Cryo-EM structure of
            <i>P. falciparum</i>
            circumsporozoite protein with a vaccine-elicited antibody is stabilized by somatically mutated inter-Fab contacts

Oyen, David; Torres, Jonathan L.; Cottrell, Christopher A.; King, C. Richter; Wilson, Ian A.; Ward, Andrew B.

doi:10.1126/sciadv.aau8529

Cited by 67 publications

(131 citation statements)

References 47 publications

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“…The overall slower dissociation rate from NANP compared to the N-terminal junction peptides suggests that NANP affinity rather than NVDP-or NPDP-binding drove the selection of these antibodies in the human host (Batista and Neuberger, 1998;Foote and Eisen, 2000;Victora and Nussenzweig, 2012). The observed accumulation of class-switched IGHV3-33-, IGKV1-5-encoded cross-reactive antibodies with somatic mutations that are known to increase NANP affinity either directly or indirectly through homotypic antibody interactions provides additional support for this hypothesis Murugan et al, 2018;Oyen et al, 2018).…”

Section: Discussionmentioning

confidence: 91%

Evolution of protective human antibodies against Plasmodium falciparum circumsporozoite protein repeat motifs

Murugan

Scally

Costa

et al. 2019

Preprint

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Circumsporozoite protein of the human malaria parasite Plasmodium falciparum (PfCSP) is the main target of antibodies that prevent the infection and disease. Protective antibodies recognize the central PfCSP domain, but our understanding of how parasite inhibition is associated with recognition of this domain and with the evolution of potent antibodies remains scattered. Here, we characterized the epitope specificity of 200 human monoclonal PfCSP antibodies. We show that the majority of PfCSP antibodies bind to NANP and NANP-like motifs with different preferences and define the molecular basis for recognition. Epitope cross-reactivity evolved with increasing antibody affinity around a conserved (N/D)P-NANP-N(V/A) core. High affinity to this motif, but not binding to NANP-like motifs, was associated with parasite inhibition and protection. Thus, NANP drives the development of potent PfCSP antibodies independently of their cross-reactivity profile, a finding with direct implications for the design of a second-generation PfCSP-based malaria vaccine. KEYWORDS Plasmodium falciparum, malaria vaccine, circumsporozoite protein, human antibodies, crystal structures, clonal selection, affinity maturation HIGHLIGHTS • The majority of human PfCSP antibodies recognize multiple epitopes • NANP affinity maturation drives the evolution of cross-reactive PfCSP antibodies • Preferential PfCSP antibody binding to a conserved core motif • High affinity not epitope specificity is associated with PfCSP antibody potency

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Section: Discussionmentioning

confidence: 91%

Evolution of protective human antibodies against Plasmodium falciparum circumsporozoite protein repeat motifs

Murugan

Scally

Costa

et al. 2019

Preprint

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“…The finding that CSP Repeat can be bound avidly by B cells from a range of immunoglobulin gene families suggested that there may be high numbers of precursors for this domain (12, 13, 24, 25). More suggestively, we and others have shown that the CSP repeat can be bound by 6 or more specific antibodies (12, 24, 26, 27), and it has been demonstrated that the repeat can crosslink multiple BCRs to enhance B cell signalling (28). Accordingly, we tested the roles of these factors in driving the dominance of the Ab response against the CSP Repeat and determined if we could manipulate the immunodominance hierarchy to develop better vaccination protocols.…”

Section: Introductionmentioning

confidence: 66%

Avid binding by B cells to thePlasmodiumcircumsporozoite protein repeat suppresses responses to protective subdominant epitopes

Lewis

Chatterjee

Kaczmarski

et al. 2020

Preprint

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18Antibodies targeting the NANP/NVDP repeat domain of the Plasmodium falciparum 19 circumsporozoite protein (CSPRepeat) can confer protection against malaria. However, it has 20 also been suggested that this repeat domain exists as a decoy that distracts the immune 21 system from mounting protective responses targeting other domains of CSP. Here we show 22 that B cell responses to the repeat domain are indeed ~10 fold higher than responses to the N-23 and C-terminal regions of CSP after sporozoite immunization. We investigated the role of 24 the number of CSPRepeat-specific naïve precursor B cells and high avidity binding by B cells 25 in driving the immunodominance of the CSPRepeat. Using adoptive transfer of germline 26 precursors specific for the CSPRepeat, we found that increasing precursor number did indeed 27 increase the responses to the repeat region, but not to the detriment of responses to other 28 epitopes. To investigate the role of avid binding by B cells to the CSPRepeat in driving 29 immunodominance we generated CSP9: a truncated CSP molecule with just 9 NANP repeats. 30

