By David N. Leff
Some macho types laugh off genital herpesvirus infection as "no worse than a bad cold." Actually, it's one of the world's most prevalent sexually transmitted diseases.
To be sure, the painful bunched blisters than infect the male and female genitalia are self-limiting. They begin to flare up four days to one week after contact, then crust over and heal within 10 days or so.
But the lesions come back, and these recurrent return engagements can last a lifetime. In between bouts, herpesvirus type 2 (HSV2, the genital version) holes up in the nervous system's sensory nerve ganglia, waiting to reemerge every time a neuron gives the signal.
Herpesvirus type 1 gives rise to cold sores - fever blisters - which also go away in days, and also recur and recur. Moreover, 20 percent of the genital afflictions are due to type 1.
But that's not all. A baby being born to a mother with herpetic vaginal lesions stands a fair chance of picking up the infection on its way down the birth canal.
"In newborns," observed research virologist David Knipe, "HSV2 causes a serious disseminated infection. Even with the antiviral acyclovir for treatment, it is marked by serious morbidity and mortality. The major risk for newborns," he explained, "is with mothers who have a primary infection, so there's no maternal antibody transferred to the baby. So that neonate, with an immature immune system of its own, is at risk, unprotected."
Unless treated, 85 percent of those infants will die, and 25 percent of the survivors will go through life with severe neurological sequellae.
Knipe, who is in the departments of Microbiology and Molecular Genetics at Harvard Medical School in Boston, has focused for a decade on developing a vaccine to prevent herpesvirus infection. He reports his latest version in the current issue of the fortnightly Proceedings of the National Academy of Sciences (PNAS), dated June 8, 1999. It is titled: "Immunization against genital herpes with a vaccine virus that has defects in productive and latent infection."
Knipe is not alone in that endeavor; many pharmaceutical and biotech companies are on the same case. "There have been attempts by several groups," he told BioWorld Today, "to make an inactivated-virus vaccine, and those weren't very immunogenic."
Hanging over all these and other attempts was a general belief - almost a dogma - among vaccinologists, Knipe pointed out. "It was the scientific rationale that only a herpesvirus fully capable of replication can achieve effective immunization." He perceived that concept as self-defeating, because such a vaccine carried the danger of infecting its recipient.
So Knipe and his co-authors set about constructing an HSV2 vaccine that would disprove the dogma.
"We genetically engineered the virus to be replication-defective in normal cells, by introducing deletions in two genes that encode viral DNA replication proteins. So it's got a double block for DNA synthesis and grows only in cells that provide the missing gene product. So when it's put into a normal host organism," Knipe explained, "it infects one round of cells and produces proteins that induce the immune response, but the virus doesn't spread on. We call it 'replication-defective' because its replication cycle is only partial."
Their vaccine's immune response engages both the humoral and cellular arms of the immune system. Its antigenic target consists of nearly all the viral proteins, which the mutant virus expresses in infected cells. "Clearly," Knipe pointed out, "the major viral glycoproteins are targets for neutralizing antibody. For the T cells' cytotoxic lymphocytes, we don't really know what the major target is, but there's certainly an immune response to a broad range of viral proteins."
Tested in vitro and in vivo, the two-mutant-gene maverick vaccine provided immunization as good as did vaccines harboring each gene separately. "But having two deletion mutations," Knipe said, "made it safer."
Score: Vaccines - 100 Percent Survival; Controls - Zero
The co-authors immunized six mice with each of the two mutant HSV2 genes separately, and with both in the double-blocking vaccine. Then they infected the animals intravaginally with a bolus of virulent virus at a dose 50 times lethal. Six untreated control animals all broke out in lesions and died by 10 days after infection. But the 18 animals immunized with the three vaccine variants all survived unscathed.
"We will try further experiments in the animal systems," Knipe went on, "but we would like to get our vaccine into Phase I clinical trials to see how immunogenic it is in humans."
With patent applications pending, Harvard has licensed the technique to Avant Immunotherapeutics Inc., of Needham, Mass. "We will be meeting soon with Avant and NIH," Knipe observed, "where we're going to be discussing how the trials might be done."
"This two-deletion herpes vaccine strain," he suggested, "provides a paradigm for the design of vaccines and vaccine vectors for other sexually transmitted diseases, such as AIDS. The idea would be to use the HSV genome as a vector to express heterologous antigens, such as the monkey SIV or HIV env and gag proteins. We have one unpublished round of vaccine recombinants that we have put into monkeys to see if we can protect against SIV as a model system.
In Future: Vaccinate Young, Old
Looking ahead, Knipe concluded: "We would like to immunize adults initially, and once we have some safety data, the ultimate goal would be to immunize children before they become sexually active. That obviously is dependant on all the safety testing that needs to be done."
Harvard vaccinologist John Mekalanos, who communicated Knipe's paper to PNAS, told BioWorld Today: "What I consider the most important breakthrough is the concept that they are building the right kind of mutations and the appropriate cell lines to complement those mutations, Thus they can produce viral particles that begin the infection cycle, but literally have no capability of replicating their own DNA, and yet still induce an immune response."
"Herpesviruses are very big," Mekalanos concluded, "around 150 kilobases, which can potentially encode well over 100 gene products. So it hasn't been a simple and easy process to just look at herpesviruses and say, 'OK, here's the obvious immunogen.'"