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

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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Software and code
Policy information about availability of computer code Data collection X-ray diffraction data were collected at the 08ID-1 beamline at the Canadian Light Source (CLS), processed, and scaled using XDS.

Data analysis
Structures were determined by molecular replacement using Phaser and Pfs25 as a search model. Refinement of the structures was carried out using phenix.refine and model building iterations in Coot. SBGrid was used to access all crystallography software. Molecular modeling of 2544 lineage: All models were generated from the 2544-Pfs25 complex crystal structure. This structure was prepared using QuickPrep in MOE, and models were generated through MOE's residue scanning function. Predicted affinities between antibodies and the antigen were determined by model generation using MOE's scoring algorithms. Resulting homology models were further analyzed using the PDBePISA server.
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Sample size
For SMFA: The mosquitoes were maintained for 8 days and then dissected to count the number of oocysts per midgut in 20 mosquitoes. The best estimate of %TRA, the 95% CI, and significance of inhibition from single or multiple feeds were calculated as previously described using a zero-inflated negative binomial model. The Bliss independence model i.e. assuming mAbs act independently was used to determine the theoretical additive effect.
Data exclusions No data were excluded from the analyses.