How can we expedite HSV-2 vaccine discovery?

Thinker

OVERVIEW

My earlier posts emphasize some of the reasons that past attempts to obtain a HSV-2 vaccine have not succeeded.

I now turn my attention to outlining two steps that, if implemented, would expedite the rate of HSV-2 vaccine development efforts, and these are:

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

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

There is too much ground to cover here in a single post.  However, I hope to provide a reasonably concise overview of these two critically important issues that, if addressed, would greatly accelerate the rate of HSV-2 vaccine discovery.  In subsequent posts, I will tie up the loose ends that are not fully covered herein.

The crux of the issue is that, for the past 30 years the FDA’s favorite HSV-2 vaccine approach, the subunit vaccine, has not made one iota of a difference in our ability to treat or prevent HSV-2 genital herpes.  During this period of time, tens of millions of people have continued to suffer with HSV-2 genital herpes, and hundreds of millions more have acquired HSV-2 genital herpes.

As we look down the road 20 years, to 2033, I would suggest that it is time for the FDA to become a little bit less singleminded in their concern about the ABSOLUTE RISK of a Phase I Clinical Trial of a new HSV-2 vaccine candidate in n=10 human volunteers.  Rather, I would suggest that it is time for the FDA to weigh the RELATIVE RISK of a clinical trial of a new type of HSV-2 vaccine versus the status quo that has allowed a vaccine-preventable disease, HSV-2 genital herpes, to continue spreading unchecked through the American public for decades.

I would suggest that the manageable risk of a live-attenuated HSV-2 vaccine would be vastly preferable to the HSV-2 genital herpes epidemic, which will still be ongoing in 2033, if the FDA continues to promote and foster a culture in which it is perfectly acceptable for scientists to say that “a live-attenuated HSV-2 vaccine would be too dangerous to test in humans.”  There is simply not a shred of evidence to support such baseless claims.  This common misconception about the “dangers” of a live-attenuated HSV-2 vaccine has been perpetuated by nothing more than ignorance of the facts.   To the contrary, there is a mountain of evidence that demonstrates that HSV-2 (or any other viral pathogen) may be very stably attenuated by using a combination of (1) the right kinds of stable genetic modifications (i.e., large deletions) placed (2) into one or more strategically-chosen viral genes.

I elaborate, as follows.

———————————————————————————————————–

 

STEP 1.  APPROPRIATE USE OF SMALL ANIMAL MODELS (i.e., DE-RISKING HSV-2 VACCINE DEVELOPMENT)

One of the primary tools by which new vaccine candidates are evaluated are small animal models, such as mice or guinea pigs.  The tests that scientists run on HSV-2 vaccines in mice or guinea pigs are an important component of “pre-clinical testing” in which we attempt to gauge how safe and effective a HSV-2 vaccine candidate would be in humans.

In recent years, increasing numbers of scientists have begun to question if mice and/or guinea pigs are really a good model for evaluating the effectiveness of new HSV-2 vaccine candidates.  Thus, some investigators have suggested that we should explore new animal models for pre-clinical testing of HSV-2 vaccines, such as mice or rabbits that have been “humanized” (i.e., to contain human immune cells) or primate models such as monkeys or apes.

I understand the desire to blame the Herpevac vaccine failure in human clinical trials on a bad animal model that “lied to us,” and told us that Herpevac would work in humans.  However, I note that in my own studies in mice and guinea pigs, I find that Herpevac-like, glycoprotein subunit vaccines are ineffective and elicit only a small fraction of the protection against HSV-2 genital herpes that is possible (Halford, et al., 2011, http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017748).  If mouse HSV-2 vaccine-challenge models were intrinsically flawed, I would expect that the mice would lie to me, in the same way that other investigators have claimed that their mice and/or guinea pigs lied to them.

