Encouraged by ongoing animal trials of their recombinanthepatitis-C vaccine, researchers at Chiron Corp. are gearing upfor Phase I human studies late this year or early in 1995.
Results to date of the 11-chimpanzee test of the viral-envelopevaccine appear in the current issue of Proceedings of theNational Academy of Sciences (PNAS).
"We've made a lot of progress with these chimp studies," saidthe PNAS report's principal author, molecular virologist MichaelHoughton, who directs Chiron's non-A, non-B hepatitis R&D.Houghton told BioWorld that "the challenges for the future areto show that in humans we get good immunogenicity with thevaccines and prolonged rather than transient protection frominfection."
Houghton and his colleagues at Chiron of Emeryville, Calif., andthe Centers for Disease Control (CDC) in Atlanta discovered thehepatitis-C virus (HCV) five years ago. "We succeeded incharacterizing it," Houghton recalled, "by a novel blind-expression screening approach rather than conventionalvirological/biochemical methods." So far, the structure andshape of the HCV virion remain a mystery; its size is estimatedat 40 to 50 nanometers.
To construct their HCV vaccine, the Chiron team cloned theviral genome, assembled it in bacteria, cut out the genesencoding two presumed envelope glycoproteins and insertedthem into a vaccinia virus expression vector, with which theythen infected HeLa cells. (This fast-growing human cell line iscommonly used to cultivate viruses.)
The HCV-infected cells, plus a proprietary adjuvant, constitutedthe experimental vaccine with which Houghton's co-workersinoculated seven chimpanzees at primate centers in New Yorkstate and New Mexico in December 1991. Seven or eightmonths later, these vaccinated animals got infectious challengeinjections of the pathogenic virus. So did four unimmunizedcontrol chimps.
A Tale of Two Chimps
All four contracted acute hepatitis, the PNAS paper reports.Five of the vaccinated seven -- those with the highest bloodlevels of reactive antibodies to the HCV-envelope antigen --experienced no infection or viremia. The remaining twovaccinees, which had showed the lowest antibody response, didbecome infected, but have since begun to shake off their viralload. Unlike the four controls, they are showing signs of fullrecovery from infection. If liver biopsies now in progressconfirm their virus-free state, it's potentially a very importantresult, said Houghton. "Often, vaccines work by preventingdisease. They do not often prevent infection," he said.
"When we vaccinate humans, if we maintain high levels ofantibodies all the time, then we've got sterilizing immunity,"Houghten added. "Those people will never get infected. End ofstory."
Not quite. In the PNAS report, Houghton surmises that hisrecombinant glycoprotein vaccine's immunogenicity "may besubstantially higher in humans than in chimpanzees."
Houghten said the vaccine might prove useful for treating aswell as preventing HCV infection. "We are doing some otherchimp studies, this time using chronically infected animals as amodel for patients. I think there's a chance that vaccinetherapy would help," he said.
He is also developing some continuously expressing permanentcell lines to replace those used thus far, "which we hope willscale up vaccine production in sufficient quantities for humanuse, so we'll be in a position to start Phase I trials." These arenow being tested in other chimpanzee cohorts.
Globally Endemic, Cellularly Persistent
Hepatitis C virus infects up to to 2 percent of the world'spopulation. In the U.S. alone it produces 100,000 new cases ayear, said Houghton, quoting figures from epidemiologists atthe CDC. About half of these patients are needle-sharing IVdrug users. Others at high risk include health care workers andperhaps heterosexuals with multiple partners.
In humans, the target of choice for the hepatitis C virus is theliver, which it attacks slowly but relentlessly. "This virus isvery good at persisting in its host," Houghton said, "probably bymutating and evading the immune system PP shades of HIV.Over time, you get this gradual progression of liver disease,which eventually can proceed to cirrhosis and liver cancer,albeit in a minority of those infected."
He suspects that HCV's onslaught on the liver reflects theimmune system trying to rid the body of virus-infectedhepatocytes, which it does by killing those liver cells. But thestubborn virus persists, infecting more hepatocytes and settingup the life-menacing liver diseases.
Chiron has an arrangement with Ortho Diagnostics to produceand market infectious disease immunodiagnostics in a broadway, Houghton said. Ortho already is supplying Chiron's HCVantigens to Abbott Laboratories to market for infection testing.Its prototype vaccine is being produced by The BiocineCompany, Chiron's joint venture with Ciba-Geigy Ltd. ofSwitzerland.
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.