First-in-human evaluation of genetically attenuated Plasmodium falciparum sporozoites administered by bite of Anopheles mosquitoes to adult volunteers

被引：101

作者：

Spring, Michele ^{[1
]}

Murphy, Jittawadee ^{[1
]}

Nielse, Robin ^{[1
]}

Dowler, Megan ^{[1
]}

Bennett, Jason W. ^{[1
]}

Zarling, Stasya ^{[1
]}

Williams, Jack ^{[1
]}

de la Vega, Patricia ^{[1
]}

Ware, Lisa ^{[1
]}

Komisar, Jack ^{[1
]}

Polhemus, Mark ^{[1
]}

Richie, Thomas L. ^{[2
]}

Epstein, Judy ^{[2
]}

Tamminga, Cindy ^{[2
]}

Chuang, Ilin ^{[2
]}

Richie, Nancy ^{[1
]}

O'Neil, Michael ^{[1
]}

Heppner, D. Gray ^{[1
]}

Healer, Julie ^{[3
]}

O'Neill, Matthew ^{[3
]}

Smithers, Hannah ^{[4
]}

Finney, Olivia C. ^{[4
]}

Mikolajczak, Sebastian A. ^{[4
]}

Wang, Ruobing ^{[4
]}

Cowman, Alan ^{[3
]}

Ockenhouse, Christian ^{[1
]}

Krzych, Urszula ^{[1
]}

Kappe, Stefan H. I. ^{[4
,5
]}

机构：

[1] Walter Reed Army Inst Res, Silver Spring, MD 20910 USA

[2] Naval Malaria Res Ctr, Silver Spring, MD 20910 USA

[3] Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3052, Australia

[4] Seattle Biomed Res Inst, Seattle, WA 98109 USA

[5] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA

来源：

VACCINE | 2013年 / 31卷 / 43期

基金：

美国国家卫生研究院;

关键词：

Genetically attenuated parasite; First-in-human; Malaria; Plasmodium falciparum; MALARIA VACCINE DEVELOPMENT; MEMORY T-CELLS; PROTECTIVE IMMUNITY; LIVER; IMMUNIZATION; MECHANISMS; CHALLENGE; INFECTION; RADIATION; PARASITES;

D O I：

10.1016/j.vaccine.2013.08.007

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Background: Immunization with genetically engineered, attenuated malaria parasites (GAP) that arrest during liver infection confers sterile protection in mouse malaria models. A first generation Plasmodium falciparum GAP (Pf p52(-)/p36(-) GAP) was previously generated by deletion of two pre-erythrocytic stage-expressed genes (P52 and P36) in the NF54 strain. Methods: A first-in-human, proof-of-concept, safety and immunogenicity clinical trial in six human volunteers was conducted. Exposure consisted of delivery of Pf p52-/p36- GAP sporozoites via infected Anopheles mosquito bite with a five-bite/volunteer exposure followed by an approximately 200-bite exposure/volunteer one month later. Results: The exposures were well tolerated with mild to moderate local and systemic reactions. All volunteers remained blood stage negative after low dose exposure. Five volunteers remained blood stage negative after high dose exposure. One volunteer developed peripheral parasitemia twelve days after high dose exposure. Together the findings indicate that Pf p52-/p36- GAP was severely but not completely attenuated. All six volunteers developed antibodies to CSP. Furthermore, IFN-gamma responses to whole sporozoites and multiple antigens were elicited in 5 of 6 volunteers, with both CD4 and CD8 cell cytokine production detected. Conclusion: Severe attenuation and favorable immune responses following administration of a first generation Pf p52-/p36- GAP suggests that further development of live-attenuated strains using genetic engineering should be pursued. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：4975 / 4983

页数：9

共 39 条

[1]

[Anonymous], N ENGL J MED

[2] Protracted protection to Plasmodium berghei malaria is linked to functionally and phenotypically heterogeneous liver memory CD8+ T cells [J].

Berenzon, D ;

Schwenk, RJ ;

Letellier, L ;

Guebre-Xabier, M ;

Williams, J ;

Krzych, U .

JOURNAL OF IMMUNOLOGY, 2003, 171 (04) :2024-2034

[3] Whole parasite vaccination approaches for prevention of malaria infection [J].

Butler, Noah S. ;

Vaughan, Ashley M. ;

Harty, John T. ;

Kappe, Stefan H. I. .

TRENDS IN IMMUNOLOGY, 2012, 33 (05) :247-254

[4] Superior Antimalarial Immunity after Vaccination with Late Liver Stage-Arresting Genetically Attenuated Parasites [J].

Butler, Noah S. ;

Schmidt, Nathan W. ;

Vaughan, Ashley M. ;

Aly, Ahmed S. ;

Kappe, Stefan H. I. ;

Harty, John T. .

CELL HOST & MICROBE, 2011, 9 (06) :451-462

[5] IMMUNIZATION OF MAN AGAINST SPOROZITE-INDUCED FALCIPARUM MALARIA [J].

CLYDE, DF ;

MOST, H ;

MCCARTHY, VC ;

VANDERBERG, JP .

AMERICAN JOURNAL OF THE MEDICAL SCIENCES, 1973, 266 (03) :169-177

[6] SPECIFICITY OF PROTECTION OF MAN IMMUNIZED AGAINST SPOROZOITE-INDUCED FALCIPARUM MALARIA [J].

CLYDE, DF ;

MCCARTHY, VC ;

MILLER, RM ;

HORNICK, RB .

AMERICAN JOURNAL OF THE MEDICAL SCIENCES, 1973, 266 (06) :398-403

[7] IMMUNIZATION OF MAN AGAINST FALCIPARUM AND VIVAX MALARIA BY USE OF ATTENUATED SPOROZOITES [J].

CLYDE, DF ;

MCCARTHY, VC ;

MILLER, RM ;

WOODWARD, WE .

AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 1975, 24 (03) :397-401

[8] Live Attenuated Malaria Vaccine Designed to Protect Through Hepatic CD8+ T Cell Immunity [J].

Epstein, J. E. ;

Tewari, K. ;

Lyke, K. E. ;

Sim, B. K. L. ;

Billingsley, P. F. ;

Laurens, M. B. ;

Gunasekera, A. ;

Chakravarty, S. ;

James, E. R. ;

Sedegah, M. ;

Richman, A. ;

Velmurugan, S. ;

Reyes, S. ;

Li, M. ;

Tucker, K. ;

Ahumada, A. ;

Ruben, A. J. ;

Li, T. ;

Stafford, R. ;

Eappen, A. G. ;

Tamminga, C. ;

Bennett, J. W. ;

Ockenhouse, C. F. ;

Murphy, J. R. ;

Komisar, J. ;

Thomas, N. ;

Loyevsky, M. ;

Birkett, A. ;

Plowe, C. V. ;

Loucq, C. ;

Edelman, R. ;

Richie, T. L. ;

Seder, R. A. ;

Hoffman, S. L. .

SCIENCE, 2011, 334 (6055) :475-480

[9] Safety and clinical outcome of experimental challenge of human volunteers with Plasmodium falciparum-infected mosquitoes:: An update [J].

Epstein, Judith E. ;

Rao, Suchitra ;

Williams, Frank ;

Freilich, Daniel ;

Luke, Thomas ;

Sedegah, Martha ;

de la Vega, Patricia ;

Sacci, John ;

Richie, Thomas L. ;

Hoffman, Stephen L. .

JOURNAL OF INFECTIOUS DISEASES, 2007, 196 (01) :145-154

[10]

FDA, COMPL LIST VACC LIC

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