Ppd As A Carrier Molecule In Animals Sensitized With

Bacille Calmette-Guerin (BCG, attenuated Mycobacterium tuberculosis var. bovis, used as a vaccine against tuberculosis) has been used in the past to non-specifically enhance the immune response to antigens coinjected with it (9). In addition to this, Lachmann and coworkers originally reported (10) that mice first primed with BCG and then immunized in the absence of adjuvants with B-cell epitopes conjugated to purified protein derivative (PPD, tuberculin, currently used for diagnostic skin testing) mounted antibody responses against the B-cell epitopes; such a response was absent in mice not primed with BCG (10,11).

The same strategy was applied in our laboratory to investigate whether it was possible to enhance the immunogenicity of defined peptides from antigens of malaria parasites. A few years ago, we had shown that the immunogenicity of a synthetic polypeptide (NANP)^, reproducing the entire repetitive sequence of the Plasmodium falciparum circumsporozoite (CS) protein and envisaged as potential malaria vaccine (5), was under strict MHC control, with only mouse haplotype (H-2b) being able to recognize it as both a B- and T-cell epitope (12,13). The MHC-controlled immune response to the (NANP)^ peptide was overcome when it was coupled with carrier molecules (12). However, both the peptide alone and the peptide conjugated to the carrier required strong (Freund's) adjuvants in order to induce detectable responses.

When strains of mice of different H-2 haplotypes were first primed with BCG and then immunized with PPD-iNANP)^ conjugate in the absence of adjuvants, it was found that anti-(NANP) IgG antibodies were detectable at titers comparable with those obtained when the Freund's complete adjuvant was used. Such antibodies persisted for a long time (at least 20 weeks) and were boosted by reinjection of the conjugate (14). Furthermore, the antipeptide antibodies recognized the natural sporozoite antigen, as shown by immunofluorescence and Western blot experiments, and functionally inhibited the penetration of sporozoite into target liver cells in vitro and their further development (14). More recent data from our laboratory have shown that this model of immunization can also be applied to nonhuman primates: Indeed the same adjuvant-free carrier effect was observed in squirrel monkeys (SaimirĂ­ sciureus guyanensis) sensitized with BCG and then immunized subcutaneously with the PPD-iNANP)^ conjugate in the absence of adjuvants (15).

This model of immunization presents several advantages. First, through PPD it supplies the T-cell epitopes necessary, for a wide proportion of individuals respond to peptide vaccine candidates, and at the same time it avoids the need for adjuvants. Second, after priming with BCG, no antimycobacterial antibodies are detectable; thus one would not expect to observe the phenomenon of epitope-specific suppression, which has been supposed to have the same role in the poor reactivity to the (NANP) epitope observed in some vaccinees when tetanus toxoid was used as a carrier (16). Third, this system may not lead to a secondary immune response on the natural exposure to the microorganisms (17), but it presents the advantage of inducing substantial levels of specific antibodies lasting for long time. Finally, the main constituents for this systems of immunization, BCG and PPD, are being widely used for vaccination against tuberculosis and for skin testing, respectively, to make one think about their use in increasing the immunogenicity of peptidic constructs in humans.

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