scholarly journals Immunofocusing humoral immunity potentiates the functional efficacy of the AnAPN1 malaria transmission-blocking vaccine antigen

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Nicole G. Bender ◽  
Prachi Khare ◽  
Juan Martinez ◽  
Rebecca E. Tweedell ◽  
Vincent O. Nyasembe ◽  
...  
Keyword(s):  
Malaria Transmission ◽  
Humoral Response ◽  
Vaccine Antigen ◽  
Mosquito Vector ◽  
Transmission Blocking ◽  
Cd1 Mice ◽  
Alanyl Aminopeptidase ◽  
Antigen Structure ◽  
Transmission Blocking Vaccines ◽  
Transmission Blocking Vaccine

AbstractMalaria transmission-blocking vaccines (TBVs) prevent the completion of the developmental lifecycle of malarial parasites within the mosquito vector, effectively blocking subsequent infections. The mosquito midgut protein Anopheline alanyl aminopeptidase N (AnAPN1) is the leading, mosquito-based TBV antigen. Structure-function studies identified two Class II epitopes that can induce potent transmission-blocking (T-B) antibodies, informing the design of the next-generation AnAPN1. Here, we functionally screened new immunogens and down-selected to the UF6b construct that has two glycine-linked copies of the T-B epitopes. We then established a process for manufacturing UF6b and evaluated in outbred female CD1 mice the immunogenicity of the preclinical product with the human-safe adjuvant Glucopyranosyl Lipid Adjuvant in a liposomal formulation with saponin QS21 (GLA-LSQ). UF6b:GLA-LSQ effectively immunofocused the humoral response to one of the key T-B epitopes resulting in potent T-B activity, underscoring UF6b as a prime TBV candidate to aid in malaria elimination and eradication efforts.

scholarly journals Immunofocusing humoral immunity potentiates the functional efficacy of the AnAPN1 malaria transmission-blocking vaccine antigen

2020 ◽  
Author(s):  
Nicole G. Bender ◽  
Prachi Khare ◽  
Juan Martinez ◽  
Rebecca E. Tweedell ◽  
Vincent O. Nyasembe ◽  
...  
Keyword(s):  
Malaria Transmission ◽  
Malaria Elimination ◽  
Humoral Response ◽  
Vaccine Antigen ◽  
Mosquito Vector ◽  
Transmission Blocking ◽  
Cd1 Mice ◽  
Alanyl Aminopeptidase ◽  
Transmission Blocking Vaccines ◽  
Transmission Blocking Vaccine

AbstractMalaria transmission-blocking vaccines (TBVs) are a critical tool for disease elimination. TBVs prevent completion of the developmental lifecycle of malarial parasites within the mosquito vector, effectively blocking subsequent infections. The mosquito midgut protein Anopheline alanyl aminopeptidase N (AnAPN1) is the leading, mosquito-based TBV antigen and structure-function studies have identified two Class II epitopes that induce potent transmission-blocking (T-B) antibodies. Here, we functionally screened new immunogens and down-selected to the UF6b construct that has two glycine-linked copies of the T-B epitopes. We established a process for manufacturing UF6b and evaluated in outbred female CD1 mice the immunogenicity of the preclinical product with the human-safe adjuvant Glucopyranosyl Lipid Adjuvant in a liposomal formulation with saponin QS21 (GLA-LSQ). UF6b:GLA-LSQ was immunogenic and immunofocused the humoral response to one of the key T-B epitopes resulting in potent T-B activity and establishing UF6b as a prime TBV candidate to aid in malaria elimination and eradication efforts.

scholarly journals The fibrinogen-like domain of FREP1 protein is a broad-spectrum malaria transmission-blocking vaccine antigen

2017 ◽  
Vol 292 (28) ◽  
pp. 11960-11969 ◽  
Author(s):  
Guodong Niu ◽  
Caio Franc̨a ◽  
Genwei Zhang ◽  
Wanlapa Roobsoong ◽  
Wang Nguitragool ◽  
...  
Keyword(s):  
Malaria Transmission ◽  
Broad Spectrum ◽  
Vaccine Antigen ◽  
Transmission Blocking ◽  
Transmission Blocking Vaccine

scholarly journals Elucidating functional epitopes within the N-terminal region of malaria transmission blocking vaccine antigen Pfs230

npj Vaccines ◽  
2022 ◽  
Vol 7 (1) ◽  
Author(s):  
Kazutoyo Miura ◽  
Eizo Takashima ◽  
Thao P. Pham ◽  
Bingbing Deng ◽  
Luwen Zhou ◽  
...  
Keyword(s):  
Malaria Transmission ◽  
Synthetic Peptide ◽  
Vaccine Antigen ◽  
Parasite Development ◽  
Transmission Blocking ◽  
Peptide Antigens ◽  
Membrane Feeding ◽  
Functional Antibodies ◽  
Enrichment Techniques ◽  
Transmission Blocking Vaccine

