Immunogenicity of Well-Characterized Synthetic<i>Plasmodium falciparum</i>Multiple Antigen Peptide Conjugates

Joshi, Manju B.; Gam, Albert A.; Boykins, Robert A.; Kumar, Sanjai; Sacci, John B.; Hoffman, Stephen L.; Nakhasi, Hira L.; Kenney, Richard T.

doi:10.1128/iai.69.8.4884-4890.2001

Cited by 28 publications

(22 citation statements)

References 46 publications

(48 reference statements)

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“…Four out of the six promiscuous peptide sequences we identified correspond to this region. In contrast, no IFN-␥ production was observed in a recent study of the immunogenicity of a series of MAP constructs representing P. falciparum MSP-1, CS, and liver stage antigen-1 epitopes (39). This study also demonstrated strong genetic restriction of these MAP immunogens in several strains of mice, including BALB/c.…”

Section: Discussionmentioning

confidence: 64%

“…The immunogenicity of the polymers was evaluated in mice in the absence of carrier molecules, as we had also hoped to be able to bypass the need for carriers and ultimately strong adjuvants. The resulting LPC immunogens were highly effective, with the resulting humoral immune response far surpassing the antibody levels previously observed for the extensively studied (NANP) 3 B-cell epitope (8,39,42,47,57). Furthermore, the ability of the LPCs to overcome genetic restriction to the (NANP) 3 B-cell epitope in BALB/c mice and the observed potential for isotype class switching and cellular recall responses add strong support for further basic and preclinical evaluation of the LPC approach for malaria vaccine development.…”

Section: Discussionmentioning

confidence: 98%

“…Nevertheless, the production of these MAPs requires very precise stoichiometry yet results in heterogeneous final products and very poor yields (2,36). The addition of cysteine residues to anchor peptides to the core matrix is a recent improvement that has facilitated the inclusion of several epitopes in MAPs, as well as the characterization of the in-process product (2,39). However, the process of developing and analyzing MAP constructs remains complex and costly compared to linear peptides.…”

Section: Discussionmentioning

confidence: 99%

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Plasmodium vivaxPromiscuous T-Helper Epitopes Defined and Evaluated as Linear Peptide Chimera Immunogens

et al. 2002

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Clinical trials of malaria vaccines have confirmed that parasite-derived T-cell epitopes are required to elicit consistent and long-lasting immune responses. We report here the identification and functional characterization of six T-cell epitopes that are present in the merozoite surface protein-1 of Plasmodium vivax (PvMSP-1) and bind promiscuously to four different HLA-DRB1‫ء‬ alleles. Each of these peptides induced lymphoproliferative responses in cells from individuals with previous P. vivax infections. Furthermore, linear-peptide chimeras containing the promiscuous PvMSP-1 T-cell epitopes, synthesized in tandem with the Plasmodium falciparum immunodominant circumsporozoite protein (CSP) B-cell epitope, induced high specific antibody titers, cytokine production, long-lasting immune responses, and immunoglobulin G isotype class switching in BALB/c mice. A linear-peptide chimera containing an allele-restricted P. falciparum T-cell epitope with the CSP B-cell epitope was not effective. Two out of the six promiscuous T-cell epitopes exhibiting the highest antipeptide response also contain B-cell epitopes. Antisera generated against these B-cell epitopes recognize P. vivax merozoites in immunofluorescence assays. Importantly, the anti-peptide antibodies generated to the CSP B-cell epitope inhibited the invasion of P. falciparum sporozoites into human hepatocytes. These data and the simplicity of design of the chimeric constructs highlight the potential of multimeric, multistage, and multispecies linear-peptide chimeras containing parasite promiscuous T-cell epitopes for malaria vaccine development.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Plasmodium vivaxPromiscuous T-Helper Epitopes Defined and Evaluated as Linear Peptide Chimera Immunogens

et al. 2002

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“…An alternative approach is the use of MAP conjugates in which distinct epitopes are chemically linked into a single molecule. Such constructs have been shown to be immunogenic, capable of inducing both humoral and cellular immune responses to Plasmodium falciparum epitopes (15). An alternative approach is to produce an Ag representing a string of select epitopes.…”

Section: Discussionmentioning

confidence: 99%

“…MAP constructs have been shown to be potent (15), but have been challenging to produce in large quantities. Linear polypeptides can be produced by recombinant techniques, thus overcoming these manufacturing concerns.…”

Section: T He Induction Of Th Lymphocytes (Htl)mentioning

confidence: 99%

A Rational Strategy to Design Multiepitope Immunogens Based on Multiple Th Lymphocyte Epitopes

Livingston

Crimi

Newman

et al. 2002

The Journal of Immunology

290

192

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Four HLA-DR-restricted HIV-derived Th lymphocyte (HTL) epitopes cross-reactive with the murine I-Ab class II molecule were used to evaluate different vaccine design strategies to simultaneously induce multiple HTL responses. All four epitopes were immunogenic in H-2b mice, demonstrating the feasibility of murine models to evaluate epitope-based vaccines destined for human use. Immunization with a pool of peptides induced responses against all four epitopes; illustrating immunodominance does not prevent the induction of balanced multispecific responses. When different delivery systems were evaluated, a multiple Ag peptide construct was found to be less efficient than a linear polypeptide encompassing all four epitopes. Further characterization of linear polypeptide revealed that the sequential arrangement of the epitopes created a junctional epitope with high affinity class II binding. Disruption of this junctional epitope through the introduction of a GPGPG spacer restored the immunogenicity against all four epitopes. Finally, we demonstrate that a GPGPG spacer construct can be used to induce HTL responses by either polypeptide or DNA immunization, highlighting the flexibility of the approach.

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Peptide Vaccines

Pütz¹

2010

Topley &Amp; Wilson's Microbiology and Microbial Infections

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Immunogenicity of Well-Characterized SyntheticPlasmodium falciparumMultiple Antigen Peptide Conjugates

Abstract: Given the emerging difficulties with malaria drug resistance and vector control, as well as the persistent lack of an effective vaccine, new malaria vaccine development strategies are needed. We used a novel methodology to synthesize and fully characterize multiple antigen peptide (

Cited by 28 publications

References 46 publications

Plasmodium vivaxPromiscuous T-Helper Epitopes Defined and Evaluated as Linear Peptide Chimera Immunogens

Plasmodium vivaxPromiscuous T-Helper Epitopes Defined and Evaluated as Linear Peptide Chimera Immunogens

A Rational Strategy to Design Multiepitope Immunogens Based on Multiple Th Lymphocyte Epitopes

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