Microbiology & Immunology - Research Publications

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Author: Kedzierska, Katherine × Author: Kent, Stephen × End date: 2019 × Start date: 2018 ×

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    Cross-lineage protection by human antibodies binding the influenza B hemagglutinin
    Liu, Y ; Tan, H-X ; Koutsakos, M ; Jegaskanda, S ; Esterbauer, R ; Tilmanis, D ; Aban, M ; Kedzierska, K ; Hurt, AC ; Kent, SJ ; Wheatley, AK (NATURE PUBLISHING GROUP, 2019-01-18)
    Influenza B viruses (IBV) drive a significant proportion of influenza-related hospitalisations yet are understudied compared to influenza A. Current vaccines target the head of the viral hemagglutinin (HA) which undergoes rapid mutation, significantly reducing vaccine effectiveness. Improved vaccines to control IBV are needed. Here we developed novel IBV HA probes to interrogate humoral responses to IBV in humans. A significant proportion of IBV HA-specific B cells recognise both B/Victoria/2/87-like and B/Yamagata/16/88-like lineages in a distinct pattern of cross-reactivity. Monoclonal antibodies (mAbs) were reconstituted from IBV HA-specific B cells, including mAbs providing broad protection in murine models of lethal IBV infection. Protection was mediated by neutralising antibodies targeting the receptor binding domain, or via Fc-mediated functions of non-neutralising antibodies binding alternative epitopes including the IBV HA stem. This work defines antigenic cross-recognition between IBV lineages and provides guidance for the rational design of improved IBV vaccines for broad and durable protection.
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    Circulating TFH cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity
    Koutsakos, M ; Wheatley, AK ; Loh, L ; Clemens, EB ; Sant, S ; Nussing, S ; Fox, A ; Chung, AW ; Laurie, KL ; Hurt, AC ; Rockman, S ; Lappas, M ; Loudovaris, T ; Mannering, SI ; Westall, GP ; Elliot, M ; Tangye, SG ; Wakim, LM ; Kent, SJ ; Nguyen, THO ; Kedzierska, K (AMER ASSOC ADVANCEMENT SCIENCE, 2018-02-14)
    Immunization with the inactivated influenza vaccine (IIV) remains the most effective strategy to combat seasonal influenza infections. IIV activates B cells and T follicular helper (TFH) cells and thus engenders antibody-secreting cells and serum antibody titers. However, the cellular events preceding generation of protective immunity in humans are inadequately understood. We undertook an in-depth analysis of B cell and T cell immune responses to IIV in 35 healthy adults. Using recombinant hemagglutinin (rHA) probes to dissect the quantity, phenotype, and isotype of influenza-specific B cells against A/California09-H1N1, A/Switzerland-H3N2, and B/Phuket, we showed that vaccination induced a three-pronged B cell response comprising a transient CXCR5-CXCR3+ antibody-secreting B cell population, CD21hiCD27+ memory B cells, and CD21loCD27+ B cells. Activation of circulating TFH cells correlated with the development of both CD21lo and CD21hi memory B cells. However, preexisting antibodies could limit increases in serum antibody titers. IIV had no marked effect on CD8+, mucosal-associated invariant T, γδ T, and natural killer cell activation. In addition, vaccine-induced B cells were not maintained in peripheral blood at 1 year after vaccination. We provide a dissection of rHA-specific B cells across seven human tissue compartments, showing that influenza-specific memory (CD21hiCD27+) B cells primarily reside within secondary lymphoid tissues and the lungs. Our study suggests that a rational design of universal vaccines needs to consider circulating TFH cells, preexisting serological memory, and tissue compartmentalization for effective B cell immunity, as well as to improve targeting cellular T cell immunity.