title: The influence of changing host immunity on 1918-19 pandemic dynamics.
abstract: The sociological and biological factors which gave rise to the three pandemic waves of Spanish influenza in England during 1918-19 are still poorly understood. Symptom reporting data available for a limited set of locations in England indicates that reinfection in multiple waves occurred, suggesting a role for loss of infection-acquired immunity. Here we explore the role that changes in host immunity, driven by a combination of within-host factors and viral evolution, may play in explaining weekly mortality data and wave-by-wave symptomatic attack-rates available for a subset of English cities. Our results indicate that changes in the phenotype of the pandemic virus are likely required to explain the closely spaced waves of infection, but distinguishing between the detailed contributions of viral evolution and changing adaptive immune responses to transmission rates is difficult given the dearth of sero-epidemiological and virological data available even for more contemporary pandemics. We find that a dynamical model in which pre-pandemic protection in older "influenza-experienced" cohorts is lost rapidly prior to the second wave provides the best fit to the mortality and symptom reporting data. Best fitting parameter estimates for such a model indicate that post-infection protection lasted of order months, while other statistical analyses indicate that population-age was inversely correlated with overall mortality during the herald wave. Our results suggest that severe secondary waves of pandemic influenza may be triggered by viral escape from pre-pandemic immunity, and thus that understanding the role of heterosubtypic or cross-protective immune responses to pandemic influenza may be key to controlling the severity of future influenza pandemics.
authors.affiliation: School of Mathematical Sciences and School of Community Health Sciences, University of Nottingham, University Park, NG7 2RD, United Kingdom; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, 3010, Australia. Electronic address: kirsty.bolton@nottingham.ac.uk.
authors.forename: K J
authors.initials: KJ
authors.lastname: Bolton
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, 3010, Australia; Murdoch Childrens Research Institute, Royal Childrens Hospital, 3052, Australia. Electronic address: jamesm@unimelb.edu.au.
authors.forename: J M
authors.initials: JM
authors.lastname: McCaw
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, 3010, Australia; Murdoch Childrens Research Institute, Royal Childrens Hospital, 3052, Australia.
authors.forename: J
authors.initials: J
authors.lastname: McVernon
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, 3010, Australia.
authors.forename: J D
authors.initials: JD
authors.lastname: Mathews
mesh_terms: D006801:Humans; D007109:Immunity; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007251:Influenza, Human / Q000453:epidemiology* / Q000276:immunology*; D008962:Models, Theoretical; D058873:Pandemics / Q000706:statistics & numerical data*; D006113:United Kingdom / Q000453:epidemiology
keywords: Immunology; Influenza; Public health; Transmission models; Viral evolution