Structural vaccinology of malaria transmission-blocking vaccines

ABSTRACT

Introduction: The development of effective vaccines remains a major health priority to combat the global burden of malaria, a life-threatening disease caused by Plasmodium parasites. Transmission-blocking vaccines (TBVs) elicit antibodies that neutralize the sexual stages of the parasite in blood meals ingested by the Anopheles mosquito, interrupting parasite development in the vector host and preventing disease spread to other individuals.

Areas covered: The P. falciparum gametocyte surface antigens Pfs230, Pfs48/45, and Pfs47, the parasite ookinete surface protein Pfs25, and the male gametocyte specific protein PfHAP2 are leading TBV candidates, some of which are in clinical development. The recent expansion of methodology to study monoclonal antibodies isolated directly from humans and animal models, coupled with effective measures for parasite neutralization, has provided unprecedented insight into TBV efficacy and development.

Expert opinion: Available structural and functional data on antigen-monoclonal antibody (Ag-mAb) complexes, as well as epitope classification studies, have identified neutralizing epitopes that may aid vaccine development and improve protection. Here, we review the clinical prospects of TBV candidates, progress in the development of novel vaccine strategies for TBVs, and the impact of structural vaccinology in TBV design.

KEYWORDS:

• Malaria
• monoclonal antibodies
• plasmodium falciparum
• standard membrane feeding assay
• structural vaccinology
• transmission blocking vaccine
• vaccine design
• ookinete
• gametocyte
• gamete
• zygote
• fertilization
• pfs230
• pfs48/45
• pfs47
• pfs25
• pfhap2

Article Highlights

• Transmission blocking vaccines (TBVs) elicit human antibodies that neutralize the sexual stages of the malaria parasite in the mosquito vector to prevent sporozoite development and transmission to another human.

• The P. falciparum gametocyte surface antigens Pfs230, Pfs48/45, and Pfs47, the parasite ookinete surface protein Pfs25, and the male gametocyte specific protein PfHAP2 are leading TBV candidates, some of which are in clinical development.

• TBV antigens contain conserved domains including the 6-Cys domain, EGF-like domain and HAP2/GCS1 domain.

• Available structure data for TBV candidates provide a guide for the development of potent novel vaccine strategies and structure-based immunogen design to focus and enhance antibody responses to sites associated with potent inhibitory activity.

• Clinical studies suggest that the nanoparticle-based platforms such as virus-like particles (VLPs) or with carriers such as exoprotein A (EPA) have elicited enhanced immune response against target antigens with great success.

Declaration of interest

N H Tolia is the recipient of NIH awards 1ZIAAI001236, 1ZIAAI001237 and 1ZIAAI001253. The authors have no other 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.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Acknowledgments

The authors would like to thank J Patrick Gorres (LMIV, NIAID for assistance with manuscript editing and Wai Kwan Tang for critical review of the manuscript.

Additional information

Funding

This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.