It took virologist Jonas Salk five years, from 1947 to 1952, to bringhis killed-virus, injectable polio vaccine from test tube to humantrials, and another three years to see it released for clinical use.
A decade later, Albert Sabin's attenuated, oral polio vaccine wentfrom laboratory to clinic in only three years, 1957 to 1960.
Fast forward to 1987, when the FDA authorized MicroGeneSys Inc.,of Meriden, Conn., to conduct the first human trial of an AIDSvaccine.
Now, nearly 10 years on, prototype vaccines against the AIDS virusare more or less on hold, despite the ongoing research anddevelopment efforts of pharmaceutical and biotech companies, plusthe late Salk himself.
With their focus on the HIV-1 virion, particularly its subunit proteinepitopes, these AIDS vaccinologists may all be beating the wronghorse. A paper in the bimonthly British journal, AIDS Science, datedApril 24, 1996, suggests as much. Its title: "Identification of the b2m-derived epitope responsible for neutralization of HIV isolates."
The epitope that report cites as a putative HIV-1 vaccine binding site,beta-2 microglobulin, is a cellular, not a viral, protein. Presumably,that's the horse to beat.
"Previous attempts to develop an AIDS vaccine producing antibodiesto viral proteins," said Douglas Eger, chairman and CEO of SheffieldMedical Technologies Inc., in New York, "have failed owing to thehighly mutational characteristics and the genomic diversity of HIVstrains."
Sheffield funds the laboratory of noted French virologist Jean-ClaudeChermann, who is the AIDS Science paper's senior author. He headsthe retroviral research unit of INSERM (France's National Instituteof Health and Medical Research), in Marseilles.
Chermann's strategy is to turn away from viral antigens in favor of animmunogenic fragment from HIV-1's CD4 T-cell target. It's an end-run around the propensity of the virus to mutate ad infinitum, and sogenerate antigenic variants that keep several jumps ahead of currentprototype vaccines.
Because cellular proteins don't mutate so promiscuously, theyrepresent a fixed rather than a moving target for vaccine antibodies.
Beta-2 microglobulin adorns the surface of all mammalian cells.Sheffield's chief operating officer and product development director,Michael Seldin, explained to BioWorld Today what it's all about asan AIDS vaccine target:
"After an HIV-1 virion has infected its host T lymphocyte andfinished its intracellular replication cycle, making lots of new viruses,it arrives at the surface of the cell's membrane on its way to buddingout. En route, it grabs the intracellular b2m protein and bumps it upto the cell's surface."
The new virion then hijacks pieces of the dying cell's outermembrane, and wraps itself in what amounts to a second viralenvelope, decorated with the b2m epitope.
As his paper reports, Chermann's team constructed 10 syntheticpeptides from amino-acid sequences of the b2m protein, raised twoneutralizing antibodies against three of the most promising stretches,and duly blocked their HIV-1 horses from galloping on andreplicating anew.
"Chermann tested his anti-b2m monoclonal antibodies against manydifferent strains of HIV," Seldin said, "especially the Zairian one,which is the most viciously cytopathic, and was uniformlysuccessful." The French virologist said the b2m epitope is present onall HIV strains, so it could be universally effective as a vaccineagainst the highly mutational virus.
Seldin summed up: "If I stop the virus from going over to the nextcell, prevent it from budding, then the game is over."
Patents are pending on Chermann's discovery, with Sheffield asexclusive worldwide licensee.
"Following testing on animal models in the U.S.," Eger said, "weplan to file an investigational new drug application with the FDA tobegin human clinical trials." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.