MF59 adjuvant: the best insurance against influenza strain diversity

MF59 is a well-established, safe and potent vaccine adjuvant that has been licensed for more than 13 years for use in an influenza vaccine focused on elderly subjects (Fluad®, Novartis, Cambridge, MA, USA). Recently, MF59 was shown to be safe in a seasonal influenza vaccine for young children and was able to increase vaccine efficacy from 43 to 89%. A key and consistent feature of MF59 is the ability of the emulsion 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. The enhanced breadth of response is valuable in the seasonal setting, but is particularly valuable in a (pre-) pandemic setting, when it is difficult to predict which strain will emerge to cause the pandemic. We have shown that the ability of MF59 to increase the breadth of immune response against influenza vaccines is mainly due to the spreading of the repertoire of the B-cell epitopes recognized on the hemagglutinin and neuraminidase of the influenza virus.

[1]  P. López,et al.  Combined, concurrent, and sequential administration of seasonal influenza and MF59-adjuvanted A/H5N1 vaccines: a phase II randomized, controlled trial of immunogenicity and safety in healthy adults. , 2011, The Journal of infectious diseases.

[2]  Mario Cortese,et al.  Vaccine adjuvants alum and MF59 induce rapid recruitment of neutrophils and monocytes that participate in antigen transport to draining lymph nodes. , 2011, Vaccine.

[3]  Gavin J. D. Smith,et al.  Feasibility of reconstructed ancestral H5N1 influenza viruses for cross-clade protective vaccine development , 2010, Proceedings of the National Academy of Sciences.

[4]  E. V. van Puijenbroek,et al.  Monitoring adverse events of the vaccination campaign against influenza A (H1N1) in the Netherlands. , 2010, Drug safety.

[5]  E. Sokal,et al.  Safety of MF59-adjuvanted versus non-adjuvanted influenza vaccines in children and adolescents: an integrated analysis. , 2010, Vaccine.

[6]  T. Vesikari,et al.  Immunogenicity and Safety of MF59-Adjuvanted H5N1 Influenza Vaccine From Infancy to Adolescence , 2010, Pediatrics.

[7]  Deborah Middleton,et al.  Multiple infections with seasonal influenza A virus induce cross-protective immunity against A(H1N1) pandemic influenza virus in a ferret model. , 2010, The Journal of infectious diseases.

[8]  R. Gasparini,et al.  A Heterologous MF59-Adjuvanted H5N1 Prepandemic Influenza Booster Vaccine Induces a Robust, Cross-Reactive Immune Response in Adults and the Elderly , 2010, Clinical and Vaccine Immunology.

[9]  R. Compans,et al.  Immunity to Pre-1950 H1N1 Influenza Viruses Confers Cross-Protection against the Pandemic Swine-Origin 2009 A (H1N1) Influenza Virus , 2010, The Journal of Immunology.

[10]  M. Kieny,et al.  Global production of seasonal and pandemic (H1N1) influenza vaccines in 2009-2010 and comparison with previous estimates and global action plan targets. , 2010, Vaccine.

[11]  K. Matsushita,et al.  Comparison of half and full doses of an MF59-adjuvanted cell culture-derived A/H1N1v vaccine in Japanese children , 2010, Advances in therapy.

[12]  L. Sticchi,et al.  Antibody response against heterogeneous circulating influenza virus strains elicited by MF59- and non-adjuvanted vaccines during seasons with good or partial matching between vaccine strain and clinical isolates. , 2010, Vaccine.

[13]  R. Webby,et al.  Recipients of vaccine against the 1976 "swine flu" have enhanced neutralization responses to the 2009 novel H1N1 influenza virus. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[14]  K. Stöhr,et al.  Vaccinate before the next pandemic? , 2010, Nature.

[15]  K. Subbarao,et al.  Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine. , 2010, The Journal of clinical investigation.

[16]  Shibo Jiang,et al.  Research and development of universal influenza vaccines. , 2010, Microbes and infection.

[17]  J. Taubenberger,et al.  Prior infection with classical swine H1N1 influenza viruses is associated with protective immunity to the 2009 pandemic H1N1 virus , 2010, Influenza and other respiratory viruses.

[18]  D. Novicki,et al.  Exposure to MF59-adjuvanted influenza vaccines during pregnancy--a retrospective analysis. , 2010, Vaccine.

[19]  A. Arguedas,et al.  Responses to 2009 H1N1 vaccine in children 3 to 17 years of age. , 2010, The New England journal of medicine.

[20]  R. Rappuoli,et al.  Vaccines with MF59 Adjuvant Expand the Antibody Repertoire to Target Protective Sites of Pandemic Avian H5N1 Influenza Virus , 2010, Science Translational Medicine.

