Rare PfCSP C-terminal antibodies induced by live sporozoite vaccination are ineffective against malaria infection

Scally, S.W.; Murugan, Rajagopal; Bosch, Alexandre; Triller, Gianna; Costa, Giulia; Mordmüller, Benjamin; Kremsner, Peter G.; Sim, B. Kim Lee; Hoffman, Stephen L.; Levashina, Elena A.; Wardemann, Hedda; Julien, Jean-Philippe

doi:10.1084/jem.20170869

Cited by 83 publications

(119 citation statements)

References 66 publications

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“…In 2012, our group established a model using direct venous inoculation of P. falciparum sporozoites in malaria‐naïve volunteers, which is highly reproducible showing an infection rate of 100% . This was seen in many more trials with all unprotected naïve volunteers having very similar parasitaemia curves . Of note, the same infection model has been used to assess causal prophylaxis at two clinical trial sites and showed that it is adequately powered to detect partial efficacy in small group sizes .…”

Section: Discussionmentioning

confidence: 98%

Ivermectin for causal malaria prophylaxis: a randomised controlled human infection trial

Metzger

Theurer

Pfleiderer

et al. 2020

Tropical Med Int Health

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Objective Ivermectin is safe and widely used for treating helminth infections. It also kills arthropods feeding on treated subjects, including malaria vectors. Thus, ivermectin mass drug administration as an additional tool for malaria control is being evaluated by WHO. As in vitro data, animal experiments and epidemiological observations suggest that ivermectin has a direct effect on the liver stages of the malaria parasite, this study was designed to assess the prophylactic effect of ivermectin on Plasmodium falciparum controlled human malaria infection. Methods A total of 4 volunteers were randomised to placebo, and 8 volunteers were randomised to receive ivermectin 0.4 mg/kg, orally, once 2 h before being experimentally infected intravenously with 3200 P. falciparum sporozoites. The primary endpoint was time to parasitaemia detected by positive thick blood smear; RT‐qPCR was performed in parallel. Results All but one volunteer became thick blood smear positive between day 11 and day 12 after infection, and there was no significant effect of ivermectin on parasitaemia. Conclusion Ivermectin – at the dose used – has no clinically relevant activity against the pre‐erythrocytic stages of P. falciparum.

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Section: Discussionmentioning

confidence: 98%

Ivermectin for causal malaria prophylaxis: a randomised controlled human infection trial

Metzger

Theurer

Pfleiderer

et al. 2020

Tropical Med Int Health

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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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“…33 However, anti-C-terminus Abs induced by live Plasmodium sporozoites in humans under chloroquine prophylaxis have weak inhibition of parasite traversal. 34 In fact, CSP attaches to hepatocytes via region I located in the N-terminus to invade liver cells, 35 whereas the repeat region mediates sporozoite infectivity in either the mosquito or mammalian host. 36 In addition, sporozoite motility is also affected by the disruption of region II at C-terminus.…”

Section: Discussionmentioning

confidence: 99%

Down‐selecting circumsporozoite protein‐based malaria vaccine: A comparison of malaria sporozoite challenge model

Amelia

Iyori

Emran

et al. 2019

Parasite Immunology

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Summary Plasmodium falciparum circumsporozoite protein (PfCSP) is the main target antigen in development of pre‐erythrocytic malaria vaccines. To evaluate PfCSP vaccines in animal models, challenge by intravenous sporozoite injection is preferentially used. However, in clinical trials, vaccinated human volunteers are exposed to the bites of malaria‐infected mosquitoes. In this study, we down‐selected Escherichia coli‐produced full‐length PfCSP (PfCSP‐F) and its three truncated PfCSPs based on their abilities to elicit immune response and protection in mice against two challenge models. We showed that immunization with three doses of PfCSP‐F elicited high anti‐PfCSP antibody titres and 100% protection against the bites of infected mosquitoes. Meanwhile, three‐dose truncated PfCSP induced 60%‐70% protection after immunization with each truncated PfCSP. Heterologous prime‐boost immunization regimen with adenovirus‐PfCSP‐F and R32LR greatly induced complete protection against intravenous sporozoite injection. Our results suggest that Abs to both anti‐repeat and anti‐nonrepeat regions induced by PfCSP‐F are required to confer complete protection against challenge by the bites of infected mosquitoes, whereas anti‐repeat Abs play an important role in protection against intravenous sporozoite injection. Our findings provide a potential clinical application that PfCSP‐F vaccine induces potent Abs capable of neutralizing sporozoites in the dermis inoculated by infected mosquitoes and subsequently sporozoites in the blood circulation.

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Rare PfCSP C-terminal antibodies induced by live sporozoite vaccination are ineffective against malaria infection

Cited by 83 publications

References 66 publications

Ivermectin for causal malaria prophylaxis: a randomised controlled human infection trial

Ivermectin for causal malaria prophylaxis: a randomised controlled human infection trial

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

Down‐selecting circumsporozoite protein‐based malaria vaccine: A comparison of malaria sporozoite challenge model

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