Heterosubtypic immunity. Professor Ajit Lalvani FMedSci Chair of Infectious Diseases 14/07/2014

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1 Protective cellular immune correlates against pandemic influenza: implications for universal vaccines 2 nd WHO Meeting on development and clinical trials of broadly protective influenza vaccines 5th 7th May 2014, Geneva Can we learn from natural resistance to pandemic flu? In a pandemic, global population is antibody-naïve and highly susceptible to infection with the antigenically-shifted strain Yet the majority of people who get infected experience minimal or no symptoms these optimal clinical outcomes during a pandemic are more common in those with prior seasonal flu Professor Ajit Lalvani FMedSci Chair of Infectious Diseases Respiratory Infection Section National Heart and Lung Institute Imperial College London NIHR Health Protection Research Unit in Respiratory Infection Imperial College London & Public Health England Bull WHO 1959 J Infect Dis 2006 Heterosubtypic immunity Heterosubtypic immunity (HSI) against influenza: immunity induced by one influenza subtype confers protection against infection or disease caused by an antigenically-shifted previously un-encountered influenza virus Role for cross-reactive T cells to conserved core proteins supported by: - animal models (since Schulman & Kilbourne J Bacteriol 1965) - human experimental challenge model (McMichael et al NEJM 1983) Key questions for universal influenza vaccine development Do unexposed, antibody-naïve individuals harbour T cells that cross-recognise new pandemic strains? If so, do T cells mediate heterosubtypic protection against naturally-acquired symptomatic pandemic flu? Which T cell subset is associated with protection against symptoms? Protective correlate to guide rational design and evaluation of universal flu vaccine NB: these questions can only be answered during a pandemic when a new viral strain spread through a susceptible antibody-niave population. 1

2 Background Pos control Flu peptides Live flu virus CMV lysate 14/07/2014 Study population recruited at start of pandemic Unique natural experiment 91 conserved CD8 epitopes from core proteins: PB1, M1, NP A/England/195/2009 ph1n1 strain Ex vivo enumeration of major Functional T cell subsets IFN-γ IL-2 IFN-γ/IL-2 dual Pre-existing ph1n1 flu-specific T cells at baseline Live ph1n1 virus Sridhar et al. Eur J Immunol 2012 Conserved CD8 epitopes from PB1, NP, M1 Predicted CD8 epitopes from PB1, M1 and NP proteins (9-mers) 2

3 Study population recruited at start of pandemic Cohort of 342 yielded 25 preciselydefined cases of incident ph1n1 flu Frequencies of pre-existing IFNg/IL-2 total cytokine-secreting CD8 + T-cells associated with limited symptom severity Significantly higher frequency of IFNg + IL-2 - subset of CD8 + T-cells associated with limited symptoms 3

4 Higher frequency of IFNg + IL-2 - subset of CD8 + T-cells associated with lower symptom scores Live ph1n1 virus CD8 conserved epitopes Heterosubtypic IFNg + IL-2 - CD8 + T-cells are associated with prevention of viral shedding Each 10-fold increase in the frequency of ph1n1 virusspecific T cells confers a 7-fold decrease in risk of developing influenza illness with fever The protection-associated CD8+IFNg+IL-2- T cell subset has a late-effector CD45RA+CCR7-phenotype and lung-homing (CCR5+) and cytotoxic capacity 4

5 Conclusions First cellular immune correlate of protection against influenza illness following natural infection In absence of antibody, cross-reactive CD8 + T-cells limit illness severity and virus shedding with a new reassortant pandemic virus strain This cellular correlate provides rationale and a surrogate marker for design and evaluation of broadly protective T-cell inducing influenza vaccines Implications for universal influenza vaccine development Target antigens and epitopes for inclusion in vaccine + protection-associated T cell subset to be induced = blueprint for vaccine and surrogate marker Respiratory Infections, Imperial College London Collaborators at Public Health England Conflict of interest statement: AL is named inventor on a patent covering development and evaluation of T cell-based universal influenza vaccines Lalvani et al, J Exp Med

6 Discussion Community cohort study provided mild to moderately symptomatic infection. Will these CD8 T-cells work against more severe disease? How long do these T-cells last following infection? This is a correlate in peripheral blood. Do these cells exist in the lung? Will vaccine-induced protection be the same as naturallyacquired protection? Study Definitions Seroconversion = 4 fold titre rise in paired serum sample Infection = Nasal swab +ve AND/OR Seroconversion without H/o pandemic vaccination Asymptomatic Infection = Individuals with seroconversion BUT NO ILI reported in survey and answered >75% of surveys Symptomatic infection = Individuals reporting at least one ILI. Total symptom score = weighted summed score of five canonical influenza symptoms (fever, myalgia, sore throat, headache, cough). Evidence for T cell-mediated heterosubtypic immunity in humans is restricted to experimental challenge studies CD8 T cells mediate hetersubtypic immunity against influenza disease in animal models In the absence of antibodies to challenge strains pre-challenge CTL responses pre-challenge CD4+ responses (Wilkinson et al., 2012 Nat Med ) J Bacteriol

7 Flourescence-linked Immunospot Cross-reactive T cells are detectable in majority of sero-negative individuals 33 ph1n1 sero-negative individuals 30/33 individuals had a IFN-γ only response 22/33 individuals had a IL-2 only response Casey et al, PLoS ONE 2010 Sridhar et al. EJI 2012 T cell responses to pandemic H1N1 Circulating, influenza-specific memory T cells cross-reactive with ph1n1 prevalent in healthy individuals naïve to ph1n1 Predominantly of IFN-γ+IL-2- cytokine secreting profile detected by fluorescence-immunospot N = 35 Sridhar S, Begom S et al. EJI 2012 These pre-existing cells could mediate protection against ph1n1 disease What is the phenotype and functional attribute of these cells? TB Preventing pandemics with T cells 1.4 million deaths 9 million new cases p.a. 2 billion infected T cell-based diagnosis & targeted treatment of latent TB T cell-based risk-stratification and vaccination to prevent influenza illness 0.5 million deaths 5 million new symptomatic cases p.a. FLU 60% asymptomatic infection 7