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Derek O'hagan - One of the best experts on this subject based on the ideXlab platform.
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Chapter 13 – MF59: A Safe and Potent Adjuvant for Human Use
Immunopotentiators in Modern Vaccines, 2017Co-Authors: Sushma Kommareddy, M. Singh, Derek O'haganAbstract:MF59 a squalene-based emulsion was used to adjuvant influenza vaccine; the product that emerged (Fluad) was licensed first in Italy in 1997 and is now licensed worldwide in 32 countries. The adjuvant was first developed for influenza vaccination in the elderly, and later it was also found to be effective in young children. A key and consistent feature of MF59 is its ability to induce fast priming of influenza antigen–specific CD4+ T-cell responses, to induce strong and long-lasting memory T- and B-cell responses, and to broaden the immune response beyond the influenza strains actually included in the vaccine. Today, MF59 has been licensed for more than 19 years and has a very well-established safety record as a potent vaccine adjuvant.
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The adjuvant effect of MF59 is due to the oil-in-water emulsion formulation, none of the individual components induce a comparable adjuvant effect.
Vaccine, 2013Co-Authors: Samuele Calabro, Barbara Baudner, Ennio De Gregorio, Derek O'hagan, Elaine Tritto, Annamaria Pezzotti, Marianna Taccone, Alessandro Muzzi, Sylvie Bertholet, Anja SeubertAbstract:MF59 is a safe and effective vaccine adjuvant that has been used in a licensed seasonal influenza vaccine for 15 years. The purpose of the present studies was to directly address a question that has been asked of us on many occasions: "which is the adjuvant active component of MF59?". Since we have recently gained a number of insights on how MF59 works as an adjuvant, we were able to use these approaches to evaluate if the individual components of MF59 (squalene oil, the surfactants Span 85 and Tween 80 or the citrate buffer) showed any direct immunostimulatory activity. We assessed the ability of the individual components to stimulate the innate and adaptive immune responses that we have shown to be indicative of MF59-mediated adjuvanticity. No immune stimulatory capacities could be attributed to squalene, Tween 80 or the citrate buffer alone. Instead, we found that the lipophilic surfactant Span 85 contributes to activation of the muscle transcriptome. However, despite this local activation, Span 85 alone - like the other single components of MF59 - is not sufficient to induce an adjuvant effect. Only the fully formulated MF59 emulsion induces all the established hallmarks of innate and adaptive immune activation, which includes activation of genes indicative of transendothelial cell migration, strong influx of immune cells into the injection site and their enhanced antigen uptake and transport to the lymph nodes. These observations may have important implications in the design of optimal emulsion-based vaccine adjuvants.
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The history of MF59® adjuvant: a phoenix that arose from the ashes
Expert review of vaccines, 2013Co-Authors: Derek O'hagan, Gary Van Nest, Gary Ott, Rino Rappuoli, Giuseppe Del GiudiceAbstract:The first clinical trial of an MF59(®)-adjuvanted influenza vaccine (Novartis) was conducted 20 years ago in 1992. The product that emerged (Fluad(®), Novartis) was licensed first in Italy in 1997 and is now licensed worldwide in 30 countries. US licensure is expected in the coming years. By contrast, many alternative adjuvanted vaccines have failed to progress. The key decisions that allowed MF59 to succeed in such a challenging environment are highlighted here and the lessons that were learned along the way are discussed. MF59 was connected to vaccines that did not succeed and was perceived as a 'failure' before it was a success. Importantly, it never failed for safety reasons and was always well tolerated. Even when safety issues have emerged for alternative adjuvants, careful analysis of the substantial safety database for MF59 have shown that there are no significant concerns with widespread use, even in more 'sensitive' populations.
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The mechanism of action of MF59 - an innately attractive adjuvant formulation.
