Concentration and avidity of antibodies to different circumsporozoite epitopes correlate with RTS,S/AS01E malaria vaccine efficacy

Dobaño, Carlota; Sanz, Héctor; Sorgho, Hermann; Dosoo, David; Mpina, Maximilian; Ubillos, Itziar; Aguilar, Ruth; Ford, Tom; Díez-Padrisa, Núria; Williams, Nana Aba; Ayestarán, Ana; Ousmane, Traore; Nhabomba, Augusto; Jairoce, Chenjerai; Waitumbi, John N.; Agnandji, Selidji Todagbé; Kariuki, Simon; Abdulla, Salim; Aponte, John J.; Mordmüller, Benjamin; Asante, Kwaku Poku; Owusu‐Agyei, Seth; Tinto, Halidou; Campo, Joseph J.; Moncunill, Gemma; Gyan, Ben; Valim, Clarissa; Daubenberger, Claudia

doi:10.1038/s41467-019-10195-z

Cited by 118 publications

(115 citation statements)

References 31 publications

(52 reference statements)

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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

View full text Add to dashboard Cite

show abstract

“…Plasmodium vivax is the second most prevalent species causing malaria in the world, occurring mainly in South and Southeast Asia, the Western Pacific, the Eastern Mediterranean, Central America, and South America [1]. Recent data estimate that 7.5 million malaria cases are caused by P. vivax Vaccines 2020, 8,190; doi:10.3390/vaccines8020190 www.mdpi.com/journal/vaccines…”

Section: Introductionmentioning

confidence: 99%

Protective Malaria Vaccine in Mice Based on the Plasmodium vivax Circumsporozoite Protein Fused with the Mumps Nucleocapsid Protein

et al. 2020

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Plasmodium vivax is the most common species of human malaria parasite found outside Africa, with high endemicity in Asia, Central and South America, and Oceania. Although Plasmodium falciparum causes the majority of deaths, P. vivax can lead to severe malaria and result in significant morbidity and mortality. The development of a protective vaccine will be a major step toward malaria elimination. Recently, a formulation containing the three allelic variants of the P. vivax circumsporozoite protein (PvCSP—All epitopes) showed partial protection in mice after a challenge with the hybrid Plasmodium berghei (Pb) sporozoite, in which the PbCSP central repeats were replaced by the VK210 PvCSP repeats (Pb/Pv sporozoite). In the present study, the chimeric PvCSP allelic variants (VK210, VK247, and P. vivax-like) were fused with the mumps virus nucleocapsid protein in the absence (NLP-CSPR) or presence of the conserved C-terminal (CT) domain of PvCSP (NLP-CSPCT). To elicit stronger humoral and cellular responses, Pichia pastoris yeast was used to assemble them as nucleocapsid-like particles (NLPs). Mice were immunized with each recombinant protein adjuvanted with Poly (I:C) and presented a high frequency of antigen-specific antibody-secreting cells (ASCs) on days 5 and 30, respectively, in the spleen and bone marrow. Moreover, high IgG titers against all PvCSP variants were detected in the sera. Later, these immunized mice with NLP-CSPCT were challenged with Pb/Pv sporozoites. Sterile protection was observed in 30% of the challenged mice. Therefore, this vaccine formulation use has the potential to be a good candidate for the development of a universal vaccine against P. vivax malaria.

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“…In contrast no relationship was observed between antibody titer and the magnitude of boosting for C-terminal antibodies at any timepoint (Figure 7F). It is notable that C-terminal antibodies have been associated with protection by the RTS, S vaccine 42, 43 . Overall these data strongly support the hypothesis that epitope masking rather than parasite clearance of Fc mediated immune regulator mechanisms account for antibody feedback not only in the mouse model but also in vaccinated individuals.…”

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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Concentration and avidity of antibodies to different circumsporozoite epitopes correlate with RTS,S/AS01E malaria vaccine efficacy

Cited by 118 publications

References 31 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

Protective Malaria Vaccine in Mice Based on the Plasmodium vivax Circumsporozoite Protein Fused with the Mumps Nucleocapsid Protein

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

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