Can growth inhibition assays (GIA) predict blood-stage malaria vaccine efficacy?

Duncan, Christopher; Hill, Adrian V. S.; Ellis, Ruth D.

doi:10.4161/hv.19712

Cited by 72 publications

(74 citation statements)

References 105 publications

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“…While a measure of antibody function would be valuable, the lack of robust assays has limited the inclusion of functional antibody measures to assess the contribution of antibody quality to immunity. The growth inhibition assay has yielded inconsistent results with respect to the role of growth inhibitory antibodies in protection (11,55,56). More recently, opsonic phagocytosis assays (14) and neutrophil-based antibody-dependent respiratory burst assays (13) have been developed and applied to a limited number of cohort studies with results suggesting that these assays may function as correlates of immunity.…”

Section: Discussionmentioning

confidence: 99%

Acquisition of Antibodies against Plasmodium falciparum Merozoites and Malaria Immunity in Young Children and the Influence of Age, Force of Infection, and Magnitude of Response

et al. 2015

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i Individuals in areas of Plasmodium falciparum endemicity develop immunity to malaria after repeated exposure. Knowledge of the acquisition and nature of protective immune responses to P. falciparum is presently limited, particularly for young children. We examined antibodies (IgM, IgG, and IgG subclasses) to merozoite antigens and their relationship to the prospective risk of malaria in children 1 to 4 years of age in a region of malaria endemicity in Papua New Guinea. IgG, IgG1, and IgG3 responses generally increased with age, were higher in children with active infection, and reflected geographic heterogeneity in malaria transmission. Antigenic properties, rather than host factors, appeared to be the main determinant of the type of IgG subclass produced. High antibody levels were not associated with protection from malaria; in contrast, they were typically associated with an increased risk of malaria. Adjustment for malaria exposure, using a novel molecular measure of the force of infection by P. falciparum, accounted for much of the increased risk, suggesting that the antibodies were markers of higher exposure to P. falciparum. Comparisons between antibodies in this cohort of young children and in a longitudinal cohort of older children suggested that the lack of protective association was explained by lower antibody levels among young children and that there is a threshold level of antibodies required for protection from malaria. Our results suggest that in populations with low immunity, such as young children, antibodies to merozoite antigens may act as biomarkers of malaria exposure and that, with increasing exposure and responses of higher magnitude, antibodies may act as biomarkers of protective immunity. In areas of malaria endemicity, immunity that protects from high (H)-density parasitemia and symptomatic disease develops over a number of years (1). Knowledge of the precise nature of the protective immune responses to Plasmodium falciparum, in terms of the immune mechanisms, the specific target antigens, the nature of responses, and the rate of acquisition of immunity, has been sought, and while advances have been made, our current understanding is still limited (2, 3). Past experiments involving the passive transfer of immunoglobulin from immune adults into P. falciparum-infected individuals provided strong evidence that antibodies (Abs) play an important role in mediating immunity and target the blood stages of infection (4-6). Targets of antibodies include antigens expressed by the merozoite stage of the parasite, and these antibodies function by inhibiting merozoite invasion of red blood cells and by opsonizing merozoites for uptake by phagocytes and antibody-dependent cellular inhibition (7)(8)(9)(10)(11)(12)(13)(14).An important approach for identifying antigens as targets of protective immunity in humans is to assess the acquisition of antibodies and the association between antigen-specific responses and protection from symptomatic malaria in malariaexposed populations (3), particularly in lo...

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Section: Discussionmentioning

confidence: 99%

Acquisition of Antibodies against Plasmodium falciparum Merozoites and Malaria Immunity in Young Children and the Influence of Age, Force of Infection, and Magnitude of Response

et al. 2015

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“…The disappointing results of a number of blood-stage vaccine trials has raised the concern of whether the in vitro invasion inhibition assay or GIA has any correlation with clinical protection or could predict vaccine efficacy in humans (47). Unfortunately, only a few blood-stage antigens have been tested in field efficacy trials.…”

Section: Discussionmentioning

confidence: 99%

“…Due to the problems cited above, more studies with parasite antigens that induce potent strain-transcending invasion inhibition are thus required to validate the correlation of in vitro invasion-inhibitory activity with clinical protection in humans. It would thus be beneficial to validate the in vitro invasion inhibitory assay or GIA with in vivo controlled human malaria infection (CHMI) studies using either a sporozoite or blood-stage challenge model (47). However, the in vitro invasion-inhibitory assay or GIA remains as the only currently available laboratory assay to measure the functionality of antibodies to inhibit erythrocyte invasion by Plasmodium merozoites.…”

