Preparation, crystallization and preliminary X-ray analysis of a complex between thePlasmodium vivaxsexual stage 25 kDa protein Pvs25 and a malaria transmission-blocking antibody Fab fragment

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.

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Crystallization and preliminary x-ray diffraction studies of the Fab fragment of a neutralizing monoclonal antibody directed against human rhinovirus serotype 2.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)44831-9 ◽

1990 ◽

Vol 265 (28) ◽

pp. 16799-16800

Author(s):

J Tormo ◽

I Fita ◽

O Kanzler ◽

D Blaas

Keyword(s):

Monoclonal Antibody ◽

Human Rhinovirus ◽

X Ray Diffraction ◽

Fab Fragment ◽

X Ray ◽

Neutralizing Monoclonal Antibody

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Structural vaccinology of malaria transmission-blocking vaccines

Expert Review of Vaccines ◽

10.1080/14760584.2021.1873135 ◽

2021 ◽

pp. 1-16 ◽

Cited By ~ 1

Author(s):

Palak N. Patel ◽

Niraj Tolia

Keyword(s):

Malaria Transmission ◽

Transmission Blocking ◽

Structural Vaccinology ◽

Transmission Blocking Vaccines

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Crystallization and preliminary X-ray investigation of a complex between a Fab fragment and its antigen, cyclosporin

Journal of Molecular Biology ◽

10.1016/0022-2836(89)90181-2 ◽

1989 ◽

Vol 209 (1) ◽

pp. 177-178 ◽

Cited By ~ 7

Author(s):

Danièle Altschuh ◽

Hans-Peter Kocher ◽

Valérie F.J. Quesniaux ◽

Doris Schmitter ◽

Marc H.V. Van Regenmortel ◽

...

Keyword(s):

Fab Fragment ◽

X Ray

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Characterization of the effector mechanisms of a transmission-blocking antibody upon differentiation ofPlasmodium bergheigametocytes into ookinetesin vitro

Parasitology ◽

10.1017/s0031182000077702 ◽

1994 ◽

Vol 109 (1) ◽

pp. 11-17 ◽

Cited By ~ 18

Author(s):

G. R. R. Ranawaka ◽

A. R. Alejo-Blanco ◽

R. E. Sinden

Keyword(s):

Mechanisms Of Action ◽

Antibody Activity ◽

Antibody Dependent Cellular Cytotoxicity ◽

Maximal Inhibition ◽

Blocking Antibody ◽

Transmission Blocking ◽

Ammonium Sulphate Precipitation ◽

Papain Digestion ◽

Peripheral Blood Leucocytes

SUMMARYThe transmission-blocking monoclonal antibody 13.1, which recognizes the ookinete surface antigen Pbs21 ofPlasmodium berghei, and an IgG2a isotype control antibody 26.37 were purified by caprylic acid and ammonium sulphate precipitation. Fab fragments were prepared by papain digestion. IgG but not Fab from antibody 13.1 reduced ookinete formation byP. bergheiin culture by as much as 94% at a concentration of 100 μg/ml. There was little difference in antibody efficacy in the range 6·25–400 μg/ml in this assay. The parasite was most sensitive to antibody activity in the first 6–9 h of culture, i.e. the gamete/zygote and early retort stages. Peripheral blood leucocytes (PBL) were essential to achieve maximal inhibition by mAb 13.1 (activity was abrogated totally if PBL were removed). Together the data suggest that one of the mechanisms of action of this antibody is antibody-mediated PBL killing. Phagocytosis of parasites was noted in these experiments in all cultures. We have not attempted in this study to distinguish between Fc-mediated opsonization, as opposed to antibody-dependent cellular cytotoxicity.

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