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Original Antigenic Sin: How First Exposure Shapes Lifelong Anti–Influenza Virus Immune Responses Ali Zhang, Hannah D

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Original Antigenic Sin: How First Exposure Shapes Lifelong Anti–Influenza Virus Immune Responses Ali Zhang, Hannah D Original Antigenic Sin: How First Exposure Shapes Lifelong Anti–Influenza Virus Immune Responses Ali Zhang, Hannah D. Stacey, Caitlin E. Mullarkey, and Matthew S. Miller The term “original antigenic sin” (OAS) was first used observed in animal models and in the context of other in- in the 1960s to describe how one’s first exposure to fectious agents. For example, additional serum absorption influenza virus shapes the outcome of subsequent ex- experiments in ferrets infected in succession with three dif- posures to antigenically related strains. In the decades ferent influenza virus strains demonstrated that nearly all of the that have passed, OAS-like responses have been shown host Abs after the infection series were reactive against the first to play an integral role in both protection from and strain, only a fraction of serum Abs could be absorbed by the susceptibility to infections. OAS may also have an im- secondary virus, and fewer yet by the tertiary virus (3). These portant deterministic role in the differential efficacy of results could be replicated using sera of human donors who influenza vaccine responses observed for various age had been vaccinated against various influenza virus strains cohorts across seasons. In this article, we review how (3–6) and also using sera from rats that had been serially the understanding of OAS has progressed from its ini- infected (7). In addition to influenza virus infections, OAS has also been reported in children who were exposed to se- tial description and highlight important outstanding quential dengue virus infections (8). In all cases, the mani- questions in need of further study. The Journal of festation of OAS is fundamentally dependent upon the Immunology, 2019, 202: 335–340. relatedness of Ags between primary and secondary infections as this phenomenon is not observed in the context of se- quential exposure to distantly related (or unrelated) Ags (9). riginal antigenic sin (OAS) describes the phenome- non whereby the development of immunity against Recent refinements O pathogens/Ags is shaped by the first exposure to a Although the hierarchical nature of the Ab response against related pathogen/Ag. influenza virus was initially described over half a century ago, there has continued to be substantial interest in developing a The original “original antigenic sin” more detailed understanding of the influence of OAS on The term was first coined by Thomas Francis in 1960 (1). In subsequent infections and vaccinations using modern cohorts. his seminal study, Francis observed that hemagglutination To this end, in 2012, a large cross-sectional study of Ab re- inhibition assay titers were highest against seasonal influenza sponses against H3N2 viruses that circulated between 1968 strains to which specific age cohorts had first been exposed and 2008 in southern China clearly reaffirmed the strong (2). These observations were supported by serum absorption correlation between Ab titers and age of encounter to particular experiments, which confirmed that the vast majority of anti– influenza virus strains. Individuals reliably had the highest influenza virus Abs in a population were cross-reactive against titers of neutralizing Abs against those strains that circulated the pioneer strain of that age group (3). within the first decade of life and progressively lower titers of Taken together, these data led Francis to postulate that Abs against strains that circulated later (10). subsequent infections with similar influenza virus strains Cohort-based studies have undoubtedly provided valuable preferentially boost the Ab response against the original strain insight into the population structure of the Ab response as a (2). Although OAS has often historically been depicted as a consequence of OAS. However, a lack of longitudinal data has problematic response, recent data have demonstrated that, in hindered a detailed understanding of how hierarchical Ab certain contexts, eliciting OAS may also be beneficial. responses develop within a given host over long periods of The critical role of primary exposure in shaping the com- time. To address this gap, our group obtained serum samples position of the Ab repertoire was not only observed in humans gathered over a 20-y period from 40 individuals enrolled in the after influenza virus infections; this phenomenon was also Framingham Heart Study and measured changes in their Ab Michael G. DeGroote Institute for Infectious Disease Research, McMaster Immunology support from a CIHR Fredrick Banting and Charles Best Canada Graduate Scholarship Research Centre, Department of Biochemistry and Biomedical Sciences, McMaster Doctoral Award. University, Hamilton, Ontario L8S 4K1, Canada Address correspondence and reprint requests to Dr. Matthew S. Miller, Michael G. ORCID: 0000-0003-3426-5069 (M.S.M.). DeGroote Institute for Infectious Disease Research, McMaster Immunology Research Centre, Department of Biochemistry and