Human CD4+ T Cells Induced by Synthetic Peptide Malaria Vaccine Are Comparable to Cells Elicited by AttenuatedPlasmodium falciparumSporozoites

Abstract

Peptide vaccines containing minimal epitopes of protective Ags provide the advantages of low cost, safety, and stability while focusing host responses on relevant targets of protective immunity. However, the limited complexity of malaria peptide vaccines raises questions regarding their equivalence to immune responses elicited by the irradiated sporozoite vaccine, the “gold standard” for protective immunity. A panel of CD4+ T cell clones was derived from volunteers immunized with a peptide vaccine containing minimal T and B cell epitopes of the Plasmodium falciparum circumsporozoite protein to compare these with previously defined CD4+ T cell clones from volunteers immunized with irradiated P. falciparum sporozoites. As found following sporozoite immunization, the majority of clones from the peptide-immunized volunteers recognized the T* epitope, a predicted universal T cell epitope, in the context of multiple HLA DR and DQ molecules. Peptide-induced T cell clones were of the Th0 subset, secreting high levels of IFN-γ as well as variable levels of Th2-type cytokines (IL-4, IL-6). The T* epitope overlaps a polymorphic region of the circumsporozoite protein and strain cross-reactivity of the peptide-induced clones correlated with recognition of core epitopes overlapping the conserved regions of the T* epitope. Importantly, as found following sporozoite immunization, long-lived CD4+ memory cells specific for the T* epitope were detectable 10 mo after peptide immunization. These studies demonstrate that malaria peptides containing minimal epitopes can elicit human CD4+ T cells with fine specificity and potential effector function comparable to those elicited by attenuated P. falciparum sporozoites.

A Linear Peptide Containing Minimal T- and B-Cell Epitopes ofPlasmodium falciparumCircumsporozoite Protein Elicits Protection against Transgenic Sporozoite Challenge

“…The fine specificity and function of CD4 ϩ -T-cell clones derived from the (T1BT*) 4 -P3C-immunized volunteers were comparable to those of clones derived from volunteers immunized with irradiated P. falciparum sporozoites (7,36). Consistent with the broad genetic restriction of the universal T-cell epitope, the majority of CD4 ϩ T cells in both the peptide-and sporozoite-immunized volunteers were specific for the T* epitope, with few clones recognizing the CS repeat epitopes.…”

“…This branched peptide elicited antisporozoite antibodies and CD4 ϩ T cells with fine specificity and function comparable to those found in volunteers immunized by irradiated P. falciparum sporozoites (7,36). In the current studies, a 48-mer linear peptide containing these minimal P. falciparum CS T-and B-cell epitopes was as immunogenic as a branched peptide when tested in inbred strains of mice and outbred nonhuman primates.…”

“…The T1 Th epitope, in contrast to the T* universal epitope, is recognized by only a limited number of HLA class II genotypes in mice and humans (6,38,43). While the mechanism by which universal epitopes overcome peptide configuration requirements remains to be defined, the presence of multiple overlapping T-cell epitopes within the universal T* epitope (6,7,36) may elicit a broad range of Th cells to enhance the immunogenicity of linear peptides.…”

Pre-Erythrocytic Vaccine Candidates in Malaria

“…The immunized volunteers developed T*-speciic Th1-type CD + T cell responses. CD + T cell clones derived from P"MC up to 10 months after peptide immunization recognized the T* epitope in the context of multiple HL" DR and DQ molecules and secreted high levels of IFN-γ and variable levels of TNF-α [111]. The immunized volunteers in this study were not challenged.…”

Protective immunity to pre-erythrocytic stage malaria

“…The Pf CS protein has N and C terminal regions which flank a central repeat region consisting of 38 to 40 copies of the B cell epitope NANP, preceded by a minor central repeat sequence of alternating NVDP and NANP. Several CD4 and CD8 T cell epitopes have been mapped to the C terminus of the CS protein, and some of these are universal epitopes [19][20][21][22]. Currently, there are also extensive efforts to identify additional sporozoite proteins [23][24][25].…”