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

guinea pigs

 

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