A Protective Glycosylphosphatidylinositol-Anchored Membrane Protein of<i>Plasmodium yoelii</i>Trophozoites and Merozoites Contains Two Epidermal Growth Factor-Like Domains

Burns, James M.; Belk, Carla C.; Dunn, Patricia D.

doi:10.1128/iai.68.11.6189-6195.2000

Cited by 29 publications

(34 citation statements)

References 45 publications

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“…Merozoite surface protein 8 (MSP8) is a target of protective, vaccine-induced antibody responses in the Plasmodium yoelii rodent model of malaria (11)(12)(13). Proof-of-concept studies showed that a high level of vaccine efficacy against challenge infection with lethal P. yoelii 17XL could be achieved by immunization of mice with a multicomponent vaccine including both P. yoelii MSP1 (PyMSP1) and PyMSP8 (14,15).…”

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A Chimeric Plasmodium falciparum Merozoite Surface Protein Vaccine Induces High Titers of Parasite Growth Inhibitory Antibodies

et al. 2013

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The C-terminal 19-kDa domain of Plasmodium falciparum merozoite surface protein 1 (PfMSP1 19 ) is an established target of protective antibodies. However, clinical trials of PfMSP1 42 , a leading blood-stage vaccine candidate which contains the protective epitopes of PfMSP1 19 , revealed suboptimal immunogenicity and efficacy. Based on proof-of-concept studies in the Plasmodium yoelii murine model, we produced a chimeric vaccine antigen containing recombinant PfMSP1 19 (rPfMSP1 19 ) fused to the N terminus of P. falciparum merozoite surface protein 8 that lacked its low-complexity Asn/Asp-rich domain, rPfMSP8 (⌬Asn/ Asp). Immunization of mice with the chimeric rPfMSP1/8 vaccine elicited strong T cell responses to conserved epitopes associated with the rPfMSP8 (⌬Asn/Asp) fusion partner. While specific for PfMSP8, this T cell response was adequate to provide help for the production of high titers of antibodies to both PfMSP1 19 and rPfMSP8 (⌬Asn/Asp) components. This occurred with formulations adjuvanted with either Quil A or with Montanide ISA 720 plus CpG oligodeoxynucleotide (ODN) and was observed in both inbred and outbred strains of mice. PfMSP1/8-induced antibodies were highly reactive with two major alleles of PfMSP1 19 (FVO and 3D7). Of particular interest, immunization with PfMSP1/8 elicited higher titers of PfMSP1 19 -specific antibodies than a combined formulation of rPfMSP1 42 and rPfMSP8 (⌬Asn/Asp). As a measure of functionality, PfMSP1/8-specific rabbit IgG was shown to potently inhibit the in vitro growth of blood-stage parasites of the FVO and 3D7 strains of P. falciparum. These data support the further testing and evaluation of this chimeric PfMSP1/8 antigen as a component of a multivalent vaccine for P. falciparum malaria.

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A Chimeric Plasmodium falciparum Merozoite Surface Protein Vaccine Induces High Titers of Parasite Growth Inhibitory Antibodies

et al. 2013

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“…MSP8 was originally identified in P. yoelii as a 46-kDa protein with an N-terminal signal sequence, a C-terminal GPI anchor, and two C-terminal EGF-like domains with significant homology to the protective EGF-like domains of MSP1 19 (10). Immunization with full-length recombinant PyMSP8 (rPyMSP8) alone confers antibody-dependent protection against lethal P. yoelii 17XL malaria (10,48).…”

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Evaluation of the Immunogenicity and Vaccine Potential of Recombinant Plasmodium falciparum Merozoite Surface Protein 8