[21]  W. Keitel,et al.  Dose ranging of adjuvant and antigen in a cell culture H5N1 influenza vaccine: safety and immunogenicity of a phase 1/2 clinical trial. , 2010, Vaccine.

[22]  G. Leroux-Roels,et al.  Priming with AS03 A-adjuvanted H5N1 influenza vaccine improves the kinetics, magnitude and durability of the immune response after a heterologous booster vaccination: an open non-randomised extension of a double-blind randomised primary study. , 2010, Vaccine.

[23]  Update Gulf War and Health , 2010 .

[24]  R. Rappuoli,et al.  Seasonal Influenza Vaccine Provides Priming for A/H1N1 Immunization , 2009, Science Translational Medicine.

[25]  K. Hoschler,et al.  Trial of 2009 influenza A (H1N1) monovalent MF59-adjuvanted vaccine. , 2009, The New England journal of medicine.

[26]  C. Wichems,et al.  Response to a monovalent 2009 influenza A (H1N1) vaccine. , 2009, The New England journal of medicine.

[27]  Shinn-Jang Hwang,et al.  Immunogenicity and tolerability of an AS03(A)-adjuvanted prepandemic influenza vaccine: a phase III study in a large population of Asian adults. , 2009, Vaccine.

[28]  N. Groth,et al.  MF59-adjuvanted versus non-adjuvanted influenza vaccines: integrated analysis from a large safety database. , 2009, Vaccine.

[29]  T. Vesikari,et al.  MF59-adjuvanted influenza vaccine (FLUAD) in children: safety and immunogenicity following a second year seasonal vaccination. , 2009, Vaccine.

[30]  R. Rappuoli,et al.  Pseudoparticle neutralization is a reliable assay to measure immunity and cross-reactivity to H5N1 influenza viruses. , 2009, Vaccine.

[31]  A cell culture (Vero)-derived H5N1 whole-virus vaccine induces cross-reactive memory responses. , 2009, The Journal of infectious diseases.

[32]  G. Leroux-Roels Prepandemic H5N1 influenza vaccine adjuvanted with AS03: a review of the pre-clinical and clinical data , 2009, Expert opinion on biological therapy.

[33]  T. Vesikari,et al.  Enhanced Immunogenicity of Seasonal Influenza Vaccines in Young Children Using MF59 Adjuvant , 2009, The Pediatric infectious disease journal.

[34]  B. Camilloni,et al.  Cross-reactive antibodies in middle-aged and elderly volunteers after MF59-adjuvanted subunit trivalent influenza vaccine against B viruses of the B/Victoria or B/Yamagata lineages. , 2009, Vaccine.

[35]  R. Webster,et al.  Single- and multiple-clade influenza A H5N1 vaccines induce cross protection in ferrets. , 2009, Vaccine.

[36]  T. Smith,et al.  Antibodies to squalene in US Navy Persian Gulf War veterans with chronic multisymptom illness. , 2009, Vaccine.

[37]  F. Ansaldi,et al.  Adjuvanted seasonal influenza vaccines and perpetual viral metamorphosis: the importance of cross-protection. , 2009, Vaccine.

[38]  M. Zambon,et al.  Fast rise of broadly cross-reactive antibodies after boosting long-lived human memory B cells primed by an MF59 adjuvanted prepandemic vaccine , 2009, Proceedings of the National Academy of Sciences.

[39]  Yan Liu,et al.  Immunogenicity, safety, and cross-reactivity of an inactivated, adjuvanted, prototype pandemic influenza (H5N1) vaccine: a phase II, double-blind, randomized trial. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[40]  Gira Bhabha,et al.  Antibody Recognition of a Highly Conserved Influenza Virus Epitope , 2009, Science.

[41]  K. Subbarao,et al.  Antigenic Fingerprinting of H5N1 Avian Influenza Using Convalescent Sera and Monoclonal Antibodies Reveals Potential Vaccine and Diagnostic Targets , 2009, PLoS medicine.

[42]  Volker Brauer,et al.  Adjuvanted H5N1 vaccine induces early CD4+ T cell response that predicts long-term persistence of protective antibody levels , 2009, Proceedings of the National Academy of Sciences.

[43]  P. Palese,et al.  Universal epitopes of influenza virus hemagglutinins? , 2009, Nature Structural &Molecular Biology.

[44]  Boguslaw Stec,et al.  Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses , 2009, Nature Structural &Molecular Biology.

[45]  Volker Brauer,et al.  MF59®-Adjuvanted H5N1 Vaccine Induces Immunologic Memory and Heterotypic Antibody Responses in Non-Elderly and Elderly Adults , 2009, PloS one.

