Immunization against the murine malaria parasite Plasmodium yoelii using a recombinant protein with adjuvants developed for clinical use

Ling, Irene T.; Ogun, Solabomi A.; Momin, P.; Richards, Roberta L.; Garçon, Nathalie; Cohen, Joe; Ballou, W. Ripley; Holder, Anthony A.

doi:10.1016/s0264-410x(97)00076-5

Cited by 49 publications

(39 citation statements)

References 35 publications

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“…Many successful P. yoelii MSP-1 efficacy studies utilized PyMSP-1 19 fused to the glutathione S-transferase of Schistosoma japonicum formulated with a variety of adjuvants (24,50,51). Use immunized with rPfMSP1/8, PfMSP8 (⌬Asn/Asp), rPfMSP1 42 , or a mixture of PfMSP8 (⌬Asn/Asp) and rPfMSP1 42 , formulated with either Quil A or M plus CpG as the adjuvant.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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“…The successful replacement of PfMSP1 19 with PyMSP1 19 is consistent with previous observations that this domain of MSP1 has a conserved function among distantly related malaria species and demonstrates that a wide range of mutations in the primary sequence of this domain can be tol- on May 9, 2018 by guest http://iai.asm.org/ erated by the parasite (10,30). To date, trials for MSP1 19 based vaccines using the P. yoelii model have been performed in various laboratories around the world with antigens produced in different host-vector systems, formulated in different adjuvants, and administered in a variety of immunization regimens (4,8,17,23,38,41). The efficiency of these regimens in inducing protective immunity has been evaluated mostly by challenge infection studies, the outcomes of which cannot be predicted by antibody levels measured by ELISA.…”

Section: Discussionmentioning

confidence: 99%

Growth-Inhibitory Antibodies Are Not Necessary for Protective Immunity to Malaria Infection

et al. 2010

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The absence of a validated surrogate marker for the immune state has complicated the design of a subunit vaccine against asexual stages of Plasmodium falciparum. In particular, it is not known whether the capacity to induce antibodies that inhibit parasite growth in vitro is an important criterion for selection of P. falciparum proteins to be assessed in human vaccine trials. We examined this issue in the Plasmodium yoelii rodent malaria model using the 19-kDa C-terminal fragment of merozoite surface protein 1 (MSP1 19 ). To examine the relationship between inhibitory antibodies in immunized mice and the immune state, as indicated by resistance to a blood-stage challenge, we used an allelic replacement strategy to generate a transgenic P. falciparum line that expresses MSP1 19 from P. yoelii. We show that MSP1 19 is functionally conserved across these two divergent Plasmodium species, and replacing PfMSP1 19 with PyMSP1 19 has no detectable effect on parasite growth in vitro. By comparing growth rates of this transgenic line with a matched transgenic line that expresses the endogenous PfMSP1 19 , we developed an assay to measure the specific growth-inhibitory activity directed exclusively to the PyMSP1 19 protein in the sera from vaccinated animals. To validate this assay, sera from rabbits immunized with recombinant PyMSP1 19 were tested and showed specific inhibitory activity in a concentration-dependent manner. In mice that were immunized with recombinant PyMSP1 19 , the levels of PyMSP1 19 -specific inhibitory activity did not correlate with the total antibody levels measured by enzymelinked immunosorbent assay. Furthermore, they did not correlate with resistance to subsequent blood-stage infection, and some mice with complete protection showed no detectable inhibitory activity in their prechallenge sera. These data indicated that growth-inhibitory activity measured in vitro was not a reliable predictor of immune status in vivo, and the reliance on this criterion to select vaccine candidates for human clinical trials may be misplaced. The transgenic lines further offer useful tools for comparing the efficacy of MSP1 19 -based vaccines that utilize different immunization regimens and antigen formulations.

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“…The feasibility of an asexual blood-stage vaccine is supported by studies in humans and animal models (8)(9)(10)(11)(12)(13). To date, research in this field has focused on a few protein candidates including merozoite surface protein (MSP)-1 (14), MSP-2 (8), MSP-3 (15)(16)(17)(18), apical membrane Ag 1 (AMA-1) (19), erythrocyte binding Ag 175 (EBA-175) (20), glutamate-rich protein (GLURP) (15,21), and serine repeat Ag 5 (SERA5) (22).…”

mentioning

confidence: 99%

Passive Immunoprotection of Plasmodium falciparum-Infected Mice Designates the CyRPA as Candidate Malaria Vaccine Antigen

Dreyer

Matile

Papastogiannidis

et al. 2012

The Journal of Immunology

114

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An effective malaria vaccine could prove to be the most cost-effective and efficacious means of preventing severe disease and death from malaria. In an endeavor to identify novel vaccine targets, we tested predicted Plasmodium falciparum open reading frames for proteins that elicit parasite-inhibitory Abs. This has led to the identification of the cysteine-rich protective Ag (CyRPA). CyRPA is a cysteine-rich protein harboring a predicted signal sequence. The stage-specific expression of CyRPA in late schizonts resembles that of proteins known to be involved in merozoite invasion. Immunofluorescence staining localized CyRPA at the apex of merozoites. The entire protein is conserved as shown by sequencing of the CyRPA encoding gene from a diverse range of P. falciparum isolates. CyRPA-specific mAbs substantially inhibited parasite growth in vitro as well as in a P. falciparum animal model based on NOD-scid IL2Rγnull mice engrafted with human erythrocytes. In contrast to other P. falciparum mouse models, this system generated very consistent results and evinced a dose-response relationship and therefore represents an unprecedented in vivo model for quantitative comparison of the functional potencies of malaria-specific Abs. Our data suggest a role for CyRPA in erythrocyte invasion by the merozoite. Inhibition of merozoite invasion by CyRPA-specific mAbs in vitro and in vivo renders this protein a promising malaria asexual blood-stage vaccine candidate Ag.

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Immunization against the murine malaria parasite Plasmodium yoelii using a recombinant protein with adjuvants developed for clinical use

Cited by 49 publications

References 35 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

Growth-Inhibitory Antibodies Are Not Necessary for Protective Immunity to Malaria Infection

Passive Immunoprotection of Plasmodium falciparum-Infected Mice Designates the CyRPA as Candidate Malaria Vaccine Antigen

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