A Next-generation Genetically Attenuated Plasmodium falciparum Parasite Created by Triple Gene Deletion

Mikolajczak, Sebastian A.; Lakshmanan, Viswanathan; Fishbaugher, Matthew; Camargo, Nelly; Harupa, Anke; Kaushansky, Alexis; Douglass, Alyse N.; Baldwin, Michael R.; Healer, Julie; O'Neill, Matthew T; Phuong, Thuan; Cowman, Alan F.; Kappe, Stefan H. I.

doi:10.1038/mt.2014.85

Cited by 71 publications

(69 citation statements)

References 39 publications

(66 reference statements)

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“…However, the possibility of blood-stage infection is unacceptable for an attenuated parasite vaccine and a second-generation GAP incorporating a third gene deletion (GAP3KO) was developed. This second-generation GAP3KO showed a much better safety profile in more stringent preclinical tests [26], and has recently completed successful Phase I safety trials in humans in which it appears safe and immunogenic [ In addition to the development of novel vaccine strategies, the access to liver stages afforded by rodent models allows for the interrogation of innate immune responses. Once thought to be immunologically inert, the liver stages of the parasite have recently been found to indeed induce innate immune responses that are capable of limiting parasite growth [27][28][29].…”

Section: Lessons Learned From Rodent Malaria Modelsmentioning

confidence: 99%

mentioning

confidence: 99%

“…(2016) Recently, we and others have incorporated human liver-chimeric mouse models into preclinical PE vaccine research. 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].…”

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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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Section: Lessons Learned From Rodent Malaria Modelsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

2016

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“…60 In consequence, a triple knockout parasite in which sap1 is deleted in addition to p36 and p52 was constructed, and recently shown to be completely attenuated in a humanized mouse model with human hepatocytes and red blood cells. 61 It will be interesting to compare the protection elicited by this strategy in human volunteers to those that use irradiated and chemically attenuated parasites. Because the deleted genes arrest parasite development during the early liver stage, it is likely that this GAP mutant will behave like RAS, although it may require lower doses to induce protection, since the vast majority of GAP parasites will invade and develop within hepatocytes until the missing functions that would have been provided by the deleted genes prevent further development.…”

Section: Genetic Attenuationmentioning

confidence: 99%

Live attenuated pre-erythrocytic malaria vaccines

Keitany

Vignali

Wang

2014

Human Vaccines & Immunotherapeutics

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“…, which in preclinical studies showed complete attenuation early after infection of hepatocytes with no evidence of breakthrough blood stage infection in a humanized mouse model [15]. A recent clinical study showed a favorable safety profile with no breakthrough to blood stage infection when PfGAP3KO was administered to human subjects by the bites of approximately 200 PfGAP3KO-infected mosquitoes [16].…”

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confidence: 99%