Original #Antigenic #Sin: Friend or Foe in Developing a Broadly Cross-Reactive #Vaccine to #Influenza? (Cell Host Microbe, summary)

[Source: Cell Host & Microbe, full page: (LINK). Summary, edited.]

Original Antigenic Sin: Friend or Foe in Developing a Broadly Cross-Reactive Vaccine to Influenza?

Priyadharshini Devarajan, Susan L. Swain

DOI: https://doi.org/10.1016/j.chom.2019.02.009


In this issue of Cell Host & Microbe, two articles ( Lee et al., 2019, Henry et al., 2019) find the influenza-specific antibody repertoire in humans becomes static over time and with age, despite repeated exposures. Identified persistent dominant clones target conserved viral epitopes, supporting the feasibility of a universal influenza vaccine.


Keywords: Influenza A; Vaccines; Original Antigenic Sin.



Broad #hemagglutinin-specific memory B cell expansion by seasonal #influenza virus #infection reflects early-life #imprinting and #adaptation to the infecting virus (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Broad hemagglutinin-specific memory B cell expansion by seasonal influenza virus infection reflects early-life imprinting and adaptation to the infecting virus

Brenda L. Tesini, Preshetha Kanagaiah, Jiong Wang, Megan Hahn, Jessica L. Halliley, Francisco A. Chaves, Phuong Q.T. Nguyen, Aitor Nogales, Marta L. DeDiego, Christopher S. Anderson,Ali H. Ellebedy, Shirin Strohmeier, Florian Krammer, Hongmei Yang, Sanjukta Bandyopadhyay, Rafi Ahmed, John J. Treanor, Luis Martinez-Sobrido, Hana Golding, Surender Khurana,Martin S. Zand, David J. Topham, Mark Y. Sangster

DOI: 10.1128/JVI.00169-19



Memory B cells (MBCs) are key determinants of the B cell response to influenza virus infection and vaccination, but the effect of different forms of influenza antigen exposure on MBC populations has received little attention. We analyzed peripheral blood mononuclear cells and plasma collected following human H3N2 influenza infection to investigate the relationship between hemagglutinin-specific antibody production and changes in the size and character of hemagglutinin-reactive MBC populations. Infection produced increased concentrations of plasma IgG reactive to the H3 head of the infecting virus, to the conserved stalk, and to a broad chronological range of H3s consistent with original antigenic sin responses. H3-reactive IgG MBC expansion after infection included reactivity to head and stalk domains. Notably, expansion of H3 head-reactive MBC populations was particularly broad and reflected original antigenic sin patterns of IgG production. Findings also suggest that early-life H3N2 infection “imprints” for strong H3 stalk-specific MBC expansion. Despite the breadth of MBC expansion, the MBC response included an increase in affinity for the H3 head of the infecting virus. Overall, our findings indicate that H3-reactive MBC expansion following H3N2 infection is consistent with maintenance of response patterns established early in life, but nevertheless includes MBC adaptation to the infecting virus.



Rapid and vigorous virus-specific antibody responses to influenza virus infection and vaccination result from activation of preexisting virus-specific memory B cells (MBCs). Understanding the effects of different forms of influenza virus exposure on MBC populations is therefore an important guide to the development of effective immunization strategies. We demonstrate that exposure to the influenza hemagglutinin via natural infection enhances broad protection through expansion of hemagglutinin-reactive MBC populations that recognize head and stalk regions of the molecule. Notably, we show that hemagglutinin-reactive MBC expansion reflects imprinting by early-life infection and that this might apply to stalk-reactive, as well as to head-reactive, MBCs. Our findings provide experimental support for the role of MBCs in maintaining imprinting effects and suggest a mechanism by which imprinting might confer heterosubtypic protection against avian influenza viruses. It will be important to compare our findings to the situation after influenza vaccination.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Seasonal Influenza; Avian Influenza; H3N2; Immunology.


Back to the Future for #Influenza #Preimmunity-Looking Back at Influenza Virus History to Infer the #Outcome of Future #Infections (Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Viruses. 2019 Jan 30;11(2). pii: E122. doi: 10.3390/v11020122.

Back to the Future for Influenza Preimmunity-Looking Back at Influenza Virus History to Infer the Outcome of Future Infections.

Francis ME1, King ML2, Kelvin AA3,4,5.

Author information: 1 Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS B3K 6R8, Canada. M.Francis@dal.ca. 2 Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS B3K 6R8, Canada. MorganKing@dal.ca.  3 Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS B3K 6R8, Canada. akelvin@dal.ca. 4 Department of Pediatrics, Division of Infectious Disease, Faculty of Medicine, Dalhousie University, Halifax, NS B3K 6R8, Canada. akelvin@dal.ca. 5 Canadian Centre for Vaccinology, IWK Health Centre, Halifax NS B3K 6R8, Canada. akelvin@dal.ca.