Vaccine, 2012Co-Authors: Derek O'hagan, G.s. Ott, E. De Gregorio, Anja SeubertAbstract:MF59 is a safe and effective vaccine adjuvant which was originally approved to be included in a licensed influenza vaccine to be used in the elderly in Europe in 1997. The MF59 adjuvanted influenza vaccine (Fluad™) is now licensed in more than 20 countries worldwide and more than 85 million doses have been administered. More recently the vaccine adjuvant has also been shown to be safe and effective in young children and resulted in a significant increase in influenza vaccine efficacy in a controlled clinical trial in Europe. Since the early days of its discovery we have explored the mechanism of action of MF59, using a variety of available techniques. In recent years we have explored more thoroughly the mechanism of action using new and more sophisticated techniques. It is remarkable how consistent the data has been, using a variety of different approaches both in several small animal models and also using human immune cells in vitro. Here we present a summary of all the work performed to date on the mechanism of action of MF59 and we present a unified theory based on the accumulated data of how it exerts its adjuvant effects. A key element of the mechanism of action appears to be the creation of a transient 'immunocompetent' local environment at the injection site, resulting in the recruitment of key immune cells, which are able to take up antigen and adjuvant and transport them to the local lymph nodes, where the immune response is induced. This recruitment appears to be triggered by the induction of a chemokine driven gradient by the impact of MF59 on local cells, which are activated to secrete further chemokines, which are recruitment factors for more immune cells.
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MF59 oil-in-water emulsion in combination with a synthetic TLR4 agonist (E6020) is a potent adjuvant for a combination Meningococcus vaccine.
Human vaccines & immunotherapeutics, 2012Co-Authors: Manmohan Singh, Barbara Baudner, Jina Kazzaz, Lynn D Hawkins, Mildred Ugozzoli, Mariagrazia Pizza, Marzia Monica Giuliani, Gillis R. Otten, Derek O'haganAbstract:The inclusion of a potent TLR4 immune potentiator to a recombinant antigen vaccine formulation enhances both the magnitude and the breadth of the engendered immune response. One such immune potentiator (TLR4 agonist E6020) was evaluated with recombinant Men B antigens delivered in MF59 sub-micron adjuvant emulsion. The ability of this formulation to enhance serum antibody and bactercidal titers was investigated. The co-delivery of E6020 within MF59 enhanced both the serum and bactericidal titers for Men B antigens and for Men B antigens combined with Men ACWY-CRM conjugate vaccine. The delivery of TLR4 agonist within MF59 emulsion oil droplets leads to a more potent response in comparison to the TLR4 when admixed with MF59 emulsion.
Barbara Baudner - One of the best experts on this subject based on the ideXlab platform.
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The adjuvant effect of MF59 is due to the oil-in-water emulsion formulation, none of the individual components induce a comparable adjuvant effect.
Vaccine, 2013Co-Authors: Samuele Calabro, Barbara Baudner, Ennio De Gregorio, Derek O'hagan, Elaine Tritto, Annamaria Pezzotti, Marianna Taccone, Alessandro Muzzi, Sylvie Bertholet, Anja SeubertAbstract:MF59 is a safe and effective vaccine adjuvant that has been used in a licensed seasonal influenza vaccine for 15 years. The purpose of the present studies was to directly address a question that has been asked of us on many occasions: "which is the adjuvant active component of MF59?". Since we have recently gained a number of insights on how MF59 works as an adjuvant, we were able to use these approaches to evaluate if the individual components of MF59 (squalene oil, the surfactants Span 85 and Tween 80 or the citrate buffer) showed any direct immunostimulatory activity. We assessed the ability of the individual components to stimulate the innate and adaptive immune responses that we have shown to be indicative of MF59-mediated adjuvanticity. No immune stimulatory capacities could be attributed to squalene, Tween 80 or the citrate buffer alone. Instead, we found that the lipophilic surfactant Span 85 contributes to activation of the muscle transcriptome. However, despite this local activation, Span 85 alone - like the other single components of MF59 - is not sufficient to induce an adjuvant effect. Only the fully formulated MF59 emulsion induces all the established hallmarks of innate and adaptive immune activation, which includes activation of genes indicative of transendothelial cell migration, strong influx of immune cells into the injection site and their enhanced antigen uptake and transport to the lymph nodes. These observations may have important implications in the design of optimal emulsion-based vaccine adjuvants.
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MF59 oil-in-water emulsion in combination with a synthetic TLR4 agonist (E6020) is a potent adjuvant for a combination Meningococcus vaccine.
