From discovery to licensure, the Adjuvant System story

Garçon, Nathalie; Pasquale, Alberta Di

doi:10.1080/21645515.2016.1225635

Cited by 176 publications

(149 citation statements)

References 99 publications

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“…QS-21 from Q. Saponaria (licensed by GSK from Antigenics Inc., a wholly owned subsidiary of Agenus Inc., Lexington, MA, USA) in the early evaluations as an adjuvant was suggested to promote high Agspecific Ab responses and CD8 + T cell responses in mice and high Agspecific Ab responses in humans (Didierlaurent et al, 2014). QS-21, as an amphiphilic compound is known for its hemolytic properties, which can be abrogated through formulation in liposomes in the presence of cholesterol such as in AS01 (Beck et al, 2015;Garçon and Di Pasquale, 2017). This resulted in an acceptable tolerability profile for its use in human vaccines.…”

Section: Adjuvant Systemsmentioning

confidence: 99%

“…QS-21 containing adjuvants have been assessed in more than 100 human clinical trials. AS01 is a key component of the recently developed malaria and HZ vaccines and other candidate vaccines under development against infectious diseases, and cancer Didierlaurent et al, 2017;Garçon and di Pasquale, 2017). Recent clinical studies of prophylactic vaccines against malaria, HZ, HIV, tuberculosis from an efficacy, immunogenicity and safety points of view (Table 1) and of therapeutic vaccines against melanoma, NSCLC and Alzheimer's disease, will be reported below.…”

Section: Clinical Applicationsmentioning

confidence: 99%

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

2019

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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.

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Section: Adjuvant Systemsmentioning

confidence: 99%

Section: Clinical Applicationsmentioning

confidence: 99%

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

2019

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“…also responsible for enhanced antigen uptake, by monocytes in particular, and antigen presentation in the dLNs; this process is mediated by the presence of α-tocopherol in AS03 [15,16]. The safety of squalene-based adjuvants (such as MF59 and AS03) has been demonstrated by toxicological studies in animal models as well as in Phase I-III studies in humans [16][17][18]…”

Section: Delivery Systemsmentioning

confidence: 99%

Selection of adjuvants for vaccines targeting specific pathogens

Sarkar

Garg

Hurk

2019

Expert Review of Vaccines

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Introduction: Adjuvants form an integral component in most of the inactivated and subunit vaccine formulations. Careful and proper selection of adjuvants helps in promoting appropriate immune responses against target pathogens at both innate and adaptive levels such that protective immunity can be elicited. Areas covered: Herein, we describe the recent progress in our understanding of the mode of action of adjuvants that are licensed for use in human vaccines or in clinical or pre-clinical stages at both innate and adaptive levels. Different pathogens have distinct characteristics, which require the host to mount an appropriate immune response against them. Adjuvants can be selected to elicit a tailor-made immune response to specific pathogens based on their unique properties. Identification of biomarkers of adjuvanticity for several candidate vaccines using omics-based technologies can unravel the mechanism of action of modern and experimental adjuvants. Expert opinion: Adjuvant technology has been revolutionized over the last two decades. In-depth understanding of the role of adjuvants in activating the innate immune system, combined with systems vaccinology approaches, have led to the development of next-generation, novel adjuvants that can be used in vaccines against challenging pathogens and in specific target populations. ARTICLE HISTORY

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“…This class of vaccine composition may therefore require the inclusion of adjuvants in order to potentiate their immunostimulatory activity. Adjuvants are immunomodulatory substances that are admixed with the vaccine to enhance their immunogenicity, potency and efficacy (Graphical Abstract), and have been employed in vaccine formulation for more than 90 years [36,50]. The principal intended use of adjuvant is to further improve the quality, magnitude and duration of an antigen specific immune response.…”

Section: Role Of the Adjuvant In Vaccinationmentioning

confidence: 99%

Adjuvant formulations for virus-like particle (VLP) based vaccines

Cimica

Galarza

2017

Clinical Immunology

103

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The development of virus-like particle (VLP) technology has had an enormous impact on modern vaccinology. In order to optimize the efficacy and safety of VLP-based vaccines, adjuvants are included in most vaccine formulations. To date, most licensed VLP-based vaccines utilize the classic aluminum adjuvant compositions. Certain challenging pathogens and weak immune responder subjects may require further optimization of the adjuvant formulation to maximize the magnitude and duration of the protective immunity. Indeed, novel classes of adjuvants such as liposomes, agonists of pathogen recognition receptors, polymeric particles, emulsions, cytokines and bacterial toxins, can be used to optimize the immunostimulatory activity of a VLP-based vaccine. This review describes the current advances in adjuvant technology for VLP-based vaccines directed at viral diseases, and discusses the basic principles for designing adjuvant formulations for enhancing the vaccine immunogenicity.

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From discovery to licensure, the Adjuvant System story

Cited by 176 publications

References 99 publications

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

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

Selection of adjuvants for vaccines targeting specific pathogens

Adjuvant formulations for virus-like particle (VLP) based vaccines

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