Linkage of Exogenous T-cell Epitopes to the 19-Kilodalton Region ofPlasmodium yoeliiMerozoite Surface Protein 1 (MSP1₁₉) Can Enhance Protective Immunity against Malaria and Modulate the Immunoglobulin Subclass Response to MSP1₁₉

Abstract

The degree of protection against Plasmodium yoeliiasexual blood stages induced by immunization of mice with the 19-kDa region of merozoite surface protein 1 (MSP119) is H-2 dependent. As a strategy to improve the protection, mouse strains with disparate H-2 haplotypes were immunized with glutathioneS-transferase (GST)–MSP119 proteins including either a universal T-cell epitope from tetanus toxin (P2) or an I-Ak-restricted T-cell epitope (P8) fromPlasmodium falciparum Pf332. In H-2k mice which are poorly protected following immunization with GST-MSP119, GST-P2-MSP119 significantly improved the protection. In mice partially (H-2k/b) or well protected by GST-MSP119 (H-2d and H-2b), P2 did not further increase the protection. However, the protection of H-2k/b mice and to some extent H-2k mice was improved by immunization with GST-P8-MSP119. The magnitudes of immunoglobulin G1 (IgG1) and IgG2a responses in mice immunized with the GST-MSP119variants correlated with low peak parasitemia, indicating a protective capacity of these IgG subclasses. In H-2k mice immunized with GST-P2-MSP119, both IgG1 and IgG2a responses were significantly enhanced. The epitope P2 appeared to have a general ability to modulate the IgG subclass response since all four mouse strains displayed elevated IgG2a and/or IgG2b levels after immunization with GST-P2-MSP119. In contrast, GST-P8-MSP119induced a slight enhancement of IgG responses in H-2k/b and H-2k mice without any major shift in IgG subclass patterns. The ability to improve the protective immunity elicited by P. yoelii MSP119 may have implications for improvement of human vaccines based on P. falciparumMSP119.

Disulfide bonds in merozoite surface protein 1 of the malaria parasite impede efficient antigen processing and affect the in vivo antibody response

“…Its capacity to elicit and restimulate native antigenspecific CD4 + helper T cells may nevertheless mean that co-administration of the unstructured antigen alongside native MSP1 19 may accordingly improve the 'quality' of the T cell response in a way that would lead to faster development of higher native protein-specific antibody titers. Earlier observations have shown that the inclusion of specific T cell epitopes together with the folded protein can boost antibody responses in a rodent model of malaria [41]. Our data here suggest that coadministration of R/A and native antigen influences the antibody response to the native protein.…”

Analysis of Immunological Nonresponsiveness to the 19-Kilodalton Fragment of Merozoite Surface Protein 1 ofPlasmodium yoelii: Rescue by Chemical Conjugation to Diphtheria Toxoid (DT) and Enhancement of Immunogenicity by Prior DT Vaccination

“…This reduction in parasite burden would allow the recipient of the vaccine to survive the infection and give the recipient time to develop additional parasite-specific immune responses independent of the vaccine (14). The results presented here expand upon a previous study that expressed a GST fusion protein containing MSP1 19 with a defined T-cell epitope inserted between GST and MSP1 19 (1).…”

“…A number of studies have focused on the use of universal helper T-cell epitopes to provide help for B cells, thereby enhancing the immunogenicity of small-subunit-based vaccines (1,17,24). While conjugating B-cell epitopes (haptens) to proteins is a more classical approach to providing T-cell help (21) and one that would result in immunological responsiveness among a greater proportion of the population, some studies have suggested that prior exposure to the protein can result in a diminished response to the hapten following protein-hapten immunization (8,11,23,(26)(27)(28).…”

Epitope-Specific Regulation of Immunoglobulin Class Switching in Mice Immunized with Malarial Merozoite Surface Proteins

“…In particular, human IgG3 shares many features with mouse IgG2b. Both human IgG3 and mouse IgG2b are minor components of normal serum, bind with high affinity to Fc receptor, fix complement, are preferentially induced during Th1 immune responses, and are especially effective at mediating immunity to blood stage malaria infection (1,8,18,23,48,50,51). These observations, together with accumulating evidence that the machinery for class switch recombination is conserved between humans and mice (27), suggest that there may also be conservation of the signals required for initiation of specific Ig isotype and subclass switching and thus that information derived from mouse models may be directly applicable to studies of human B cells.…”