[46]  Y. Guan,et al.  Heterosubtypic Neutralizing Monoclonal Antibodies Cross-Protective against H5N1 and H1N1 Recovered from Human IgM+ Memory B Cells , 2008, PloS one.

[47]  M. Zambon,et al.  Antigenically distinct MF59-adjuvanted vaccine to boost immunity to H5N1. , 2008, The New England journal of medicine.

[48]  Thomas D Szucs,et al.  Stockpiling prepandemic influenza vaccines: a new cornerstone of pandemic preparedness plans. , 2008, The Lancet. Infectious diseases.

[49]  G. Leroux-Roels,et al.  An adjuvanted, low-dose, pandemic influenza A (H5N1) vaccine candidate is safe, immunogenic, and induces cross-reactive immune responses in healthy adults. , 2008, The Journal of infectious diseases.

[50]  R. Rappuoli,et al.  Molecular and cellular signatures of human vaccine adjuvants , 2008, Proceedings of the National Academy of Sciences.

[51]  D. Novicki,et al.  Safety of MF59 adjuvant. , 2008, Vaccine.

[52]  H. Ehrlich,et al.  A clinical trial of a whole-virus H5N1 vaccine derived from cell culture. , 2008, The New England journal of medicine.

[53]  Mariagrazia Pizza,et al.  The Adjuvants Aluminum Hydroxide and MF59 Induce Monocyte and Granulocyte Chemoattractants and Enhance Monocyte Differentiation toward Dendritic Cells1 , 2008, The Journal of Immunology.

[54]  A. Monto,et al.  Seasonal and pandemic influenza: a 2007 update on challenges and solutions. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[55]  L. Sticchi,et al.  Cross-protection by MF59-adjuvanted influenza vaccine: neutralizing and haemagglutination-inhibiting antibody activity against A(H3N2) drifted influenza viruses. , 2008, Vaccine.

[56]  D. Bernstein,et al.  Effects of adjuvants on the safety and immunogenicity of an avian influenza H5N1 vaccine in adults. , 2008, The Journal of infectious diseases.

[57]  G. Leroux-Roels,et al.  Broad Clade 2 Cross-Reactive Immunity Induced by an Adjuvanted Clade 1 rH5N1 Pandemic Influenza Vaccine , 2008, PloS one.

[58]  J. Treanor,et al.  Evaluation of the safety and immunogenicity of a booster (third) dose of inactivated subvirion H5N1 influenza vaccine in humans. , 2008, The Journal of infectious diseases.

[59]  R. Rappuoli,et al.  Combination adjuvants for the induction of potent, long-lasting antibody and T-cell responses to influenza vaccine in mice. , 2008, Vaccine.

[60]  A. Osterhaus,et al.  Cross-Protection against Lethal H5N1 Challenge in Ferrets with an Adjuvanted Pandemic Influenza Vaccine , 2008, PloS one.

[61]  R. Rappuoli,et al.  Waiting for a pandemic , 2008 .

[62]  G. Hui,et al.  The requirement of CD80, CD86, and ICAM-1 on the ability of adjuvant formulations to potentiate antibody responses to a Plasmodium falciparum blood-stage vaccine. , 2007, Vaccine.

[63]  J. Díez-Domingo,et al.  Effectiveness of MF59-adjuvanted subunit influenza vaccine in preventing hospitalisations for cardiovascular disease, cerebrovascular disease and pneumonia in the elderly. , 2007, Vaccine.

[64]  D. O’hagan MF59 is a safe and potent vaccine adjuvant that enhances protection against influenza virus infection , 2007, Expert review of vaccines.

[65]  A Flahault,et al.  Influenza vaccine: the challenge of antigenic drift. , 2007, Vaccine.

[66]  A. Floreani,et al.  Response of Influenza Vaccines Against Heterovariant Influenza Virus Strains in Adults with Chronic Diseases , 2007, Journal of Clinical Immunology.

[67]  A. Floreani,et al.  MF59-adjuvanted influenza vaccine confers superior immunogenicity in adult subjects (18-60 years of age) with chronic diseases who are at risk of post-influenza complications. , 2007, Vaccine.

[68]  A. Flahault,et al.  Real-time monitoring of the influenza vaccine field effectiveness. , 2006, Vaccine.

[69]  R. Rappuoli,et al.  Vaccines with the MF59 Adjuvant Do Not Stimulate Antibody Responses against Squalene , 2006, Clinical and Vaccine Immunology.

