Collaborative study by the University of Cincinnati, Northwestern University and the University of Nebraska-Lincoln demonstrate potential of a new vaccine candidate against herpes virus.
In a study published in the journalNature Vaccines, reported that vaccinating guinea pigs with the modified live herpes simplex 1 virus significantly increased the production of virus-combating antibodies. When challenged with a virulent strain of herpes simplex virus, the vaccinated animals displayed fewer genital lesions, less viral replication and less of the viral shedding that most readily spreads infection to others.
The researchers shared that the modified live herpes simplex 1 virus (HSV-1) demonstrated cross-protection against herpes simplex 2 virus (HSV-2), suggesting that an HSV-2-specific edition of the vaccine could prove even more effective.
Despite the prevalence of HSV-1 and HSV-2, decades of research have yet to yield an approved vaccine for HSV-1 or HSV-2. The ability of alphaherpesviruses in evading immune responses has made it all the more difficult.
Gary Pickard and Patricia Sollars from the University of Nebraska-Lincoln, alongside Gregory Smith from Northwestern University and Ekaterina Heldwein from Tufts University, have spent years studying how to prevent HSV from affecting the nervous system. Ekaterina Heldwein advanced those efforts when she characterized the architecture of a certain alphaherpesvirus protein, pUL37, that the team suspected was integral to the virus moving along nerve fibres. Computer analyses based on that architecture suggested that three regions of the protein might prove important to the process.
Gregory Smith then carefully plucked out and replaced five codons, the fundamental coding information in the DNA, from the viral genome of each region. The researchers hoped that those mutations might help impede the virus from invading the nervous system. dResearchers from the University of Nebraska-Lincoln then injected mice with a virus modified in region 2 (R2). From this modification, the virus did not cross the nerve terminal.
Further studies showed that the R2-mutated virus performed well as a vaccine in mice. Moreover, it circumvented certain stubborn issues that have cropped up with other vaccine approaches. Some approaches have involved challenging the immune system with only a subset of HSV components, or antigens, priming the body to recognize them but potentially miss others. Some have modified the virus so that it can replicate just once, preventing long-term persistence in the nervous system but also reducing spread in mucosal tissues and, by extension, a stout immune response.
David Bernstein, a researcher at Cincinnati Children's Hospital Medical Center who evaluates herpesvirus vaccine candidates through a program supported by the National Institutes of Health, took note of the team's success and reached out to Northwestern's Smith in 2018. Using the R2-modified form of HSV-1, Bernstein decided to test its effectiveness against HSV-2 infection in guinea pigs. As promising as their prior results had been, Pickard conceded that he wasn't sure an HSV-1 vaccine would be up to the task of generating immunity against HSV-2.
But just one of the dozens R2-inoculated guinea pigs developed acute lesions after being injected with HSV-2, compared with five of 12 animals receiving another promising vaccine candidate that recently failed a human clinical trial. Whereas that latter vaccine candidate had no discernible effect on the number of days that guinea pigs shed the virus, the team's R2 vaccine cut the shedding period from 29 days to about 13. Unlike the guinea pigs receiving no vaccine or the other candidate, those receiving the R2 vaccine showed no sign of HSV-2 in the cluster of brain cells that normally house it. Neutralizing antibodies, meanwhile, registered about three times higher in the R2-inoculated guinea pigs than in those inoculated with the other vaccine candidate.
With an HSV-1 version of the R2 vaccine showing such promising cross-protection against HSV-2, the researchers will be studying for the development of vaccine against HSV-2.
Around the time that Bernstein and his NIH program were expressing interest in the R2 vaccine design, Pickard and Smith were launching a startup, Thyreos LLC, aimed at further developing and eventually licensing their R2 vaccine design.
Pickard and Smith are working on vaccines for livestock, specifically cattle and hogs, that contend with alphaherpesviruses of their own. In cattle, the bovine herpesvirus can cause respiratory disease, curb appetite and even contribute to aborted calves, all of which add up to billions of dollars in lost revenue annually. Though a modified live-virus vaccine for cattle does exist, it also gets into the bovine nervous system.
As they prepare to embark on a new series of studies that the researchers hope will show the R2 design's superiority to the current industrywide vaccine, Pickard and Smith are also kicking off an initial round of seed funding for the enterprise. Given that the team initially developed its R2 design in the alphaherpesvirus that infects pigs, Pickard also expressed confidence in the design's promise for protecting hogs.
“These pathogens can survive trans-Pacific transport in feed ingredients or feed products. When you talk to people who are concerned about biosecurity, they say that whatever is going on elsewhere in the world in terms of these viruses, eventually, they may show up here. It's just a matter of time.” Said Pickard.