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  • 1
    Language: English
    In: Science (New York, N.Y.), 12 August 2011, Vol.333(6044), pp.843-50
    Description: Current flu vaccines provide only limited coverage against seasonal strains of influenza viruses. The identification of V(H)1-69 antibodies that broadly neutralize almost all influenza A group 1 viruses constituted a breakthrough in the influenza field. Here, we report the isolation and characterization of a human monoclonal antibody CR8020 with broad neutralizing activity against most group 2 viruses, including H3N2 and H7N7, which cause severe human infection. The crystal structure of Fab CR8020 with the 1968 pandemic H3 hemagglutinin (HA) reveals a highly conserved epitope in the HA stalk distinct from the epitope recognized by the V(H)1-69 group 1 antibodies. Thus, a cocktail of two antibodies may be sufficient to neutralize most influenza A subtypes and, hence, enable development of a universal flu vaccine and broad-spectrum antibody therapies.
    Keywords: Antibodies, Monoclonal -- Immunology ; Antibodies, Neutralizing -- Immunology ; Antibodies, Viral -- Immunology ; Antigens, Viral -- Immunology ; Hemagglutinin Glycoproteins, Influenza Virus -- Immunology ; Influenza A Virus -- Immunology
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 2
    Language: English
    In: Frontiers in Immunology, 01 September 2016, Vol.7
    Description: Interactions with receptors for the Fc region of IgG (FcγRs) have been shown to contribute to the in vivo protection against influenza A viruses provided by broadly neutralizing antibodies (bnAbs) that bind to the viral hemagglutinin (HA) stem. In particular, Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) has been shown to contribute to protection by stem-binding bnAbs. Fc-mediated effector functions appear not to contribute to protection provided by strain-specific HA head-binding antibodies. We used a panel of anti-stem and anti-head influenza A and B monoclonal antibodies with identical human IgG1 Fc domains and investigated their ability to mediate ADCC associated FcγRIIIa activation. Antibodies which do not interfere with sialic acid binding of HA can mediate FcγRIIIa activation. However, the FcγRIIIa activation was inhibited when a mutant HA, unable to bind sialic acids, was used. Antibodies which block sialic acid receptor interactions of HA interfered with FcγRIIIa activation. The inhibition of FcγRIIIa activation by HA head-binding and sialic acid receptor blocking antibodies was confirmed in plasma samples of H5N1 vaccinated human subjects. Together, these results suggest that in addition to Fc–FcγR binding, interactions between HA and sialic acids on immune cells are required for optimal Fc-mediated effector functions by anti-HA antibodies.
    Keywords: Sialic Acids ; Adcc ; Hai ; Stem-Binder ; Head-Binder ; Cr9114 ; Biology
    E-ISSN: 1664-3224
    Source: Directory of Open Access Journals (DOAJ)
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  • 3
    Language: English
    In: PLoS ONE, 2015, Vol.10(9), pp.urn:issn:1932-6203
    Description: There is a constant threat of zoonotic influenza viruses causing a pandemic outbreak in humans. It is virtually impossible to predict which virus strain will cause the next pandemic and it takes a considerable amount of time before a safe and effective vaccine will be available once a pandemic occurs. In addition, development of pandemic vaccines is hampered by the generally poor immunogenicity of avian influenza viruses in humans. An effective pre-pandemic vaccine is therefore required as a first line of defense. Broadening of the protective efficacy of current seasonal vaccines by adding an adjuvant may be a way to provide such first line of defense. Here we evaluate whether a seasonal trivalent virosomal vaccine (TVV) adjuvated with the saponin-based adjuvant Matrix-M (MM) can confer protection against avian influenza H5 and H7 virus strains in mice and ferrets. We demonstrate that mice were protected from death against challenges with H5N1 and H7N7, but that the protection was not complete as evidenced by severe clinical signs. In ferrets, protection against H7N9 was not observed. In contrast, reduced upper and lower respiratory tract viral loads and reduced lung pathology, was achieved in H5N1 challenged ferrets. Together these results suggest that, at least to some extent, Matrix-M adjuvated seasonal virosomal influenza vaccine can serve as an interim measure to decrease morbidity and mortality associated with a pandemic outbreak
