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Developing a Herpes Vaccine: A New Approach

Editors’ Note: In March 2015, Einstein researchers announced successful results on a vaccine that completely prevented herpes infections in mice. The study, published in the journal eLIFE, prompted hundreds of inquiries to Einstein from people around the globe seeking more information about clinical trials. As we’ve explained to those who’ve contacted us, there are several steps that must first be taken before human trials can begin. The research team is working hard to bring this novel vaccine forward and hopes that the work it is doing will lead to a Phase 1 clinical study within the next two years.

We asked one of the study’s co-leaders, Betsy Herold, M.D., to explain the work she did with co-study leader William Jacobs, Jr., Ph.D. Below, she provides a clear understanding of why herpes is so challenging and how innovative scientific thinking helped serve up an entirely different approach to potentially preventing a disease that affects more than 500 million people worldwide.

By Betsy Herold, M.D.
As a pediatrician and translational scientist, I have devoted much of my career to the prevention of viral infections such as herpes. There are two common types of herpes simplex viruses (HSV). Type 1 typically causes cold sores and infects about half of the U.S. population, and both type 1 and type 2 cause genital ulcers, although type 2 is the main cause of genital disease worldwide. In addition, both types are leading causes of encephalitis (infection of the brain), which can result in devastating disease in newborns who are infected during delivery, and are also major causes of sporadic encephalitis in children and adults. HSV-1 is also a leading cause of corneal blindness worldwide.

Once a person is infected with either type of HSV, the virus persists in a latent (asleep) form for life—but periodically awakens to cause recurrent disease. In infants and those with impaired immune systems, such as transplantation recipients, the viruses can spread throughout the body, resulting in substantial morbidity and mortality. I have treated infants and children with herpes encephalitis or disseminated disease and seen the devastation firsthand, fueling my passion to help develop a vaccine to prevent HSV.

Scientists have pursued the development of a safe and effective vaccine against HSV for decades. Vaccines work by exposing the host to viral proteins (referred to as antigens) that stimulate the body to produce antibodies or immune cells that rapidly clear the pathogen before it establishes infection and causes disease.

Scientists have long assumed that the best antigen for an HSV vaccine is a protein called glycoprotein D (gD). One of the major proteins on the envelope of the virus, gD is required for the virus to enter and spread from cell to cell. Several vaccines containing gD alone or combined with another viral antigen have been advanced into the clinic, but have had disappointing results so far. The most recent vaccine to be evaluated induced high levels of antibodies directed against gD, but still failed to protect men and women from HSV-2 infection when tested in large clinical studies.

These results suggested that we needed to adopt a completely different approach to developing an HSV vaccine.

We deleted the gD gene from HSV-2 to test the hypothesis that deletion of the virus’ dominant protein would result in a different—and, we hoped, more effective—type of immune response. We grew this “deletion virus” on cells that expressed HSV-1 gD to allow the vaccine virus to initiate a first round of infection. (The gD protein is required for viral entry.) However, any new virus particles produced would be gD-negative, because the virus would be missing the gene needed to make it. Therefore, it would not be able to spread further but would allow the immune system to recognize the viral proteins.

When we tested the vaccine in immuodeficient mice, it proved completely safe: The vaccine caused no signs of disease and no virus was ever detected in nervous tissue—the site where latent HSV lurks. To test the vaccine’s effectiveness, we gave it to mice and then challenged them with high doses of HSV-2 or HSV-1 administered intravaginally or through the skin. The mice were completely protected from infection, and, again, no latent virus could be detected in nervous tissue.

No other HSV vaccine candidate had ever completely prevented HSV viruses from becoming latent.

Finally, we transferred antibodies from vaccinated mice to unvaccinated mice, and we found that mice receiving the antibodies were fully protected from subsequent HSV infection. The vaccine elicits very high levels of antibodies that recognize a broad array of viral proteins and are rapidly transported into the skin and mucosa to prevent the virus from spreading. We are now studying why deletion of the gD gene caused this different and more protective type of antibody response.

We are working to optimize models to test whether the vaccine will be effective in reducing recurrences in people already infected with HSV and we are completing the preclinical work required to test this new vaccine in people.

While there are many more steps to take, we are confident we will learn more about immune responses to HSV and perhaps other pathogens and, hopefully we will be able to take a significant step toward reducing the scourge of HSV.

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Betsy Herold, M.D.

Betsy Herold, M.D.

Dr. Herold is professor of pediatrics (infectious diseases), of microbiology & immunology and of obstetrics & gynecology and women's health at Albert Einstein College of Medicine and chief, division of pediatric infectious diseases at the Children's Hospital at Montefiore.

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