Animal models of HSV-1 and HSV-2 infection are the primary area of my research expertise. During my graduate training with two herpes immunologists, Dan Carr and Bryan Gebhardt (1992-1996), I became quite familiar with the literature on herpes immunology which dates back to the 1970s and earlier.  Over four decades, herpes immunology studies in mice have repeatedly informed us of new principles about the response of the verterbrate immune system to HSV, and these findings have generally translated well to the human condition.  There are nuances about the mouse model that don’t correlate with the human situation; for example, mice catch on to HSV-1 and HSV-2 reactivation REALLY FAST, as several viral immune evasion mechanisms that work well in humans don’t do their job in the mouse (e.g., ICP47 and gE-gI).  However, setting these minor differences aside, I see no hard evidence to support claims from other investigators that mice and guinea pigs are not a perfectly effective model for screening HSV-2 vaccines to figure out which approaches work (live-attenuated HSV-2 vaccine) and which are hopelessly ineffective (gD-2 subunit vaccine) at eliciting a protective immune response against HSV-2 genital herpes.

I once heard a vaccine researcher from Italy (working on a meningitis vaccine) express the same sentiment in a talk, but he was far more eloquent in his choice of words.  Apparently a similar dialogue about the reliability of mice was playing out in his field.  What he said went something like this: “Many people in my field think that vaccine studies in mice are unreliable and have no value in predicting which meningitis vaccines will work in humans.  Personally, I have not found that the mice lie to me, but I do find that it is extremely important to ask them the right questions.”

One of the most fundamental limitations of HSV-2 vaccine-challenge studies performed in small animal models is the CHRONIC ABSENCE OF A POSITIVE CONTROL, which may be used to empirically define what “100% protection” against HSV-2 genital herpes should look like.  Rather, most HSV-2 vaccine studies only compare naïve animals (0% protected) versus vaccinated animals, and conclude that the vaccinated animals were better protected than the naïve animals.  This is a good starting point, but the next, essential step is to measure whether the HSV-2 vaccine candidate elicits 0.3% protection against HSV-2 genital herpes (i.e., statistically significant, but useless) or alternatively elicits something close to complete (~100%) protection against disease.

To define how good a HSV-2 vaccine is on a scale of 0 to 100% protection, an investigator must include a positive control to define what one should consider as “100% protection against HSV-2.”  Such a positive control group may be established in a vaccine study by infecting a control group of animals with wild-type HSV-2 under conditions that limit the virus’s capacity to spread and cause disease.  A simple way to achieve this goal is to provide animals with oral acyclovir (anti-herpes drug) in their drinking water during the first 3 weeks of exposure to wild-type HSV-2, which limits but does not completely prevent viral replication and spread.  It is well established that any species of animal (mouse, guinea pigs, or rabbits) that survives a 1st exposure to HSV-2 will become latently-infected and uber-resistant to exogenous challenge with a 2nd dose of wild-type HSV-2.  This is one of many ways that a researcher may create a group of “HSV-2 latently infected animals” that would serve as a positive control that roughly approximates what “100% protection against HSV-2 vaginal challenge” might look like.

This technology has been around since the 1980s.  The chronic absence of “HSV-2 latently infected animals” in HSV-2 vaccine studies means that most HSV-2 vaccine researchers either (1) don’t know how to run a properly controlled animal experiment (which I doubt), or (2) don’t want to include a positive-control group that might reveal that their test HSV-2 vaccine is not terribly effective.

I close by noting that the mouse and guinea pig vaccine-challenge studies that initially served as proof that a Herpevac-like, glycoprotein D subunit vaccine “should be effective” did not include a positive-control group of HSV-2 latently infected animals.   Had such a positive control group been included, I am confident that a Herpevac-like, glycoprotein D subunit vaccine would have never advanced to human clinical trials because it would have been painfully apparent that this approach only elicits 2 to 5% of the protection against HSV-2 that is possible.

