Last Thursday, at the University of Pennsylvania Medical Center, a34-year-old woman, HIV-positive but without symptoms, received avaccination against AIDS. She thus became the first patient ever to beinoculated with a vaccine based on viral genes rather than theproteins those genes encode.
She was also the first of 16 subjects in a Phase I/II clinical trial to testthe safety of this new concept in anti-HIV immunization.
"The other 15 will all be enrolled over the course of this year," saidmolecular pathologist David Weiner, who heads the university'slaboratory on viral replication and immunology. "The way we set upthe study," Weiner told BioWorld Today, "this first patient is beingevaluated in detail, her blood drawn to monitor safety and immuneresponse; the skin area where she was intramuscularly injectedexamined for inflammation."
Only after her initial work-up is completed, Weiner went on, "will weenroll a second patient, probably at a different dose level. This trial ispredicated on really moving along and acquiring the safety data," headded. "Once we go through several different doses, accrual will bequicker."
Because this initial study is based on immunological rather thanclinical parameters, he pointed out, it is possible, but not probable,that some of the 15 subjects will be symptomatic, not just sero-positive.
"We're hoping the whole trial will take one to two years," saidVincent Zurawski Jr., president and CEO of Apollon Inc., ofMalvern, Pa., which is collaborating with Weiner. "Before this year isout," Zurawski told BioWorld Today, "we hope to be looking at a Tcell lymphoma trial of our genetically engineered vaccine construct,for which we have already filed an IND [investigational new drugapplication]."
Apollon, spun off in mid-1992 from neighboring Centocor Inc., is theuniversity's licensee for initial patents on the genetically engineeredvaccine construct. Weiner is a co-inventor on some of these. Thecompany has since filed for several additional patents of its own.
"Our role in the Phase I/II exercise," Zurawski explained, "is thatApollon developed all the manufacturing technology, and did all theimportant preclinical work toward the IND, on mice, rats, rabbits andsubhuman primates."
Vaccine Construct: Plasmid, Three Genes And A Facilitator
Last year, the company, through the university, applied to theNational Institute of Allergy and Infectious Diseases (NIAID) forfinancial support, and received a $4.2 million grant.
The prototype vaccine injected into that first patient last weekconsisted of a proprietary bacterial plasmid containing two non-infectious HIV genes that encode the viral envelope glycoproteins, gp120 and gp 41, plus a third gene, rev, which increases expression ofthose two env genes.
The same syringe delivered a "facilitating agent," bupivacaine,known to physicians as a potent local anesthetic. "At very lowlevels," Weiner said, "a couple of hundred microliters, we'vedemonstrated that bupivacaine significantly increases plasmid uptakein vivo _ inside an animal so far. Now we'll see if that's true inhumans."
He observed that the facilitator's original anesthetic property "didn'tdeaden the pain of the injection. It was too late; the patient hadalready been stuck."
Weiner emphasized that "none of the replicative viral genes" isincluded in his construct.
"I think what's really different here," Weiner observed, "is that we'redelivering something that induces both branches of the immunesystem in a conceptually safe fashion. Classically, two vaccineapproaches have been used, historically, to express viral vaccines _live, attenuated pathogens, and killed ones, or their fragments.
Triple-Threat Immune Counter-Attack
"The live, attenuated viruses," Weiner continued, "grow inside thecells of the body. By doing so they stimulate three immune responses,at least."
* antibodies, which eradicate free virus in the bloodstream.
* killer T cells, which destroy virus-infected cells.
* and helper T cells, which expand the overall immuneresponse.
"The killed-pathogen vaccines actually wind up outside the body'scells," Weiner explained, "and stimulate only antibody and helperresponses, so you don't get killer T cells, which destroy viralfactories."
His and Apollon's experimental construct, Weiner said, "combinesthe power of the live, attenuated with the safety and focus of thesubunit, or killed, vaccines. That's what makes it different from allother currently known AIDS vaccines."
If this approach proves itself with HIV, he said, "there are clearlyother pathogens that could be directly targeted, and which might be alittle easier than HIV."
Besides its upcoming T cell lymphoma trial, Apollon has on itsdrawing board product INDs to be filed this year for viral hepatitis,genital warts, tuberculosis, certain cancers and autoimmune diseases.
Weiner concluded earnestly, "If we get through this safety andimmunogenicity trial, it has broad implications. But it's a preliminary_ a baby _ step. People shouldn't think we think we've made anAIDS vaccine out of it. That's going to take a while." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.