Low 2018/19 #vaccine #effectiveness against #influenza A(#H3N2) among 15–64-year-olds in #Europe: exploration by birth cohort (Euro Surveill., abstract)

[Source: Eurosurveillance, full page: (LINK). Abstract, edited.]

Low 2018/19 vaccine effectiveness against influenza A(H3N2) among 15–64-year-olds in Europe: exploration by birth cohort

Esther Kissling1, Francisco Pozo2, Silke Buda3, Ana-Maria Vilcu4, Alin Gherasim5,6, Mia Brytting7, Lisa Domegan8,9, Verónica Gómez10, Adam Meijer11, Mihaela Lazar12, Vesna Višekruna Vučina13, Ralf Dürrwald14, Sylvie van der Werf15,16, Amparo Larrauri5,6, Theresa Enkirch7, Joan O’Donnell8, Raquel Guiomar17, Mariëtte Hooiveld18, Goranka Petrović13, Elena Stoian12, Pasi Penttinen19, Marta Valenciano1, I-MOVE primary care study team20

Affiliations: 1 Epidemiology Department, Epiconcept, Paris, France; 2 National Centre for Microbiology, National Influenza Reference Laboratory, WHO-National Influenza Centre, Institute of Health Carlos III, Madrid, Spain; 3 Robert Koch Institute, Department of Infectious Disease Epidemiology, Respiratory Infections Unit, Berlin, Germany; 4 Sorbonne Université, INSERM, Institut Pierre Louis d’épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France; 5 National Epidemiology Centre, Institute of Health Carlos III, Madrid, Spain; 6 CIBER de Epidemiología y Salud Pública (CIBERESP), Institute of Health Carlos III, Madrid, Spain; 7 Public Health Agency of Sweden, Stockholm, Sweden; 8 Health Service Executive- Health Protection Surveillance Centre, Dublin, Ireland; 9 European Programme for Intervention Epidemiology Training (EPIET), European Centre for Disease Prevention and Control (ECDC), Stockholm, Sweden; 10 Departamento de Epidemiologia, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisbon, Portugal; 11 National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands; 12 ”Cantacuzino” National Military-Medical Institute for Research and Development, Bucharest, Romania; 13 Croatian Institute of Public Health, Division for epidemiology of communicable diseases, Zagreb, Croatia; 14 Robert Koch Institute, National Reference Center for Influenza, Germany; 15 Unité de Génétique Moléculaire des Virus à ARN, Institut Pasteur, CNRS UMR3569, Université Paris Diderot SPC, France: 16 CNR des virus des infections respiratoires, WHO National Influenza Center, Institut Pasteur, Paris, France; 17 Departamento de Doenças Infeciosas, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisbon, Portugal; 18 Nivel (Netherlands Institute for Health Services Research), Utrecht, the Netherlands; 19 European Centre for Disease Prevention and Control (ECDC), Stockholm, Sweden; 20 The I-MOVE primary care study team members are listed at the end of the article

Correspondence:  Esther Kissling

Citation style for this article: Kissling Esther, Pozo Francisco, Buda Silke, Vilcu Ana-Maria, Gherasim Alin, Brytting Mia, Domegan Lisa, Gómez Verónica, Meijer Adam, Lazar Mihaela, Vučina Vesna Višekruna, Dürrwald Ralf, van der Werf Sylvie, Larrauri Amparo, Enkirch Theresa, O’Donnell Joan, Guiomar Raquel, Hooiveld Mariëtte, Petrović Goranka, Stoian Elena, Penttinen Pasi, Valenciano Marta, I-MOVE primary care study team. Low 2018/19 vaccine effectiveness against influenza A(H3N2) among 15–64-year-olds in Europe: exploration by birth cohort. Euro Surveill. 2019;24(48):pii=1900604. https://doi.org/10.2807/1560-7917.ES.2019.24.48.1900604

Received: 30 Sep 2019;   Accepted: 06 Nov 2019




Influenza A(H3N2) clades 3C.2a and 3C.3a co-circulated in Europe in 2018/19. Immunological imprinting by first childhood influenza infection may induce future birth cohort differences in vaccine effectiveness (VE).


The I-MOVE multicentre primary care test-negative study assessed 2018/19 influenza A(H3N2) VE by age and genetic subgroups to explore VE by birth cohort.


We measured VE against influenza A(H3N2) and (sub)clades. We stratified VE by usual age groups (0–14, 15–64, ≥ 65-years). To assess the imprint-regulated effect of vaccine (I-REV) hypothesis, we further stratified the middle-aged group, notably including 32–54-year-olds (1964–86) sharing potential childhood imprinting to serine at haemagglutinin position 159.


Influenza A(H3N2) VE among all ages was −1% (95% confidence interval (CI): −24 to 18) and 46% (95% CI: 8–68), −26% (95% CI: −66 to 4) and 20% (95% CI: −20 to 46) among 0–14, 15–64 and ≥ 65-year-olds, respectively. Among 15–64-year-olds, VE against clades 3C.2a1b and 3C.3a was 15% (95% CI: −34 to 50) and −74% (95% CI: −259 to 16), respectively. VE was −18% (95% CI: −140 to 41), −53% (95% CI: −131 to −2) and −12% (95% CI: −74 to 28) among 15–31-year-olds (1987–2003), 32–54-year-olds (1964–86) and 55–64-year-olds (1954–63), respectively.