Section: Discussionmentioning

confidence: 99%

Bacterially Expressed Full-Length Recombinant Plasmodium falciparum RH5 Protein Binds Erythrocytes and Elicits Potent Strain-Transcending Parasite-Neutralizing Antibodies

et al. 2014

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Plasmodium falciparum reticulocyte binding-like homologous protein 5 (PfRH5) is an essential merozoite ligand that binds with its erythrocyte receptor, basigin. PfRH5 is an attractive malaria vaccine candidate, as it is expressed by a wide number of P. falciparum strains, cannot be genetically disrupted, and exhibits limited sequence polymorphisms. Viral vector-induced PfRH5 antibodies potently inhibited erythrocyte invasion. However, it has been a challenge to generate full-length recombinant PfRH5 in a bacterial-cell-based expression system. In this study, we have produced full-length recombinant PfRH5 in Escherichia coli that exhibits specific erythrocyte binding similar to that of the native PfRH5 parasite protein and also, importantly, elicits potent invasion-inhibitory antibodies against a number of P. falciparum strains. Antibasigin antibodies blocked the erythrocyte binding of both native and recombinant PfRH5, further confirming that they bind with basigin. We have thus successfully produced full-length PfRH5 as a functionally active erythrocyte binding recombinant protein with a conformational integrity that mimics that of the native parasite protein and elicits potent strain-transcending parasite-neutralizing antibodies. P. falciparum has the capability to develop immune escape mechanisms, and thus, blood-stage malaria vaccines that target multiple antigens or pathways may prove to be highly efficacious. In this regard, antibody combinations targeting PfRH5 and other key merozoite antigens produced potent additive inhibition against multiple worldwide P. falciparum strains. PfRH5 was immunogenic when immunized with other antigens, eliciting potent invasion-inhibitory antibody responses with no immune interference. Our results strongly support the development of PfRH5 as a component of a combination blood-stage malaria vaccine.

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“…Their antigenic targets and protective mechanisms remain unclear, but such information is urgently needed for malaria vaccine development. Correlations between direct growth inhibition of Plasmodium blood stages in vitro, as measured in the GIA, and protection against malaria have been weak and inconsistent (reviewed in reference 16), suggesting that protective antibodies may act via other functional mechanisms. Indeed, recent studies strongly implicated the importance of opsonizing antibodies for naturally acquired immunity…”

Section: Discussionmentioning

confidence: 99%

“…However, it remains unclear which antibody mechanisms determine protection against malaria. The direct growth inhibition assay (GIA) of Plasmodium blood stages remains the most commonly used functional assay for blood-stage vaccine candidates and merozoite antigens (15,16), although whether direct growth inhibitory activity in vitro correlates with protection against clinical malaria is controversial (16).…”

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confidence: 99%

Merozoite Surface Protein 1 from Plasmodium falciparum Is a Major Target of Opsonizing Antibodies in Individuals with Acquired Immunity against Malaria

Jäschke

Coulibaly

Remarque

et al. 2017

Clin Vaccine Immunol

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Naturally acquired immunity against malaria is largely mediated by serum antibodies controlling levels of blood-stage parasites. A limited understanding of the antigenic targets and functional mechanisms of protective antibodies has hampered the development of efficient malaria vaccines. Besides directly inhibiting the growth of Plasmodium parasites, antibodies can opsonize merozoites and recruit immune effector cells such as monocytes and neutrophils. Antibodies against the vaccine candidate merozoite surface protein 1 (MSP-1) are acquired during natural infections and have been associated with protection against malaria in several epidemiological studies. Here we analyzed serum antibodies from semi-immune individuals from Burkina Faso for their potential (i) to directly inhibit the growth of P. falciparum blood stages in vitro and (ii) to opsonize merozoites and to induce the antibody-dependent respiratory burst (ADRB) activity of neutrophils. While a few sera that directly inhibited the growth of P. falciparum blood stages were identified, immunoglobulin G (IgG) from all individuals clearly mediated the activation of neutrophils. The level of neutrophil activation correlated with levels of antibodies to MSP-1, and affinity-purified MSP-1-specific antibodies elicited ADRB activity. Furthermore, immunization of nonhuman primates with recombinant full-size MSP-1 induced antibodies that efficiently opsonized P. falciparum merozoites. Reversing the function by preincubation with recombinant antigens allowed us to quantify the contribution of MSP-1 to the antiparasitic effect of serum antibodies. Our data suggest that MSP-1, especially the partially conserved subunit MSP-1 83 , is a major target of opsonizing antibodies acquired during natural exposure to malaria. Induction of opsonizing antibodies might be a crucial effector mechanism for MSP-1-based malaria vaccines.KEYWORDS P. falciparum MSP-1, opsonizing antibodies, ADRB, respiratory burst, neutrophil D espite remarkable progress over the past years, malaria remains a major global health issue, with approximately 438,000 deaths and 214 million clinical cases worldwide in 2015, most of which occur in Africa due to infection with Plasmodium falciparum (1). The emergence of multidrug-resistant parasites emphasizes the need for effective vaccines, which are currently not available (2). For vaccine development, it is important to understand protective immune mechanisms, to identify antigenic targets, and to establish robust and reliable assays measuring correlates of protection. Individuals living in regions in which malaria is endemic naturally acquire immunity against

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Can growth inhibition assays (GIA) predict blood-stage malaria vaccine efficacy?

Cited by 72 publications

References 105 publications

Acquisition of Antibodies against Plasmodium falciparum Merozoites and Malaria Immunity in Young Children and the Influence of Age, Force of Infection, and Magnitude of Response

Acquisition of Antibodies against Plasmodium falciparum Merozoites and Malaria Immunity in Young Children and the Influence of Age, Force of Infection, and Magnitude of Response

Bacterially Expressed Full-Length Recombinant Plasmodium falciparum RH5 Protein Binds Erythrocytes and Elicits Potent Strain-Transcending Parasite-Neutralizing Antibodies

Merozoite Surface Protein 1 from Plasmodium falciparum Is a Major Target of Opsonizing Antibodies in Individuals with Acquired Immunity against Malaria

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