    Keywords: Sciences (General);
    ISSN: 1932-6203
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  • 4
    Language: English
    In: PLoS ONE, 2015, Vol.10(12), pp.urn:issn:1932-6203
    Description: Background It remains important to develop the next generation of influenza vaccines that can provide protection against vaccine mismatched strains and to be prepared for potential pandemic outbreaks. To achieve this, the understanding of the immunological parameters that mediate such broad protection is crucial. Method In the current study we assessed the contribution of humoral and cellular immune responses to heterosubtypic protection against H5N1 induced by a Matrix-M (MM) adjuvanted seasonal influenza vaccine by serum transfer and T-cell depletion studies. Results We demonstrate that the heterosubtypic protection against H5N1 induced by MM adjuvanted vaccine is partially mediated by antibodies. The serum contained both H5N1 cross-reactive hemagglutinin (HA)- and neuraminidase (NA)-specific antibodies but with limited virus neutralizing and no hemagglutination inhibiting activity. The cross-reactive antibodies induced antibody-dependent cellular cytotoxicity (ADCC) in vitro, suggesting a role for the Fc part of the antibodies in protection against H5N1. Besides H5N1 specific antibody responses, cross-reactive HA- and NA-specific T-cell responses were induced by the adjuvanted vaccine. T-cell depletion experiments demonstrated that both CD4(+) and CD8(+) T cells contribute to protection. Conclusion Our study demonstrates that cross-protection against H5N1 induced by MM adjuvanted seasonal virosomal influenza vaccine requires both the humoral and cellular arm of the immune system
    Keywords: Influenza Vaccines ; Lectins ; T Cells ; B Cells ; Avian Influenza;
    ISSN: 1932-6203
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  • 5
    In: Future Virology, June 2016, Vol.11(6), p.451-467
    Description: Influenza infections are responsible for a large health and economic burden. Vaccination is the best strategy to reduce influenza-related disease burden, but current vaccines have limited breadth and need near-annual reformulation. Developing new influenza vaccines that provide broad and long-lasting protection is an important goal. This review represents an overview of the current knowledge of the universal vaccine approach that focuses on the induction of broadly neutralizing antibodies targeting the hemagglutinin (HA) stem of influenza viruses. Adjuvation of existing influenza vaccines has so far had limited effect on the induction of broadly neutralizing antibodies. HA stem-based immunogens that lack the immunodominant HA head have shown promising results in preclinical models, providing evidence that a universal influenza vaccine is within reach.
    Keywords: adjuvants ; broadly neutralizing antibodies ; HA ; HA stem ; HA stem-based immunogens ; influenza ; vaccines
    ISSN: 1746-0794
    E-ISSN: 1746-0808
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  • 6
    Language: English
    In: PLoS ONE, 2018, Vol.13(8), pp.urn:issn:1932-6203
    Description: In 2015, there was a large outbreak of Zika virus (ZIKV) in Brazil. Despite its relatively mild impact on healthy adults, ZIKV infection during pregnancy has been associated with severe birth defects. Currently, there is no ZIKV vaccine available, but several vaccine candidates based on the ZIKV membrane (M) and envelope (Env) structural proteins showed promising results in preclinical and clinical studies. Here, the immunogenicity and protective efficacy of a non-replicating adenoviral vector type 26 (Ad26) that encodes the ZIKV M-Env antigens (Ad26.ZIKV.M-Env) was evaluated in mice and non-human primates (NHP). Ad26.ZIKV.M-Env induced strong and durable cellular and humoral immune responses in preclinical models. Humoral responses were characterized by Env-binding and ZIKV neutralizing antibody responses while cellular responses were characterized by ZIKV reactive CD4+ and CD8+ T cells. Importantly, a single immunization with a very low dose of 4x107 vp of Ad26.ZIKV.M-Env protected mice from ZIKV challenge. In NHP, a single immunization with a typical human dose of 1x1011 vp of Ad26.ZIKV.M-Env also induced Env-binding and ZIKV neutralizing antibodies and Env and M specific cellular immune responses that associated with complete protection against viremia from ZIKV challenge as measured in plasma and other body fluids. Together these data provide the rationale to progress the Ad26.ZIKV.M-Env candidate vaccine to clinical testing.
