AS01 is a liposome-based vaccine adjuvant system containing two immunostimulants: 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and saponin QS-21. In clinical trials across multiple age groups, AS01-adjuvanted vaccines for tuberculosis, malaria, herpes zoster, and respiratory syncytial virus have demonstrated efficacy and an acceptable safety profile.
MPL binds to the innate immune receptor Toll-like receptor 4 (TLR4), which belongs to the family of pattern recognition receptors (PRRs). PRRs, such as TLR4, recognize pathogen-associated molecular patterns (PAMPs) and use them to identify threats to immune homeostasis. Upon activation, TLR4 triggers proinflammatory immune responses through a complex signaling pathway involving two adaptor molecules, including: Myd88 (myeloid differentiation primary response 88), which controls the release of cytokines, and TRIF (TIR domain-containing adaptor-inducing interferon [IFN]-β), which induces the release of type 1 IFN. However, unlike in mice, MPL signaling in human cells is less efficient at engaging the interferon-regulated transcription factor 3 pathway and does not induce type 1 IFN in vitro.
QS-21 accumulates in resident macrophages of draining lymph nodes (dLNs) and activates caspase-1, an enzyme that cleaves proteins such as interleukin-1β (IL-1β) and IL-18 into their active, mature forms. These events stimulate the production of proinflammatory cytokines and the recruitment and activation of innate immune cells, such as dendritic cells. The adjuvant effect of QS-21 depends on the integration of caspase-1 and Myd88 pathways, along with the release of HMGB1 (high mobility group protein B1).
The combination of MPL and QS-21 induces an innate signature that is not observed when the individual components are administered alone. This may result from two combined effects. First, MPL and QS-21 share signaling pathways, and complex signal integration may occur when innate cells are exposed to both immunostimulants. Second, MPL and QS-21 activate different cell types, creating a network of innate effector functions. Both mechanisms have been reported as a means of signal amplification in initiating antimicrobial responses and may lead to improved responses to vaccine antigens.
Figure. 1 Schematic representation of the cellular mechanism signaling pathways triggered by MPL and QS-21. (Roman, F., et al. 2024)
Following injection, AS01 and the antigen rapidly travel to the draining lymph node, where they initiate multiple layers of cell–cell interactions that enhance AS01's adjuvant effect. a) Chemokines involved in cell recruitment are released, leading to the infiltration of various dendritic cell populations, likely increasing the presenting frequency of antigen-presenting cells (APCs). Concurrently, resident macrophages are activated. b) These dendritic cells and macrophages secrete cytokines, such as IL-12 and IL-18, which amplify innate immune responses and activate resident NK cells within the lymph node. c) These processes effectively prime antigen-specific T cells, which, in turn, support the activation and maturation of B cells. This promotes a robust CD4+ T cell helper response and broad humoral immunity following vaccination.
Figure. 2 Schematic representation of the mode of action of AS01. (Roman, F., et al. 2024)
Advantages of Adjuvant System AS01
1. Enhanced immune response: AS01 adjuvants enhance the immune response of vaccines by increasing the immune system's resistance to antigens. They activate antigen-presenting cells, promote immune cell activity, enhance antibody specificity, and induce cellular immune responses, thereby increasing the immunogenicity of vaccines.
2. Long-term protective effect: AS01 adjuvants provide longer-term immune protection. They stimulate the production and survival of immune memory cells, which can quickly initiate immune responses upon re-infection, leading to the production of a large number of antibodies and cellular immune responses, thus prolonging the duration of immune protection.
3. Good safety: AS01 adjuvants have demonstrated good safety and tolerability in clinical trials. They have been thoroughly studied and evaluated, with a low incidence of adverse reactions, and meet relevant safety standards and regulations.
Applications of Adjuvant System AS01
1. Malaria vaccine: AS01 is used in the RTS,S/AS01 malaria vaccine, designed to prevent Plasmodium falciparum malaria. The RTS,S/AS01 vaccine was jointly developed by GlaxoSmithKline (GSK) and the Walter Reed Army Institute of Research (WRAIR) over 35 years and was eventually approved by the WHO for use in children in moderately to highly malaria-endemic areas of Africa.
2. Herpes zoster vaccine: The AS01 adjuvant is a component of the Shingrix vaccine, which is used to prevent herpes zoster (shingles) in adults. Shingrix contains recombinant VZV glycoprotein E (gE), the most abundant glycoprotein on the surface of VZV, along with the potent adjuvant AS01B. The vaccine is over 90% effective in preventing herpes zoster and postherpetic neuralgia in individuals aged 50 and above.
3. Tuberculosis vaccine: M72/AS01E is a subunit vaccine candidate composed of an immunogenic fusion protein (M72) derived from two Mycobacterium tuberculosis antigens (MTB32A and MTB39A) and AS01E adjuvant. In humans, the M72/AS01E vaccine stimulates high levels of cytokines and NK cells.
4. HIV vaccine: The AS01 adjuvant is also being studied for use in HIV vaccine candidates to elicit a stronger immune response against the virus. The F4/AS01B vaccine is an investigational HIV-1 vaccine consisting of a recombinant fusion protein (F4), which contains four HIV-1 subtype B antigens combined with the AS01B adjuvant system. The F4/AS01B vaccine has demonstrated a clinically acceptable safety profile and induces polyfunctional F4-specific CD4+ T cell responses in both HIV-1 seronegative adults and HIV-1-infected adults.
5. Other infectious diseases: Due to its ability to enhance both humoral and cellular immune responses, the AS01 adjuvant may have broader applications in vaccines targeting other infectious diseases, including respiratory syncytial virus (RSV) and cytomegalovirus (CMV).
References
- Roman F, et al.; Adjuvant system AS01: from mode of action to effective vaccines. Expert Rev Vaccines. 2024, 23(1):715-729.
- Pulendran, B., et al.; Emerging concepts in the science of vaccine adjuvants. Nature Reviews Drug Discovery. 2021, 20(6), 454-475.
