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

what-we-have-tested

“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