Human vaccines & immunotherapeutics, 2012Co-Authors: Manmohan Singh, Barbara Baudner, Jina Kazzaz, Lynn D Hawkins, Mildred Ugozzoli, Mariagrazia Pizza, Marzia Monica Giuliani, Gillis R. Otten, Derek O'haganAbstract:The inclusion of a potent TLR4 immune potentiator to a recombinant antigen vaccine formulation enhances both the magnitude and the breadth of the engendered immune response. One such immune potentiator (TLR4 agonist E6020) was evaluated with recombinant Men B antigens delivered in MF59 sub-micron adjuvant emulsion. The ability of this formulation to enhance serum antibody and bactercidal titers was investigated. The co-delivery of E6020 within MF59 enhanced both the serum and bactericidal titers for Men B antigens and for Men B antigens combined with Men ACWY-CRM conjugate vaccine. The delivery of TLR4 agonist within MF59 emulsion oil droplets leads to a more potent response in comparison to the TLR4 when admixed with MF59 emulsion.
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MF59 and Pam3CSK4 Boost Adaptive Responses to Influenza Subunit Vaccine through an IFN Type I-Independent Mechanism of Action
Journal of immunology (Baltimore Md. : 1950), 2012Co-Authors: Elena Caproni, Anja Seubert, Barbara Baudner, Elaine Tritto, Alessandro Muzzi, Mario Cortese, Elisabetta Monaci, Flaviana Mosca, Ennio De GregorioAbstract:The innate immune pathways induced by adjuvants required to increase adaptive responses to influenza subunit vaccines are not well characterized. We profiled different TLR-independent (MF59 and alum) and TLR-dependent (CpG, resiquimod, and Pam3CSK4) adjuvants for the ability to increase the immunogenicity to a trivalent influenza seasonal subunit vaccine and to tetanus toxoid (TT) in mouse. Although all adjuvants boosted the Ab responses to TT, only MF59 and Pam3CSK4 were able to enhance hemagglutinin Ab responses. To identify innate immune correlates of adjuvanticity to influenza subunit vaccine, we investigated the gene signatures induced by each adjuvant in vitro in splenocytes and in vivo in muscle and lymph nodes using DNA microarrays. We found that flu adjuvanticity correlates with the upregulation of proinflammatory genes and other genes involved in leukocyte transendothelial migration at the vaccine injection site. Confocal and FACS analysis confirmed that MF59 and Pam3CSK4 were the strongest inducers of blood cell recruitment in the muscle compared with the other adjuvants tested. Even though it has been proposed that IFN type I is required for adjuvanticity to influenza vaccines, we found that MF59 and Pam3CSK4 were not good inducers of IFN-related innate immunity pathways. By contrast, resiquimod failed to enhance the adaptive response to flu despite a strong activation of the IFN pathway in muscle and lymph nodes. By blocking IFN type I receptor through a mAb, we confirmed that the adjuvanticity of MF59 and Pam3CSK4 to a trivalent influenza vaccine and to TT is IFN independent.
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Vaccine adjuvants alum and MF59 induce rapid recruitment of neutrophils and monocytes that participate in antigen transport to draining lymph nodes.
Vaccine, 2011Co-Authors: Samuele Calabro, Anja Seubert, Marco Tortoli, Barbara Baudner, Ennio De Gregorio, Derek O'hagan, Alessandra Pacitto, Mario Cortese, Andreas WackAbstract:Vaccine adjuvants such as alum and the oil-in-water emulsion MF59 are used to enhance immune responses towards pure soluble antigens, but their mechanism of action is still largely unclear. Since most adjuvanted vaccines are administered intramuscularly, we studied immune responses in the mouse muscle and found that both adjuvants were potent inducers of chemokine production and promoted rapid recruitment of CD11b(+) cells. The earliest and most abundantly recruited cell type are neutrophils, followed by monocytes, eosinophils and later dendritic cells (DCs) and macrophages. Using fluorescent forms of MF59 and ovalbumin (OVA) antigen, we show that all recruited cell types take up both adjuvant and antigen to transport them to the draining lymph nodes (LNs). There, we found antigen-positive neutrophils and monocytes within hours of injection, later followed by B cells and DCs. Compared to alum, MF59-injection lead to a more prominent neutrophil recruitment and a more efficient antigen re-localization from the injection site to the LN. As antigen-transporting neutrophils were observed in draining LNs, we asked whether these cells play an essential role in MF59-mediated adjuvanticity. However, antibody-mediated neutrophil ablation left MF59-adjuvanticity unaltered. Further studies will reveal whether other single cell types are crucial or whether the different recruited cell populations are redundant with overlapping functions.