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“…These mutations in the IGHV3-33 gene commonly encode for S32N and V55I mutations at the protein level (Figure 1F). Structural analysis of a potent repeat binding antibody (mAb311) that carries both these mutations in the IGHV3-33 heavy chain has shown that these residues are important for binding to PfCSP 22 further suggesting that these antibodies are under selection. Collectively, our data are consistent with specific PfCSP-binding memory cells being initially primed at V1, and then responding robustly in a secondary response to PfSPZ; however, on subsequent boosting these cells become eliminated, exhausted or limited in their expansion.…”

Section: Resultsmentioning

confidence: 99%

Antibody feedback limits the expansion of cognate memory B cells but drives the diversification of vaccine-induced antibody responses

et al. 2019

Preprint

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23Generating sufficient antibody to block infection is a key challenge for vaccines against malaria. 24Here we show that antibody titres to a key target, the repeat region of the Plasmodium 25 falciparum circumsporozoite protein (PfCSP), plateaued after two immunizations in a clinical 26 trial of the radiation-attenuated sporozoite vaccine. To understand the mechanisms limiting 27 vaccine responsiveness, we developed Ig-knockin mice with elevated numbers of PfCSP-binding 28 B cells. We determined that recall responses were inhibited by antibody feedback via epitope 29 masking of the immunodominant PfCSP repeat region. Importantly, the amount of antibody that 30 prevents boosting is below the amount of antibody required for protection. Finally, while 31 antibody feedback limited responses to the PfCSP-repeat region in vaccinated volunteers, 32 potentially protective subdominant responses to C-terminal regions did expand with subsequent 33 boosts. These data suggest that antibody feedback drives the diversification of immune responses 34 and that vaccination for malaria will require the targeting of multiple antigens. 35 36 6 . Anti-(NANP)n repeat responses saturate after 2 immunizations and a booster at 18 months 55 provides only a modest increase in antibody and protection 4, 5, 6, 7 . 56 57 An alternative vaccine approach has been to develop an attenuated whole parasite vaccine using 58 radiation attenuated P. falciparum sporozoites (PfSPZ) 8 . This vaccine confers sterile protection 59 in malaria-naïve individuals for ~1 year which is thought to be mediated largely by T cells in the 60 liver 8, 9, 10, 11 . However, there is also evidence that PfSPZ Vaccine-induced antibodies may have 61 some short-term protective role and utility as a correlate of protection 8, 10 . 62 63 Given the limited capacity of these current malaria vaccine approaches to induce sustained 64 antibody mediated protection, it is critical to determine the mechanisms underlying B cell 65 responses to Plasmodium sporozoites and PfCSP in particular 12, 13, 14, 15 . Analysis of antibody 66 titer, breadth and single cell antigen specific B cell responses to RTS,S and PfSPZ vaccines in 67 humans provides critical hypothesis generating data for developing mouse models to establish 68 mechanisms 8, 10, 16, 17, 18 . Here we show that following immunization with PfSPZ Vaccine in 69 humans, B cells lose responsiveness after 2 vaccinations. To dissect the mechanism of this non-70 responsiveness in vivo, we developed Ig-knockin mice specific for PfCSP that facilitate tracking 71 of the B cell responses to PfCSP. The data reported herein show that the lack of B cell boosting 72 was mediated by antibody feedback by repeat-specific antibodies. However, boosting led to the 73 emergence of subdominant epitopes and increased the diversity of the antibody response over 74 time. This suggests that effective vaccination may depend on inducing responses to a diverse 75 range of protective epitopes. 76Analysis of the antibody sequences revealed that the level ...

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Cryo-EM structure of P. falciparum circumsporozoite protein with a vaccine-elicited antibody is stabilized by somatically mutated inter-Fab contacts

Abstract: An unprecedented spiral structure of the malarial CSP protein in complex with a protective antibody is revealed by cryo-EM.

Cited by 67 publications

References 47 publications

Evolution of protective human antibodies against Plasmodium falciparum circumsporozoite protein repeat motifs

Evolution of protective human antibodies against Plasmodium falciparum circumsporozoite protein repeat motifs

Avid binding by B cells to thePlasmodiumcircumsporozoite protein repeat suppresses responses to protective subdominant epitopes

Antibody feedback limits the expansion of cognate memory B cells but drives the diversification of vaccine-induced antibody responses

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