Warts come in two main persuasions, cutaneous andmucosal. In both, they are the work of the humanpapillomavirus (HPV).
On a child's skin, a wart is no big deal. Tom Sawyer andHuck Finn used to prescribe a tail-swung cat in acemetery at midnight to ablate those rough little bumps.Absent such alternative therapy, a juvenile skin wartwould likely disappear in three or four months.
But on the mucosal epithelium lining of the male andfemale reproductive tracts, genital warts and cervicalcancer are among the commonest sexually transmitteddiseases in the U.S. Recombinant interferon-alpha, bothnative and recombinant, is used to treat genital warts, butthere is no vaccine.
In the U.S. alone, HPV causes more than 65,000 annualcases of malignant cervical cancers, 15,800 of which areinvasive, and result in over 4,800 fatalities a year.Elsewhere in the world, particularly in developingcountries of Southeast Asia and Latin America, whereaccess to pap smears is virtually nil, HPV-inducedcervical cancer is the leading cause of cancer death inwomen.
Virologist JoAnn Suzich is project manager of a crashprogram at MedImmune Inc., of Gaithersburg, Md., toproduce the world's first anti-HPV vaccine. TheProceedings of the National Academy of Sciences,published today, carries her paper titled, "Systemicimmunization with papillomavirus L1 protein completelyprevents the development of viral mucosal papillomas."
MedImmune provided this prophylactic protection to aseries of beagle puppies, in whom canine papilloma virusclosely parallels the human genital pathogen. Infectedbeagles quickly and reliably sprout warts inside theirmouths. "You just have to pull the dog's cheek open andlook," Suzich told BioWorld Today. "It's a mucosalinfection that's easy to monitor."
Mucosotropic papillomavirus, she explained, "is anicosohedron about 55 nanometers in diameter, consistingof two main protein components, L1 and L2. Five L1proteins come together to form the viral capsomeres.Seventy-two of these subunits form the icosohedron."
She continued: "L1, with 90 to 95 percent of the virion'sprotein content, is clearly the major component; it self-assembles into a virus-like particle. L2 doesn't."
MedImmune's HPV vaccine strategy is to construct anartificial, recombinant virus-like L1 particle, rather thanattempt to modify the native virus. To express this non-infective immunogen, they chose the insect baculovirus,Autographa californica.
"You can get HPV's L1 protein to express perfectly wellin Escherichia coli host cells," Suzich observed, "but itdoesn't go on to form a virus-like particle, which is theimmune system's antibody target.
"But that did happen," she went on, "when we expressedthe protein using recombinant vaccinia or baculoviruses,instead of E. coli. When you take antibodies that aregenerated against intact virions, like canine oralpapilloma virus, you find that those antibodies recognizethe protein generated in the eukaryotic system, where youget the formation of those virus-like particles."
Between late 1993 and early 1995, Suzich and her co-authors injected their prototype vaccines, or controlsolutions, into the accessory foot pads of six- to eight-week-old beagle puppies. Those are the rough bumps,part way up a dog's leg, that don't interfere with walking,she explained.
A booster shot followed two weeks after the initialvaccination, and two weeks later, the dogs' oral mucussurfaces received challenge exposure to caninepapillomavirus.
Three different vaccine preparations, with and withoutadjuvants, chalked up perfect protective scores: none ofthe seven beagles in each of these trials developed oralwarts. By contrast, with one exception, all seven in eachof four control trials did.
Here is how Suzich explained the oddball control puppywho somehow escaped infection after a non-papillomavirus vaccine formulation:
"When we did our first study, and saw such incredibleprotection, we began to worry: Is this one an artifact? Sowe ran a number of controls; we immunized animals justwith saline solution. They were not protected. Seven ofseven came down with warts."
So they prepared a dummy vector of baculovirusexpressing an irrelevant parvovirus antigen. That waswhen only six of seven developed lesions.
Tracking back blood samples taken from that seventhpuppy who escaped infection, they discovered that it "hada high titer of anti-canine oral papillomavirus antibodiesat the very beginning of the experiment _ before it hadever been immunized. As though it had either beenexposed to the virus naturally, or had maternalantibodies."
What happened next, Suzich recalled, was that,"Naturally, when the company saw this dramaticprotection, we had a clash of wills between what thescientists wanted to do _ some more very interesting dogexperiments _ and what the business people wanted usto do _ move on from canine to human papillomaviruses."
In consequence, she and her collaborators "have beenvery busy in trying to prepare materials to begin tests inthe clinic."
MedImmune's manager of strategic planning and investorrelations, Mark Kaufmann, told BioWorld Today, "Wehope to start Phase I trials of vaccines for selected HPVtypes by mid-1996, to examine immunogenicity andsafety. Within a year after that, we should have finalPhase I results."
MedImmune holds exclusive rights to patents in thepapillomavirus field from Georgetown University and theUniversity of Rochester.
"We are actively working with researchers in bothinstitutions," Suzich observed, "and trying to get all ourintellectual property ducks in a row," she added, "so we'llbe in place for the summer Phase I starts." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.