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MF59 emulsion is an effective delivery system for a synthetic tlr4 agonist e6020
Pharmaceutical Research, 2009Co-Authors: Barbara Baudner, Marco Tortoli, Vanessa Ronconi, Daniele Casini, Jina Kazzaz, Manmohan Singh, Lynn D Hawkins, Andreas Wack, Derek T OhaganAbstract:Purpose The effectiveness of vaccines depends on the age and immunocompetence of the vaccinee. Conventional non-adjuvanted influenza vaccines are suboptimal in the elderly and vaccines with improved ability to prevent influenza are required. The TLR4 agonist E6020, either given alone or co-delivered with MF59, was evaluated and compared to MF59 and the TLR9 agonist CpG. Its ability to enhance antibody titres and to modulate the quality of the immune response to a subunit influenza vaccine was investigated.
Manmohan Singh - One of the best experts on this subject based on the ideXlab platform.
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MF59 oil-in-water emulsion in combination with a synthetic TLR4 agonist (E6020) is a potent adjuvant for a combination Meningococcus vaccine.
Human vaccines & immunotherapeutics, 2012Co-Authors: Manmohan Singh, Barbara Baudner, Jina Kazzaz, Lynn D Hawkins, Mildred Ugozzoli, Mariagrazia Pizza, Marzia Monica Giuliani, Gillis R. Otten, Derek O'haganAbstract:The inclusion of a potent TLR4 immune potentiator to a recombinant antigen vaccine formulation enhances both the magnitude and the breadth of the engendered immune response. One such immune potentiator (TLR4 agonist E6020) was evaluated with recombinant Men B antigens delivered in MF59 sub-micron adjuvant emulsion. The ability of this formulation to enhance serum antibody and bactercidal titers was investigated. The co-delivery of E6020 within MF59 enhanced both the serum and bactericidal titers for Men B antigens and for Men B antigens combined with Men ACWY-CRM conjugate vaccine. The delivery of TLR4 agonist within MF59 emulsion oil droplets leads to a more potent response in comparison to the TLR4 when admixed with MF59 emulsion.
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MF59 emulsion is an effective delivery system for a synthetic tlr4 agonist e6020
Pharmaceutical Research, 2009Co-Authors: Barbara Baudner, Marco Tortoli, Vanessa Ronconi, Daniele Casini, Jina Kazzaz, Manmohan Singh, Lynn D Hawkins, Andreas Wack, Derek T OhaganAbstract:Purpose The effectiveness of vaccines depends on the age and immunocompetence of the vaccinee. Conventional non-adjuvanted influenza vaccines are suboptimal in the elderly and vaccines with improved ability to prevent influenza are required. The TLR4 agonist E6020, either given alone or co-delivered with MF59, was evaluated and compared to MF59 and the TLR9 agonist CpG. Its ability to enhance antibody titres and to modulate the quality of the immune response to a subunit influenza vaccine was investigated.
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Microparticles in MF59, a potent adjuvant combination for a recombinant protein vaccine against HIV-1.
Vaccine, 2000Co-Authors: D.t. O'hagan, Manmohan Singh, Mildred Ugozzoli, John San Leandro Barackman, J Kazzaz, Keith W. Higgins, T.c Vancott, Gary OttAbstract:Novel adjuvant formulations involving PLG microparticles with entrapped recombinant protein antigens (env gp120 and p24 gag) from human immunodeficiency virus type-1 (HIV-1), dispersed in the emulsion adjuvant MF59 were evaluated as potential HIV-1 vaccine candidates in mice and baboons. In mice, the adjuvant combination induced significantly enhanced antibody responses in comparison to either adjuvant used alone. In addition, the polylactide co-glycolide polymer (PLG) microparticles and MF59 combination induced CTL activity against HIV-1 p24 gag. In baboons, the adjuvant combination induced significantly enhanced antibody titers after a single dose of gp120, but the responses were comparable to gp120 in MF59 alone after boosting. Both MF59+gp120 alone and PLG/gp120 in MF59 induced neutralizing antibodies against a T cell line-adapted (TCLA) strain and a primary isolate of HIV-1. In contrast to the observations with gp120, immunization in baboons with PLG/p24 in MF59 induced significantly enhanced antibody responses after boosting, in comparison to immunization with MF59 alone + p24.
