Intravenous Vaccination as a Paradigm for Inducing Tissue Resident T Cells and Protection against Malaria and TB

Dr Robert Alan Seder, Chief of the Cellular Immunology Section, Vaccine Research Centre, National Institute of Allergy and Infectious Disease (NIAID) Division of Intramural Research, Bethesda, USA.

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.

Dr. Seder did his postdoctoral training in the Laboratory of Immunology at the National Institute of Allergy and Infectious Diseases (NIAID) under Dr. William Paul from 1989-1993 and in 1994 became Chief of the Clinical Immunology Section in the Laboratory of Clinical Investigation, NIAID.  Dr. Seder was then appointed as Chief of the Cellular Immunology Section in the Vaccine Research Center (VRC) in 2000.  Since joining the VRC, Dr. Seder has focused on understanding the innate and adaptive mechanisms by which various vaccines, adjuvants and delivery approaches mediate protective immunity in pre-clinical models of HIV, Malaria and Tuberculosis infection and tumors.  A major emphasis of Dr. Seder’s work is the translation of these scientific discoveries into clinical vaccine trials against malaria, TB and cancer.  In addition to these vaccine efforts, Dr. Seder will assess whether passive immunization with a recently discovered monoclonal antibody can prevent malaria infection.