Updated insights into the mechanism of action and clinical profile of the immunoadjuvant QS-21: A review

Abstract

Background: Vaccine adjuvants are compounds that significantly enhance/prolong the immune response to a coadministered antigen. The limitations of the use of aluminium salts that are unable to elicite cell responses against intracellular pathogens such as those causing malaria, tuberculosis, or AIDS, have driven the development of new alternative adjuvants such as QS-21, a triterpene saponin purified from Quillaja saponaria. Purpose: The aim of this review is to attempt to clarify the mechanism of action of QS-21 through either receptors or signaling pathways in vitro and in vivo with special emphasis on the co-administration with other immunostimulants in new adjuvant formulations, called adjuvant systems (AS). Furthermore, the most relevant clinical applications will be presented. Methods: A literature search covering the period 2014-2018 was performed using electronic databases from Sci finder, Science direct, Medline/Pubmed, Scopus, Google scholar. Results: Insights into the mechanism of action of QS-21 can be summarized as follows: 1) in vivo stimulation of Th2 humoral and Th1 cell-mediated immune responses through action on antigen presenting cells (APCs) and T cells, leading to release of Th1 cytokines participating in the elimination of intracellular pathogens. 2) activation of the NLRP3 inflammasome in mouse APCs with subsequent release of caspase-1 dependent cytokines, Il-1β and Il-18, important for Th1 responses. 3) synthesis of nearly 50 QS-21 analogs, allowing structure/activity relationships and mechanistic studies. 4) unique synergy mechanism between monophosphoryl lipid A (MPL A) and QS-21, formulated in a liposome (AS01) in the early IFN-γ response, promoting vaccine immunogenicity. The second part of the review is related to phase I-III clinical trials of QS-21, mostly formulated in ASs, to evaluate efficacy, immunogenicity and safety of adjuvanted prophylactic vaccines against infectious diseases, e.g. malaria, herpes zoster, tuberculosis, AIDS and therapeutic vaccines against cancer and Alzheimer's disease. Conclusion: The most advanced phase III clinical applications led to the development of two vaccines containing QS-21 as part of the AS, the Herpes Zoster vaccine (HZ/su) (Shingrix™) which received a license in 2017 from the FDA and a marketing authorization in the EU in 2018 and the RTS,S/AS01 vaccine (Mosquirix™) against malaria, which was approved by the EMA in 2015 for further implementation in Sub-Saharan countries for routine use.2014 have made the research on vaccines very attractive in the last decades (Lee and Nguyen, 2015). Modern subunit vaccines comprising homogeneous molecular antigens have been developed to prevent and treat many human diseases, but they are weakly immunogenic and must be administered with an adjuvant to elicit a potent immune response. Adjuvants whose name originates from the Latin word adjuvare https://doi.

Targeting Inflammation and Immunosenescence to Improve Vaccine Responses in the Elderly

“…Whist the molecular mechanisms underlying the adjuvant effect of QS-21 are not yet fully understood, it has been demonstrated that it induces strong and persistent Th2 humoral and Th1 cell-mediated immune responses ( 105 ). It is thought that the use of liposomal formulations facilitates the escape of the antigen into the cytosol enhancing antigen-presentation through MHC-I pathway leading to cross-presentation to CD8 + T cells and an early IFN-gamma response that promotes vaccine immunogenicity ( 106 ). Interestingly, the AS01B adjuvant system seems to require the synergistic action of the three components together for optimal adjuvant effect ( 107 ).…”

Inflammasomes as Targets for Adjuvants

“…They were used in more than 100 human clinical trials [70,71] where they demonstrated the ability to induce humoral and cell-mediated immune response against a wide range of antigens [72]. Also, the QS-21 fraction was superior to aluminum salts because they induced a Th1-type immune response, which is essential for controlling intracellular pathogens [73].…”

Respiratory Syncytial Virus F Subunit Vaccine With AS02 Adjuvant Elicits Balanced, Robust Humoral and Cellular Immunity in BALB/c Mice

“…Additionally MPL is a TLR-4 receptor agonist, which stimulates helper T cells to produce interferon-γ (IFN-γ) and induces plasma cells to express IgG2a antibodies (30). QS-21, a saponin extracted from Q. saponaria tree bark, promotes antigen-specific antibody responses and CD8+ T-cell responses in mice (31). Besides squalene-based adjuvants, chitosan has also attracted attention as a vaccine adjuvant.…”