AbstractPfs230 is a leading malaria transmission blocking vaccine (TBV) candidate. Comprising 3135 amino acids (aa), the large size of Pfs230 necessitates the use of sub-fragments as vaccine immunogens. Therefore, determination of which regions induce functional antibody responses is essential. We previously reported that of 27 sub-fragments spanning the entire molecule, only five induced functional antibodies. A “functional” antibody is defined herein as one that inhibits Plasmodium falciparum parasite development in mosquitoes in a standard membrane-feeding assay (SMFA). These five sub-fragments were found within the aa 443–1274 range, and all contained aa 543–730. Here, we further pinpoint the location of epitopes within Pfs230 that are recognized by functional antibodies using antibody depletion and enrichment techniques. Functional epitopes were not found within the aa 918–1274 region. Within aa 443–917, further analysis showed the existence of functional epitopes not only within the aa 543–730 region but also outside of it. Affinity-purified antibodies using a synthetic peptide matching aa 543–588 showed activity in the SMFA. Immunization with a synthetic peptide comprising this segment, formulated either as a carrier-protein conjugate vaccine or with a liposomal vaccine adjuvant system, induced antibodies in mice that were functional in the SMFA. These findings provide key insights for Pfs230-based vaccine design and establish the feasibility for the use of synthetic peptide antigens for a malaria TBV.

scholarly journals Murine Model for Assessment of Plasmodium falciparum Transmission-Blocking Vaccine Using Transgenic Plasmodium berghei Parasites Expressing the Target Antigen Pfs25

2008 ◽  
Vol 76 (5) ◽  
pp. 2018-2024 ◽  
Author(s):  
Godfree Mlambo ◽  
Jorge Maciel ◽  
Nirbhay Kumar
Keyword(s):  
Animal Model ◽  
Plasmodium Falciparum ◽  
Malaria Transmission ◽  
Plasmodium Berghei ◽  
Target Antigen ◽  
Wild Type ◽  
Transmission Blocking ◽  
Transmission Blocking Vaccines ◽  
Transmission Blocking Vaccine

ABSTRACT Currently, there is no animal model for Plasmodium falciparum challenge to evaluate malaria transmission-blocking vaccines based on the well-established Pfs25 target antigen. The biological activity of transmission-blocking antibodies is typically assessed using an assay known as the membrane feeding assay (MFA). It is an in vitro method that involves mixing antibodies with cultured P. falciparum gametocytes and feeding them to mosquitoes through an artificial membrane followed by assessment of infection in the mosquitoes. We genetically modified Plasmodium berghei to express Pfs25 and demonstrated that the transgenic parasites (TrPfs25Pb) are susceptible to anti-Pfs25 antibodies during mosquito-stage development. The asexual growth kinetics and mosquito infectivity of TrPfs25Pb were comparable to those of wild-type parasites, and TrPfs25Pb displayed Pfs25 on the surface of ookinetes. Immune sera from nonhuman primates immunized with a Pfs25-based vaccine when passively transferred to mice blocked transmission of TrPfs25Pb to Anopheles stephensi. Furthermore, mice immunized with Pfs25 DNA vaccine and challenged with TrPfs25Pb displayed reduced malaria transmission compared to mice immunized with wild-type plasmid. These studies describe development of an animal malaria model alternative to the in vitro MFA and show that the model can facilitate P. falciparum transmission-blocking vaccine evaluation based on the target antigen Pfs25. We believe that an animal model to test transmission-blocking vaccines would be superior to the MFA, since there may be additional immune factors that synergize the transmission-blocking activity of antibodies in vivo.

scholarly journals Nasal Immunization with a Malaria Transmission-Blocking Vaccine Candidate, Pfs25, Induces Complete Protective Immunity in Mice against Field Isolates of Plasmodium falciparum

