Toward the development of effective transmission-blocking vaccines for malaria

Abstract

The continued global burden of malaria can in part be attributed to a complex lifecycle, with both human hosts and mosquito vectors serving as transmission reservoirs. In preclinical models of vaccine-induced immunity, antibodies to parasite sexual-stage antigens, ingested in the mosquito blood meal, can inhibit parasite survival in the insect midgut as judged by ex vivo functional studies such as the membrane feeding assay. In an era of renewed political momentum for malaria elimination and eradication campaigns, such observations have fueled support for the development and implementation of so-called transmission-blocking vaccines. While leading candidates are being evaluated using a variety of promising vaccine platforms, the field is also beginning to capitalize on global ‘-omics’ data for the rational genome-based selection and unbiased characterization of parasite and mosquito proteins to expand the candidate list. This review covers the progress and prospects of these recent developments.

Keywords:

• genome
• malaria
• membrane feeding assay
• Plasmodium falciparum
• transmission-blocking vaccine

Acknowledgements

The authors are grateful to C Long and K Miura for useful discussions and comments on the manuscript.

Financial & competing interests disclosure

D Nikolaeva is a student of the NIH-Oxford/Cambridge Scholars Program; this publication was supported in part by the Intramural Research Program of the NIAID/NIH. SJ Draper is a UK Medical Research Council Career Development Fellow (Grant G1000527), Jenner Investigator and Lister Institute Research Prize Fellow. He is a named inventor on patent applications covering malaria vaccines and immunization regimes. S Biswas is a NDM Leadership Fellow and Junior Research Fellow of St Catherine’s College, Oxford University. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The sexual stages of the malaria parasite can be targeted through vaccine strategies that induce transmission-blocking antibodies in the human host.

• Existing protein-in-adjuvant formulations with leading candidate antigens Pfs25 and Pvs25 have not consistently generated high titer, durable antibody responses in early clinical studies of safety and immunogenicity.

• Preclinical studies suggest that the immune response to Pfs25 and Pvs25 can be improved by protein conjugation strategies and novel delivery platforms.

• Existing transcriptomic and proteomic datasets emphasize that the existing list of proteins shown to elicit transmission-blocking antibodies may only be a small subset of available transmission-blocking vaccine targets.

• At this time, there is no comparative preclinical testing pipeline for previously uncharacterized candidate antigens.

• Promoting more candidates into clinical studies is necessary to improve the preclinical process by evaluating the biological relevance of the standard membrane feeding assay and other functional studies.

• A safe and effective transmission-blocking vaccine will be a necessary tool in meeting the goals of the elimination and eradication agenda.