Enhancement of Adaptive Immunity by the Human Vaccine Adjuvant AS01 Depends on Activated Dendritic Cells

TLDR

AS01 is a liposome‑based adjuvant comprising MPL and QS‑21 that has been selected for phase III development of several candidate vaccines, including RTS,S malaria and varicella‑zoster subunit vaccines. This study aimed to characterize the early immune response after AS01‑adjuvanted vaccination and to relate these early events to the ensuing antigen‑specific adaptive immunity. Rapid cytokine production and innate cell recruitment at the injection site and draining lymph node, coupled with a transient increase in activated MHCII^high dendritic cells, were required for robust antigen‑specific antibody and T‑cell responses, indicating that AS01 enhances adaptive immunity by transient innate stimulation that generates efficient antigen‑presenting dendritic cells.

Abstract

Abstract Adjuvant System AS01 is a liposome-based vaccine adjuvant containing 3-O-desacyl-4′-monophosphoryl lipid A and the saponin QS-21. AS01 has been selected for the clinical development of several candidate vaccines including the RTS,S malaria vaccine and the subunit glycoprotein E varicella zoster vaccine (both currently in phase III). Given the known immunostimulatory properties of MPL and QS-21, the objective of this study was to describe the early immune response parameters after immunization with an AS01-adjuvanted vaccine and to identify relationships with the vaccine-specific adaptive immune response. Cytokine production and innate immune cell recruitment occurred rapidly and transiently at the muscle injection site and draining lymph node postinjection, consistent with the rapid drainage of the vaccine components to the draining lymph node. The induction of Ag-specific Ab and T cell responses was dependent on the Ag being injected at the same time or within 24 h after AS01, suggesting that the early events occurring postinjection were required for these elevated adaptive responses. In the draining lymph node, after 24 h, the numbers of activated and Ag-loaded monocytes and MHCIIhigh dendritic cells were higher after the injection of the AS01-adjuvanted vaccine than after Ag alone. However, only MHCIIhigh dendritic cells appeared efficient at and necessary for direct Ag presentation to T cells. These data suggest that the ability of AS01 to improve adaptive immune responses, as has been demonstrated in clinical trials, is linked to a transient stimulation of the innate immune system leading to the generation of high number of efficient Ag-presenting dendritic cells.