#Childhood immune #imprinting to #influenza A shapes birth year-specific #risk during seasonal #H1N1 and #H3N2 #epidemics (PLOS Pathog., abstract)

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


Childhood immune imprinting to influenza A shapes birth year-specific risk during seasonal H1N1 and H3N2 epidemics

Katelyn M. Gostic , Rebecca Bridge, Shane Brady, Cécile Viboud, Michael Worobey, James O. Lloyd-Smith


Published: December 19, 2019 / DOI: https://doi.org/10.1371/journal.ppat.1008109



Across decades of co-circulation in humans, influenza A subtypes H1N1 and H3N2 have caused seasonal epidemics characterized by different age distributions of cases and mortality. H3N2 causes the majority of severe, clinically attended cases in high-risk elderly cohorts, and the majority of overall deaths, whereas H1N1 causes fewer deaths overall, and cases shifted towards young and middle-aged adults. These contrasting age profiles may result from differences in childhood imprinting to H1N1 and H3N2 or from differences in evolutionary rate between subtypes. Here we analyze a large epidemiological surveillance dataset to test whether childhood immune imprinting shapes seasonal influenza epidemiology, and if so, whether it acts primarily via homosubtypic immune memory or via broader, heterosubtypic memory. We also test the impact of evolutionary differences between influenza subtypes on age distributions of cases. Likelihood-based model comparison shows that narrow, within-subtype imprinting shapes seasonal influenza risk alongside age-specific risk factors. The data do not support a strong effect of evolutionary rate, or of broadly protective imprinting that acts across subtypes. Our findings emphasize that childhood exposures can imprint a lifelong immunological bias toward particular influenza subtypes, and that these cohort-specific biases shape epidemic age distributions. As a consequence, newer and less “senior” antibody responses acquired later in life do not provide the same strength of protection as responses imprinted in childhood. Finally, we project that the relatively low mortality burden of H1N1 may increase in the coming decades, as cohorts that lack H1N1-specific imprinting eventually reach old age.


Author summary

Influenza viruses of subtype H1N1 and H3N2 both cause seasonal epidemics in humans, but with different age-specific impacts. H3N2 causes a greater proportion of cases in older adults than H1N1, and more deaths overall. People tend to gain the strongest immune memory of influenza viruses encountered in childhood, and so differences in H1N1 and H3N2’s age-specific impacts may reflect that individuals born in different eras of influenza circulation have been imprinted with different immunological risk profiles. Another idea is that H3N2 may be more able to infect immunologically experienced adults because it evolves slightly faster than H1N1 and can more quickly escape immune memory. We analyzed a large epidemiological data set and found that birth year-specific differences in childhood immune imprinting, not differences in evolutionary rate, explain differences in H1N1 and H3N2’s age-specific impacts. These results can help epidemiologists understand how epidemic risk from specific influenza subtypes is distributed across the population and predict how population risk may shift as differently imprinted birth years grow older. Further, these results provide immunological clues to which facets of immune memory become biased in childhood, and then later play a strong role in protection during seasonal influenza epidemics.


Citation: Gostic KM, Bridge R, Brady S, Viboud C, Worobey M, Lloyd-Smith JO (2019) Childhood immune imprinting to influenza A shapes birth year-specific risk during seasonal H1N1 and H3N2 epidemics. PLoS Pathog 15(12): e1008109. https://doi.org/10.1371/journal.ppat.1008109

Editor: Sabra L. Klein, Johns Hopkins Bloomberg School of Public Health, UNITED STATES

Received: July 9, 2019; Accepted: September 25, 2019; Published: December 19, 2019

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Data Availability: All relevant data are available as Supporting Information files. All data are also archived alongside the full suite of code used to perform analyses and generate plots, at https://zenodo.org/badge/latestdoi/160883450.

Funding: KMG was supported by the National Institutes of Health (F31AI134017, T32-GM008185). JOLS was supported by NSF grants OCE-1335657 and DEB-1557022, SERDP RC-2635, and DARPA PREEMPT D18AC00031. MW was supported by the David and Lucile Packard Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Seasonal Influenza; Immunology; H1N1; H3N2.