2005 ◽  
Vol 73 (11) ◽  
pp. 7375-7380 ◽  
Author(s):  
Takeshi Arakawa ◽  
Ai Komesu ◽  
Hitoshi Otsuki ◽  
Jetsumon Sattabongkot ◽  
Rachanee Udomsangpetch ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Transmission ◽  
Vaccine Candidate ◽  
Expression Patterns ◽  
Serum Antibody ◽  
Biologically Active ◽  
Mucosal Transmission ◽  
Transmission Blocking ◽  
Transmission Blocking Vaccines ◽  
Transmission Blocking Vaccine

ABSTRACT Malaria transmission-blocking vaccines based on antigens expressed in sexual stages of the parasites are considered one promising strategy for malaria control. To investigate the feasibility of developing noninvasive mucosal transmission-blocking vaccines against Plasmodium falciparum, intranasal immunization experiments with Pichia pastoris-expressed recombinant Pfs25 proteins were conducted. Mice intranasally immunized with the Pfs25 proteins in the presence of a potent mucosal adjuvant cholera toxin induced robust systemic as well as mucosal antibodies. All mouse immunoglobulin G (IgG) subclasses except IgG3 were found in serum at comparable levels, suggesting that the immunization induced mixed Th1 and Th2 responses. Consistent with the expression patterns of the Pfs25 proteins in the parasites, the induced immune sera specifically recognized ookinetes but not gametocytes. In addition, the immune sera recognized Pfs25 proteins with the native conformation but not the denatured forms, indicating that mucosal immunization induced biologically active antibodies capable of recognizing conformational epitopes of native Pfs25 proteins. Feeding Anopheles dirus mosquitoes with a mixture of the mouse immune sera and gametocytemic blood derived from patients infected with P. falciparum resulted in complete interference with oocyst development in mosquito midguts. The observed transmission-blocking activities were strongly correlated with specific serum antibody titers. Our results demonstrated for the first time that a P. falciparum transmission-blocking vaccine candidate is effective against field-isolated parasites and may justify the investigation of noninvasive mucosal vaccination regimens for control of malaria, a prototypical mucosa-unrelated mosquito-borne parasitic disease.

scholarly journals Potent antibody lineage against malaria transmission elicited by human vaccination with Pfs25

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Brandon McLeod ◽  
Kazutoyo Miura ◽  
Stephen W. Scally ◽  
Alexandre Bosch ◽  
Ngan Nguyen ◽  
...  
Keyword(s):  
Malaria Transmission ◽  
Affinity Maturation ◽  
Human Antibody ◽  
Blocking Antibody ◽  
Transmission Blocking ◽  
Clinical Models ◽  
Humoral Responses ◽  
Transmission Blocking Vaccines ◽  
Transmission Blocking Vaccine

Abstract Transmission-blocking vaccines have the potential to be key contributors to malaria elimination. Such vaccines elicit antibodies that inhibit parasites during their development in Anopheles mosquitoes, thus breaking the cycle of transmission. To date, characterization of humoral responses to Plasmodium falciparum transmission-blocking vaccine candidate Pfs25 has largely been conducted in pre-clinical models. Here, we present molecular analyses of human antibody responses generated in a clinical trial evaluating Pfs25 vaccination. From a collection of monoclonal antibodies with transmission-blocking activity, we identify the most potent transmission-blocking antibody yet described against Pfs25; 2544. The interactions of 2544 and three other antibodies with Pfs25 are analyzed by crystallography to understand structural requirements for elicitation of human transmission-blocking responses. Our analyses provide insights into Pfs25 immunogenicity and epitope potency, and detail an affinity maturation pathway for a potent transmission-blocking antibody in humans. Our findings can be employed to guide the design of improved malaria transmission-blocking vaccines.

scholarly journals Structural delineation of human antibody responses against malaria transmission-blocking vaccine antigen Pfs25

2018 ◽  
Vol 74 (a1) ◽  
pp. a255-a255
Author(s):  
Brandon McLeod ◽  
Kazutoyo Miura ◽  
Stephen W. Scally ◽  
Alexandre Bosch ◽  
Sebastian Rämisch ◽  
...  
Keyword(s):  
Malaria Transmission ◽  
Antibody Responses ◽  
Vaccine Antigen ◽  
Human Antibody ◽  
Transmission Blocking ◽  
Transmission Blocking Vaccine
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