High-Level Expression of the Malaria Blood-Stage Vaccine Candidate
            <i>Plasmodium falciparum</i>
            Apical Membrane Antigen 1 and Induction of Antibodies That Inhibit Erythrocyte Invasion

Kocken, Clemens H. M.; Withers‐Martinez, Chrislaine; Dubbeld, Martin A.; Wel, Annemarie van der; Hackett, Fiona; Valderrama, Augusto; Blackman, Michael J.; Thomas, Alan W.

doi:10.1128/iai.70.10.5901.2002

Cited by 38 publications

(67 citation statements)

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“…From these results, we deduce that the protection-associated epitopes of CyRPA are likely to be free of sequence polymorphisms, suggesting that a CyRPA-based vaccine would target the entire P. falciparum population. This represents a clear advantage compared with polymorphic vaccine Ags like AMA-1, where several studies showed significant allele specificity in the inhibitory activity of anti-AMA-1 Abs (94)(95)(96).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…The quality of protein expression and folding had been validated previously for some of the protein constructs used by demonstrating that vaccine-induced Abs raised against the recombinant protein recognize native protein (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37); vaccine-induced Abs have functional antiparasite activity in growthinhibition assays (GIAs) or Ab-dependent cellular-inhibition (ADCI) assays (12,28,30,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43); or the recombinant protein has appropriate biological function by binding its receptor (25,28,34,35,38,39) (Supplemental Table I). Validation of WGCF as an appropriate system for expression of P. falciparum merozoite proteins has also been established in several ways.…”

Section: Expression Of Ragsmentioning

confidence: 99%

Identification and Prioritization of Merozoite Antigens as Targets of Protective Human Immunity to Plasmodium falciparum Malaria for Vaccine and Biomarker Development

Richards

Arumugam

Reiling

et al. 2013

The Journal of Immunology

216

240

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The development of effective malaria vaccines and immune biomarkers of malaria is a high priority for malaria control and elimination. Ags expressed by merozoites of Plasmodium falciparum are likely to be important targets of human immunity and are promising vaccine candidates, but very few Ags have been studied. We developed an approach to assess Ab responses to a comprehensive repertoire of merozoite proteins and investigate whether they are targets of protective Abs. We expressed 91 recombinant proteins, located on the merozoite surface or within invasion organelles, and screened them for quality and reactivity to human Abs. Subsequently, Abs to 46 proteins were studied in a longitudinal cohort of 206 Papua New Guinean children to define Ab acquisition and associations with protective immunity. Ab responses were higher among older children and those with active parasitemia. High-level Ab responses to rhoptry and microneme proteins that function in erythrocyte invasion were identified as being most strongly associated with protective immunity compared with other Ags. Additionally, Abs to new or understudied Ags were more strongly associated with protection than were Abs to current vaccine candidates that have progressed to phase 1 or 2 vaccine trials. Combinations of Ab responses were identified that were more strongly associated with protective immunity than responses to their single-Ag components. This study identifies Ags that are likely to be key targets of protective human immunity and facilitates the prioritization of Ags for further evaluation as vaccine candidates and/or for use as biomarkers of immunity in malaria surveillance and control.

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“…Sero-epidemiologic evidence [35], and the limited GIA data presented here, suggest a PfAMA-1-based vaccine may elicit allele-specific antibodies. Consequently, in addition to monovalent PfAMA-1 vaccines [14][15][16][17]21] there are also bivalent PfAMA-1 vaccines in development in an effort to broaden protective immune responses [18,19,21]. With FMP2.1/AS02A, we intend to determine if high titer antibodies elicited against sporozoite and asexual stages, as well as potent anti-PfAMA-1 cellular responses, might act against diverse alleles.…”

Section: Pfama-1 Vaccine Designmentioning

confidence: 99%

“…Immunization of New World monkeys with recombinant PfAMA-1 formulated with Freund's adjuvant has conferred significant protection against homologous P. falciparum challenge [12,13], but limited protection when formulated with adjuvants intended for human use such as Montanide or AS02A [Barnwell, unpublished]. Several PfAMA-1 vaccines are in development, but none have been tested for clinical efficacy [14][15][16][17][18][19][20]. A recent Phase I clinical trial of a recombinant PfAMA-1 antigen adjuvanted with alhydrogel showed that this formulation elicited functional antibodies that, after affinity purification, exhibited growth inhibition of P. falciparum in vitro [21].…”

Section: Introductionmentioning

confidence: 99%

Phase I dose escalation safety and immunogenicity trial of Plasmodium falciparum apical membrane protein (AMA-1) FMP2.1, adjuvanted with AS02A, in malaria-naïve adults at the Walter Reed Army Institute of Research

Polhemus¹,

Magill²,

Cummings³

et al. 2007

Vaccine

130

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We report the first safety and immunogenicity trial of the Plasmodium falciparum vaccine candidate FMP2.1/AS02A, a recombinant E. coli-expressed protein based upon the apical membrane antigen-1 (AMA-1) of the 3D7 clone formulated with the AS02A adjuvant. We conducted an open-label, staggered-start, dose-escalating Phase I trial in 23 malaria-naïve volunteers who received 8, 20 or 40 g of FMP2.1 in a fixed volume of 0.5 mL of AS02A on a 0, 1, and 2 month schedule. Nineteen of 23 volunteers received all three scheduled immunizations. The most frequent solicited local and systemic adverse events associated with immunization were injection site pain (68%) and headache (29%). There were no significant laboratory abnormalities or vaccine-related serious adverse events. All volunteers seroconverted after second immunization as determined by ELISA. Immune sera recognized sporozoites and merozoites by immunofluorescence assay (IFA), and exhibited both growth inhibition and processing inhibition activity against homologous (3D7) asexual stage parasites. Post-immunization, peripheral blood mononuculear cells exhibited FMP2.1-specific lymphoproliferation and IFN-␥ and IL-5 ELISPOT assay responses. This is the first PfAMA-1-based vaccine shown to elicit both potent humoral and cellular immunity in humans. Encouraged by the potential of FMP1/AS02A to target host immunity against PfAMA-1 that is known to be expressed by sporozoite, hepatic and erythrocytic stages, we have initiated field trials of FMP2.1/AS02A in an endemic population in the Republic of Mali.

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High-Level Expression of the Malaria Blood-Stage Vaccine Candidate Plasmodium falciparum Apical Membrane Antigen 1 and Induction of Antibodies That Inhibit Erythrocyte Invasion

Cited by 38 publications

References 0 publications

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

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

Identification and Prioritization of Merozoite Antigens as Targets of Protective Human Immunity to Plasmodium falciparum Malaria for Vaccine and Biomarker Development

Phase I dose escalation safety and immunogenicity trial of Plasmodium falciparum apical membrane protein (AMA-1) FMP2.1, adjuvanted with AS02A, in malaria-naïve adults at the Walter Reed Army Institute of Research

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