Herpes Vaccine!
Sounds like one may be available in the not-too-distant future:
http://focus.hm s.harvard.edu/2 … crobiology.html
A new study provides evidence that a herpes vaccine developed by David Knipe, the Higgins professor of microbiology and molecular genetics at HMS, is a strong candidate for testing in humans. The research, in the January Journal of Virology, compared three different experimental vaccines for herpes simplex virus 2 (HSV-2), which causes most cases of genital herpes.
Lead author Stephen Straus, senior investigator in the Medical Virology Section in the Laboratory of Clinical Infectious Diseases at the National Institute of Allergy and Infectious Diseases, tested the vaccines in two established animal models of herpes infection. Knipe’s vaccine, 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 dl5-29’s biological and immunological properties, it appears to be the most compelling new vaccine candidate for genital herpes,” he said.
Danger to Developing Countries
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.
Herpes vaccines so far have been disappointing in clinical trials. Beginning in the late 1980s, Straus helped design and conduct clinical studies of vaccines for genital herpes. “It was a very instructive process,” he said. “It taught us that developing a vaccine for a chronic and recurrent viral infection such as genital herpes was harder than we imagined.”
Straus said that dl5-29 seemed especially promising because it works in a way that previous candidate vaccines have been known to fail. The dominant approach to herpes vaccine development over the past two decades has been to deliver one or two glycoproteins found in the outer envelope of the virus to induce an antibody response. One glycoprotein vaccine failed to protect people from HSV-2 infection, while a second version showed a protective effect only in a subset of women who had not been infected previously with either HSV-2 or HSV-1, the common cause of cold sores.
In contrast, dl5-29 is a live, mutant strain of HSV-2 that is missing a set of genes enabling 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 was a co-author 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 its proteins within them, it not only elicits many 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.
The story in many ways parallels the early trials of HIV vaccines, which also failed because they only elicited antibodies. “For herpes or HIV, you need a good T cell response and T cell immunity. Those are more difficult vaccines to get,” Knipe said.
Test Design
Straus compared dl5-29 with a glycoprotein vaccine previously tested in humans and a third vaccine comprising a circular strand of DNA that encoded the glycoprotein. Such naked DNA vaccines have generated interest in recent years for their potential to bring out a stronger cellular immune response than 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,” in order to get a better sense of how well the vaccine performed. His team tested the vaccines in mice and in guinea pigs. The latter is the best known model of HSV-2 infection 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 existing infection.
Straus and his team 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. When given therapeutically to infected guinea pigs, dl5-29 reduced the rate of recurrent infections slightly better than the other candidates. The vaccine also induced a stronger T cell response than either of the other two vaccines.
Dl5-29 even stimulated a stronger antibody response in animals than either of the other vaccines. Straus and Knipe said this result was surprising because it was thought that a single glycoprotein alone was enough to stimulate sufficient 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 other vaccines have prevented infection in animals, but failed in humans, the results do not guarantee success. Yet Straus said that the stronger T cell response provides a theoretical reason to think dl5-29 would be better. “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,” he said. “With dl5-29, we believe there are now sufficient data to justify clinical studies.”
Straus hopes to be involved in those trials and to help Knipe realize a longstanding dream. Knipe first began developing the vaccine nearly 15 years ago, but has had difficulty finding an industry partner to bring it to human trials. “It has been frustrating,” he said. Vaccines have never been seen as lucrative investments for drug companies, and the disappointments of previous trials also have made companies wary. Knipe believes that the new results will provide the evidence needed to move the vaccine forward.
