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ABSTRACT: A novel human papillomavirus (HPV) vaccine has been formulated with virus-like particles of the L1 protein of HPV-16 and HPV-18, and the Adjuvant System 04 (AS04). AS04 is a combination of the toll-like receptor 4 agonist monophosphoryl lipid A (MPL) and aluminum hydroxide. The AS04-adjuvanted HPV vaccine induces a high and sustained immune response against HPV, including high levels of neutralizing antibodies at the cervical mucosa in women aged 15-55 years. Recently, the mechanism of action of AS04 has been evaluated in vitro in human cells and in vivo in mice and the data provide evidence for the molecular and cellular basis of the observed immunogenicity, efficacy, and safety profile of this formulation. In this review, we discuss how the results of GlaxoSmithKline's clinical studies on immunogenicity, protection, and reactogenicity with the AS04-adjuvanted HPV vaccine are supported by the observed mechanism of action for the adjuvant. The adjuvant activity of AS04, as measured by enhanced antibody response to HPV antigens, was found to be strictly dependent on AS04 and the HPV antigens being injected at the same intramuscular site within 24 hours of each other. The addition of MPL to aluminum salt enhances humoral and cell-mediated response by rapidly triggering a local and transient cytokine response that leads to an increased activation of antigen-presenting cells and results in an improved presentation of antigen to CD4+ T cells. The added value of MPL in AS04 for an HPV vaccine was demonstrated in clinical studies by high vaccine-elicited antibody responses and the induction of high levels of memory B cells. The vaccine elicits cross protection against some other oncogenic HPV types (specifically HPV-31, -33, and -45) not contained in the vaccine. The localized and transient nature of the innate immune response supports the acceptable safety profile observed in clinical studies.
BioDrugs 08/2011; 25(4):217-26. · 3.44 Impact Factor
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ABSTRACT: Novel adjuvants that contain immunoenhancer molecules are now present in human vaccines either registered or in clinical trials. These adjuvants have the potential to provide clear benefits in improving the magnitude and duration of various aspects of the adaptive immune response. However, the use of immunoenhancers in vaccine formulations may be perceived as introducing theoretical safety risks that need to be addressed during the course of vaccine development. In addition to classical clinical safety evaluation, the licensing authorities recommend that novel adjuvants should be evaluated in non-clinical toxicology studies, both as separate entities and as part of the final vaccine formulation. We present here our approach for the safety evaluation of adjuvanted vaccines using AS04-adjuvanted vaccines as example. This evaluation consists of three tiers: non-clinical toxicology, adjuvant mode-of-action investigations and clinical safety assessment in controlled clinical trials and post-marketing surveillance. We also discuss how the knowledge of adjuvant mode of action can support the current practice of safety evaluation.
Vaccine 06/2011; 29(27):4453-9. · 3.77 Impact Factor
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ABSTRACT: INTRODUCTION: Understanding the mode of action of adjuvants is important for the interpretation of clinical studies. AREAS COVERED: This paper discusses how the results of GSK's clinical studies with an AS04-adjuvanted human papillomavirus (HPV) vaccine are supported by the mode of action of AS04. AS04 and antigens must be injected at the same intramuscular site together or within 24 h of each other. AS04 induces local cytokine production leading to increased recruitment of dendritic cells and monocytes and raised numbers of antigen presenting cells in the draining lymph node. The localized and transient nature of the innate immune response supports the acceptable safety profile observed in clinical studies. The readers will gain a comprehensive understanding of the mode of action of AS04 and how it relates to results of clinical studies. EXPERT OPINION: The AS04-adjuvanted HPV vaccine has an acceptable safety profile and induces an enhanced and sustained immune response and high protection against HPV types 16/18. Cross-protection against oncogenic HPV types 31/33/45 not contained in the vaccine is also observed. The mode of action of AS04 supports the clinical profile of the AS04-adjuvanted HPV vaccine.
Expert opinion on biological therapy 04/2011; 11(5):667-77. · 3.22 Impact Factor
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ABSTRACT: The immunostimulants 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and the saponin QS-21 are part of licensed or candidate vaccines. MPL and QS-21 directly affect the innate immune response to orchestrate the quality and intensity of the adaptive immune response to the vaccine antigens. The combination of immunostimulants in different adjuvant formulations forms the basis of Adjuvant Systems (AS) as a way to promote appropriate protective immune responses following vaccination. MPL and aluminum salts are present in AS04, and both MPL and QS-21 are present in AS01 and AS02, which are liposome- and emulsion-based formulations, respectively. The recent clinical performance of AS01-, AS02- and AS04-adjuvanted vaccines will be discussed in the context of the diseases being targeted. The licensing of two AS04-adjuvanted vaccines and the initiation of Phase III trials with an AS01-adjuvanted vaccine demonstrate the potential to develop new or improved human vaccines that contain MPL or MPL and QS-21.