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A comparison of biodegradable microparticles and MF59 as systemic adjuvants for recombinant gD from HSV-2.
Vaccine, 1998Co-Authors: Manmohan Singh, Jina Kazzaz, Mildred Ugozzoli, Gary Ott, Julia R. Carlson, Maylene Briones, John Barackman, Derek O'haganAbstract:Abstract A recombinant form of glycoprotein D from herpes simplex virus type-2 (gD2) was encapsulated into polylactide-co-glycolide (PLG) microparticles using a previously established solvent evaporation technique. The mean size of the microparticles was about 1 μm and high encapsulation efficiency of the antigen was achieved (70–80%). The microparticles were administered intramuscularly to Balb C mice and the immune reponses were compared with those obtained with the oil in water adjuvant MF59. The serum IgG response to gD2 induced by the microparticles was comparable with that induced by MF59. The serum neutralization titres were also comparable for microparticles and the emulsion. However, the microparticles induced a higher IgG2a isotype response and a more potent serum IFN-γ response than MF59, suggesting a more Th1 type of response. The MF59 induced higher levels of serum IL-4 and IL-5 cytokines, suggesting a more Th2 type of response.
Jina Kazzaz - One of the best experts on this subject based on the ideXlab platform.
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MF59 oil-in-water emulsion in combination with a synthetic TLR4 agonist (E6020) is a potent adjuvant for a combination Meningococcus vaccine.
Human vaccines & immunotherapeutics, 2012Co-Authors: Manmohan Singh, Barbara Baudner, Jina Kazzaz, Lynn D Hawkins, Mildred Ugozzoli, Mariagrazia Pizza, Marzia Monica Giuliani, Gillis R. Otten, Derek O'haganAbstract:The inclusion of a potent TLR4 immune potentiator to a recombinant antigen vaccine formulation enhances both the magnitude and the breadth of the engendered immune response. One such immune potentiator (TLR4 agonist E6020) was evaluated with recombinant Men B antigens delivered in MF59 sub-micron adjuvant emulsion. The ability of this formulation to enhance serum antibody and bactercidal titers was investigated. The co-delivery of E6020 within MF59 enhanced both the serum and bactericidal titers for Men B antigens and for Men B antigens combined with Men ACWY-CRM conjugate vaccine. The delivery of TLR4 agonist within MF59 emulsion oil droplets leads to a more potent response in comparison to the TLR4 when admixed with MF59 emulsion.
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MF59 emulsion is an effective delivery system for a synthetic tlr4 agonist e6020
Pharmaceutical Research, 2009Co-Authors: Barbara Baudner, Marco Tortoli, Vanessa Ronconi, Daniele Casini, Jina Kazzaz, Manmohan Singh, Lynn D Hawkins, Andreas Wack, Derek T OhaganAbstract:Purpose The effectiveness of vaccines depends on the age and immunocompetence of the vaccinee. Conventional non-adjuvanted influenza vaccines are suboptimal in the elderly and vaccines with improved ability to prevent influenza are required. The TLR4 agonist E6020, either given alone or co-delivered with MF59, was evaluated and compared to MF59 and the TLR9 agonist CpG. Its ability to enhance antibody titres and to modulate the quality of the immune response to a subunit influenza vaccine was investigated.
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A comparison of biodegradable microparticles and MF59 as systemic adjuvants for recombinant gD from HSV-2.
