• Learning From Failures

    Herpes simplex vaccine trial provides valuable lessons despite missing the mark

    By Tim Bonfield

    As vaccine studies go, the Herpevac Trial for Women was a massive undertaking. Fifty medical centers in the US and Canada screened about 31,000 women to find 8,323 who had not been infected with HSV-1 or HSV-2, the two common types of herpes simplex virus. The study ran for eight years.

    When initial results came out in late 2010, the data showed that an investigational glycoprotein D adjuvanted vaccine was safe, well-tolerated – and ineffective at protecting women from genital herpes. Results were reported in January 2012 in the New England Journal of Medicine.

    David Bernstein, MD, MA, Director of the Vaccine and Treatment Evaluation Unit (VTEU) at Cincinnati Children’s, was a co-author of the 2012 study and lead author of a related paper published in February 2013 in the journal Clinical Infectious Diseases.

    “Although it did protect against HSV-1 infections, we found that this version isn’t worth pursuing,” Bernstein says. “The prevailing thought is that we need something that prevents genital herpes infection or disease whether it’s caused by HSV-1 or HSV-2.”

    MIXED RESULTS NOT GOOD ENOUGH

    In previous trials led at Cincinnati Children’s, the vaccine did not work in men at all, and was not effective in women against HSV-2, long considered the more serious health threat. This result was unexpected because the vaccine was based on a protein found on HSV-2. Researchers are not yet sure why the vaccine did not work against HSV-2.

    A pessimist might see the Herpevac trial as another failure in a long line of attempts since the 1940s to develop a vaccine against herpes simplex. But Bernstein does not see it that way.

    “For me, one of the lessons is that this can be done,” he says. “If we can find something that’s effective against HSV-1, then we must be able to find something for HSV-2.”

    MAJOR SHIFT IN EPIDEMIOLOGY

    For many years, herpes simplex disease had two classifications: HSV-1 caused oral “cold sores” and HSV-2 affected the genitals. The medical community worries more about HSV-2 because flare-ups tend to occur more often, making HSV-2 more likely to spread and to harm infants exposed to the virus during birth. Herpes simplex can be lethal to an infant without aggressive medical care.

    But data gathered in the Herpevac trial challenged this understanding. As expected, the study found that HSV-1 caused most of the oral infections among study participants. But HSV-1 also was the more frequent cause of genital disease, with interesting differences by race and age, Bernstein and colleagues reported in 2013.

    An editorial that appeared with Bernstein’s study linked this change in pattern of disease to changes in sexual behaviors.

    “For so many of us, HSV-1 was thought to be only a trivial infection of the mouth or lips,” wrote Richard Whitley, MD, of the University of Alabama at Birmingham. “Now that sexual practices have changed with increased oral-genital sex, it is likely that we can account for the displacement of HSV-2 as the most common cause of initial infection. Because of this changing epidemiology of genital HSV infections, future vaccine trials will need to be rethought.”

    WHY THE VACCINE HUNT IS SO DIFFICULT

    Herpes simplex infections are forever, which complicates vaccine development.

    Some consider infecting people with live attenuated herpes virus, no matter how weak, too risky. Even killed-virus formulations pose a risk.

    “Unless you know you have killed every single one, there’s still a chance of an infection that can last a lifetime, and we still don’t know what all the lifetime risks are,” Bernstein says.

    Now researchers are using various HSV proteins, presented to the immune system in different ways, to trigger an immune response without causing infection.

    FUEL FOR FUTURE RESEARCH

    Although the Herpevac trial did not produce an effective vaccine, it did produce a first, and an incentive for future clinical trials:  researchers found a correlation between higher antibody levels in women and protection from HSV-1. Having a measurable correlate for immunity makes it easier to decide when to go forward with clinical trials, Bernstein says.

    Now, researchers are looking for what they need to include in the vaccine to boost the response.

    “To be effective against type 2, maybe we just need to trigger twice the amount of antibodies than was protective for type 1,” Bernstein says. “Maybe we need other adjuvants that can get more T-cells or other elements of the immune system involved.”

    NEW VACCINE MAY REDUCE TRANSMISSION

    While the search continues for a vaccine that prevents HSV infections from occurring altogether, there may be value in preventing infected people from shedding persistent virus that can infect others.

    A formulation called GEN003 appears to do exactly that. After pre-clinical trials conducted by Bernstein and colleagues showed promise, a clinical trial involving 143 people already infected with HSV-2 was conducted. The vaccine significantly reduced the number of days that virus could be found in participants’ genital tracts. Initial findings from the trial were presented in October 2013 at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). The study was led by Anna Wald, MD, MPH, of the University of Washington. Bernstein was second author.

    “It wasn’t a home run. It didn’t eliminate shedding, but it did make a big dent and that’s very important,” Bernstein says. “Existing antiviral medications have to be taken every day, so adherence is a major issue. But a vaccine, either by itself or in combination with antivirals, could be effective for several years.”


    A Common Disease

    About one in every four US women has genital herpes, making it one of the nation’s most common infectious diseases.

    The herpes simplex virus spreads through sexual or other skin-to-skin contact, and the virus can spread even when the infected person shows no symptoms. Once in the body, HSV migrates to nerve cells and remains there permanently where it can reactivate to cause painful outbreaks.

    HSV can cause severe illness in infants born to HSV-infected women, and the virus has been identified as a risk factor for HIV transmission in adults.

    Source: National Institute of Allergy and Infectious Diseases (NIAID).

    Ongoing Vaccine Research

    Cincinnati Children’s is one of nine medical centers in the US at the forefront of vaccine research, serving as a federal Vaccine and Treatment Evaluation Unit since 2002. A recently renewed contract with the government could provide up to $135 million to fund research over the next seven years. Current projects include evaluating potential vaccines for annual influenza, avian flu, norovirus, HPV, cytomegalovirus, shigella, cholera and anthrax.

  • Dr. David Bernstein leads the Vaccine and Treatment Evaluation Unit (VTEU) at Cincinnati Children’s.

    Dr. David Bernstein leads the Vaccine and Treatment Evaluation Unit (VTEU) at Cincinnati Children’s.