About 250 happily married couples have been labeled "discordant" inan ongoing Phase III clinical trial of Chiron Corp.'s vaccine againstgenital herpes infection.
Where these highly compatible husbands and wives differ is in theirimmune systems' pre-trial exposure to herpes-simplex virus, type 2(HSV-2), which causes the sexually transmitted disease. HSV-2differs medically from HSV-1, which is mainly responsible for coldsores.
"There are two arms to our present prophylactic HSV-2 vaccinetrial," Chiron's vice-president for corporate communications, LarryKurtz, told BioWorld Today. "The `discordant' study arm," heexplained, "involves people who are one partner of a monogamouscouple, one HSV-2-positive, the other negative. Because the virus isshed asymptomatically," he went on, "you typically have _ despitesafe sex _ a higher infection-transmission rate among these peoplethan the normal population. That makes it a good study group ascandidates for such a vaccine," Kurtz pointed out, "because of theexposure they have in their personal situation."
Nearly 1,900 individuals of a different lifestyle are taking part in thesecond arm of the preventive vaccine trial. "These are unmarried,sexually active people with multiple partners," Kurtz related, "whopresent at a clinic for sexually transmitted diseases with someproblem other than herpes."
Chiron, based in Emeryville, Calif., also has a separate Phase III trialof its HSV-2 vaccine under way, for therapy rather than prevention. Itenrolls some 250 sufferers. "This is a post-infection, immunizationregimen," Kurtz said, "where our goal is to diminish the severity andfrequency of these recurrent genital lesions in HSV-2 people."
The three pivotal studies are ongoing at 20 university and privateoutpatient clinics in the U.S. Final analysis of all three will end latenext year.
In a Phase II study two years ago, Kurtz recalled, "a prototypeversion of the vaccine showed a 30-percent reduction in thoselesions. (See BioWorld Today, May 4, 1993, p. 1.)
Phase I/II Results Warranted Phase III Launch
A paper in the Annals of Internal Medicine dated June 15 reportsresults of open-label Phase I and II studies, which paved the way tothe present Phase III trials. Its title: "A recombinant glycoproteinvaccine for herpes simplex type 2: safety and efficacy."
Ever since genital herpes flared up with the sexual revolution in the1960s and 1970s, constructing a vaccine against this most intimate ofnon-lethal bodily torments has been both the Holy Grail and will-o'-the-wisp of virologists.
Rae Lyn Burke, a co-author of the Annals article, is director ofvirology at Chiron, and responsible for the research and preclinicalaspects of HSV vaccine development by that company, and itssubsidiary, Biocine.
"Our vaccine," she told BioWorld, "is made of two viralglycoproteins _ gD and gB. There are 12 glycoproteins in the HSVenvelope," she noted, "but these two are the predominant ones." Bothare essential for virus infectivity, Burke explained: "gB is responsiblefor fusion of the viral membrane and its target cell membrane,whereas gD binds to a receptor on that mucosal cell's surface."
A leading designer of the vaccine is virologist Lawrence Corey, ofthe University of Washington in Seattle. He is a pioneer herpesinvestigator, senior author of the Annals paper, and a consultant toChiron Biocine's research program.
The group chose gB and gD as its bull's-eye, subunit antigens, Burkeexplained, "because we certainly knew they were predominant targetsof antibodies and neutralizing antibodies both."
She pointed out that these proteins "have a high degree of molecularidentity between HSV-2 and HSV-1 _ about 80 to 84 percent at theamino-acid sequence level." Animal experiments had led the team topredict that the vaccine would confer a degree of cross-protectiveimmunity between both viral types, "as well as protecting againstganglionic latency."
HSV-2 Hits Below The Waist, Sneaks Off To Hide
This refers to HSV's cunning propensity for hiding away in thebody's nervous-system network between bouts of infection. Where ithibernates, Burke explained, "depends entirely on the route of initialinfection. If the virus enters into the mucosa of the genital region, itshidden lair is the lumbo-sacral sensory ganglion between ribs andpelvis. If by the oral or ocular route, in the trigeminal ganglion, nearthe temples."
Besides combining recombinant replicas of those two top-ratedherpesvirus antigens, Kurtz emphasized, Chiron's vaccine owes muchof its immunogenic efficacy to its squalene-based adjuvant. Squalene,a cholesterol precursor, occurs naturally in shark's liver oil.
That HSV-2 efficacy, as reported in the Annals, produced thesetypical Phase I/II results in eliciting humoral (antibody) and cellular(T cell) immune responses:
* Among 137 HSV-seronegative patients, neutralizing antibody titersincreased to levels "equal to or higher than those seen in naturallyacquired infection" after the full three-dose, six-month immunizationschedule.
* Among seronegative subjects, the precursor frequency of gD2- andgB2-specific T cells "showed a marked increase after vaccination."
* Persons negative for HSV-2, who received the full vaccine regimen"developed antibodies to the major neutralizing glycoproteins ofHSV-2 that are 100 times greater than that achieved by previousglycoprotein preparations," _ constructed by legendaryvaccinologist Maurice Hilleman in the early 1980s at the MerckInstitute for Therapeutic Research in West Point, Pa.
Once all three Phase III, open-label, clinical trials end next year, ifsafety and efficacy results hold up, Kurtz said, Chiron will apply tothe FDA for marketing approval of its genital herpes vaccine.
"We haven't advocated at this point," Burke observed, "that one startvaccinating newborns. If, as we believe, our vaccine could protectpregnant women, and those of child-bearing age, it should have adramatic effect on the incidence of neonatal herpes."
She concluded: "We would have to wait until we have clear proof ofefficacy in the adult population first." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.