Flawed experimental designs, not bad rodents, are the real culprit that explains why small animal models have not served as a more realistic gauge of HSV-2 vaccine efficacy in the past.

A recent publication from my lab (http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0065523) elaborates on another misconception propagated by inappropriate use of animal models in the past; namely, the erroneous belief that there are no “correlates of immunity” available to quickly and easily differentiate a robust versus an anemic HSV-2 vaccine candidate.

BOTTOM LINE:  If the pharmaceutical industry wishes to “de-risk” HSV-2 vaccine development, then an important step in that direction will be to quit making multi-million dollar decisions based on subpar animal studies.  As with all other areas of scientific inquiry, the inclusion of a positive control group in HSV-2 vaccine-challenge studies would be a huge step in the right direction.

———————————————————————————————————–

 

STEP 2.  STREAMLINE THE PATH TO PHASE I HUMAN CLINICAL TESTING OF HSV-2 VACCINES

The FDA regulatory process is intended to protect the public against potentially harmful products that could be sold or peddled as “medical treatments.”  In the complete absence of any safety regulations or oversight, all forms of snake oil and worse could be sold under the guise of medical treatments.  As a consumer, I greatly appreciate what the FDA does for us U.S. citizens in terms of ensuring that the food and drugs we ingest are safe.  This is a critical public service whose value cannot be overemphasized.

In the realm of vaccines, the FDA applies the exact same logic to vaccines that they apply to food.  This is an error in logic.  Food items such as jelly beans are either safe, or they are not.  In contrast, when one obsesses over the safety of a HSV-2 vaccine and keeps it out of clinical trials for years to decades, this action has the consequence of allowing millions of people per year to continue to be infected with disease-causing strains of wild-type HSV-2.  Therefore, I would suggest that it is inappropriate to singlemindedly obsess about whether or not a new HSV-2 vaccine poses ANY RISK.  All vaccines pose a risk in the absolute sense of the word, but good vaccines pose a risk that is vanishingly small.  Therefore, a vaccine’s risk should be weighed in terms of RELATIVE RISK.  That is, what is the risk of adverse events associated with injecting people with a new HSV-2 vaccine candidate versus the risk of doing nothing and letting 20 million people per year continue to be newly infected with wild-type HSV-2?

Right now, the FDA regulatory approach towards new HSV-2 vaccine candidates focuses on assessing whether there is ANY RISK AT ALL that a HSV-2 vaccine might cause overt symptoms or disease if injected into a million vaccine recipients.  Importantly, the FDA regulatory process seeks to address this hypothetical question BEFORE A SINGLE HUMAN SUBJECT CAN BE IMMUNIZED in a clinical trial.  Of course, in the absence of the FDA allowing small-scale testing of new HSV-2 vaccines in humans (e.g., 10  subjects), it is impossible for a scientist to counter these hypothetical concerns with data that directly demonstrates safety in humans.

Hence, the FDA has created a “Catch-22″situation, which goes something like this:

1.  The FDA won’t allow a new HSV-2 vaccine to proceed to Phase I clinical trials in 10 – 20 human subjects until a laundry list of hypothetical concerns are addressed through pre-clinical testing in animal models.  No matter how strong the animal data, the pre-clinical data may always be met with a new set of “concerns” from the FDA that “OK, aspect A of the safety of the HSV-2 vaccine candidate looks good in animals, but what about aspects B, C, D, etc. which you have not addressed.”  Moreover, no matter how many iterations of tests you run in animals, the FDA may still tell you 5 years later that, “Well your HSV-2 vaccine is clearly very safe in animals, but how can we know that it will be safe enough in human recipients?”

2.  The formula for sufficiently addressing all of the FDA’s concerns about the safety of a new HSV-2 vaccine candidate may easily require 10 years and $30 million dollars in legal and paperwork filing fees, which a sponsoring company may or may not recover.  If all goes swimmingly well, then a company that backed a given HSV-2 vaccine might break even on their investment in 15 or 20 years.  This is obviously a huge disincentive for companies to get involved with sponsoring a new HSV-2 vaccine approach, as it will take 10 years just to figure out whether or not the approach has the potential to fly in humans.

