Transmission blocking vaccines (TBVs) against malaria are intended to induce immunity against the stages of the parasite that infect mosquitoes so that malaria transmission is reduced or halted. Malaria transmission occurs locally and 'focally', i.e. spatially confined to an infectious source, thus TBVs used in a community can effectively suppress malaria transmission to others. TBVs will induce antibodies that will target antigens expressed on the surface of sexual and mosquito midgut stages of the malaria parasite. The target antigens include proteins synthesized in the gametocytes (pre-fertilization antigens, in P. falciparum: Pfs230 and Pfs48/45) and in the zygotes-ookinetes (post-fertilization antigens, in P. falciparum: Pfs25 and Pfs28) and the epitopes recognized by transmission blocking antibodies are cysteine-rich reduction-sensitive conformational in nature. The inability to express properly folded proteins is one of the major factors that have severely hampered protein based TBV development. DNA based vaccination was envisaged to overcome the conformational problem in recombinant proteins, and indeed studies in mice and monkeys have firmly established the value of DNA based TBV approach. This vaccine platform can facilitate evaluation of a cocktail of pre- and post-fertilization antigens in pre clinical setting. Studies proposed are aimed at (1) identifying immunologically relevant domains in the pre-fertilization antigens, (2) optimizing the combination of pre- and post-fertilization antigens by vaccine formulation in cationic lipids and vaccine delivery by in vivo electroporation, (3) evaluating a candidate DNA vaccine by in vivo electroporation in nonhuman primates (Macaca mulatta) and testing the concept that immunity against pre-fertilization antigens can be maintained by boosting during natural infection using an Aotus model for P. falciparum infection. Moreover, the development of Pfs25 transgenic P. berghei will provide an approach for in vivo evaluation of human malaria TBV based on Pfs25, as compared to a standard in vitro membrane feeding assay. These are critical and essential issues that need to be systematically addressed in pre clinical studies prior to the development of an ideal and effective TBV for clinical trials in human volunteers. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047089-06
Application #
7431702
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
MO, Annie X Y
Project Start
2000-03-01
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
6
Fiscal Year
2008
Total Cost
$388,975
Indirect Cost
Name
Johns Hopkins University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kumar, Nirbhay (2017) Modulation of transmission success of Plasmodium falciparum gametocytes (sexual stages) in various species of Anopheles by erythrocytic asexual stage parasites. Acta Trop 176:263-269
Datta, Dibyadyuti; Bansal, Geetha P; Grasperge, Brooke et al. (2017) Comparative functional potency of DNA vaccines encoding Plasmodium falciparum transmission blocking target antigens Pfs48/45 and Pfs25 administered alone or in combination by in vivo electroporation in rhesus macaques. Vaccine 35:7049-7056
Heidari, Zahra; Arora, Jaspreet S; Datta, Dibyadyuti et al. (2017) Impact of the Charge Ratio on the In Vivo Immunogenicity of Lipoplexes. Pharm Res 34:1796-1804
Datta, Dibyadyuti; Bansal, Geetha P; Gerloff, Dietlind L et al. (2017) Immunogenicity and malaria transmission reducing potency of Pfs48/45 and Pfs25 encoded by DNA vaccines administered by intramuscular electroporation. Vaccine 35:264-272
Bansal, Geetha P; Weinstein, Corey S; Kumar, Nirbhay (2016) Insight into phagocytosis of mature sexual (gametocyte) stages of Plasmodium falciparum using a human monocyte cell line. Acta Trop 157:96-101
Kumar, Rajesh; Ray, Paresh C; Datta, Dibyadyuti et al. (2015) Nanovaccines for malaria using Plasmodium falciparum antigen Pfs25 attached gold nanoparticles. Vaccine 33:5064-71
Kumar, Rajesh; Ledet, Grace; Graves, Richard et al. (2015) Potent Functional Immunogenicity of Plasmodium falciparum Transmission-Blocking Antigen (Pfs25) Delivered with Nanoemulsion and Porous Polymeric Nanoparticles. Pharm Res 32:3827-36
Datta, Dibyadyuti; Bansal, Geetha P; Kumar, Rajesh et al. (2015) Evaluation of the Impact of Codon Optimization and N-Linked Glycosylation on Functional Immunogenicity of Pfs25 DNA Vaccines Delivered by In Vivo Electroporation in Preclinical Studies in Mice. Clin Vaccine Immunol 22:1013-9
Lukianova-Hleb, Ekaterina; Bezek, Sarah; Szigeti, Reka et al. (2015) Transdermal Diagnosis of Malaria Using Vapor Nanobubbles. Emerg Infect Dis 21:1122-7
Kumar, Rajesh; Angov, Evelina; Kumar, Nirbhay (2014) Potent malaria transmission-blocking antibody responses elicited by Plasmodium falciparum Pfs25 expressed in Escherichia coli after successful protein refolding. Infect Immun 82:1453-9

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