Adjuvant system AS01: helping to overcome the challenges of modern vaccines

Figures & data

Figure 1. Current model of innate control of adaptive immunity. Adapted from Ishii et al. Curr Pharm Des 2006;12: 4135–42 © Bentham Science Publishers. Reproduced with permission. Immune responses to infection occur over a timescale of minutes to years (upper graph). Innate immune responses act minutes after infection, begin to clear the pathogen, and lasts for several days. While the adaptive immune responses are mount during the following weeks to generate a long lasting immunological memory. Minutes after a pathogen or vaccine enters the body, antigens are detected by the immune system (lower graph). Antigen-presenting cells take up, process and present these antigens to T cells. This first signal (1) is antigen-specific. It is provided through the T cell receptor which interacts with peptide-MHC molecules on the membrane of antigen presenting cells (APC). When additional signals (2) (pathogen defence triggers or adjuvants) are also recognized by pattern recognition receptors, pro-inflammatory cytokine production and up-regulation of co-stimulatory molecules occur (3). APCs activated by signals (1 + 2 (3)) promote naïve T cells to initiate adaptive immune responses, including T cell help for B cells and development of immune memory. Vaccine adjuvants can mimic immune defence triggers bore by pathogens (2) and contribute to elicit the activation of T-cells by antigen-presenting cells. Activation of T cells without defence triggers and co-stimulatory molecules/cytokines (ie. only signal (1)) may lead to tolerance/ignorance.

Figure 2. Immune responses following vaccination with AS01-adjuvanted vaccine at the injection site (muscle). The immune response to an AS01-adjuvanted vaccine injected into a muscle involves multiple cellular interactions. The adjuvant effect requires the spatial and temporal co-localization of AS01 and antigen. The two immune-stimulatory components of AS01, MPL and QS-21, act synergistically together to stimulate the release of immune mediators by innate cells allowing an enhanced neutrophil and monocyte recruitment at the injection site. The AS01-adjuvanted vaccine induces an early and transient activation of the innate immune response. Cellular and cytokine responses peak at day 1 and are fully resolved by day 7.

Figure 3. Concentrations of cytokines in muscle and draining lymph node after injection with AS01 and gE antigen (data from [34]). In mice, AS01 induced rapid and transient cytokine production at the injection site in muscle and in the draining lymph node compared with antigen alone (gE/AS01 versus gE/no adjuvant). Graphs show geometric mean of cytokine concentrations (IL6, CXCL1, CCL2 and CXCL9 (ng/ml)) from tissue homogenates at 3, 6, 24, 48 and 168 hours (7 days) after injection.

Figure 4. Immune responses following vaccination with AS01-adjuvanted vaccine in the draining lymph node. Some early immunological events occurring at the injection site contribute to the immune response in the draining lymph node. Those include (i) the rapid drainage of some antigen and adjuvant within 30 minutes after vaccination and (ii) hours later, the migration, among other innate cells, of dendritic cells recruited from the injection site. While migrating to the draining lymph node, those dendritic cells breakdown/ present antigens and mature into efficient antigen presenting cells. In the draining lymph node, AS01 and antigen may activate resident dendritic cells. Those latter forms, with dendritic cells coming from the injection site form, a broad population of highly activated dendritic cells efficient at activating T cells. Activated T cells differentiate into effector populations and at a later stage into memory cells, meant to persist in our body to provide long term protection. Cytokines secreted by effector CD4 positive T cells stimulate antigen-specific B cells to divide into antibody-secreting cells and memory B cells. Ultimately, those memory and effector T or B cells, as well as antibodies, will leave the lymph node and enter the bloodstream.

Didierlaurent AM, Collignon C, Bourguignon P, et al. Enhancement of adaptive immunity by the human vaccine adjuvant AS01 depends on activated dendritic cells. J Immunol. 2014;193:1920–1930.

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