3.  Companies are reluctant to invest 10 years and $30 million in a fundamentally new HSV-2 vaccine candidate that differs from the types of HSV-2 vaccines that the FDA has approved in the past.  Thus, even if HSV-2 subunit vaccines are lame, most companies would rather invest in a lame HSV-2 subunit vaccine that the FDA is likely to approve for clinical trials, rather than support a new type of HSV-2 vaccine that is more effective, but may never get the green light from the FDA to advance to human clinical trials.

BOTTOM LINE:  The FDA regulatory process with the respect to vaccines has grown so onerous, that it has stymied the interest of most companies in pursuing HSV-2 vaccine research.  While I appreciate the FDA’s desire for safety, the potential risks of new HSV-2 vaccines should be weighed against the risks of continuing the status quo of focusing only on “uber-safe” HSV-2 subunit vaccines that are unlikely to be effective, and thus permitting the HSV-2 genital herpes epidemic to continue to spread in an unchecked manner.

If a vaccine is well designed, then the odds of serious adverse event approach the odds of winning the lottery (i.e., one-in-a-million).  In contrast, the continued, unchecked spread of HSV-2 genital herpes in the human population means that tens of millions of people will continue to live with recurrent HSV-2 genital herpes, and hundreds of millions more will be newly infected with disease-causing strains of wild-type HSV-2 by 2033.

HSV-2 genital herpes is almost certainly a vaccine-preventable disease.  However, to achieve this goal, and bring the power of vaccinations to bear, the FDA will need to re-think its position on the pros and cons (RELATIVE RISK) of testing new classes of live-attenuated HSV-2 vaccines, which will likely be at least 100 times more effective than the HSV-2 subunit vaccines that we have been exclusively testing in human clinical trials for the past 25 years.

I would suggest that small-scale “Compassionate Use Trials of HSV-2 Vaccines” are a compromise that could be struck to achieve a more appropriate balance between (1) ensuring the continued safety of HSV-2 vaccine trials versus (2) offering people with HSV-2 genital herpes some real hope that a therapeutic HSV-2 vaccine may be identified in their lifetime.  Specifically, Compassionate Use Trials of a therapeutic, live-attenuated HSV-2 vaccines would achieve the dual goal of (1) timely testing of a new HSV-2 vaccine modality in humans and (2) testing of a HSV-2 vaccine candidate that offers the greatest odds for success of a therapeutic vaccine capable of reducing the frequency and duration of genital herpes outbreaks in those already infected with HSV-2.

In a subsequent post, I will elaborate more fully on the concept of Compassionate Use Trials, and how this might be coupled with human trials of a therapeutic HSV-2 vaccine to greatly accelerate human testing of new classes of HSV-2 vaccine.

– Bill H.

Live HSV-2 vaccine vs subunit HSV-2 vaccine…..what’s the difference?

GP vaginas

 

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.


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 any 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

Why don’t we have a HSV-2 vaccine yet?

HSV-2 Vaccine Publications (small)

“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.

————————————————————————————————————————————————–

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.

———————————————————————————————————————————————-

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.

———————————————————————————————————————————————-

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.

—————————————————————————————————————————————————–

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.

————————————————————————————————————————————————-

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

————–

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

Purpose of the Herpes Vaccine Blog

Bill Halford
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 “[email protected]

 

DISCLAIMER

The author of this website, Bill Halford, is an employee of the Southern Illinois University School of Medicine in Springfield, Illinois.  The viewpoints expressed on this website are solely that of the author, and should not be construed as an official statement of the policies, procedures, or opinions of Southern Illinois University, the School of Medicine, or any of the academic departments contained therein.

 

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 [email protected])

 

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