Vaccine, 1998Co-Authors: Manmohan Singh, Jina Kazzaz, Mildred Ugozzoli, Gary Ott, Julia R. Carlson, Maylene Briones, John Barackman, Derek O'haganAbstract:Abstract A recombinant form of glycoprotein D from herpes simplex virus type-2 (gD2) was encapsulated into polylactide-co-glycolide (PLG) microparticles using a previously established solvent evaporation technique. The mean size of the microparticles was about 1 μm and high encapsulation efficiency of the antigen was achieved (70–80%). The microparticles were administered intramuscularly to Balb C mice and the immune reponses were compared with those obtained with the oil in water adjuvant MF59. The serum IgG response to gD2 induced by the microparticles was comparable with that induced by MF59. The serum neutralization titres were also comparable for microparticles and the emulsion. However, the microparticles induced a higher IgG2a isotype response and a more potent serum IFN-γ response than MF59, suggesting a more Th1 type of response. The MF59 induced higher levels of serum IL-4 and IL-5 cytokines, suggesting a more Th2 type of response.
Giuseppe Del Giudice - One of the best experts on this subject based on the ideXlab platform.
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MF59 Mediates Its B Cell Adjuvanticity by Promoting T Follicular Helper Cells and Thus Germinal Center Responses in Adult and Early Life
Journal of immunology (Baltimore Md. : 1950), 2015Co-Authors: Beatris Mastelic Gavillet, Giuseppe Del Giudice, Anja Seubert, Ennio De Gregorio, Flora Castellino, Christiane Sigrid Eberhardt, Floriane Auderset, John S. Tregoning, Paul-henri Lambert, Claireanne SiegristAbstract:The early life influenza disease burden calls for more effective vaccines to protect this vulnerable population. Influenza vaccines including the MF59 oil-in-water adjuvant induce higher, broader, and more persistent Ab responses in adults and particularly in young, through yet undefined mechanisms. In this study, we show that MF59 enhances adult murine IgG responses to influenza hemagglutinin (HA) by promoting a potent T follicular helper cells (TFH) response, which directly controls the magnitude of the germinal center (GC) B cell response. Remarkably, this enhancement of TFH and GC B cells is already fully functional in 3-wk-old infant mice, which were fully protected by HA/MF59 but not HA/PBS immunization against intranasal challenge with the homologous H1N1 (A/California/7/2009) strain. In 1-wk-old neonatal mice, MF59 recruits and activates APCs, efficiently induces CD4(+) effector T cells and primes for enhanced infant responses but induces few fully functional TFH cells, which are mostly follicular regulatory T cells, and poor GC and anti-HA responses. The B cell adjuvanticity of MF59 appears to be mediated by the potent induction of TFH cells which directly controls GC responses both in adult and early life, calling for studies assessing its capacity to enhance the efficacy of influenza immunization in young infants.
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heterologous prime boost vaccination with MF59 adjuvanted h5 vaccines promotes antibody affinity maturation towards the hemagglutinin ha1 domain and broad h5n1 cross clade neutralization
PLOS ONE, 2014Co-Authors: Surender Khurana, Giuseppe Del Giudice, Flora Castellino, Elizabeth M Coyle, Milena Dimitrova, Karl G Nicholson, Hana GoldingAbstract:In an open label clinical study (2007), MF59-adjuvanted hemagglutinin (HA) vaccine from H5N1-A/Vietnam/1194/2004 (clade 1) was administered to subjects previously vaccinated (primed) with clade 0 H5N3 (A/duck/Singapore/97) vaccine at least 6 years earlier (in 1999 or 2001). The primed individuals responded rapidly and generated high neutralizing antibody titers against the H5N1-Vietnam strain within 7 days of a single booster vaccination. Furthermore, significant cross-neutralization titers were measured against H5N1 clade 0, 1, and 2 viruses. In the current study, the impact of MF59 adjuvant during heterologous priming on the quality of humoral polyclonal immune response in different vaccine arms were further evaluated using real time kinetics assay by surface plasmon resonance (SPR). Total anti-H5N1 HA1 polyclonal sera antibody binding from the heterologous prime-boost groups after a single MF59-H5N1 boost was significantly higher compared with sera from unprimed individuals that received two MF59-H5N1 vaccinations. The antigen-antibody complex dissociation rates (surrogate for antibody affinity) of the polyclonal sera against HA1 of H5N1-A/Vietnam/1194/2004 from the MF59-H5N3 primed groups were significantly higher compared to sera from unadjuvanted primed groups or unprimed individuals that received two MF59-H5N1 vaccines. Furthermore, strong inverse correlations were observed between the antibody dissociation off-rates of the immune sera against HA1 (but not HA2) and the virus neutralization titers against H5 vaccine strains and heterologous H5N1 strains. These findings supports the use of oil-in-water-adjuvanted pandemic influenza vaccines to elicit long term memory B cells with high affinity BCR capable of responding to potential variant pandemic viruses likely to emerge and adapt to human transmissions.
