Complete attenuation of genetically engineered Plasmodium falciparum sporozoites in human subjects

James G. Kublin; Sebastian A. Mikolajczak; Brandon K. Sack; Matt E. Fishbaugher; Annette Seilie; Lisa Shelton; Tracie VonGoedert; Melike Firat; Sara Magee; Emma Fritzen; Will Betz; Heather S. Kain; Dorender A. Dankwa; Ryan W.J. Steel; Ashley M. Vaughan; D. Noah Sather; Sean C. Murphy; Stefan H.I. Kappe

doi:10.1126/scitranslmed.aad9099

Complete attenuation of genetically engineered Plasmodium falciparum sporozoites in human subjects

James G. Kublin, Sebastian A. Mikolajczak, Brandon K. Sack, Matt E. Fishbaugher, Annette Seilie, Lisa Shelton, Tracie VonGoedert, Melike Firat, Sara Magee, Emma Fritzen, Will Betz, Heather S. Kain, Dorender A. Dankwa, Ryan W.J. Steel, Ashley M. Vaughan, D. Noah Sather, Sean C. Murphy, Stefan H.I. Kappe

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64 Scopus citations

Abstract

Immunization of humans with whole sporozoites confers complete, sterilizing immunity against malaria infection. However, achieving consistent safety while maintaining immunogenicity of whole parasite vaccines remains a formidable challenge. We generated a genetically attenuated Plasmodium falciparum (Pf) malaria parasite by deleting three genes expressed in the pre-erythrocytic stage (Pf p52^-/p36^-/sap1^-). We then tested the safety and immunogenicity of the genetically engineered (Pf GAP3KO) sporozoites in human volunteers. Pf GAP3KO sporozoites were delivered to 10 volunteers using infected mosquito bites with a single exposure consisting of 150 to 200 bites per subject. All subjects remained blood stage-negative and developed inhibitory antibodies to sporozoites. GAP3KO rodent malaria parasites engendered complete, protracted immunity against infectious sporozoite challenge in mice. The results warrant further clinical testing of Pf GAP3KO and its potential development into a vaccine strain.

Original language	English (US)
Article number	eaad9099
Journal	Science translational medicine
Volume	9
Issue number	371
DOIs	https://doi.org/10.1126/scitranslmed.aad9099
State	Published - Jan 4 2017
Externally published	Yes

ASJC Scopus subject areas

Medicine(all)

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Kublin, J. G., Mikolajczak, S. A., Sack, B. K., Fishbaugher, M. E., Seilie, A., Shelton, L., VonGoedert, T., Firat, M., Magee, S., Fritzen, E., Betz, W., Kain, H. S., Dankwa, D. A., Steel, R. W. J., Vaughan, A. M., Sather, D. N., Murphy, S. C., & Kappe, S. H. I. (2017). Complete attenuation of genetically engineered Plasmodium falciparum sporozoites in human subjects. Science translational medicine, 9(371), [eaad9099]. https://doi.org/10.1126/scitranslmed.aad9099

Kublin, JG, Mikolajczak, SA, Sack, BK, Fishbaugher, ME, Seilie, A, Shelton, L, VonGoedert, T, Firat, M, Magee, S, Fritzen, E, Betz, W, Kain, HS, Dankwa, DA, Steel, RWJ, Vaughan, AM, Sather, DN, Murphy, SC & Kappe, SHI 2017, 'Complete attenuation of genetically engineered Plasmodium falciparum sporozoites in human subjects', Science translational medicine, vol. 9, no. 371, eaad9099. https://doi.org/10.1126/scitranslmed.aad9099

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title = "Complete attenuation of genetically engineered Plasmodium falciparum sporozoites in human subjects",

abstract = "Immunization of humans with whole sporozoites confers complete, sterilizing immunity against malaria infection. However, achieving consistent safety while maintaining immunogenicity of whole parasite vaccines remains a formidable challenge. We generated a genetically attenuated Plasmodium falciparum (Pf) malaria parasite by deleting three genes expressed in the pre-erythrocytic stage (Pf p52-/p36-/sap1-). We then tested the safety and immunogenicity of the genetically engineered (Pf GAP3KO) sporozoites in human volunteers. Pf GAP3KO sporozoites were delivered to 10 volunteers using infected mosquito bites with a single exposure consisting of 150 to 200 bites per subject. All subjects remained blood stage-negative and developed inhibitory antibodies to sporozoites. GAP3KO rodent malaria parasites engendered complete, protracted immunity against infectious sporozoite challenge in mice. The results warrant further clinical testing of Pf GAP3KO and its potential development into a vaccine strain.",