Selective induction of #antibody effector functional responses using #MF59-adjuvanted #vaccination (J Clin Invest., abstract)

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

Research Article / Immunology / Vaccines / Free access | DOI: 10.1172/JCI129520

Selective induction of antibody effector functional responses using MF59-adjuvanted vaccination

Carolyn M. Boudreau,1,2 Wen-Han Yu,1 Todd J. Suscovich,1 H. Keipp Talbot,3,4 Kathryn M. Edwards,5 and Galit Alter1

First published December 17, 2019



Seasonal and pandemic influenza infection remains a major public health concern worldwide. Driving robust humoral immunity has been a challenge given preexisting, often cross-reactive, immunity and in particular, poorly immunogenic avian antigens. To overcome immune barriers, the adjuvant MF59 has been used in seasonal influenza vaccines to increase antibody titers and improve neutralizing activity, translating to a moderate increase in protection in vulnerable populations. However, its effects on stimulating antibody effector functions, including NK cell activation, monocyte phagocytosis, and complement activity, all of which have been implicated in protection against influenza, have yet to be defined. Using systems serology, we assessed changes in antibody functional profiles in individuals who received H5N1 avian influenza vaccine administered with MF59, with alum, or delivered unadjuvanted. MF59 elicited antibody responses that stimulated robust neutrophil phagocytosis and complement activity. Conversely, vaccination with MF59 recruited NK cells poorly and drove moderate monocyte phagocytic activity, both likely compromised because of the induction of antibodies that did not bind FCGR3A. Collectively, defining the humoral antibody functions induced by distinct adjuvants may provide a path to designing next-generation vaccines that can selectively leverage the humoral immune functions, beyond binding and neutralization, resulting in better protection from infection.

Keywords: Influenza A; Seasonal Influenza; Pandemic Influenza; Vaccines; Immunology; MF59.


#Affinity maturation in a #human #humoral response to #influenza #hemagglutinin (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Affinity maturation in a human humoral response to influenza hemagglutinin

Kevin R. McCarthy, Donald D. Raymond, Khoi T. Do, Aaron G. Schmidt, and Stephen C. Harrison

PNAS first published December 16, 2019 / DOI: https://doi.org/10.1073/pnas.1915620116

Contributed by Stephen C. Harrison, November 7, 2019 (sent for review September 10, 2019; reviewed by Steven Gamblin and Scott E. Hensley)



Influenza virus and some other human pathogens evolve to evade herd immunity and, hence, to reinfect previously immune individuals. Individual humoral immune responses also evolve, through somatic mutation and selection in a process known as affinity maturation. We describe a detailed molecular “case history” of this coevolution (to our knowledge, the most thorough such study so far) through structural and biophysical analysis of a lineage of human antibodies directed at the influenza hemagglutinin receptor binding site. We show how affinity maturation in this lineage has maintained adaptability (“breadth” of neutralizing activity) by generating a branched and, hence, diversifying phylogeny. The mechanisms underlying affinity maturation appear to ensure such diversification while also enhancing affinity of the most potent resulting antibodies.



Affinity maturation of the B cell antigen receptor (BCR) is a conserved and crucial component of the adaptive immune response. BCR lineages, inferred from paired heavy- and light-chain sequences of rearranged Ig genes from multiple descendants of the same naive B cell precursor (the lineages’ unmutated common ancestor, “UCA”), make it possible to reconstruct the underlying somatic evolutionary history. We present here an extensive structural and biophysical analysis of a lineage of BCRs directed against the receptor binding site (RBS) of subtype H1 influenza virus hemagglutinin (HA). The lineage includes 8 antibodies detected directly by sequencing, 3 in 1 principal branch and 5 in the other. When bound to HA, the heavy-chain third complementarity determining region (HCDR3) fits with an invariant pose into the RBS, but in each of the 2 branches, the rest of the Fab reorients specifically, from its position in the HA-bound UCA, about a hinge at the base of HCDR3. New contacts generated by the reorientation compensate for contacts lost as the H1 HA mutated during the time between the donor’s initial exposure and the vaccination that preceded sampling. Our data indicate that a “pluripotent” naive response differentiated, in each branch, into 1 of its possible alternatives. This property of naive BCRs and persistence of multiple branches of their progeny lineages can offer broader protection from evolving pathogens than can a single, linear pathway of somatic mutation.

influenza virus – antibody – B cell – vaccine – X-ray crystallography

Keywords: Influenza A; Vaccines; Immunology.


