Characterisation of cellular responses to pandemic influenza in naturally infected individuals

Understanding the relevance of T cells in limiting influenza illness severity will facilitate the rational design and evaluation of T cell-based universal influenza vaccines. The aim of this thesis was to characterise pre-existing T cell responses to influenza and follow the kinetics of these T cell responses to infection by exploiting the 2009 H1N1 pandemic (pH1N1). Peripheral blood mononuclear cells (PBMCs) were collected from healthy adults naïve to pH1N1 who were longitudinally followed over 2 influenza seasons from 2009 – 2011. Ex vivo pH1N1-specific memory CD4+ and CD8+ T cell responses were characterised by IFN-γ/IL-2 fluorescence-immunospot and 14-colour flow cytometry. In pH1N1 seronegative adults in a community setting, pre-existing influenza-specific T cells cross-reacting with pH1N1 were prevalent, pre-dominantly of a single-cytokine positive (IFN-γ+, IL-2+ or TNF-α+) and effector memory (CD45RA-CCR7-) or late effector (CD45RA+CCR7-) phenotype and expressed lung homing receptor (CCR5+) and cytotoxic degranulation marker (CD107ab+). Pre-existing CD8+IFN-γ+IL-2- Temra (CD45RA+CCR7-) cells limited disease severity following incident pH1N1 infection in the absence of protective strain-specific antibodies. Furthermore, we show that this protection-associated T cell subset is durably maintained in the absence of re-infection up to 1.5 years post-infection. The identification of a protection-associated immune correlate, the frequencies of which were increased and durably maintained by natural infection, is highly relevant for the development of a universal influenza vaccine inducing long-lasting, protective T cells.Open Acces

Longevity and determinants of protective humoral immunity after pandemic influenza infection

Rationale: Antibodies to influenza hemagglutinin are the primary correlate of protection against infection. The strength and persistence of this immune response influences viral evolution and consequently the nature of influenza epidemics. However, the durability and immune determinants of induction of humoral immunity after primary influenza infection remain unclear. Objectives: The spread of a novel H1N1 (A[H1N1]pdm09) virus in 2009 through an unexposed population offered a natural experiment to assess the nature and longevity of humoral immunity after a single primary influenza infection. Methods: We followed A(H1N1)pdm09-seronegative adults through two influenza seasons (2009–2011) as they developed A(H1N1)pdm09 influenza infection or were vaccinated. Antibodies to A(H1N1)pdm09 virus were measured by hemagglutination-inhibition assay in individuals with paired serum samples collected preinfection and postinfection or vaccination to assess durability of humoral immunity. Preexisting A(H1N1)pdm09-specific multicytokine-secreting CD4 and CD8 T cells were quantified by multiparameter flow cytometry to test the hypothesis that higher frequencies of CD4+ T-cell responses predict stronger antibody induction after infection or vaccination. Measurements and Main Results: Antibodies induced by natural infection persisted at constant high titer for a minimum of approximately 15 months. Contrary to our initial hypothesis, the fold increase in A(H1N1)pdm09-specific antibody titer after infection was inversely correlated to the frequency of preexisting circulating A(H1N1)pdm09-specific CD4+IL-2+IFN-γ−TNF-α− T cells (r = −0.4122; P = 0.03). Conclusions: The longevity of protective humoral immunity after influenza infection has important implications for influenza transmission dynamics and vaccination policy, and identification of its predictive cellular immune correlate could guide vaccine development and evaluation

Формирование иноязычной коммуникативной компетенции при обучении чтению

We conducted a longitudinal community cohort study of healthy adults in the UK. We found significantly higher incidence of influenza A(H1N1)pdm09 infection in 2010–11 than in 2009–10, a substantial proportion of subclinical infection, and higher risk for infection during 2010–11 among persons with lower preinfection antibody titers

Cellular immune correlates of protection against symptomatic pandemic influenza

The role of T cells in mediating heterosubtypic protection against natural influenza illness in humans is uncertain. The 2009 H1N1 pandemic (pH1N1) provided a unique natural experiment to determine whether crossreactive cellular immunity limits symptomatic illness in antibody-naive individuals. We followed 342 healthy adults through the UK pandemic waves and correlated the responses of pre-existing T cells to the pH1N1 virus and conserved core protein epitopes with clinical outcomes after incident pH1N1 infection. Higher frequencies of pre-existing T cells to conserved CD8 epitopes were found in individuals who developed less severe illness, with total symptom score having the strongest inverse correlation with the frequency of interferon-γ (IFN-γ)+ interleukin-2 (IL-2)− CD8+ T cells (r = −0.6, P = 0.004). Within this functional CD8+IFN-γ+IL-2− population, cells with the CD45RA+ chemokine (C-C) receptor 7 (CCR7)− phenotype inversely correlated with symptom score and had lung-homing and cytotoxic potential. In the absence of crossreactive neutralizing antibodies, CD8+ T cells specific to conserved viral epitopes correlated with crossprotection against symptomatic influenza. This protective immune correlate could guide universal influenza vaccine development