Expert Review of Vaccines 04/2011; 10(4):471-86. · 4.25 Impact Factor
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Sandra Morel,
Arnaud Didierlaurent,
Patricia Bourguignon,
Sophie Delhaye,
Benoît Baras,
Valérie Jacob,
Camille Planty,
Abdelatif Elouahabi,
Pol Harvengt,
Harald Carlsen,
Anders Kielland,
Patrick Chomez,
Nathalie Garçon, Marcelle Van Mechelen
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ABSTRACT: AS03 is an Adjuvant System (AS) containing α-tocopherol and squalene in an oil-in-water (o/w) emulsion. AS03 has been considered for the development of pandemic and seasonal influenza vaccines. Key features of AS03's mode of action were investigated in vivo in mice and ex vivo in human cells. AS03's adjuvant activity was superior to that of aluminium hydroxide and required the spatio-temporal co-localisation of AS03 with the antigen. This requirement coincided with AS03 triggering a transient production of cytokines at the injection site and in the draining lymph nodes (dLNs). The nature of the cytokines produced was consistent with the enhanced recruitment of granulocytes and of antigen-loaded monocytes in the dLNs. The presence of α-tocopherol in AS03 was required for AS03 to achieve the highest antibody response. The presence of α-tocopherol also modulated the expression of some cytokines, including CCL2, CCL3, IL-6, CSF3 and CXCL1; increased the antigen loading in monocytes; and increased the recruitment of granulocytes in the dLNs. Hence, AS03's promotion of monocytes as the principal antigen-presenting cells, and its effects on granulocytes and cytokines, may all contribute to enhancing the antigen-specific adaptive immune response.
Vaccine 01/2011; 29(13):2461-73. · 3.77 Impact Factor
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ABSTRACT: Adjuvantation of an H5N1 split-virion influenza vaccine with AS03(A) substantially reduces the antigen dose required to produce a putatively protective humoral response and promotes cross-clade neutralizing responses. We determined the effect of adjuvantation on antibody persistence and B- and T-cell-mediated immune responses.
Two vaccinations with a split-virion A/Vietnam/1194/2004 (H5N1, clade 1) vaccine containing 3.75-30 μg hemagglutinin and formulated with or without adjuvant were administered to groups of 50 volunteers aged 18-60 years.
Adjuvantation of the vaccine led to better persistence of neutralizing and hemagglutination-inhibiting antibodies and higher frequencies of antigen-specific memory B cells. Cross-reactive and polyfunctional H5N1-specific CD4 T cells were detected at baseline and were amplified by vaccination. Expansion of CD4 T cells was enhanced by adjuvantation.
Formulation of the H5N1 vaccine with AS03(A) enhances antibody persistence and induces stronger T- and B-cell responses. The cross-clade T-cell immunity indicates that the adjuvanted vaccine primes individuals to respond to either infection and/or subsequent vaccination with strains drifted from the primary vaccine strain.
Journal of Clinical Immunology 12/2010; 31(3):443-54. · 3.08 Impact Factor
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Arnaud M Didierlaurent,
Sandra Morel,
Laurence Lockman,
Sandra L Giannini,
Michel Bisteau,
Harald Carlsen,
Anders Kielland,
Olivier Vosters,
Nathalie Vanderheyde,
Francesca Schiavetti,
Daniel Larocque, Marcelle Van Mechelen,
Nathalie Garçon
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ABSTRACT: Adjuvant System 04 (AS04) combines the TLR4 agonist MPL (3-O-desacyl-4'-monophosphoryl lipid A) and aluminum salt. It is a new generation TLR-based adjuvant licensed for use in human vaccines. One of these vaccines, the human papillomavirus (HPV) vaccine Cervarix, is used in this study to elucidate the mechanism of action of AS04 in human cells and in mice. The adjuvant activity of AS04 was found to be strictly dependent on AS04 and the HPV Ags being injected at the same i.m. site within 24 h of each other. During this period, AS04 transiently induced local NF-kappaB activity and cytokine production. This led to an increased number of activated Ag-loaded dendritic cells and monocytes in the lymph node draining the injection site, which further increased the activation of Ag-specific T cells. AS04 was also found to directly stimulate those APCs in vitro but not directly stimulate CD4(+) T or B lymphocytes. These AS04-induced innate responses were primarily due to MPL. Aluminum salt appeared not to synergize with or inhibit MPL, but rather it prolonged the cytokine responses to MPL at the injection site. Altogether these results support a model in which the addition of MPL to aluminum salt enhances the vaccine response by rapidly triggering a local cytokine response leading to an optimal activation of APCs. The transient and confined nature of these responses provides further supporting evidence for the favorable safety profile of AS04 adjuvanted vaccines.