author = "Kublin, {James G.} and Mikolajczak, {Sebastian A.} and Sack, {Brandon K.} and Fishbaugher, {Matt E.} and Annette Seilie and Lisa Shelton and Tracie VonGoedert and Melike Firat and Sara Magee and Emma Fritzen and Will Betz and Kain, {Heather S.} and Dankwa, {Dorender A.} and Steel, {Ryan W.J.} and Vaughan, {Ashley M.} and Sather, {D. Noah} and Murphy, {Sean C.} and Kappe, {Stefan H.I.}",

note = "Funding Information: This research and development program was made possible by a cooperative agreement that was awarded and administered by the U.S. Army Medical Research and Materiel Command and the Telemedicine and Advanced Technology Research Center at Fort Detrick, MD, under contract number W81XWH-11-2-0184. The views, opinions, and/or findings contained in this publication are those of the author(s) and do not necessarily reflect the views of the U.S. Department of Defense (DoD) and should not be construed as an official DoD/Army position, policy, or decision unless so designated by official documentation. No official endorsement should be made. Humanized mouse experiments in this study were funded by the Bill and Melinda Gates Foundation (investment ID, 24922).",

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doi = "10.1126/scitranslmed.aad9099",

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AU - Kublin, James G.

AU - Mikolajczak, Sebastian A.

AU - Sack, Brandon K.

AU - Fishbaugher, Matt E.

AU - Seilie, Annette

AU - Shelton, Lisa

AU - VonGoedert, Tracie

AU - Firat, Melike

AU - Magee, Sara

AU - Fritzen, Emma

AU - Betz, Will

AU - Kain, Heather S.

AU - Dankwa, Dorender A.

AU - Steel, Ryan W.J.

AU - Vaughan, Ashley M.

AU - Sather, D. Noah

AU - Murphy, Sean C.

AU - Kappe, Stefan H.I.

N1 - Funding Information: This research and development program was made possible by a cooperative agreement that was awarded and administered by the U.S. Army Medical Research and Materiel Command and the Telemedicine and Advanced Technology Research Center at Fort Detrick, MD, under contract number W81XWH-11-2-0184. The views, opinions, and/or findings contained in this publication are those of the author(s) and do not necessarily reflect the views of the U.S. Department of Defense (DoD) and should not be construed as an official DoD/Army position, policy, or decision unless so designated by official documentation. No official endorsement should be made. Humanized mouse experiments in this study were funded by the Bill and Melinda Gates Foundation (investment ID, 24922).

PY - 2017/1/4

Y1 - 2017/1/4

N2 - Immunization of humans with whole sporozoites confers complete, sterilizing immunity against malaria infection. However, achieving consistent safety while maintaining immunogenicity of whole parasite vaccines remains a formidable challenge. We generated a genetically attenuated Plasmodium falciparum (Pf) malaria parasite by deleting three genes expressed in the pre-erythrocytic stage (Pf p52-/p36-/sap1-). We then tested the safety and immunogenicity of the genetically engineered (Pf GAP3KO) sporozoites in human volunteers. Pf GAP3KO sporozoites were delivered to 10 volunteers using infected mosquito bites with a single exposure consisting of 150 to 200 bites per subject. All subjects remained blood stage-negative and developed inhibitory antibodies to sporozoites. GAP3KO rodent malaria parasites engendered complete, protracted immunity against infectious sporozoite challenge in mice. The results warrant further clinical testing of Pf GAP3KO and its potential development into a vaccine strain.

AB - Immunization of humans with whole sporozoites confers complete, sterilizing immunity against malaria infection. However, achieving consistent safety while maintaining immunogenicity of whole parasite vaccines remains a formidable challenge. We generated a genetically attenuated Plasmodium falciparum (Pf) malaria parasite by deleting three genes expressed in the pre-erythrocytic stage (Pf p52-/p36-/sap1-). We then tested the safety and immunogenicity of the genetically engineered (Pf GAP3KO) sporozoites in human volunteers. Pf GAP3KO sporozoites were delivered to 10 volunteers using infected mosquito bites with a single exposure consisting of 150 to 200 bites per subject. All subjects remained blood stage-negative and developed inhibitory antibodies to sporozoites. GAP3KO rodent malaria parasites engendered complete, protracted immunity against infectious sporozoite challenge in mice. The results warrant further clinical testing of Pf GAP3KO and its potential development into a vaccine strain.

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Complete attenuation of genetically engineered Plasmodium falciparum sporozoites in human subjects

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