The influenza virus-host interaction is a classic arms race. The recurrent and evolving nature of the influenza virus family allows a single host to be infected several times. Locked in co-evolution, recurrent influenza virus infection elicits continual refinement of the host immune system. Here we give historical context of circulating influenza viruses to understand how the individual immune history is mirrored by the history of influenza virus circulation. Original Antigenic Sin was first proposed as the negative influence of the host’s first influenza virus infection on the next and Imprinting modernizes Antigenic Sin incorporating both positive and negative outcomes. Building on imprinting, we refer to preimmunity as the continual refinement of the host immune system with each influenza virus infection. We discuss imprinting and the interplay of influenza virus homology, vaccination, and host age establishing preimmunity. We outline host signatures and outcomes of tandem infection according to the sequence of virus and classify these relationships as monosubtypic homologous, monosubtypic heterologous, heterosubtypic, or heterotypic sequential infections. Finally, the preimmunity knowledge gaps are highlighted for future investigation. Understanding the effects of antigenic variable recurrent influenza virus infection on immune refinement will advance vaccination strategies, as well as pandemic preparedness.

KEYWORDS: Spanish influenza; antigenic drift; antigenic shift; immune response; imprinting; influenza virus; original antigenic sin; orthomyxoviridae; pandemic; preimmunity

PMID: 30704019 DOI: 10.3390/v11020122

Keywords: Influenza A; Pandemic Influenza; Immunology.


Loose Ends in the #Epidemiology of the 1918 #Pandemic: Explaining the Extreme #Mortality #Risk in #Young Adults (Am J Epidemiol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Am J Epidemiol. 2018 Sep 6. doi: 10.1093/aje/kwy148. [Epub ahead of print]

Loose Ends in the Epidemiology of the 1918 Pandemic: Explaining the Extreme Mortality Risk in Young Adults.

van Wijhe M1, Ingholt MM1, Andreasen V1, Simonsen L1.

Author information: 1 Department of Science and Environment, Roskilde University, Roskilde, Denmark.



In the century since the 1918 influenza pandemic, insights have been sought to explain the pandemic’s signature pattern of high death rates in young adults and low death rates in the elderly and infants. Our understanding of the origin and evolution of the pandemic has shifted considerably. We review evidence of the characteristic age-related pattern of death during the 1918 pandemic relative to the “original antigenic sin” hypothesis. We analyze age-stratified mortality data from Copenhagen around 1918 to identify break points associated with unusual death risk. Whereas infants had no meaningful risk elevation, death risk gradually increased, peaking for young adults 20-34 years of age before dropping sharply for adults ages 35-44 years, suggesting break points for birth cohorts around 1908 and 1878. Taken together with data from previous studies, there is strong evidence that those born before 1878 or after 1908 were not at increased risk of dying of 1918 pandemic influenza. Although the peak death risk coincided with the 1889-1892 pandemic, the 1908 and 1878 break points do not correspond with known pandemics. An increasing number of interdisciplinary studies covering fields such as virology, phylogenetics, death, and serology offer exciting insights into patterns and reasons for the unusual extreme 1918 pandemic mortality risk in young adults.

PMID: 30192906 DOI: 10.1093/aje/kwy148

Keywords: Pandemic Influenza; Spanish Flu; H1N1; Denmark.


#Epidemiology and Relative #Severity of #Influenza Subtypes in #Singapore in the Post-Pandemic Period from 2009 to 2010 (Clin Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Clin Infect Dis. 2017 Sep 23. doi: 10.1093/cid/cix694. [Epub ahead of print]

Epidemiology and Relative Severity of Influenza Subtypes in Singapore in the Post-Pandemic Period from 2009 to 2010.

Goh EH1, Jiang L1, Hsu JP1,2, Tan LWL1, Lim WY1, Phoon MC3, Leo YS2, Barr IG4, Chow VTK3, Lee VJ1,5, Lin C6, Lin R3,6, Sadarangani SP2, Young B2, Chen MI1,7.

Author information: 1 Saw Swee Hock School of Public Health, National University Health System, National University of Singapore. 2 Department of Infectious Diseases, Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital. 3 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore. 4 World Health Organization (WHO) Collaborating Centre for Reference and Research on Influenza, VIDRL, Doherty Institute, University of Melbourne, Victoria, Australia. 5 Biodefence Centre, Singapore Armed Forces. 6 National Public Health Laboratory, Ministry of Health, Singapore, Singapore. 7 Department of Clinical Epidemiology, Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital.




After 2009, pandemic influenza A(H1N1) [A(H1N1)pdm09] cocirculated with A(H3N2) and B in Singapore.


A cohort of 760 participants contributed demographic data and up to 4 blood samples each from October 2009 to September 2010. We compared epidemiology of the 3 subtypes and investigated evidence for heterotypic immunity through multivariable logistic regression using a generalized estimating equation. To examine age-related differences in severity between subtypes, we used LOESS (locally weighted smoothing) plots of hospitalization to infection ratios and explored birth cohort effects referencing the pandemic years (1957; 1968).