The Journal of Immunology 11/2009; 183(10):6186-97. · 5.79 Impact Factor
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Isabel Leroux-Roels,
François Roman,
Sheron Forgus,
Cathy Maes,
Fien De Boever,
Mamadou Dramé,
Paul Gillard,
Robbert van der Most, Marcelle Van Mechelen,
Emmanuel Hanon,
Geert Leroux-Roels
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ABSTRACT: An influenza vaccine with cross-immunogenic potential could play a key role in pandemic mitigation by promoting a rapid immune response to infection and/or subsequent vaccination with strains drifted from the primary vaccine strain. Here we assess the role of AS03(A) (an oil-in-water emulsion based Adjuvant System containing tocopherol) in this prime-boost concept using H5N1 as a model shift influenza antigen. In this open, non-randomised study (NCT00506350; an extension of an earlier randomised study) we assessed immunogenicity in nine groups of 35-50 volunteers aged 19-61 years following administration of AS03(A)-adjuvanted split-virion H5N1 vaccine containing 3.75mug of haemagglutinin (HA) from the A/Indonesia/5/2005(IBCDC-RG2) clade 2.1 strain. A single booster dose of vaccine was administered to four groups primed 14 months previously with different HA levels of AS03(A)-adjuvanted clade 1 A/Vietnam/1194/2004 H5N1 vaccine. Two booster doses (given 21 days apart) were administered to four groups primed 14 months previously with different HA levels of non-adjuvanted A/Vietnam/1194/2004 H5N1 vaccine and also to a control group of un-primed subjects. In individuals primed 14 months earlier with AS03(A)-adjuvanted A/Vietnam/1194/2004 vaccines, a single booster dose of AS03(A)-adjuvanted A/Indonesia/5/2005 induced rapid immune responses (licensure criteria met in 7-14 days) comparable to that observed in the un-primed control group following two doses of adjuvanted vaccine. In contrast, individuals primed with non-adjuvanted formulations exhibited minimal immune responses which, even after two doses, were unexpectedly much lower than that observed in un-primed subjects. AS03(A) enhances the initial priming effect of pandemic influenza vaccination enabling a rapid humoral response to single dose boosting with a heterologous strain at 14 months. In contrast, priming without adjuvant appears to inhibit the response to subsequent vaccination with a heterologous strain. These findings should guide the development of vaccines to combat the present influenza A/H1N1 pandemic.
Vaccine 10/2009; 28(3):849-57. · 3.77 Impact Factor
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Pierre Vandepapelière,
Yves Horsmans,
Philippe Moris, Marcelle Van Mechelen,
Michel Janssens,
Marguerite Koutsoukos,
Pascale Van Belle,
Frédéric Clement,
Emmanuel Hanon,
Martine Wettendorff,
Nathalie Garçon,
Geert Leroux-Roels
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ABSTRACT: A randomised, double-blind study assessing the potential of four adjuvants in combination with recombinant hepatitis B surface antigen has been conducted to evaluate humoral and cell-mediated immune responses in healthy adults after three vaccine doses at months 0, 1 and 10. Three Adjuvant Systems (AS) contained 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and QS21, formulated either with an oil-in-water emulsion (AS02B and AS02V) or with liposomes (AS01B). The fourth adjuvant was CpG oligonucleotide. High levels of antibodies were induced by all adjuvants, whereas cell-mediated immune responses, including cytolytic T cells and strong and persistent CD4(+) T cell response were mainly observed with the three MPL/QS21-containing Adjuvant Systems. The CD4(+) T cell response was characterised in vitro by vigorous lymphoproliferation, high IFN-gamma and moderate IL-5 production. Antigen-specific T cell immune response was further confirmed ex vivo by detection of IL-2- and IFN-gamma-producing CD4(+) T cells, and in vivo by measuring increased levels of IFN-gamma in the serum and delayed-type hypersensitivity (DTH) responses. The CpG adjuvanted vaccine induced consistently lower immune responses for all parameters. All vaccine adjuvants were shown to be safe with acceptable reactogenicity profiles. The majority of subjects reported local reactions at the injection site after vaccination while general reactions were recorded less frequently. No vaccine-related serious adverse event was reported. Importantly, no increase in markers of auto-immunity and allergy was detected over the whole study course. In conclusion, the Adjuvant Systems containing MPL/QS21, in combination with hepatitis B surface antigen, induced very strong humoral and cellular immune responses in healthy adults. The AS01B-adjuvanted vaccine induced the strongest and most durable specific cellular immune responses after two doses. These Adjuvant Systems, when added to recombinant protein antigens, can be fundamental to develop effective prophylactic vaccines against complex pathogens, e.g. malaria, HIV infection and tuberculosis, and for special target populations such as subjects with an impaired immune response, due to age or medical conditions.
