An unconventional take on vaccine design has been shown to protect mice against HSV-1 and HSV-2, the two most common forms of herpes that cause cold sores and genital ulcers, respectively.
Above: TEM micrograph of a herpes simplex virus | Credit: CDC/Dr. Erskine Palmer
Researchers led by Albert Einstein College of Medicine researcher William Jacobs reported their findings Tuesday in the journal eLife. HHMI News provides a tidy summary of past research into HSV inoculation and the surprising inroads that Jacobs and his colleagues have made with their new, unconventional vaccine:
Most prior attempts to construct a herpes vaccine have focused on a glycoprotein called gD that is embedded in the virus's outer envelope. This protein is required for the microbe to enter into and out of cells and to spread from cell-to-cell. gD also elicits a vigorous antibody response that many in the field believe is necessary to produce immunity. However, no gD-based vaccine has proven effective.
"It was necessary to shake the field up and go another route," says Betsy Herold, a virologist and infectious disease physician at the Albert Einstein College of Medicine and co-study leader of the new research.
As part of a separate ongoing study of the signaling pathway that the herpes virus uses to enter cells, Herold asked Jacobs's lab to engineer a mutant with gD deleted. Though it was not necessarily obvious beforehand, "once we had this mutant in our hands," Herold says, "it was a logical, scientifically driven hypothesis to say, 'This strain would be 100 percent safe and might elicit a very different immune response than the gD subunit vaccines that have been tried.'" The hypothesis followed from the increasing understanding that, in addition to its critical role in viral entry, gD also has the ability to change the host immune response.
In order to test the gD deletion virus as a vaccine, the researchers grew the virus in a cell line that expresses the HSV-1 version of gD. The HSV-2 virus, with gD deleted from its genome, grabbed the available HSV-1 gD proteins from the cell. When introduced to a mouse, HSV-2 was able to use the HSV-1 gD to enter the mouse's cells. Once inside, HSV-2 replicated abundantly, but because it could not produce gD, future progeny were unable to infect new cells. According to Herold, infected cells then became "little factories for making viral proteins" that spurred the immune system to produce antibodies to HSV-2.
The vaccine completely immunized two common strains of lab mice against HSV-2 when challenged with virus intravaginally or on the skin. In fact, no virus could be detected in vaginal washes four days post-challenge and even more importantly, no virus could be found in the nerve tissue, the site where HSV often hides in a latent form only to emerge later to cause disease. Protection against HSV-1, which shares considerable homology with HSV-2, was also demonstrated in both models. The vaccine produced no adverse health effects in a strain of mice with severely compromised immune systems, reflecting the vaccine's overall safety.
Blood serum passively transferred from immunized mice was found to protect wild-type mice, providing a powerful demonstration of the vaccine's efficacy. "No one has ever shown for a skin disease that you can protect against infection with passive transfer," Jacobs says.
You can read more about the vaccine and its surprising mechanism of action at HHMI News, but the big takeaway is aptly summarized in a quote from Jacobs. "With herpes sores you continually get them," he said, commenting on the tendency for herpes to lie dormant for months or years between recurring flareups, a hallmark characteristic of the virus that underlies its prevalence and continued spread. "If our vaccine works in humans as it does in mice, administering it early in life could completely eliminate herpes latency."
The next step, of course, is demonstrating its human efficacy in an FDA-approved cell line. The researchers are also reportedly seeking industry partners in bringing large quantities of the vaccine to advanced clinical trials.