A delayed fractionated dose RTS,S AS01 vaccine regimen mediates protection via improved T follicular helper and B cell responses
Suresh Pallikkuth,
Sidhartha Chaudhury,
Pinyi Lu,
Li Pan,
Erik Jongert,
Ulrike Wille-Reece,
Savita Pahwa
Affiliations
Suresh Pallikkuth
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, United States
Sidhartha Chaudhury
Biotechnology HPC Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, United States
Pinyi Lu
Biotechnology HPC Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, United States; Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, United States
Li Pan
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, United States
Erik Jongert
GSK Vaccine, Rixensart, Belgium
Ulrike Wille-Reece
PATH’s Malaria Vaccine Initiative, Washington DC, United States
Malaria-071, a controlled human malaria infection trial, demonstrated that administration of three doses of RTS,S/AS01 malaria vaccine given at one-month intervals was inferior to a delayed fractional dose (DFD) schedule (62.5% vs 86.7% protection, respectively). To investigate the underlying immunologic mechanism, we analyzed the B and T peripheral follicular helper cell (pTfh) responses. Here, we show that protection in both study arms was associated with early induction of functional IL-21-secreting circumsporozoite (CSP)-specific pTfh cells, together with induction of CSP-specific memory B cell responses after the second dose that persisted after the third dose. Data integration of key immunologic measures identified a subset of non-protected individuals in the standard (STD) vaccine arm who lost prior protective B cell responses after receiving the third vaccine dose. We conclude that the DFD regimen favors persistence of functional B cells after the third dose.