The lowest 2018/19 influenza A(H3N2) VE was against clade 3C.3a and among those born 1964–86, corresponding to the I-REV hypothesis. The low influenza A(H3N2) VE in 15–64-year-olds and the public health impact of the I-REV hypothesis warrant further study.

©  This work is licensed under a Creative Commons Attribution 4.0 International License.

Keywords: Seasonal Influenza; H3N2; Vaccines; Original Antigenic Sin.


#Paradoxical clade- and age-specific #vaccine #effectiveness during the 2018/19 #influenza A #H3N2 #epidemic in #Canada: potential imprint-regulated effect of vaccine (I-REV) (Euro Surveill., abstract)

[Source: Eurosurveillance, full page: (LINK). Abstract, edited.]

Paradoxical clade- and age-specific vaccine effectiveness during the 2018/19 influenza A(H3N2) epidemic in Canada: potential imprint-regulated effect of vaccine (I-REV)

Danuta M Skowronski 1,2, Suzana Sabaiduc 1, Siobhan Leir 1, Caren Rose 1,2, Macy Zou 1, Michelle Murti 3,4, James A Dickinson 5, Romy Olsha 3, Jonathan B Gubbay 3,4, Matthew A Croxen 6,7, Hugues Charest 8, Nathalie Bastien 9, Yan Li 9, Agatha Jassem 1,2, Mel Krajden 1,2, Gaston De Serres 8,10,11

Affiliations: 1 British Columbia Centre for Disease Control, Vancouver, Canada; 2 University of British Columbia, Vancouver, Canada; 3 Public Health Ontario, Toronto, Canada; 4 University of Toronto, Toronto, Canada; 5 University of Calgary, Calgary, Canada; 6 Alberta Precision Laboratories, Edmonton, Alberta; 7 University of Alberta, Edmonton, Canada; 8 Institut National de Santé Publique du Québec, Québec, Canada; 9 National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada; 10 Laval University, Quebec, Canada11 Centre Hospitalier Universitaire de Québec, Québec, Canada

Correspondence:  Danuta M Skowronski

Citation style for this article: Skowronski Danuta M, Sabaiduc Suzana, Leir Siobhan, Rose Caren, Zou Macy, Murti Michelle, Dickinson James A, Olsha Romy, Gubbay Jonathan B, Croxen Matthew A, Charest Hugues, Bastien Nathalie, Li Yan, Jassem Agatha, Krajden Mel, De Serres Gaston. Paradoxical clade- and age-specific vaccine effectiveness during the 2018/19 influenza A(H3N2) epidemic in Canada: potential imprint-regulated effect of vaccine (I-REV). Euro Surveill. 2019;24(46):pii=1900585. https://doi.org/10.2807/1560-7917.ES.2019.24.46.1900585

Received: 19 Sep 2019;   Accepted: 04 Nov 2019




The Canadian Sentinel Practitioner Surveillance Network reports vaccine effectiveness (VE) for the 2018/19 influenza A(H3N2) epidemic.


To explain a paradoxical signal of increased clade 3C.3a risk among 35–54-year-old vaccinees, we hypothesise childhood immunological imprinting and a cohort effect following the 1968 influenza A(H3N2) pandemic.


We assessed VE by test-negative design for influenza A(H3N2) overall and for co-circulating clades 3C.2a1b and 3C.3a. VE variation by age in 2018/19 was compared with amino acid variation in the haemagglutinin glycoprotein by year since 1968.


Influenza A(H3N2) VE was 17% (95% CI: −13 to 39) overall: 27% (95% CI: −7 to 50) for 3C.2a1b and −32% (95% CI: −119 to 21) for 3C.3a. Among 20–64-year-olds, VE was −7% (95% CI: −56 to 26): 6% (95% CI: −49 to 41) for 3C.2a1b and −96% (95% CI: −277 to −2) for 3C.3a. Clade 3C.3a VE showed a pronounced negative dip among 35–54-year-olds in whom the odds of medically attended illness were > 4-fold increased for vaccinated vs unvaccinated participants (p < 0.005). This age group was primed in childhood to influenza A(H3N2) viruses that for two decades following the 1968 pandemic bore a serine at haemagglutinin position 159, in common with contemporary 3C.3a viruses but mismatched to 3C.2a vaccine strains instead bearing tyrosine.


Imprinting by the first childhood influenza infection is known to confer long-lasting immunity focused toward priming epitopes. Our findings suggest vaccine mismatch may negatively interact with imprinted immunity. The immunological mechanisms for imprint-regulated effect of vaccine (I-REV) warrant investigation.

©  This work is licensed under a Creative Commons Attribution 4.0 International License.

Keywords: Seasonal Influenza; Vaccines; H3N2; Origin Antigenic Sin; Canada.


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.