    Keywords: Pregnancy Complications -- Risk Factors ; Gene Expression -- Research ; Immune Response -- Analysis ; Viral Vaccines -- Usage ; Zika Virus -- Prevention;
    ISSN: 1932-6203
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  • 7
    Language: English
    In: Virology journal, 2015, Vol.12(1), pp.urn:issn:1743-422x
    Description: Background: Influenza virus infections are responsible for significant morbidity worldwide and therefore it remains a high priority to develop more broadly protective vaccines. Adjuvation of current seasonal influenza vaccines has the potential to achieve this goal. Methods: To assess the immune potentiating properties of Matrix-M (TM), mice were immunized with virosomal trivalent seasonal vaccine adjuvated with Matrix-M (TM). Serum samples were isolated to determine the hemagglutination inhibiting (HAI) antibody titers against vaccine homologous and heterologous strains. Furthermore, we assess whether adjuvation with Matrix-M (TM) broadens the protective efficacy of the virosomal trivalent seasonal vaccine against vaccine homologous and heterologous influenza viruses. Results: Matrix-M (TM) adjuvation enhanced HAI antibody titers and protection against vaccine homologous strains. Interestingly, Matrix-M (TM) adjuvation also resulted in HAI antibody titers against heterologous influenza B strains, but not against the tested influenza A strains. Even though the protection against heterologous influenza A was induced by the adjuvated vaccine, in the absence of HAI titers the protection was accompanied by severe clinical scores and body weight loss. In contrast, in the presence of heterologous HAI titers full protection against the heterologous influenza B strain without any disease symptoms was obtained. Conclusion: The results of this study emphasize the promising potential of a Matrix-M (TM)-adjuvated seasonal trivalent virosomal influenza vaccine. Adjuvation of trivalent virosomal vaccine does not only enhance homologous protection, but in addition induces protection against heterologous strains and thus provides overall more potent and broad protective immunity
    Keywords: Influenza Vaccines -- Health Aspects ; Medical Research -- Health Aspects ; Influenza -- Health Aspects;
    ISSN: 1743-422x
    ISSN: 1743422X
    E-ISSN: 1743422X
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  • 8
    Language: English
    In: Journal of Molecular Biology, 2009, Vol.387(3), pp.548-558
    Description: To study the contribution of antibody light (L) chains to the diversity and binding properties of immune repertoires, a phage display repertoire was constructed from a single human antibody L chain and a large collection of antibody heavy (H) chains harvested from the blood of two human donors immunized with tetanus toxoid (TT) vaccine. After selection for binding to TT, 129 unique antibodies representing 53 variable immunoglobulin H chain (V ) gene rearrangements were isolated. This panel of anti-TT antibodies restricted to a single variable immunoglobulin L chain (V ) could be organized into 17 groups binding non-competing epitopes on the TT molecule. Comparison of the V regions in this V -restricted panel with a previously published repertoire of anti-TT V regions with cognate V –V pairing showed a very similar distribution of V , D and J gene segment utilization and length of the complementarity-determining region 3 of the H chain. Surface plasmon resonance analysis of the single-V anti-TT repertoire unveiled a range of affinities, with a median monovalent affinity of 2 nM. When the single-V anti-TT V repertoire was combined with a collection of naïve V regions and again selected for binding to TT, many of the V genes were recovered in combination with a diversity of V regions. The affinities of a panel of antibodies consisting of a single promiscuous anti-TT V combined with 15 diverse V chains were determined and found to be identical to each other and to the original isolate restricted to a single-V chain. Based on previous estimates of the clonal size of the human anti-TT repertoire, we conclude that up to 25% of human anti-TT-encoding V regions from an immunized repertoire have promiscuous features. These V regions readily combine with a single antibody L chain to result in a large panel of anti-TT antibodies that conserve the expected epitope diversity, V region diversity and affinity of a natural repertoire.
    Keywords: Promiscuous ; Tetanus ; Antibody ; V H Gene ; Repertoire ; Biology ; Chemistry
    ISSN: 0022-2836
    E-ISSN: 1089-8638
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  • 9
    Language: English
    ISBN: 9789461827340
    Source: NARCIS (National Academic Research and Collaborations Information System)
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  • 10
    Language: English
    In: PLoS ONE, 2008, Vol.3(12), p.e3942
    Description: The hemagglutinin (HA) glycoprotein is the principal target of protective humoral immune responses to influenza virus infections but such antibody responses only provide efficient protection against a narrow spectrum of HA antigenic variants within a given virus subtype. Avian influenza viruses such as H5N1 are currently panzootic and pose a pandemic threat. These viruses are antigenically diverse and protective strategies need to cross protect against diverse viral clades. Furthermore, there are 16 different HA subtypes and no certainty the next pandemic will be caused by an H5 subtype, thus it is important to develop prophylactic and therapeutic interventions that provide heterosubtypic protection. ; Here we describe a panel of 13 monoclonal antibodies (mAbs) recovered from combinatorial display libraries that were constructed from human IgM memory B cells of recent (seasonal) influenza vaccinees. The mAbs have broad heterosubtypic neutralizing activity against antigenically diverse H1, H2, H5, H6, H8 and H9 influenza subtypes. Restriction to variable heavy chain gene IGHV1-69 in the high affinity mAb panel was associated with binding to a conserved hydrophobic pocket in the stem domain of HA. The most potent antibody (CR6261) was protective in mice when given before and after lethal H5N1 or H1N1 challenge. ; The human monoclonal CR6261 described in this study could be developed for use as a broad spectrum agent for prophylaxis or treatment of human or avian influenza infections without prior strain characterization. Moreover, the CR6261 epitope could be applied in targeted vaccine strategies or in the design of novel antivirals. Finally our approach of screening the IgM memory repertoire could be applied to identify conserved and functionally relevant targets on other rapidly evolving pathogens.
    Keywords: Research Article ; Biotechnology ; Immunology -- Immunity To Infections ; Immunology -- Innate Immunity ; Microbiology -- Innate Immunity ; Virology -- Antivirals, Including Modes Of Action And Resistance ; Virology -- New Therapies, Including Antivirals And Immunotherapy ; Infectious Diseases -- Respiratory Infections ; Infectious Diseases -- Viral Infections ; Respiratory Medicine -- Respiratory Infections
    E-ISSN: 1932-6203
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