A delayed fractionated dose RTS,S AS01 vaccine regimen mediates protection via improved T follicular helper and B cell responses.

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 2(nd) dose that persisted after the 3(rd) 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 3(rd) vaccine dose. We conclude that the DFD regimen favors persistence of functional B cells post 3(rd) dose.