Vaccine-induced monoclonal antibodies targeting circumsporozoite protein prevent Plasmodium falciparum infection

Foquet, Lander; Hermsen, Cornelus C.; Gemert, Geert-Jan van; Braeckel, Eva Van; Weening, Karin; Sauerwein, Robert W.; Meuleman, Philip; Leroux‐Roels, Geert

doi:10.1172/jci70349

Cited by 140 publications

(127 citation statements)

References 39 publications

(48 reference statements)

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“…While progress towards a malaria vaccine continues [30,31], the continued development of antimalarial agents that work via novel mechanisms is absolutely required. We have described the design, synthesis and characterisation of novel compounds that inhibit the essential Pf MAPs, PfA-M1 and PfA-M17.…”

Section: Discussionmentioning

confidence: 99%

Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions

Drinkwater

Vinh

Mistry

et al. 2016

European Journal of Medicinal Chemistry

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Section: Discussionmentioning

confidence: 99%

Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions

Drinkwater

Vinh

Mistry

et al. 2016

European Journal of Medicinal Chemistry

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“…Given their high susceptibility to P. falciparum sporozoite infection and support of complete liver-stage development [36], they can be used both to validate complete attenuation of whole parasite P. falciparum vaccine strains [26,84] and enable the testing of antibody efficacy in protecting against sporozoite challenge by passive immunization. These analyses were previously only possible using NHPs [34,85]. Mouse models which allow xeno-engrafting of primary human hepatocytes carry genetic backgrounds that render them immunodeficient with congenital hepatotoxicity.…”

Section: Current Strategies To Identify and Validate Novel Pe Vaccine Tmentioning

confidence: 99%

“…These studies are conducted by passive transfer of antibodies against human parasite antigens, establishing a robust link between rodent malaria models and CHMI trials. This has been demonstrated using mAbs targeting CSP of P. falciparum [85,87] and IgG from whole sporozoite-immunized human volunteers [55]. While liver humanized mice are still costly, they are far less so than NHPs both in terms of animal purchase price and housing.…”

Section: Current Strategies To Identify and Validate Novel Pe Vaccine Tmentioning

confidence: 99%

An Expanding Toolkit for Preclinical Pre-Erythrocytic Malaria Vaccine Development: Bridging Traditional Mouse Malaria Models and Human Trials

2016

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Malaria remains a significant public health burden with 214 million new infections and over 400,000 deaths in 2015. Elucidating relevant Plasmodium parasite biology can lead to the identification of novel ways to control and ultimately eliminate the parasite within geographic areas. Particularly, the development of an effective vaccine that targets the clinically silent pre-erythrocytic stages of infection would significantly augment existing malaria elimination tools by preventing both the onset of blood-stage infection/disease as well as spread of the parasite through mosquito transmission. In this Perspective, we discuss the role of small animal models in pre-erythrocytic stage vaccine development, highlighting how human liver-chimeric and human immune system mice are emerging as valuable components of these efforts. Malaria continues to cause significant morbidity and mortality despite renewed and concerted efforts to eliminate the causative agents, parasites of the genus Plasmodium. These efforts have largely focused on control of the Anopheles mosquito vectors, and antimalarial drug treatment of symptomatic infected individuals. The 214 million new malaria infections and 438,000 deaths due to malaria in 2015 were disproportionately borne by low income countries where malaria is endemic, and declines in malaria infections since 2000 have been slowest in countries with low resource availability and high malaria burden [1]. In the fight against malaria, effective vaccines preventing both disease and transmission will be important tools to achieve WHO goals of a 90% reduction in disease burden by 2030 [1,2]. In humans, malaria is caused predominantly by the parasite species Plasmodium falciparum and Plasmodium vivax, with the remainder of infections caused by three additional parasite species, Plasmodium malariae, Plasmodium ovale and Plasmodium knowlesi [1].Malaria parasite transmission occurs when a Plasmodium-infected Anopheles mosquito bites and by probing the skin for a blood meal, deposits motile sporozoite stages into the host. Sporozoites pass through the dermis using active motility, enter a capillary and then rapidly home to the liver. Once in the liver sporozoites enter the parenchyma and infect hepatocytes, wherein they then transmogrify into liver stages, which grow, replicate and ultimately differentiate into tens of thousands of first-generation merozoites. Merozoites of human malaria parasites emerge from the liver into the blood stream 7-10 days after transmission, where they undergo cyclic erythrocytic infection and intraerythrocytic replication. This blood-stage infection is responsible for all mortality and clinical symptoms of malaria, as well as infection of a new mosquito vector by sexual stage parasites for onward transmission [3,4]. Stages prior to blood-stage infection (i.e., the sporozoite and liver stages) are collectively known as preerythrocytic (PE) stages of infection and vaccine candidates targeting these stages are collectively termed PE vaccines. By preventing progression to ...

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“…Continuous emergence and spread of resistance to newly developed antimalarials (Cohen et al, 2010;Na-Bangchang and Karbwang, 2013;Price et al, 2014;WWARN, 2015) as well as vector resistance to insecticides (Dhiman and Veer, 2014;Strode et al, 2014) are key challenges against existing malaria control measures and highlights the urgent need for an effective vaccine. Despite several preclinical and clinical trials with the aim of developing an effective malaria vaccines (Moreno and Joyner, 2015), the most advanced malaria vaccine candidate in phase 3 trial, RTS,S/AS01, has only shown 31% and 50% efficacy in infants and children respectively (Foquet et al, 2014). RTS,S/AS01 was designed based on the discovery of the sporozoites major surface protein, CSP, with the aim of interfering with the ability of the parasite to infect hepatocytes (Casares et al, 2010;Cohen et al, 2010).…”

Section: Challenges Of Previous Intervention Strategiesmentioning

confidence: 99%

Pre-erythrocytic Stage of Malaria Infection and the Molecular Targets Available for Interventions

Adah¹,

Yang²,

Liu³

et al. 2016

J. Adv. Parasitol.

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Vaccine-induced monoclonal antibodies targeting circumsporozoite protein prevent Plasmodium falciparum infection

Abstract: Malaria, which is the result of

Cited by 140 publications

References 39 publications

Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions

Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions

An Expanding Toolkit for Preclinical Pre-Erythrocytic Malaria Vaccine Development: Bridging Traditional Mouse Malaria Models and Human Trials

Pre-erythrocytic Stage of Malaria Infection and the Molecular Targets Available for Interventions

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