Diverse Antibody Responses to Conserved Structural Motifs in Plasmodium falciparum Circumsporozoite Protein

Pholcharee, Tossapol; Oyen, David; Torres, Jonathan L.; Flores-García, Yevel; Gm, Martin; Ge, González-Páez; Emerling, Daniel; Volkmuth, Wayne; Locke, Emily; Cr, King; Zavala, Fidel; Ward, A.B.; Ia, Wilson

doi:10.1016/j.jmb.2019.12.029

Cited by 33 publications

(58 citation statements)

References 68 publications

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“…CSP is one of the leading malaria vaccine antigens [12]; the magnitude of antibody responses to either full length CSP [13] or its fragments has been identified as a potential biomarker of protection [14,15]. While the role of CSP-repeat-specific antibodies has been well documented [8,13,15,16], there are conflicting data on the role of C-terminus-specific antibodies [7,14,17] and their ability to contribute to protection against infection. The method described here enables high-throughput testing and permits profiling of large samples sets even when sample volumes are limited to determine the role of epitope specificity of CSP-specific antibodies.…”

Section: Discussionmentioning

confidence: 99%

Comparison of ELISA with electro-chemiluminescence technology for the qualitative and quantitative assessment of serological responses to vaccination

Bolton¹,

Chaudhury

Dutta³

et al. 2020

Malar J

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Background: Profiling immune responses induced by either infection or vaccination can provide insight into identification of correlates of protection. Furthermore, profiling of serological responses can be used to identify biomarkers indicative of exposure to pathogens. Conducting such immune surveillance requires readout methods that are highthroughput, robust, and require small sample volumes. While the enzyme-linked immunosorbent assay (ELISA) is the classical readout method for assessing serological responses, the advent of multiplex assays has significantly increased the throughput and capacity for immunoprofiling. This report describes the development and assay performance (sensitivity, linearity of detection, requirement for multiple dilutions for each sample, intra-and inter-assay variability) of an electro-chemiluminescence (ECLIA)-based multiplex assay. Methods:The current study describes the development of a multiplex ECLIA-based assay and characterizes the sensitivity, linear range, and inter-and intra-assay variability of the ECLIA platform and its agreement with the traditional ELISA. Special emphasis was placed on potential antigenic competition when testing closely related antigens in the multiplex format. Results:Multiplexing of antigens in ECLIA provides significant practical benefits in terms of reducing sample volume requirements and experimental time. Beyond the practical advantages of multiplexing, the ECLIA provides superior assay performance when compared to the ELISA. Not only does ECLIA show good agreement with the ELISA assay, but the linear range of ECLIA is also sufficiently wide to permit single-dilution measurements of concentration without the need to do serial dilutions. The lack of antigenic competition allows the simultaneous testing of closely related antigens, such as plate antigens representing different alleles of the same protein, which can inform about cross-reactivities-or lack thereof-of serological responses.

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Section: Discussionmentioning

confidence: 99%

Comparison of ELISA with electro-chemiluminescence technology for the qualitative and quantitative assessment of serological responses to vaccination

Bolton¹,

Chaudhury

Dutta³

et al. 2020

Malar J

Self Cite

View full text Add to dashboard Cite

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“…The antibodies in this study were derived from protected volunteers in a phase 2a trial of RTS,S/AS01 seven days after the third fractional dose, as previously reported (27)(28)(29). Antibodies were selected from among expanded sequence families with a focus on prevalent IGHV families.…”

Section: Many Anti-nanp Antibodies Examined In This Study Show Potentmentioning

confidence: 99%

“…However, recent evidence suggests that anti-junction mAbs can also cross-react with the NANP repeats, and their protective capacity can be correlated with their binding promiscuity to NANP (24,25). Epitopes of anti-NANP antibodies typically contain 2-3 NPNA structural motifs, which can adopt local conformations of a type I β-turn and an Asn pseudo 310 turn (22,23,(26)(27)(28)(29)(30). Anti-NANP antibodies often utilize a germline-encoded Trp residue to interact with the Pro or Asn in the NPNA turns (29).…”

Section: Introductionmentioning

confidence: 99%

“…Epitopes of anti-NANP antibodies typically contain 2-3 NPNA structural motifs, which can adopt local conformations of a type I β-turn and an Asn pseudo 310 turn (22,23,(26)(27)(28)(29)(30). Anti-NANP antibodies often utilize a germline-encoded Trp residue to interact with the Pro or Asn in the NPNA turns (29). Additionally, some of these Abs exhibit unusual homotypic inter-Fab contacts when they simultaneously recognize the adjacent repeating epitopes on the NANP region of CSP (26,27).…”

Section: Introductionmentioning

confidence: 99%

“…Here, we characterized eight monoclonal antibodies (mAb) derived from protected volunteers who participated in a phase 2a clinical trial of RTS,S/AS01 (31) with a delayed fractional dosing regimen, and compared them with three previously published mAbs derived from the same clinical trial (28,29). Our data suggest a correlation between antibody affinity, driven by the off rate, and in vivo protection, which could serve as an important basis for subsequent characterization and engineering of anti-NANP mAbs.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structural and biophysical correlation of anti-NANP antibodies within vivoprotection againstP. falciparum

Pholcharee

Oyen

Flores-García

et al. 2020

Preprint

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The most advanced P. falciparum circumsporozoite protein (PfCSP)-based malaria vaccine, RTS,S/AS01 (RTS,S), confers partial protection but with antibody titers that wane relatively rapidly, highlighting the need to elicit more potent and durable antibody responses. Here, we elucidate crystal structures, binding affinities and kinetics, and in vivo protection of eight anti-NANP antibodies (Abs) derived from an RTS,S phase 2a trial and encoded by three different heavy-chain germline genes. The structures reinforce the importance of homotypic Fab-Fab interactions in protective Abs and the overwhelmingly dominant preference for a germline-encoded aromatic residue for recognition of the NANP motif. A number of biophysical properties were analyzed and antibody affinity correlated best with protection in an in vivo mouse model, with the more potent antibodies also recognizing epitopes with repeating secondary structural motifs of type I β- and Asn pseudo 310 turns. Such insights can be incorporated into design of more effective immunogens as well as antibodies for passive immunization.

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Live attenuated rubella vectors expressing Plasmodium falciparum circumsporozoite protein (Pf-CSP) provide a novel malaria vaccine platform in the rhesus macaque

Virnik

Zhou

Медведев

et al. 2021

Biochemical and Biophysical Research Communications

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Diverse Antibody Responses to Conserved Structural Motifs in Plasmodium falciparum Circumsporozoite Protein

Cited by 33 publications

References 68 publications

Comparison of ELISA with electro-chemiluminescence technology for the qualitative and quantitative assessment of serological responses to vaccination

Comparison of ELISA with electro-chemiluminescence technology for the qualitative and quantitative assessment of serological responses to vaccination

Structural and biophysical correlation of anti-NANP antibodies within vivoprotection againstP. falciparum

Live attenuated rubella vectors expressing Plasmodium falciparum circumsporozoite protein (Pf-CSP) provide a novel malaria vaccine platform in the rhesus macaque

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