Inability of Malaria Vaccine to Induce Antibodies to a Protective Epitope Within Its Sequence

Abstract

Saimiri monkeys immunized with a recombinant protein containing 20 copies of the nine amino acid repeat of the Plasmodium vivax circumsporozoite (CS) protein developed high concentrations of antibodies to the repeat sequence and to sporozoites, but were not protected against challenge. After intravenous injection of an immunoglobulin G3 monoclonal antibody (NVS3) against irradiated P. vivax sporozoites, four of six monkeys were protected against sporozoite-induced malaria, and the remaining two animals took significantly longer to become parasitemic. Epitope mapping demonstrated that NVS3 recognizes only four (AGDR) of the nine amino acids within the repeat region of the P. vivax CS protein. The monkeys immunized with (DRAADGQPAG)20 did not produce antibodies to the protective epitope AGDR. Thus, determination of the fine specificity of protective immune responses may be critical to the construction of successful subunit vaccines.

Enhancing humoral responses to a malaria antigen with nanoparticle vaccines that expand T fh cells and promote germinal center induction

“…Here we have made the important advance of achieving broad antibody responses using clinically relevant adjuvant materials. Previous studies using recombinant proteins or multipeptide constructs to target multiple vivax CSP regions showed evidence of immunodominance with some peptide combinations, with antibody responses focused on only a single epitope (19) or responses that failed to bind the critical protective AGDR sequence (26). Although the precise mechanism underlying NP-mediated broadening of the antibody response is the subject of further studies beyond the scope of this first report, we speculate that multivalent display of VMP001 on ICMVs may stimulate a more diverse set of naïve B cells, by allowing some lower-avidity B cells to compete for the antigen.…”

Safety and Elicitation of Humoral and Cellular Responses in Colombian Malaria-Naive Volunteers by a Plasmodium Vivax Circumsporozoite Protein–derived Synthetic Vaccine

“…Fragments N and C include functional domains (RI and RII plus) that bind to hepatocyte ligands and are involved in sporozoite invasion of the hepatocyte, [17][18][19] whereas the central repetitive domain represented by peptide R has been shown to contain B cell epitopes 16 able to induce invasion-blocking antibodies. 20 Preclinical studies conducted by our group in mice and Aotus monkeys have indicated that the synthetic peptides described are safe and immunogenic in animal models. 21,22 We report here the results of a randomized, double-blind, phase I clinical trial conducted in healthy, malaria-naive volunteers at the Malaria Vaccine and Drug Development Center in Cali, Colombia.…”

Evaluation of the Safety and Immunogenicity in Rhesus Monkeys of a Recombinant Malaria Vaccine for Plasmodium vivax with a Synthetic Toll-Like Receptor 4 Agonist Formulated in an Emulsion

“…2D to F), in particular to the AGDR motif within the type 1 repeat sequence, are thought to play an important role in protection (7,34). All monkeys generated responses to the type 1 repeat peptide.…”