If a certain baboon lives up to expectations, planning forhuman trials of a whole new concept in vaccines will reachConstantin Bona's drawing board in a matter of months.
Bona, a microbiologist and immunologist at New York's MountSinai Hospital, has already shown that his geneticallyengineered antigen-activating strategy works in mice.
In that demonstrator-model experiment, Bona and hisassociate, Habib Zaghouani, transfected a mouseimmunoglobulin (Ig) gene with an influenza virus subunitpeptide, recognized by T cells that help B cells make antibody.That in vivo trial, reported in last Friday's Science, found that"chimeric Ig-peptide was presented 100 to 1,000 times moreefficiently (than synthetic peptide alone), and was able toprime virus-specific T cells in vivo."
Synthetic peptides used as antigenic targets for the immuneresponse have at least three major drawbacks, Bona points out:
-- With extremely short half-lives, they disappear from thebloodstream in a few minutes.
-- Their immunogenicity is poor, at best.
-- Therefore, such antigens must be beefed up with immuneadjuvants, which have their own problems.
Since submitting his paper to Science last April, Bona has scaledup from rodents to primates. "We now have a preclinical trialin a baboon," he told BioWorld, "in which we put the V3 loop ofthe HIV gp160 viral envelope. This is a major antigenicdeterminant, to which an important fraction of people withAIDS make antibody." He melded this peptide with ahumanized Ig, in which half of the mouse antibody moleculewas replaced by the human constant region. "If it works in thebaboon," he said, "we can go very fast in humans."
"It all depends on the baboon," Bona said. He expects toevaluate its peptide-activating performance "in three months,maximum."
Farther down the road, Bona foresees cloning and expressingpeptides from tumor-associated antigens in antibodymolecules, in order to induce anti-tumor immunity againstdysfunctional mutants of tumor-suppressing P53.
Mount Sinai has applied to patent the recombinant-vaccineconcept.
It is based on the principle that the antigen-binding CDreceptors of immunoglobulin antibody molecules represent anarray of peptides as diverse as T cell epitopes.
The technique, which Bona describes as "standard, kitchen-typemolecular biology," involves isolating the DNA sequenceencoding the heavy-chain variable region of a specific antibodymolecule, replacing its D (for "diversity") segment with a 45-nucleotide sequence encoding (in the case of the mice) a helperT cell epitope of the influenza virus hemagglutinin subunit.This epitope matches a suite of that peptide's amino acidresidues, recognized by CD4-positive killer T cells.
Bona counts the advantages his recombinant vaccine has overcurrent whole virus or peptide subunit antigens:
-- Safety. It escapes the danger of an attenuated virus escapingfrom its inactivation.
-- Immunogenic. It avoids immunosuppression, caused, forexample, by some sequences of the HIV's gp160 coat, andrequires no foreign adjuvant.
-- Long life. It lasts days, as compared with typical peptidehalf-life of only minutes.
-- The transformed, chimeric Ig packs its own antigenicepitopes, which can stimulate the helper T cells, thus enhancingthe immune response.
"Antigenized recombinant Ig can be used as a universal carrierto generate immunogenic peptides," Bona concluded.
Immunologist Hildegund C. J. Ertl of the Wistar Institute inPhiladelphia sees cons as well as pros in Mount Sinai'sgenetically engineered vaccine. On the plus side, she toldBioWorld, "because peptides are so poorly immunogenic, theymake for high-dose, low-efficiency vaccines. Therefore, Bona'sconcept permits much lower doses."
But she sees two problematic aspects, one major, one minor:
-- A lot of T cell epitopes are under Ir-(immune response) genecontrol, she pointed out, to which animals and people react onthe basis of differing genetic backgrounds. So the biggestdrawback to the concept is that only a few individuals willrespond to most epitopes expressed by the chimeric Ig.
-- A lesser hindrance: Whole-virus vaccines induce a fullspectrum of immune responses against a panoply of viralantigens, whereas Bona's construct presumably elicits amonospecific response by a selected immuno-effectormechanism, she said.
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.