the first time) a fundamentally different approach in the next human clinical trial of a HSV-2 genital herpes vaccine.

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PROBLEM DEFINED

In principle, we have at least 5 potential approaches at our disposal to develop a safe and effective HSV-2 vaccine, and these are:

1.  A live, attenuated variant of the HSV-2 virus (this approach accounts for most of our medically successful viral vaccines);

2.  A replication-defective HSV-2 virus (e.g., the ACAM-529 vaccine developed by David Knipe and Sanofi Pasteur);

3.  A killed, inactivated HSV-2 virus (e.g., the Skinner vaccine described in the 1970s and 80s);

4.  A subunit vaccine based on some of HSV-2′s other 75 proteins;

5.  A HSV-2 glycoprotein subunit vaccine based on gB and/or gD (~3% of HSV-2′s total proteins).

At the top of this post, I provide two pieces of data that illustrate that HSV-2 vaccine researchers have effectively become overinvested in the HSV-2 glycoprotein subunit vaccine approach, and have not given an equal level of attention to other HSV-2 vaccine approaches that may be far more effective.

The graph on the left illustrates that over the past 40 years (1973 – 2013), scientists and clinicians  have published 250 papers on gB- and/or gD-based vaccines to prevent HSV-2 genital herpes.   During that same period of time, 11 papers have been published on live-attenuated HSV-2 vaccines.  By this measure, we have invested ~25-fold more effort into exploring the glycoprotein subunit vaccine approach relative to a live-attenuated HSV-2 vaccine.

The graph on the right illustrates that over the past 40 years (1973 – 2013), scientists and clinicians  have enrolled nearly 15,000 human patients in U.S. clinical trials of gB- and/or gD-based subunit vaccines to prevent HSV-2 genital herpes.   During that same period of time, not a single human patients has been enrolled in a U.S. clinical trial investigating the safety or efficacy of a live-attenuated HSV-2 vaccine.  Although scientists often speak of the potential dangers of a live-attenuated HSV-2 vaccine, rarely do they discuss the relative risks associated with singlemindedly testing a HSV-2 glycoprotein subunit vaccine that keeps failing in clinical trials; each year that we continue to lack an effective HSV-2 vaccine means that another 20 million people will continue to be infected with wild-type (disease-causing) strains of wild-type HSV-2.

Perhaps it is time to go out on a limb and consider, for the first time, a different HSV-2 vaccine approach in the next U.S. clinical trial that might be more likely to actually prevent genital herpes.

In subsequent posts, I will elaborate on the published data that says that either a live-attenuated HSV-2 vaccine or a replication-defective HSV-2 virus (ACAM-529) would be very safe, and should be at least 10 to 100 times more effective at preventing HSV-2 genital herpes than the type of glycoprotein-based subunit vaccines that have been failing in human clinical trials since 1990.

- Bill Halford

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

Bill Halford

WHO AM I?

My name is Bill Halford and I am an Associate Professor of Microbiology and Immunology at Southern Illinois University School of Medicine in Springfield, Illinois.  I have studied herpes simplex virus (HSV) biology since 1991, and I became interested in trying to develop a safe and effective HSV-2 vaccine in 2006.  There are at least 100 individuals in the world who are actively pursuing a HSV-2 vaccine, and I am one of these many researchers.  In this blog, I will try to cut through the nomenclature and statistics and explain in relatively straightforward terms what we know about HSV-2 vaccines and what we need to do next to advance a safe and effective HSV-2 vaccine to human clinical trials.  If you wish to contact me, you can do so via this blog or e-mail me at “halford@siumed.edu.”

BACKGROUND ON HSV-2 INFECTIONS AND GENITAL HERPES

Genital herpes caused by herpes simplex virus type 2 (HSV-2) remains a huge medical and public health problem.  About 1 billion people (out of ~7 billion total) are life-long carriers of the HSV-2 virus.  About 40 million of those HSV-2 infected persons live with genital herpes outbreaks that recur once every 2 to 12 months over the duration of their lives.  Each outbreak can last from 2 to 20 days in duration, and is physically uncomfortable and emotionally distressing.  Antiviral drugs such as acyclovir or valacyclovir (valtrex) reduce, but do not prevent. the symptoms of recurrent genital herpes.  Likewise, antiviral drugs have not slowed the spread of HSV-2 infection at all; ~20 million per year continue to acquire new HSV-2 infections from the 1 billion people who already carry the HSV-2 virus.

