title: Natural T Cell-mediated Protection against Seasonal and Pandemic Influenza. Results of the Flu Watch Cohort Study.
abstract: BACKGROUND
  A high proportion of influenza infections are asymptomatic. Animal and human challenge studies and observational studies suggest T cells protect against disease among those infected, but the impact of T-cell immunity at the population level is unknown.
  
  
  OBJECTIVE
  To investigate whether naturally preexisting T-cell responses targeting highly conserved internal influenza proteins could provide cross-protective immunity against pandemic and seasonal influenza.
  
  
  METHODS
  We quantified influenza A(H3N2) virus-specific T cells in a population cohort during seasonal and pandemic periods between 2006 and 2010. Follow-up included paired serology, symptom reporting, and polymerase chain reaction (PCR) investigation of symptomatic cases.
  
  
  RESULTS
  A total of 1,414 unvaccinated individuals had baseline T-cell measurements (1,703 participant observation sets). T-cell responses to A(H3N2) virus nucleoprotein (NP) dominated and strongly cross-reacted with A(H1N1)pdm09 NP (P < 0.001) in participants lacking antibody to A(H1N1)pdm09. Comparison of paired preseason and post-season sera (1,431 sets) showed 205 (14%) had evidence of infection based on fourfold influenza antibody titer rises. The presence of NP-specific T cells before exposure to virus correlated with less symptomatic, PCR-positive influenza A (overall adjusted odds ratio, 0.27; 95% confidence interval, 0.11-0.68; P = 0.005, during pandemic [P = 0.047] and seasonal [P = 0.049] periods). Protection was independent of baseline antibodies. Influenza-specific T-cell responses were detected in 43%, indicating a substantial population impact.
  