Biomedical Sciences, McMaster University, Received for publication August 20, 2018. Accepted for publication October 10, 2018. Hamilton, ON L8S 4K1, Canada. E-mail address: [email protected] This work was supported in part by a Canadian Institutes of Health Research (CIHR) Abbreviations used in this article: bnAb, broadly neutralizing Ab; HA, hemagglutinin; operating grant (to M.S.M.). M.S.M. was also supported by a CIHR New Investigator OAS, original antigenic sin. Award and an Early Researcher Award from the Province of Ontario. A.Z. and H.D.S. were supported in part by Michael G. DeGroote Doctoral Scholarships of Excellence. Ó H.D.S. was also supported by an Ontario Graduate Scholarship, and A.Z. received Copyright 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1801149 336 BRIEF REVIEWS: ORIGINAL ANTIGENIC SIN titers against H1, H2, and H3 viruses in ∼5-y intervals (11). which they were initially elicited but bind poorly to drifted We observed that exposure to strains encountered later in life variants. Despite this, cross-reactive OAS Abs were found to “back-boosted” the Ab response to strains of the same subtype bind to the same general regions of HA as those generated encountered earlier in life. Thus, the strains of a given subtype during a primary exposure. These Abs were often clonally encountered earliest in life experienced the greatest number of related and remained capable of protecting against challenge back-boosting events, leading them to be consistently main- from antigenically drifted strains in vivo (35). Thus, OAS tained at the highest Ab titers (Fig. 1A) (11). The way in responses can offer protective benefits during secondary ex- which infections and vaccinations affect Ab titers to strains posures to drifted viruses as well. encountered earlier in life has also been elegantly studied and described by the Smith Laboratory (12). Importantly, their Effects of OAS on susceptibility to infection work using “Ab landscapes” demonstrated that antigenically Although the effects of OAS can in certain cases be beneficial advanced viruses were capable of both boosting Abs against by enhancing an individual’s or cohort’s relative protection antecedent strains and inducing Abs against antigenically against future infections when the strains are antigenically advanced strains. Recent high-throughput analyses of plas- related, it follows that this phenomenon can be problematic mablast repertories induced by vaccination have also sup- when strains are distantly related, leading to increased sus- ported the supposition that many Abs are derived from ceptibility to later infections. Using single year of age data, memory B cells specific for previously encountered strains our group reanalyzed the infamous “W-shaped” mortality (13–15). curve caused by the 1918/19 H1N1 Spanish Flu pandemic. Effects of OAS on protection from infection We reported that those born in 1890, the year of the H3Nx “Russian Flu” pandemic, experienced an unusual peak in Clearly, one of the most profound implications of OAS is the mortality (23). This phenomenon recurred when we exam- influence it exerts on an individual’s or cohort’s relative ined the single-year mortality data from the 2009 H1N1 protection against infections. A well-known recent example of Swine Flu pandemic and found an unexpected peak in a situation in which OAS conferred protection later in life mortality for those born during the 1957 H2N2 Asian Flu occurred during the 2009 H1N1 “Swine Flu” pandemic. pandemic (36). This led us to hypothesize that early-life During this pandemic, older individuals who had been ex- imprinting by pandemic strains of influenza virus might in- posed to the 1918 H1N1 “Spanish Flu” (and closely related crease susceptibility during subsequent pandemics caused by strains) experienced substantially lower relative mortality rates antigenically distinct strains. than those usually observed for an advanced age group OAS-like responses were also problematic during the 2013– (16–19). Exposure to earlier H1 viruses has also been pro- 2014 influenza season, when H1N1 viruses acquired a mu- posed as an explanation for the relatively low mortality ob- tation in an HA epitope that was the primary target of the Ab served by older individuals during the 1918 Spanish Flu response mounted by middle-aged individuals. The cohort pandemic (20–23). generated a focused Ab response against this epitope during In recent years, there has been a substantial renewal of in- early life exposure to seasonal H1N1 viruses that circulated in terest in understanding how and when OAS and pre-existing the 1970s. As reported by the Hensley laboratory, this epitope immunity affect incidence and mortality of influenza virus was conserved in the original 2009 H1N1 pandemic strain. infections (24). A detailed examination of age-specific mor- However, the drifted H1N1 strain that emerged in 2013– tality during the 1957 H2N2 “Asian Flu” pandemic led Ma 2014 contained a mutation in this region of HA that resulted and colleagues to conclude that “antigenic imprinting,” or in poor Ab binding and subsequently unusually high mor- OAS, was the most parsimonious explanation for the observed tality for middle-aged individuals (37, 38).
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