A Totally Synthetic Polyoxime Malaria Vaccine Containing Plasmodium falciparum B Cell and Universal T Cell Epitopes Elicits Immune Responses in Volunteers of Diverse HLA Types

Abstract

This open-labeled phase I study provides the first demonstration of the immunogenicity of a precisely defined synthetic polyoxime malaria vaccine in volunteers of diverse HLA types. The polyoxime, designated (T1BT*)4-P3C, was constructed by chemoselective ligation, via oxime bonds, of a tetrabranched core with a peptide module containing B cell epitopes and a universal T cell epitope of the Plasmodium falciparum circumsporozoite protein. The triepitope polyoxime malaria vaccine was immunogenic in the absence of any exogenous adjuvant, using instead a core modified with the lipopeptide P3C as an endogenous adjuvant. This totally synthetic vaccine formulation can be characterized by mass spectroscopy, thus enabling the reproducible production of precisely defined vaccines for human use. The majority of the polyoxime-immunized volunteers (7/10) developed high levels of anti-repeat Abs that reacted with the native circumsporozoite on P. falciparum sporozoites. In addition, these seven volunteers all developed T cells specific for the universal epitope, termed T*, which was originally defined using CD4+ T cells from protected volunteers immunized with irradiated P. falciparum sporozoites. The excellent correlation of T*-specific cellular responses with high anti-repeat Ab titers suggests that the T* epitope functioned as a universal Th cell epitope, as predicted by previous peptide/HLA binding assays and by immunogenicity studies in mice of diverse H-2 haplotypes. The current phase I trial suggests that polyoximes may prove useful for the development of highly immunogenic, multicomponent synthetic vaccines for malaria, as well as for other pathogens.

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

“…The immunodominance of T*-specific T cell clones, and the limited repeat-specific responses, are consistent with the fine specificity noted with PBMCs (6). PBMC from these seven volunteers all responded to T* stimulation, and PBMC of only one volunteer (09) gave a positive response to a CS repeat epitope.…”

“…Although DRB1* 0701-restricted clones were isolated from a sporozoite-immunized volunteer (9) and soluble DRB5*0101 (DR51) can bind T* peptide in vitro (10), these DR molecules were not used as restriction elements by T*-specific clones from donors expressing these alleles (volunteers 04, 09, and 10) (Table III) (6). Overall there was a pattern of allelic dominance of DR 4 molecules in the presentation of the T* peptide.…”

“…A synthetic Plasmodium falciparum peptide vaccine, termed (T1BT*) 4 -N-palmitoyl-S-(2,3-bis(palmitoyloxy)-(2RS)-propyl)-(R)-cysteinyl) (P3C), 4 comprised of repetitive B cell epitopes and a universal T cell epitope from the circumsporozoite (CS) protein, was shown in a phase I trial to elicit anti-repeat Ab titers comparable in magnitude to those observed following sporozoite immunization (6). The CS repeat region is a target of protective Abs that inhibit sporozoite infectivity by immobilizing the parasite and blocking invasion of host cells (1,7).…”

Effect of muramyl dipeptide and alum adjuvants on immunization with Filarial multi antigen peptide vaccine in mice model

“…A new approach in vaccine technology is using recombinant protein subunits as peptide vaccines. Synthetic peptide vaccines and B-T cell chimera's containing immunodominant regions from antigens have been developed for malaria (Nardin et al, 2001), Schistosomiasis (Arnon et al, 2000) and many other viral and parasitic diseases. Thioredoxin and transglutaminase, though being reported as promising vaccine candidates cannot be used as whole antigen due to the homology that it shares with host proteins (Kunchithapautham et al, 2003;Vanam et al, 2009;Madhumathi et al, 2010).…”

Toll-Like Receptor 2 Ligands as Adjuvants for Human Th1 Responses

“…Synthetic lipopeptides comprising the active portion of bacterial lipoproteins as well as other TLR ligands are increasingly being used as adjuvants in animal vaccine models (13,14), have been shown to be safe in human vaccine trials for HIV (15) and stimulate immunity against malaria (16) and hepatitis B virus (17) in human volunteers. However, the mechanism of TLR-mediated adjuvant function is not fully characterized.…”