A genetically edited form of herpes simplex virus (HSV)–altered to prevent it from hiding in the nervous system and avoiding an immune response—has outperformed a leading vaccine candidate, according to new research.

According to a press release, investigators found that vaccinating guinea pigs with the modified live virus significantly increased the production of antibodies. When challenged with a virulent strain of HSV, the vaccinated animals had fewer genital lesions, less viral replication, and less viral shedding. According to the investigators, the fact that the modified form of HSV virus type 1 (HSV-1) demonstrated cross-protection against HSV type 2 (HSV-2) means that an HSV-2-specific version could be even more effective.

HSV-2 affects more than 500 million people globally, according to data from the World Health Organization, and persists for a lifetime with flare-ups in response to stress. In addition to painful blisters and lesions, HSV-2 also increases the risk for HIV infection and may contribute to Alzheimer disease or other forms of dementia. Despite these concerns, experts say the alphaherpesviruses have evolved a sophisticated way of avoiding immune responses, making a vaccine difficult to develop.

Earlier research has shown that the virus takes refuge in the nervous system after infecting mucosal tissues of the mouth or genitourinary tract. Whereas the mucosal system is cleared by the immune response, HSV leaves the infected neurons only in response to rises in steroids or other stress-elevated hormones in the host. Based on these findings, investigators have aimed to create a vaccine that prevents the virus from entering the nervous system, although this approach has had its own challenges.

“You can keep the virus from getting into the nervous system,” said investigator Gary Pickard, PhD, in a statement. “That’s not that hard to do by making broadly debilitating mutations. But when you knock down the virus so much that it doesn’t replicate well, you are not rewarded with a robust immune response that can protect you from future exposures.”

Investigators focused on region 2 (R2) of a certain alphaherpesvirus protein, pUL37, which they believed was integral to the virus’s movement along nerve fibers and into the nervous system. By modifying this protein in the vaccines, researchers found that this mutation performed well in mice while circumventing challenges found in other vaccine approaches. Still, Pickard was not sure whether an HSV-1 vaccine would generate immunity against HSV-2.

When tested in guinea pigs, however, investigators found that just 1 of the dozen R2-inoculated guinea pigs developed acute lesions after being injected with HSV-2, compared with 5 of 12 animals receiving another promising vaccine candidate. According to a press release, the latter candidate had no discernible effect on the number of days that guinea pigs shed the virus, whereas the R2 vaccine candidate cut the shedding period from 29 days to approximately 13. Moreover, the R2-inoculated guinea pigs showed no sign of HSV-2 in the cluster of brain cells that normally house it.

“The fact that the viral shedding was knocked down so much with the R2 vaccine is really important, because it’s the viral shedding—even if it doesn’t cause lesions—that can then pass on the virus,” Pickard said. “If you have genital herpes, you can pass that on to your significant other, not knowing that you’re doing it. It’s very problematic. So, the fact that the shedding was knocked down so much is a really good sign.”

Pickard and his colleague Gregory Smith, PhD, have launched a startup aimed at further developing and eventually licensing their R2 vaccine design, and a series of new studies are being launched to investigate the vaccine’s superiority to the current industrywide vaccine.

REFERENCE
Vaccine shows promise against herpes virus [news release]. University of Nebraska-Lincoln; November 6, 2020. Accessed November 10, 2020. https://news.unl.edu/newsrooms/today/article/vaccine-shows-promise-against-herpes-virus/.