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The history of MF59® adjuvant: a phoenix that arose from the ashes
Expert review of vaccines, 2013Co-Authors: Derek O'hagan, Gary Van Nest, Gary Ott, Rino Rappuoli, Giuseppe Del GiudiceAbstract:The first clinical trial of an MF59(®)-adjuvanted influenza vaccine (Novartis) was conducted 20 years ago in 1992. The product that emerged (Fluad(®), Novartis) was licensed first in Italy in 1997 and is now licensed worldwide in 30 countries. US licensure is expected in the coming years. By contrast, many alternative adjuvanted vaccines have failed to progress. The key decisions that allowed MF59 to succeed in such a challenging environment are highlighted here and the lessons that were learned along the way are discussed. MF59 was connected to vaccines that did not succeed and was perceived as a 'failure' before it was a success. Importantly, it never failed for safety reasons and was always well tolerated. Even when safety issues have emerged for alternative adjuvants, careful analysis of the substantial safety database for MF59 have shown that there are no significant concerns with widespread use, even in more 'sensitive' populations.
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Superior immunogenicity of seasonal influenza vaccines containing full dose of MF59 (®) adjuvant: results from a dose-finding clinical trial in older adults.
Human vaccines & immunotherapeutics, 2012Co-Authors: Giovanni Della Cioppa, Uwe Nicolay, Kelly Lindert, Nicola Groth, Geert Leroux-roels, Grazia Galli, Flora Castellino, Frédéric Clement, Giuseppe Del GiudiceAbstract:Background: MF59-adjuvanted influenza vaccines have superior immunogenicity in older adults compared with non-adjuvanted vaccines. We assessed whether changing formulation (i.e., increasing H3N2 antigen or decreasing the quantity of adjuvant) of the licensed, MF59-adjuvanted trivalent influenza subunit vaccine Fluad® (Novartis Vaccines and Diagnostics) improves the risk-benefit profile in vaccinees aged ≥65 years. Results: A significant dose-response relationship was observed between antibody levels and MF59 dose; full dose formulations elicited the strongest immune responses, meeting immunogenicity licensure criteria by Day 8. Doubling H3N2 antigen content did not increase the response to this antigen. Increased frequency of circulating CD4+ T-cells specific for vaccine antigens were detected by Day 8; magnitude and functional profile of the CD4+ T-cell response was comparable across the different vaccination groups. Mild to moderate solicited local reactions were more common with vaccines formulated w...
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superior immunogenicity of seasonal influenza vaccines containing full dose of MF59 adjuvant results from a dose finding clinical trial in older adults
Human Vaccines & Immunotherapeutics, 2012Co-Authors: Giovanni Della Cioppa, Uwe Nicolay, Kelly Lindert, Nicola Groth, Grazia Galli, Flora Castellino, Frédéric Clement, Geert Lerouxroels, Giuseppe Del GiudiceAbstract:Background: MF59-adjuvanted influenza vaccines have superior immunogenicity in older adults compared with non-adjuvanted vaccines. We assessed whether changing formulation (i.e., increasing H3N2 antigen or decreasing the quantity of adjuvant) of the licensed, MF59-adjuvanted trivalent influenza subunit vaccine Fluad® (Novartis Vaccines and Diagnostics) improves the risk-benefit profile in vaccinees aged ≥65 years. Results: A significant dose-response relationship was observed between antibody levels and MF59 dose; full dose formulations elicited the strongest immune responses, meeting immunogenicity licensure criteria by Day 8. Doubling H3N2 antigen content did not increase the response to this antigen. Increased frequency of circulating CD4+ T-cells specific for vaccine antigens were detected by Day 8; magnitude and functional profile of the CD4+ T-cell response was comparable across the different vaccination groups. Mild to moderate solicited local reactions were more common with vaccines formulated w...