  
  CONCLUSIONS
  Naturally occurring cross-protective T-cell immunity protects against symptomatic PCR-confirmed disease in those with evidence of infection and helps to explain why many infections do not cause symptoms. Vaccines stimulating T cells may provide important cross-protective immunity.
authors.affiliation: 1 Department of Infectious Disease Informatics, Farr Institute of Health Informatics Research.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Hayward
authors.affiliation: 2 Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: 2 Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.|3 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Nilu
authors.initials: N
authors.lastname: Goonetilleke
authors.affiliation: 1 Department of Infectious Disease Informatics, Farr Institute of Health Informatics Research.|4 Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Ellen B
authors.initials: EB
authors.lastname: Fragaszy
authors.affiliation: 5 Respiratory Virus Unit, Centre for Infections, Public Health England, Colindale, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Bermingham
authors.affiliation: 6 Research Department of Infection and Population Health, and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Copas
authors.affiliation: 1 Department of Infectious Disease Informatics, Farr Institute of Health Informatics Research.
authors.forename: Oliver
authors.initials: O
authors.lastname: Dukes
authors.affiliation: 6 Research Department of Infection and Population Health, and.|4 Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Elizabeth R C
authors.initials: ER
authors.lastname: Millett
authors.affiliation: 7 Department of Primary Care and Population Health, University College London, London, United Kingdom.
authors.forename: Irwin
authors.initials: I
authors.lastname: Nazareth
authors.affiliation: 8 Health Protection and Influenza Research Group, Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom; and.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Nguyen-Van-Tam
authors.affiliation: 9 Department of Health, London, United Kingdom.
authors.forename: John M
authors.initials: JM
authors.lastname: Watson
authors.affiliation: 5 Respiratory Virus Unit, Centre for Infections, Public Health England, Colindale, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Zambon
authors.affiliation: 6 Research Department of Infection and Population Health, and.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Johnson
authors.affiliation: 2 Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McMichael
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004739:England / Q000453:epidemiology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology*; D007251:Influenza, Human / Q000453:epidemiology* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D058873:Pandemics / Q000706:statistics & numerical data*; D016133:Polymerase Chain Reaction; D012621:Seasons; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
keywords: T lymphocytes; cellular immunity; cohort studies
references.citation: Vaccine. 2007 Jan 8;25(4):612-20
references.pmid: 17005299
references.citation: Med Sci Monit. 2011 Apr;17(4):CR185-8
references.pmid: 21455103
references.citation: Clin Exp Immunol. 1981 Feb;43(2):276-84
references.pmid: 6974066
references.citation: J Exp Med. 2012 Jul 30;209(8):1391-5
references.pmid: 22851641
references.citation: J Exp Med. 1997 Sep 15;186(6):859-65
references.pmid: 9294140
references.citation: Clin Infect Dis. 2009 Feb 15;48(4):389-96
references.pmid: 19133796
references.citation: Nat Med. 2012 Feb;18(2):274-80
references.pmid: 22286307
references.citation: J Infect Dis. 2012 Oct 1;206(7):1078-84
references.pmid: 22837493
references.citation: Clin Infect Dis. 2011 Jan 1;52(1):1-7
references.pmid: 21148512
references.citation: Health Technol Assess. 2010 Dec;14(55):115-92
references.pmid: 21208549
references.citation: J Virol. 2006 May;80(10):4717-28
references.pmid: 16641265
references.citation: Int Immunol. 2000 Jan;12(1):91-101
references.pmid: 10607754
references.citation: N Engl J Med. 1983 Jul 7;309(1):13-7
references.pmid: 6602294
references.citation: J Infect Dis. 1979 Oct;140(4):610-3
references.pmid: 512419
references.citation: Hum Immunol. 2011 Aug;72(8):632-5
references.pmid: 21571020
references.citation: PLoS One. 2013;8(5):e62778
references.pmid: 23658773
references.citation: J Exp Med. 2009 Jul 6;206(7):1525-34
references.pmid: 19564353
references.citation: J Exp Med. 1984 Sep 1;160(3):814-26
references.pmid: 6206190
references.citation: Eur J Immunol. 1980 May;10(5):396-401
references.pmid: 6967815
references.citation: Nature. 2013 Apr 25;496(7446):399
references.pmid: 23619655
references.citation: J Gen Virol. 2002 Aug;83(Pt 8):1851-9
references.pmid: 12124449
references.citation: Am J Epidemiol. 2008 Apr 1;167(7):775-85
references.pmid: 18230677
references.citation: Euro Surveill. 2009 Jun 4;14(22). pii: 19230
references.pmid: 19497254
references.citation: Euro Surveill. 2015;20(5):21025
references.pmid: 25677050
references.citation: Cell Immunol. 1979 Mar 15;43(2):341-51
references.pmid: 113108
references.citation: Epidemiology. 2010 Sep;21(5):726-8
references.pmid: 20585253
references.citation: N Engl J Med. 2005 Nov 24;353(21):2209-11
references.pmid: 16306515
references.citation: J Immunol. 2004 Jul 15;173(2):721-5
references.pmid: 15240656
references.citation: Am J Respir Crit Care Med. 2014 Feb 15;189(4):449-62
references.pmid: 24308446
references.citation: J Immunol. 1999 Feb 1;162(3):1827-35
references.pmid: 9973448
references.citation: J Virol. 1994 May;68(5):3065-70
references.pmid: 7908699
references.citation: J Exp Med. 1991 Oct 1;174(4):875-80
references.pmid: 1919440
references.citation: Mayo Clin Proc. 2012 Jun;87(6):548-54
references.pmid: 22551906
references.citation: Influenza Other Respir Viruses. 2013 Jan;7(1):35-45
references.pmid: 22405488
references.citation: Lancet. 2002 Dec 7;360(9348):1831-7
references.pmid: 12480361
references.citation: PLoS One. 2012;7(10):e48322
references.pmid: 23118984
references.citation: Cell. 2009 Feb 6;136(3):402-10
references.pmid: 19203576
references.citation: Lancet Respir Med. 2014 Jun;2(6):445-54
references.pmid: 24717637
references.citation: Nat Med. 2013 Oct;19(10):1305-12
references.pmid: 24056771
references.citation: J Immunol. 1998 Jan 1;160(1):322-7
references.pmid: 9551987
references.citation: Br Med J. 1937 Mar 27;1(3977):655-7
references.pmid: 20780563
references.citation: Nature. 1977 May 26;267(5609):354-6
references.pmid: 194164
references.citation: J Clin Invest. 2008 Oct;118(10):3273-5
references.pmid: 18802488
references.citation: J Exp Med. 1981 Aug 1;154(2):225-34
references.pmid: 6267157
references.citation: J Clin Invest. 2008 Oct;118(10):3478-90
references.pmid: 18802496
references.citation: Clin Infect Dis. 2012 Jul;55(1):19-25
references.pmid: 22441650
references.citation: Lancet Infect Dis. 2012 Sep;12(9):687-95
references.pmid: 22738893
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3330-5
references.pmid: 19211791