Using Reference Quantitative Polymerase Chain Reaction to Assess the Clinical Performance of the Paracheck-Pf® Rapid Diagnostic Test in a Field Setting in Uganda

Mitran, Catherine J.; Mbonye, Anthony K.; Hawkes, Michael; Yanow, Stephanie K.

doi:10.4269/ajtmh.18-0112

Cited by 3 publications

(2 citation statements)

References 17 publications

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“…Serum samples from 50 unexposed individuals living in Medellín, Colombia, were also collected and used as negative controls. In Bugiri, Uganda, plasma samples were collected from individuals over 1 year of age who presented to the clinic with suspected malaria, as part of another study (72). The samples used in this study were collected from male children and multigravid women, who were pregnant at the time of collection.…”

Section: Methodsmentioning

confidence: 99%

Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity betweenPlasmodium vivaxPvDBP andPlasmodium falciparumVAR2CSA

Mitran

Mena

Gnidehou

et al. 2019

mBio

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Many pathogens evolve extensive genetic variation in virulence proteins as a strategy to evade host immunity. This poses a significant challenge for the host to develop broadly neutralizing antibodies. In Plasmodium falciparum, we show that a mechanism to circumvent this challenge is to elicit antibodies to cryptic epitopes that are not under immune pressure. We previously discovered that antibodies to the Plasmodium vivax invasion protein, PvDBP, cross-react with P. falciparum VAR2CSA, a distantly related virulence factor that mediates placental malaria. Here, we describe the molecular mechanism underlying this cross-species immunity. We identified an epitope in subdomain 1 (SD1) within the Duffy binding-like (DBL) domain of PvDBP that gives rise to cross-reactive antibodies to VAR2CSA and show that human antibodies affinity purified against a synthetic SD1 peptide block parasite adhesion to chondroitin sulfate A (CSA) in vitro. The epitope in SD1 is subdominant and highly conserved in PvDBP, and in turn, SD1 antibodies target cryptic epitopes in P. falciparum VAR2CSA. The epitopes in VAR2CSA recognized by vivax-derived SD1 antibodies (of human and mouse origin) are distinct from those recognized by VAR2CSA immune serum. We mapped two peptides in the DBL5ε domain of VAR2CSA that are recognized by SD1 antibodies. Both peptides map to regions outside the immunodominant sites, and antibodies to these peptides are not elicited following immunization with VAR2CSA or natural infection with P. falciparum in pregnancy, consistent with the cryptic nature of these target epitopes. IMPORTANCE In this work, we describe a molecular mechanism of heterologous immunity between two distant species of Plasmodium. Our results suggest a mechanism that subverts the classic parasite strategy of presenting highly polymorphic epitopes in surface antigens to evade immunity to that parasite. This alternative immune pathway can be exploited to protect pregnant women from falciparum placental malaria by designing vaccines to cryptic epitopes that elicit broadly inhibitory antibodies against variant parasite strains.

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Section: Methodsmentioning

confidence: 99%

Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity betweenPlasmodium vivaxPvDBP andPlasmodium falciparumVAR2CSA

Mitran

Mena

Gnidehou

et al. 2019

mBio

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“…West-African countries including Monrovia (43) , Mali (44) and Nigeria (45) , as well as other African countries, including Zimbabwe (46) , Uganda (47) , Malawi (48) , Ethiopia (49) , and Tanzania (50) . The most cited reasons for this phenomenon included, but were not limited to, variations in geo-demographics of the clinical population (33)(34)(35) , and impact of experience microscopy (38).…”

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confidence: 99%

Clinical Utility of Monobiomaker-Based Malaria Rapid Diagnostic Test Kits at a Military Medical Centre in Ghana: An Exploration Pilot Study

Hamid

Yovelanywe

Frimpomaa

et al. 2023

Preprint

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Background: Proliferation of non-falciparum species of plasmodium into predominant falciparum populations compromises the utility of monobiomaker based malaria Rapid Diagnostic Test (mRDT). This study evaluated the validity of a mono-biomarker based Carestart®) and Paracheck™ mRDTs in use at a Military Medical Centre in Ghana. Methodology: The study was designed to assess the validity of named mRDTs in a setting in Ghana. Blood samples collected from a consecutive series of 207 febrile patients in the months of June and July 2020, were tested for malaria parasites, using the mRDTs and microscopy as the gold standard. Prevalence, validity, and reliability metrics were determined using Frequentist, Receiver Operating Characteristics (ROC), and Kappa statistics, respectively. Results: The prevalence was 23.2% and 12.3% using microscopy and candidate mRDT, respectively. Sensitivities and specificities were 53.2% and 98.1% (Carestart®), 45.8% and 99.4% (Paracheck), respectively. Neither ROC analysis showed a significant disparity between mRDTs (Carestart®: AUROC=0.75 vs Paracheck™: AUROC=0.73), nor the reliability index showed disagreement between both mRDTs (Cronbach’s α = 0.92). But there was significant disagreement between microscopy and mRDTs (Carestart®: Kappa=0.58 vs Paracheck™: Kappa=0.55). Conclusion: The use of a monobiomaker mRDTs in this study led to a significant variation between the ‘internal’ and ‘ecological’ validity metrics. Averagely, 84% mRDT false negatives was non-falciparum. It is therefore, critical to accelerate the implementation of WHO’s recommendation to switch from mono to multiple biomarker (s)-based mRDTs for detecting both falciparum and non-falciparum species. Extended research is needed to consolidate our understanding of the dynamics of malaria among our military personnel exposed to non-falciparum plasmodium.

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Investigation of the immunological cross-reactivity between Plasmodium vivax Duffy Binding Protein and Plasmodium falciparum VAR2CSA for vaccine development

Mitran¹

2021

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Using Reference Quantitative Polymerase Chain Reaction to Assess the Clinical Performance of the Paracheck-Pf® Rapid Diagnostic Test in a Field Setting in Uganda

Cited by 3 publications

References 17 publications

Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity betweenPlasmodium vivaxPvDBP andPlasmodium falciparumVAR2CSA

Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity betweenPlasmodium vivaxPvDBP andPlasmodium falciparumVAR2CSA

Clinical Utility of Monobiomaker-Based Malaria Rapid Diagnostic Test Kits at a Military Medical Centre in Ghana: An Exploration Pilot Study

Investigation of the immunological cross-reactivity between Plasmodium vivax Duffy Binding Protein and Plasmodium falciparum VAR2CSA for vaccine development

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