HSV-2 genital herpes has been described as a silent epidemic.  This term is apt, as HSV-2 exists all around us and is carried by friends and family members, but people are reluctant to disclose that they are infected with HSV-2 as there remains a historical stigma associated with this infection.  Many people who have the HSV-2 virus have not had many sexual partners, and many teenagers who acquire HSV-2 have the misfortune of acquiring HSV-2 with their first sexual partner.  Nonetheless, the social stigma that people with HSV-2 wish to avoid is the perception that they have slept with dozens of people.  For this and a variety of other reasons, the ~200 million people who have experienced symptoms of HSV-2 genital herpes do not tend to share this information with many people.  Thus, it is hard to estimate the magnitude of the problems caused by HSV-2 genital herpes.  One number helps put the problem into perspective; each of our children has a 1-in-10 chance of contracting a HSV-2 infection before they are married.

Aside from the individual suffering caused by recurrent genital herpes, HSV-2 infections can cause more severe complications such as HSV-2 infections of newborns as they pass through the vagina / birth canal.  The immune system of neonates is not yet developed, and thus HSV-2 infections in newborn babies can be devastating often resulting in death or severe mental / cognitive impairment, as HSV-2 infection can spread to the central nervous system of newborns.

THE POTENTIAL UTILITY OF A HSV-2 VACCINE

Effective vaccines have been responsible for the eradication and/or control of many viral diseases such as smallpox, yellow fever, red measles, mumps, German Measles, hepatitis B, chickenpox, and poliomyelitis.  In principle, there is no reason that a safe and effective HSV-2 vaccine could not be deployed in the human population to prevent HSV-2 genital herpes.

The applications of a safe and effective genital herpes vaccine would be two-fold.

First, an effective HSV-2 vaccine could be given to adolescents or prospective sexual partners of those who already carry the HSV-2 virus.  Exposure to an effective HSV-2 vaccine would bolster the immune system of such individuals such that their bodies were at least 100 times better prepared to repel the real (wild-type) HSV-2 pathogen if they were exposed later in life.  Such a “preventative HSV-2 vaccine” could be used to prevent ~20 million per year from newly acquiring the HSV-2 virus.

Second, an effective HSV-2 vaccine could be given to those who suffer from frequent outbreaks of recurrent genital herpes.  Such a “therapeutic HSV-2 vaccine” could be used to reduce the frequency and duration of genital herpes outbreaks in those ~40 million people worldwide who suffer from this chronic viral disease.  This latter application of a HSV-2 vaccine (i.e., to reduce symptoms in those who already carry the HSV-2 virus) would be more experimental, and less of a sure thing than a preventative HSV-2 vaccine.  Nonetheless, there are several publications dating back to the 1950s that claim such an effect has been obtained by treatment with a variety of vaccine formulations including inactivated-preparations of HSV virion particles.  Therefore, once a safe and effective HSV-2 preventative vaccine is identified, it will be relevant to determine if it has potential  to also serve as a therapeutic HSV-2 vaccine.

WHY DO WE STILL LACK AN EFFECTIVE HSV-2 VACCINE?

This is the million dollar question, and will be precisely the focus of the Herpes Vaccine Blog.

I envision posts on the Herpes Vaccine Blog serving one of three general purposes, and these will be discussions of:

1.  The science of HSV-2 vaccines

2.  Moving a safe and effective HSV-2 vaccine into human trials

3.  Answers to specific reader queries (which may be sent to halford@siumed.edu)

What I hope to make clear through the development of this blog is that a safe and effective HSV-2 vaccine lies within our grasp, but what we lack is a critical mass of support to advance such a HSV-2 vaccine to human clinical trials.  The primary barriers to the advancement of an effective HSV-2 vaccine are (1) misinformation and (2) a pre-conceived notion that certain types of HSV-2 vaccines (e.g., live-attenuated) should not be investigated or considered for use as a human vaccine.

One of the central purposes of this blog will be to (try to) simply explain why past HSV-2 vaccines have not worked, and define what we need to do differently in the future if we intend to end the needless suffering caused by genital herpes.  Make no mistake…..HSV-2 genital herpes is a vaccine-preventable disease.  However, the field of HSV-2 vaccine research is long overdue for a “course correction.”  I hope that this blog serves as a vehicle to increase the public’s understanding of what we need to be doing differently if we hope to make HSV-2 genital herpes a disease of the past.

- Bill Halford