Monoclonal Antibody Blocking of Malaria in FRG Mice
A Human Monoclonal Antibody Prevents Malaria Infection by Targeting a New Site of Vulnerability on the Parasite
Kisalu et. al, 2018
Mice containing human liver cells can model early-stage malaria infection and test antibody efficacy. A major obstacle in malaria vaccine development is the lack of relevant preclinical models to study how to prevent malaria infection. In this collaboration, scientists use the liver humanized FRG mouse model in which the mouse liver cells have been largely replaced with human liver cells. They demonstrated that their model mirrors infection with the malaria-causing parasite Plasmodium falciparum from mosquito bite through the week-long liver development, and harnessed this to discern the efficacy of a monoclonal antibody derived from Sanaria’s attenuated parasite vaccine. Passive transfer of this antibody conferred high-level, sterile protection against challenge with infected mosquito bites in vivo. This research could hugely benefit our understanding of malaria infection and reduce the high failure rate of human vaccine clinical trials.
Neville K Kisalu1, Azza H Idris, Connor Weidle, Yevel Flores-Garcia, Barbara J Flynn, Brandon K Sack, Sean Murphy, Arne Schon, Ernesto Freire, Joseph R Francica, Alex B Miller, Jason Gregory, Sandra March, Hua-Xin Liao, Barton F Haynes, Kevin Wiehe, Ashley M Trama, Kevin O Saunders, Morgan A Gladden, Anthony Monroe, Mattia Bonsignori, Masaru Kanekiyo , Adam K Wheatley, Adrian B McDermott, S Katie Farney, Gwo-Yu Chuang, Baoshan Zhang, Natasha Kc, Sumana Chakravarty, Peter D Kwong, Photini Sinnis, Sangeeta N Bhatia, Stefan H I Kappe, B Kim Lee Sim, Stephen L Hoffman, Fidel Zavala, Marie Pancera & Robert A Seder
Nat Med. 2018 May;24(4):408-416
Development of a highly effective vaccine or antibodies for the prevention and ultimately elimination of malaria is urgently needed. Here we report the isolation of a number of human monoclonal antibodies directed against the Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) from several subjects immunized with an attenuated Pf whole-sporozoite (SPZ) vaccine (Sanaria PfSPZ Vaccine). Passive transfer of one of these antibodies, monoclonal antibody CIS43, conferred high-level, sterile protection in two different mouse models of malaria infection. The affinity and stoichiometry of CIS43 binding to PfCSP indicate that there are two sequential multivalent binding events encompassing the repeat domain. The first binding event is to a unique ‘junctional’ epitope positioned between the N terminus and the central repeat domain of PfCSP. Moreover, CIS43 prevented proteolytic cleavage of PfCSP on PfSPZ. Analysis of crystal structures of the CIS43 antigen-binding fragment in complex with the junctional epitope determined the molecular interactions of binding, revealed the epitope’s conformational flexibility and defined Asn-Pro-Asn (NPN) as the structural repeat motif. The demonstration that CIS43 is highly effective for passive prevention of malaria has potential application for use in travelers, military personnel and elimination campaigns and identifies a new and conserved site of vulnerability on PfCSP for next-generation rational vaccine design.