[70]  R. Rappuoli,et al.  An MF59-adjuvanted inactivated influenza vaccine containing A/Panama/1999 (H3N2) induced broader serological protection against heterovariant influenza virus strain A/Fujian/2002 than a subunit and a split influenza vaccine. , 2006, Vaccine.

[71]  Manmohan J. Singh,et al.  A preliminary evaluation of alternative adjuvants to alum using a range of established and new generation vaccine antigens. , 2006, Vaccine.

[72]  Cécile Viboud,et al.  Antibody response to influenza vaccination in the elderly: a quantitative review. , 2006, Vaccine.

[73]  M. Singh,et al.  MF59: A Safe and Potent Adjuvant for Human Use , 2006 .

[74]  R. Bugarini,et al.  Cross-reactivity to highly pathogenic avian influenza H5N1 viruses after vaccination with nonadjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a potential priming strategy. , 2005, The Journal of infectious diseases.

[75]  J. Díez-Domingo,et al.  Effectiveness of the MF59-adjuvanted influenza vaccine in preventing emergency admissions for pneumonia in the elderly over 64 years of age. , 2004, Vaccine.

[76]  R. Bugarini,et al.  Antibody responses and HIV-1 viral load in HIV-1-seropositive subjects immunised with either the MF59-adjuvanted influenza vaccine or a conventional non-adjuvanted subunit vaccine during highly active antiretroviral therapy. , 2003, Vaccine.

[77]  A. Podda,et al.  A New MF59-Adjuvanted Influenza Vaccine Enhances the Immune Response in the Elderly with Chronic Diseases: Results from an Immunogenicity Meta-Analysis , 2003, Gerontology.

[78]  Maria Zambon,et al.  Boosting immunity to influenza H5N1 with MF59-adjuvanted H5N3 A/Duck/Singapore/97 vaccine in a primed human population. , 2003, Vaccine.

[79]  Giuseppe Del Giudice,et al.  MF59-adjuvanted vaccines: increased immunogenicity with an optimal safety profile , 2003, Expert review of vaccines.

[80]  L. Biasio,et al.  Comparison of the reactogenicity and immunogenicity of a split and a subunit-adjuvanted influenza vaccine in elderly subjects. , 2003, Vaccine.

[81]  Marc Dupuis,et al.  Immunization with the adjuvant MF59 induces macrophage trafficking and apoptosis , 2001, European journal of immunology.

[82]  M. Zambon,et al.  Safety and antigenicity of non-adjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza , 2001, The Lancet.

[83]  A. Podda The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine. , 2001, Vaccine.

[84]  A. Osterhaus,et al.  Mismatch between the 1997/1998 influenza vaccine and the major epidemic A(H3N2) virus strain as the cause of an inadequate vaccine‐induced antibody response to this strain in the elderly , 2000, Journal of medical virology.

[85]  Harold C. Sox,et al.  Gulf War and Health , 2000 .

[86]  D. McDonald,et al.  Distribution of adjuvant MF59 and antigen gD2 after intramuscular injection in mice. , 1999, Vaccine.

[87]  M. Faccini,et al.  Safety and immunogenicity of MF59-adjuvanted influenza vaccine in the elderly. , 1999, Vaccine.

[88]  A. Podda,et al.  Safety and immunogenicity of an inactivated subunit influenza virus vaccine combined with MF59 adjuvant emulsion in elderly subjects, immunized for three consecutive influenza seasons. , 1999, Vaccine.

[89]  D. McDonald,et al.  Dendritic cells internalize vaccine adjuvant after intramuscular injection. , 1998, Cellular immunology.

[90]  G. Van Nest,et al.  The adjuvant MF59 increases the immunogenicity and protective efficacy of subunit influenza vaccine in mice. , 1997, Vaccine.

[91]  D. Granoff,et al.  MF59 adjuvant enhances antibody responses of infant baboons immunized with Haemophilus influenzae type b and Neisseria meningitidis group C oligosaccharide-CRM197 conjugate vaccine , 1997, Infection and immunity.

[92]  G. Nest,et al.  MF59 adjuvant enhances the antibody response to recombinant hepatitis B surface antigen vaccine in primates. , 1996, The Journal of infectious diseases.

[93]  Y. Isegawa,et al.  A common neutralizing epitope conserved between the hemagglutinins of influenza A virus H1 and H2 strains , 1993, Journal of virology.

[94]  I. Wilson,et al.  Structural identification of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic variation , 1981, Nature.

[95]  R. Webster,et al.  Disquisitions of Original Antigenic Sin. I. Evidence in man. , 1966, The Journal of experimental medicine.

[96]  R. Webster,et al.  DISQUISITIONS ON ORIGINAL ANTIGENIC SIN , 1966, The Journal of experimental medicine.