Vaccine 04/2008; 26(10):1375-86. · 3.77 Impact Factor
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ABSTRACT: The need for potentiating immune responses to recombinant or subunit antigens has prompted GlaxoSmithKline (GSK) Biologicals to develop various Adjuvant Systems for the design of prophylactic and therapeutic vaccines. Adjuvant Systems are formulations of classical adjuvants mixed with immunomodulators, specifically adapted to the antigen and the target population. They can activate the appropriate innate immune system and subsequently impact on adaptive immune responses. AS04 is an Adjuvant System that has demonstrated significant achievements in several vaccines against viral diseases. AS02, another Adjuvant System, is being evaluated in various contexts, where a strong T-cell response is needed to afford protection. Likewise, AS01 has been developed for vaccines where the induction of a yet stronger T-cell-mediated immune response is required. Altogether, the promising clinical results strongly support the concept of Adjuvant Systems and allow for further development of new vaccines, best adapted to the target population and the immune mechanisms of protection.
Expert Review of Vaccines 11/2007; 6(5):723-39. · 4.25 Impact Factor
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Sandra L Giannini,
Emmanuel Hanon,
Philippe Moris, Marcelle Van Mechelen,
Sandra Morel,
Francis Dessy,
Marc A Fourneau,
Brigitte Colau,
Joann Suzich,
Genevieve Losonksy,
Marie-Thérèse Martin,
Gary Dubin,
Martine A Wettendorff
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ABSTRACT: An effective virus-like particle (VLP) based prophylactic vaccine designed to protect against persistent infection with human papillomavirus (HPV) types 16 and 18 and subsequent lesion development will need to induce a strong humoral and cellular immune response capable of providing long-term protection. Our objective was to evaluate the ability of an HPV16/18 L1 VLP vaccine formulated with the AS04 adjuvant system (3-O-desacyl-4'-monophosphoryl lipid A (MPL) and aluminium salt) to induce an immune response of higher magnitude and persistence compared to a vaccine formulated with aluminium salt only. We demonstrated that MPL adsorbed onto aluminium salt retains its capacity to activate an innate immune response as assessed by the production of TNFalpha by human monocytes (U937). In addition, vaccination of mice, monkeys or human subjects with AS04 formulations induced higher total anti-L1 VLP16 and L1 VLP18 antibody responses (1.6-8.5-fold) than the aluminium salt only formulations. The enhanced antibody response induced by the AS04 vaccine formulation (1.6-4.1-fold) in monkeys and humans was shown to be targeted to functional neutralising L1 VLP16 and L1 VLP18 epitopes as assessed by V5/J4 specific ELISAs or HPV16 and HPV18 pseudo-neutralization assays. The enhanced immune profile observed with the AS04 formulation in terms of both total, V5/J4 specific and neutralizing antibodies was shown to persist for at least 3.5-year post-vaccination in human subjects. Finally, using the newly developed B cell ELISPOT assay we also demonstrated that the AS04 formulation elicited an increased frequency (2.2-5.2-fold) of HPV L1 VLP specific memory B cells when compared with the aluminium salt only formulations. These data strongly support the role of the AS04 adjuvant, which includes the immunostimulant MPL, in triggering a persistent vaccine-induced immune response of high quality.
Vaccine 09/2006; 24(33-34):5937-49. · 3.77 Impact Factor
