Antibody responses to a synthetic peptide‐based malaria vaccine candidate: influence of sequence variants of the peptide

Abstract

A synthetic peptide (Asn-Ala-Asn-Pro)3, representing a protective sequence from the sporozoite stage of Plasmodium falciparum, conjugated to tetanus toxoid has undergone clinical testing. Although some protection was obtained, anti-parasite responses were generally low. In attempting to improve the anti-parasite protein antibody response, we evaluated the efficacy of tetanus toxoid conjugates containing seven sequence variants of the peptide. Most of the conjugates tested in both mice and monkeys elicited anti-peptide antibodies with fine specificity differences, although there was a broad degree of cross-reactivity. In general, each conjugate tested evoked similarly high anti-sporozoite antibody responses in both species and, thus, based on antibody titer no evidence for a superior vaccine candidate was obtained. The biological activity of one antiserum actually increased the penetration of sporozoites into human liver cells. In contrast, antisera against the other conjugates inhibited sporozoite penetration, but to a similar degree. Based on these two criteria, none of the other conjugates would appear to be better vaccine candidates than the original conjugate. The lack of concordance between anti-peptide or anti-sporozoite titers and inhibitory activity in the case of one antiserum indicates that these two measures of antibody cannot always be used for predicting anti-sporozoite activity.

Synthesis, Conformational Properties, and Immunogenicity of a Cyclic Template-Bound Peptide Mimetic Containing an NPNA Motif from the Circumsporozoite Protein ofPlasmodiumfalciparum

“…The key issue in this case was to create a constrained and conformationally defined peptide that can elicit antibodies able to bind the parasite. Both linear and cyclic peptides containing multiple NPNA-motifs have been shown already to act in this way, ,,, albeit with varying levels of effectiveness, but their preferred conformations are less well defined. An improved understanding of the secondary structure of the repeat region, and its sequence dependence, might be useful for the design of more effective synthetic malaria vaccines.…”

“…Improved immunogenicity can be expected by conjugation to a carrier containing multiple T-cell epitopes. It was noted earlier, , that the fine specificity of antibodies to the repeat sequence of the CS protein could be manipulated by using sequence variants of (NANP) n . In particular, the major epitopes in the repeat region on the parasite seem from serological studies − to encompass at least two or three NANP repeats.…”

Identification of the MAGE-1 gene product by monoclonal and polyclonal antibodies.

“…A similar approach has been used to generate mAbs and polyclonal antibodies toward various viral (e.g., refs. 11 and 12), parasitic (13), and cellular proteins (e.g., refs. 14-18).…”