Having more household members aged 5-19 years and frequent public transport use increased risk of infection, while preexisting antibodies against the same subtype (odds ratio [OR], 0.61; P = .002) and previous influenza infection against heterotypic infections (OR, 0.32; P = .045) were protective. A(H1N1)pdm09 severity peaked in those born around 1957, while A(H3N2) severity was least in the youngest individuals and increased until it surpassed A(H1N1)pdm09 in those born in 1952 or earlier. Further analysis showed that severity of A(H1N1)pdm09 was less than that for A(H3N2) in those born in 1956 or earlier (P = .021) and vice versa for those born in 1968 or later (P < .001), with no difference in those born between 1957 and 1967 (P = .632).


Our findings suggest that childhood exposures had long-term impact on immune responses consistent with the theory of antigenic sin. This, plus observations on short-term cross-protection, have implications for vaccination and influenza epidemic and pandemic mitigation strategies.

KEYWORDS: H1N1pdm09; birth cohort effect; cross-protection; seroepidemiology; severity

PMID: 29028950 DOI: 10.1093/cid/cix694

Keywords: Seasonal Influenza; Singapore; H1N1pdm09; H3N2; Original Antigenic Sin.


Beyond #antigenic #match: possible agent-host and immuno-epidemiological influences on #influenza #vaccine effectiveness during the 2015–16 season in #Canada (J Infect Dis., abstract)

[Source: The Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Beyond antigenic match: possible agent-host and immuno-epidemiological influences on influenza vaccine effectiveness during the 2015–16 season in Canada

Danuta M Skowronski, Catharine Chambers, Suzana Sabaiduc, Gaston De Serres, Anne-Luise Winter, James A Dickinson, Jonathan B Gubbay, Steven J Drews, Christine Martineau, Hugues Charest, Mel Krajden, Nathalie Bastien, Yan Li Yan Li

The Journal of Infectious Diseases, jix526, https://doi.org/10.1093/infdis/jix526

Published: 04 October 2017 – Received: 07 June 2017

Citation: Danuta M Skowronski, Catharine Chambers, Suzana Sabaiduc, Gaston De Serres, Anne-Luise Winter, James A Dickinson, Jonathan B Gubbay, Steven J Drews, Christine Martineau, Hugues Charest, Mel Krajden, Nathalie Bastien, Yan Li; Beyond antigenic match: possible agent-host and immuno-epidemiological influences on influenza vaccine effectiveness during the 2015–16 season in Canada, The Journal of Infectious Diseases, , jix526, https://doi.org/10.1093/infdis/jix526

© 2017 Oxford University Press




Vaccine effectiveness (VE) estimates are reported from Canada’s Sentinel Practitioner Surveillance Network (SPSN) for the 2015–16 influenza season, characterized by a delayed A(H1N1)pdm09 epidemic and concurrent B(Victoria) activity. Potential influences beyond antigenic match are explored including viral genomic variation, birth cohort effects, prior vaccination and epidemic period.


VE was estimated by test-negative design comparing adjusted-odds ratio for influenza test-positivity among vaccinated vs. unvaccinated participants. Vaccine-virus relatedness was assessed by gene-sequencing and hemagglutination-inhibition assay.


Analyses included 596 influenza A(H1N1)pdm09 and 305 B(Victoria) cases compared to 926 test-negative controls. A(H1N1)pdm09 viruses were considered antigenically-related to vaccine (unchanged since 2009) despite phylogenetic clustering within emerging clade-6B.1. Adjusted-VE for A(H1N1)pdm09 was 43%(95%CI=25–57%), lower in adults born 1957–1976 (25%;95%CI=-16–51%); in those consecutively vaccinated both current and prior season (41%;95%CI=18–57%) vs. current season only (75%;95%CI=45–88%); and among participants presenting in March-April (19%;95%CI=-15–44%) vs. January-February 2016 (62%;95%CI=44–75%). VE for B(Victoria) viruses was 54%(95%CI=32–68%) despite lineage-level mismatch to B(Yamagata) vaccine and without further variation as observed for A(H1N1)pdm09.


Influenza VE findings may require consideration of other agent-host and immuno-epidemiologic influences on vaccine performance beyond antigenic match, including viral genomic variation, birth (immunological) cohort and repeat vaccination effects, and potential within-season waning of vaccine protection.

influenza, influenza vaccine, vaccine effectiveness, influenza A subtype, influenza B lineage, sequencing, hemagglutination inhibition, cohort effects, original antigenic sin, repeat vaccination

Topic: influenza – adult – canada – cohort effect – genes – genome – hemagglutination inhibition tests – influenza virus vaccine – vaccination – vaccines – influenzavirus a
viruses – epidemic – surveillance, medical – influenza a virus, h1n1 subtype – swine influenza – swine-origin influenza virus – host (organism) – mismatch

Issue Section: Major Article

© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Keywords: Seasonal Influenza; H1N1pdm09; H3N2; B; Vaccines; Canada.