HSV Strains Recombining, Potentially Impacting Vaccine Development

By Marilynn Larkin

May 13, 2019

NEW YORK (Reuters Health) - Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) are recombining, suggesting that live attenuated HSV-2 vaccine candidates carry a "significant risk" of recombining with circulating HSV-1 strains to form an infectious virus, researchers say.

Both HSV-1, which typically causes oral lesions, and HSV-2, which typically causes genital lesions, are lifelong infections that often lead to mild, intermittent symptoms but can cause significant morbidity and mortality, particularly in immunocompromised individuals and neonates, Dr. Alex Greninger of the University of Washington in Seattle and colleagues explain.

Although antivirals can reduce symptoms, they don't cure the infection or prevent transmission, leading to an "urgent need" for an HSV vaccine, they say.

It was known that at least four small interspecies (human/chimpanzee) recombination events affected the HSV-2 genome millions of years ago, and that these viruses are circulating today. To determine whether recombination is still occurring, and how that might affect vaccine development, the researchers sequenced oral, genital and mixed anogenital samples collected as part of research studies from 1994 to 2016.

As reported online April 23 in the Journal of Infectious Diseases, the researchers generated genome sequences for 59 HSV-1 samples collected from 47 individuals; for HSV-2, they generated 196 new genome sequences from 118 individuals.

Using the 255 newly sequenced HSV genome sequences and 230 existing sequences, they determined that the sizes and locations of interspecies recombination events in HSV-2 are significantly more variable than previously thought and that they can impact species-specific T-cell recognition of HSV.

Further, they found two large (>5kb) recombination events, one of which was in a sample from a Seattle woman with HSV-1/HSV-2 coinfection - i.e., the event arose in its current host. That finding meant that interspecies recombination is still occurring, according to the authors. "These results raise concerns about the use of live attenuated HSV-2 vaccines in high HSV-1 prevalence areas," they note.

Dr. Greninger added in an email to Reuters Health, "If you have a vaccine that only protects against HSV-1 or HSV-2, given the amount of recombination we're seeing after sampling only (approximately) 250 viruses, there could be a recombinant out there that could be resistant to a more narrowly focused vaccine."

"Ideally, we need a vaccine that protects against both HSV-1 and HSV-2; similar to how the drug acyclovir treats both HSV-1 and HSV-2," he said. "Also, our results indicate that HSV-1 and HSV-2 are still recombining today, so who knows what we will see in the future, especially with the growing proportion of HSV-1 genital infection and potential for co-infection with HSV-2 there."

"HSV genomics is still in its infancy when you compare it to human genomics or even other viruses such as influenza," he continued. "This study was mostly conducted on samples from Seattle... so we need to sample more geographic diversity. Then we just need more samples in order to understand prevalence of the variety of HSV strains out there in the world today."

Dr. Christopher Snyder, an associate professor of microbiology and immunology at the Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia, told Reuters Health that clinically, "there is no evidence yet that any of these recombination events would make the virus more or less virulent."

"The study authors raise the concern that recombination could rescue attenuated viruses given for therapeutic or vaccine purposes," he said by email. "This would likely be a very rare event... but it could be a problem if someone were given an attenuated HSV-2 vaccine that then recombined with their own naturally-acquired HSV-1, rescuing the defects that made the vaccine attenuated and thereby making it virulent and disease-causing again."

SOURCE: http://bit.ly/2E1f5w6 and http://bit.ly/2E2Cqxk

J Infect Dis 2019.