AIDSWEEKLY Plus, Monday, 22 September 1997
Daniel J. DeNoon, Senior Editor
Vaccines that efficiently elicit T-cell mediated immune responses can be created via genetic, enzymatic, and/or chemical engineering.
These various approaches create immunogenic chimeric molecules by combining T-cell antigens with self molecules.
"Viral peptides delivered by chimeric self molecules are more immunogenic than peptides alone and can induce a strong cellular immune response in vitro and in vivo," said Constatin A. Bona of the Mt. Sinai School of Medicine, New York.
Bona described the approach in an address to the first annual International Society for Vaccines Symposium on Vaccinology, held September 8-11, 1997, in Leesburg, Virginia.
Bona noted that high-efficiency stimulation of T cells occurs when antigen-presenting cells (APCs) internally process antigens and then present them on their surfaces in association with major histocompatibility complex (MHC) molecules.
To bypass this process and directly bind to the surface of APCs, Bona and colleagues developed an "antigenized antibody vaccine." The antigen for such a vaccine is a genetically engineered molecule combining immunoglobulin (Ig) with a peptide antigen.
A chimeric Ig-antigen incorporating the influenza HA peptide was 400 times more efficient than the synthetic peptide alone, Bona said.
But an even more efficient antigen could be created by using a series of bioactive enzymes to covalently couple the antigen to the sugar moiety of an Ig molecule.
"Six peptides can be attached to IgG, 10 peptides can be attached to IgM, and 40 peptides can be attached to IgA," Bona reported.
The best enzymatically engineered chimera tested to date was IgG2b-gal-HA, which was 10 times more antigenic than genetically engineered Ig-HA. Bona described experiments in which this IgG-glycopeptide conjugate (IGP) stimulated T cells after binding to killed APCs, suggesting that it binds directly to the APC surface.
"Peptide presented by IGP is not released by serum proteases but is presented to MHC class II molecules," Bona said. "IGP could be used in T-cell vaccines or for delivery of antagonist peptides as immunotherapeutic agents in autoimmune diseases."
Extension of this approach led to chemical engineering of MHC class II molecules covalently linked to T-cell antigens. Bona suggested that this approach could be used to develop T- cell vaccines or, in higher doses, to induce tolerance to self antigens as a therapy for autoimmune disease.
"I think the major development in humans is to find promiscuous epitopes because of the proliferation of HLA [human leukocyte antigen] types," Bona noted.
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