et al. 2012

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ABSTRACTThe C-terminal 19-kDa domain of merozoite surface protein 1 (MSP119) is the target of protective antibodies but alone is poorly immunogenic. Previously, using thePlasmodium yoeliimurine model, we fusedP. yoeliiMSP119(PyMSP119) with full-lengthP. yoeliimerozoite surface protein 8 (MSP8). Upon immunization, the MSP8-restricted T cell response provided help for the production of high and sustained levels of protectivePyMSP119- andPyMSP8-specific antibodies. Here, we assessed the vaccine potential of MSP8 of the human malaria parasite,Plasmodium falciparum. Distinct fromPyMSP8,P. falciparumMSP8 (PfMSP8) contains an N-terminal asparagine and aspartic acid (Asn/Asp)-rich domain whose function is unknown. Comparative analysis of recombinant full-lengthPfMSP8 and a truncated version devoid of the Asn/Asp-rich domain,PfMSP8(ΔAsn/Asp), showed that both proteins were immunogenic for T cells and B cells. All T cell epitopes utilized mapped within rPfMSP8(ΔAsn/Asp). The dominant B cell epitopes were conformational and common to both rPfMSP8 and rPfMSP8(ΔAsn/Asp). Analysis of nativePfMSP8 expression revealed thatPfMSP8 is present intracellularly in late schizonts and merozoites. Following invasion,PfMSP8 is found distributed on the surface of ring- and trophozoite-stage parasites. Consistent with a low and/or transient expression ofPfMSP8 on the surface of merozoites,PfMSP8-specific rabbit IgG did not inhibit thein vitrogrowth ofP. falciparumblood-stage parasites. These studies suggest that the further development ofPfMSP8 as a malaria vaccine component should focus on the use ofPfMSP8(ΔAsn/Asp) and its conserved, immunogenic T cell epitopes as a fusion partner for protective domains of poor immunogens, includingPfMSP119.

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“…Production and purification of rPyMSP-8 have been previously described in detail (38,40). Mice (4 -5 per group) were immunized subcutaneously with 5 g of purified rPyMSP-8 with 25 g of Quil A as adjuvant (Accurate Chemical & Scientific Corporation).…”

Section: Active Immunization and Challenge Protocolsmentioning

confidence: 99%

“…MSP-8 is another blood-stage Ag that is structurally similar to MSP-1, as both possess two related C-terminal epidermal growth factor-like domains (38,39). In previous studies using the P. yoelii model, we showed that immunization with recombinant Plasmodium yoelii MSP-8 (rPyMSP-8) protects mice against lethal malaria (38,40).…”

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Suppression of LethalPlasmodium yoeliiMalaria following Protective Immunization Requires Antibody-, IL-4-, and IFN-γ-Dependent Responses Induced by Vaccination and/or Challenge Infection

Petritus

Burns

2008

The Journal of Immunology

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Immunization with Plasmodium yoelii merozoite surface protein (PyMSP)-8 protects mice from lethal malaria but does not prevent infection. Using this merozoite surface protein-based vaccine model, we investigated vaccine- and infection-induced immune responses that contribute to protection. Analysis of prechallenge sera from rPyMSP-8-immunized C57BL/6 and BALB/c mice revealed high and comparable levels of Ag-specific IgG, but differences in isotype profile and specificity for conformational epitopes were noted. As both strains of mice were similarly protected against P. yoelii, we could not correlate vaccine-induced responses with protection. However, passive immunization studies suggested that protection resulted from differing immune responses. Studies with cytokine-deficient mice showed that protection was induced by immunization of C57BL/6 mice only when IL-4 and IFN-γ were both present. In BALB/c mice, the absence of either IL-4 or IFN-γ led to predictable shifts in the IgG isotype profile but did not reduce the magnitude of the Ab response induced by rPyMSP-8 immunization. Immunized IL-4−/− BALB/c mice were solidly protected against P. yoelii. To our surprise, immunized IFN-γ−/− BALB/c mice initially controlled parasite growth but eventually succumbed to infection. Analysis of cytokine production revealed that P. yoelii infection induced two distinct peaks of IFN-γ that correlated with periods of controlled parasite growth in intact, rPyMSP-8-immunized BALB/c mice. Maximal parasite growth occurred during a period of sustained TGF-β production. Combined, the data indicate that induction of protective responses by merozoite surface protein-based vaccines depends on IL-4 and IFN-γ-dependent pathways and that vaccine efficacy is significantly influenced by host responses elicited upon infection.

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A Protective Glycosylphosphatidylinositol-Anchored Membrane Protein ofPlasmodium yoeliiTrophozoites and Merozoites Contains Two Epidermal Growth Factor-Like Domains

Cited by 29 publications

References 45 publications

A Chimeric Plasmodium falciparum Merozoite Surface Protein Vaccine Induces High Titers of Parasite Growth Inhibitory Antibodies

A Chimeric Plasmodium falciparum Merozoite Surface Protein Vaccine Induces High Titers of Parasite Growth Inhibitory Antibodies

Evaluation of the Immunogenicity and Vaccine Potential of Recombinant Plasmodium falciparum Merozoite Surface Protein 8

Suppression of LethalPlasmodium yoeliiMalaria following Protective Immunization Requires Antibody-, IL-4-, and IFN-γ-Dependent Responses Induced by Vaccination and/or Challenge Infection

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