A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein

Tan, Joshua; Sack, Brandon K.; Oyen, David; Zenklusen, Isabelle; Piccoli, Luca; Barbieri, Sonia; Foglierini, Mathilde; Fregni, Chiara Silacci; Marcandalli, Jessica; Jongo, Said; Abdulla, Salim; Perez, Laurent; Corradin, Giampietro; Varani, Luca; Sallusto, Federica; Sim, B. Kim Lee; Hoffman, Stephen L.; Kappe, Stefan H. I.; Daubenberger, Claudia; Wilson, Ian A.; Lanzavecchia, Antonio

doi:10.1038/nm.4513

Cited by 189 publications

(302 citation statements)

References 67 publications

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“…All truncated PfCSPs in Imject® Alum conferred high protection (60%‐70%), indicating that all regions contribute to this protection. This result is consistent with other studies identifying protective human mAbs that potently bind to the “junctional” epitope between the N‐terminus and the central repeat of PfCSP . The present study demonstrated that PfCSP‐C immunization conferred protection and anti‐PfCSP‐C Abs reacted with the sporozoites.…”

Section: Discussionsupporting

confidence: 93%

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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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Section: Discussionsupporting

confidence: 93%

“…Recently, the most effective mAbs isolated from a protected Tanzanian volunteer immunized with PfSPZ were shown to be associated with the repeat region of CSP . In the present study, the heterologous AdHu5‐PfCSP‐F‐prime/R32LR‐boost immunization regimen conferred complete protection against challenge by iv sporozoite injection.…”

Section: Discussionsupporting

confidence: 51%

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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“…Recent studies have described mAbs CIS23, CIS34, CIS42 and CIS43 isolated from P. falciparum CSPspecific memory B-cells from volunteers who had been immunized with the PfSPZ vaccine [41][42][43]. CIS43 and MGG4 mAb had cross-reactivity with NPDP, NVDP and NANP repeat regions and the CTD fragment, thereby enabling them to bind to this protein and alter its cleavage after processing to limit hepatocyte invasion in an animal model [42][43][44]. The next step will involve clinical trials being run by PATH's Malaria Vaccine Initiative for determining whether mAbs can induce protection against P. falciparum infection.…”

Section: Genetically-attenuated Sporozoite Vaccinesmentioning

confidence: 99%

Plasmodium falciparum pre-erythrocytic stage vaccine development

Molina-Franky

Cuy-Chaparro

Camargo

et al. 2020

Malar J

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Worldwide strategies between 2010 and 2017 aimed at controlling malarial parasites (mainly Plasmodium falciparum) led to a reduction of just 18% regarding disease incidence rates. Many biologically-derived anti-malarial vaccine candidates have been developed to date; this has involved using many experimental animals, an immense amount of work and the investment of millions of dollars. This review provides an overview of the current state and the main results of clinical trials for sporozoite-targeting vaccines (i.e. the parasite stage infecting the liver) carried out by research groups in areas having variable malaria transmission rates. However, none has led to promising results regarding the effective control of the disease, thereby making it necessary to complement such efforts at finding/introducing new vaccine candidates by adopting a multi-epitope, multi-stage approach, based on minimal subunits of the main sporozoite proteins involved in the invasion of the liver.

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“…Currently there are 3 mAbs published with potent activity against the circumsporozoite protein, CSP, and these can reduce the parasitaemia in sporozoite-infected FRG (triple mutant Fah/Raγ2/IL2Rγ) mice that carry a human liver implant [132]. These mAbs include mAb317, cloned from B cells obtained from a patient in the recent RTS,S vaccine trial [133], CIS43 (circumsporozoite protein 43 [56]), and a set that included MGU12 [134], cloned from patients vaccinated with irradiated sporozoites. Antibodies that block the invasion process of the red blood cells by merozoites represent another possible approach.…”

Section: Malariamentioning

confidence: 99%

Reassessing therapeutic antibodies for neglected and tropical diseases

et al. 2020

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In the past two decades there has been a significant expansion in the number of new therapeutic monoclonal antibodies (mAbs) that are approved by regulators. The discovery of these new medicines has been driven primarily by new approaches in inflammatory diseases and oncology, especially in immuno-oncology. Other recent successes have included new antibodies for use in viral diseases, including HIV. The perception of very high costs associated with mAbs has led to the assumption that they play no role in prophylaxis for diseases of poverty. However, improvements in antibody-expression yields and manufacturing processes indicate this is a cost-effective option for providing protection from many types of infection that should be revisited. Recent technology developments also indicate that several months of protection could be achieved with a single dose. Moreover, new methods in B cell sorting now enable the systematic identification of high-quality antibodies from humanized mice, or patients. This Review discusses the potential for passive immunization against schistosomiasis, fungal infections, dengue, and other neglected diseases.PLOS Neglected Tropical Diseases | https://doi.interactions have proved difficult to block. In addition, there has been great progress in the development of technology. Early generations of antibodies for human use were developed from mAbs developed in mice, antibodies that were then humanized. Recently, the technology used peptide and antibody display on phages, for which part of the 2018 Nobel Prize in Chemistry was awarded to Sir Gregory P. Winter [6]. More recently, new technologies have been developed to clone antibodies from memory B cells [7] or plasma B cells [8, 9], allowing the isolation of individual antibodies from patients with viral infections-approaches that can be applied to any infectious disease.A second reason for the popularity of antibodies in recent years is their success rate in clinical development. Once an antibody reaches testing in humans, it has a success rate of 17% to 25% for approval as a new medicine [10], compared with 5% to 10% for small molecules. This success rate is partly due to the exquisite selectivity of mAbs, enabling them to distinguish between closely related molecular targets. In the case of infectious disease, this selectivity can be absolute, since antibodies can be generated that are specific for the invading pathogen and do not cross-react with host tissues. This lack of cross-reactivity with human tissue can be confirmed by immunohistochemistry on both adult and embryonic tissues prior to the start of clinical trials. This is in stark contrast to small molecules, in which sometimes unexpected onand off-target safety signals are frequently seen in the later stages of clinical development, resulting in expensive late-stage attrition. In addition, antibodies show a relatively narrow range of variation in pharmacokinetic exposure, facilitating early estimation of the human effective dose. This is unlike true xenobiotics, whose metabolism an...

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A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein

Cited by 189 publications

References 67 publications

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

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

Plasmodium falciparum pre-erythrocytic stage vaccine development

Reassessing therapeutic antibodies for neglected and tropical diseases

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