Dec. 24, 2004 BOSTON (December 14, 2004) -- A new study provides evidence that a herpes vaccine developed by a Harvard Medical School researcher is a strong candidate for testing in humans. The study, published online Dec. 14 in the Journal of Virology, compared three different experimental vaccines for herpes simplex virus 2 (HSV-2), the virus that causes most cases of genital herpes.
HSV-2 infects one in five Americans, and its prevalence has reached 50 percent in some developing countries, where it also seems to be helping to fuel the spread of HIV. HSV-2 infection, though incurable, typically does not cause major health problems, but can be life-threatening in immunocompromised people and newborn babies infected by their mothers.
Lead author Stephen E. Straus, MD, senior investigator in the Medical Virology Section in the Laboratory of Clinical Infectious Diseases at the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, tested the vaccines in two established animal models of herpes infection. The HMS vaccine, developed by David Knipe, HMS professor of microbiology and molecular genetics, called dl5-29, outperformed the other two vaccines, one of which has already been tested in humans.
Straus said that the results argue strongly for taking dl5-29 into human trials. "Based upon d15-29's biological and immunological properties, it appears to be the most compelling new vaccine candidate for genital herpes," he said.
Straus said that dl5-29 seemed especially promising because it solves a critical problem that is believed to underlie the failure of previous candidate vaccines. The dominant approach to herpes vaccine development over the past 20 years has been the delivery of one or two pure glycoproteins found in the outer envelope of the virus in order to induce an antibody response. But in trials of HSV-2 vaccines, a healthy antibody response has not seemed sufficient to protect against infection. One version of the herpes glycoprotein vaccine failed to protect research subjects from HSV-2 infection, while a second version of the glycoprotein vaccine failed to protect men, but showed a protective effect only in the subset of women who also had not been infected previously with HSV-1, the common cause of cold sores.
In contrast, dl5-29 is a live, mutant strain of HSV-2 that is missing two of the genes necessary for it to replicate and persist inside its host. "The proteins that are expressed are able to induce immune responses but the virus can't spread," said Knipe, who is a coauthor on the paper. Normally, HSV-2 infects the cells lining genital areas, but makes its way into nearby sensory neurons, where it persists in a latent state. Because dl5-29 actually enters host cells and expresses many of its proteins within them, it not only elicits a broad spectrum of antibodies but also stimulates T cells, which directly attack infected host cells and release cytokines that further strengthen the immune response. The clinical trials of previous herpes vaccines suggested that T cells as well as antibodies must be activated to launch an effective defense.
Straus compared dl5-29 with a glycoprotein vaccine previously tested in humans and a third vaccine comprising a naked circular strand of DNA encoding the glycoprotein. Naked DNA vaccines have generated interest in recent years for their potential to elicit a stronger cellular immune response than by simply injecting the protein. Straus said that he tested dl5-29 against "the best tested standard vaccine plus the competing new concept in the field, DNA vaccines," in order to get a better sense of how well the dl 5-29 vaccine performed. His team tested the vaccines both in mice and in guinea pigs. The latter is the best model of human HSV-2 disease because it is the only one that mimics many of the aspects of the human disease, such as a recurring infection interspersed with periods of latency. The researchers studied how well the vaccines worked prophylactically-to prevent infection-and therapeutically to help control an existing infection.
Straus and his colleagues at the NIH found that in all measures dl5-29 performed as well or better than the other two candidates. It was as effective as the glycoprotein vaccine in preventing acute and recurrent disease in guinea pigs. Moreover, when given therapeutically to previously infected guinea pigs, dl5-29 reduced the rate of recurrent infections slightly better than the other candidates. A key finding was that dl5-29 also induced a substantially stronger T cell response than either of the two other vaccines.
Additionally, dl5-29 stimulated stronger antibody responses in animals than either of the other vaccines. Straus and Knipe said this result was surprising because it was thought that the large quantities of a single glycoprotein, as used in many recent human trials, was enough to stimulate sufficient levels of antibodies. Knipe said that as a live virus, dl5-29 produces many more viral proteins, and perhaps the resulting broader antibody response is important in preventing infection.
Because many other candidate vaccines have prevented infection in animals but failed in humans, the results do not guarantee success. But Straus observed that the stronger T cell response provides a major theoretical advantage for dl5-29 that could translate into greater clinical effectiveness in people. "The vaccine induced very good levels of immunity of the antibody type. It induced far better levels of immunity of the cellular type. It was enormously safe, and didn't seem to persist in the animals," said Straus. "With dl5-29, we believe there are now sufficient data to justify clinical studies."
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