#Immunity to #Influenza is dependent on #MHC II polymorphism: study with 2 HLA transgenic strains (Sci Rep., abstract)

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

Immunity to Influenza is dependent on MHC II polymorphism: study with 2 HLA transgenic strains

David Luckey, Eric A. Weaver, Douglas G. Osborne, Daniel D. Billadeau & Veena Taneja

Scientific Reports, volume 9, Article number: 19061 (2019)



Major histocompatibility complex II (MHC II) molecules are involved in antigen presentation and the development of a functional adaptive immune response. Evolutionary selection for MHC molecules that effectively clear infectious agents provides an advantage to humans. However, certain class II molecules are associated with autoimmune diseases. In this study we infected autoimmune-susceptible DRB1*0401.AEo and non-susceptible *0402.AEo mice with H1N1 influenza and determined clearance and protective immunity to H3N2 virus. *0401 mice generated a robust TLR-triggered immune response and cleared H1N1 influenza virus infection. After vaccination and challenge with H1N1, *0401 mice, when challenged with H3N2, generated cross-protective immunity to heterosubtypic H3N2 influenza strain whereas *0402 mice cleared the H1N1 infection but did not generate cross-protective immunity against the H3N2 influenza strain. The intracellular trafficking route of MHCII revealed that *0401 molecules traffic through the late endosome/lysosomes while *0402 molecules traffic into early endosomes. This suggested that trafficking of MHCII could affect the functional output of the innate immune response and clearance of viral infections. Also, DRB1*0401 mice live longer than HLA-DRB1*0402 mice. The study provides a potential hypothesis for evolutionary selection of *0401 molecule, even though it is associated with autoreactivity, which may be dependent on the availability of peptide repertoire of self-antigens.

Keywords: Influenza A; Immunology.


#Antibody-Dependent #NK Cell #Activation after #Ebola #Vaccination (J Infect Dis., abstract)

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

Antibody-Dependent Natural Killer Cell Activation after Ebola Vaccination

Helen R Wagstaffe, Elizabeth A Clutterbuck, Viki Bockstal, Jeroen N Stoop, Kerstin Luhn, Macaya Douoguih, Georgi Shukarev, Matthew D Snape, Andrew J Pollard, Eleanor M Riley, Martin R Goodier

The Journal of Infectious Diseases, jiz657, https://doi.org/10.1093/infdis/jiz657

Published: 10 December 2019




Antibody Fc-mediated functions, such as antibody-dependent cellular cytotoxicity, contribute to vaccine-induced protection against viral infections. Fc-mediated function of anti-Ebola glycoprotein antibodies suggest that Fc-dependent activation of effector cells, including NK cells, could play a role in vaccination against Ebola virus disease.


We analysed the effect of anti-Ebola glycoprotein antibody in the serum of U.K.-based volunteers vaccinated with the novel 2-dose heterologous Adenovirus type 26.ZEBOV, Modified Vaccinia Ankara-BN-Filo vaccine regimen, on primary human NK cell activation.


We demonstrate primary human NK cell CD107a and IFN-γ expression, combined with downregulation of CD16, in response to recombinant Ebola virus glycoprotein and post-vaccine dose 1 and dose 2 sera. These responses varied significantly with vaccine regimen and NK cell activation was found to correlate with anti-glycoprotein antibody concentration. We also reveal an impact of NK cell differentiation phenotype on antibody-dependent NK cell activation, with highly differentiated CD56dimCD57+ NK cells being the most responsive.


This study thus highlights the dual importance of vaccine-induced antibody concentration and NK cell differentiation status in promoting Fc-mediated activation of NK cells after vaccination, raising a potential role for antibody-mediated NK cell activation in vaccine-induced immune responses.

antibody, Ebola, vaccine, natural killer cell

This content is only available as a PDF.

© The Author(s) 2019. 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: Ebola; Vaccines; Immunology.


#SIV #Infection of Rhesus #Macaques Results in Delayed #Zika Virus #Clearance (MBio, abstract)

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

Simian Immunodeficiency Virus Infection of Rhesus Macaques Results in Delayed Zika Virus Clearance

Carol L. Vinton, Samuel J. Magaziner, Kimberly A. Dowd, Shelly J. Robertson, Emerito Amaro-Carambot, Erik P. Karmele, Alexandra M. Ortiz, Carly E. Starke, Joseph C. Mudd, Stephen S. Whitehead, Sonja M. Best, Theodore C. Pierson, Heather D. Hickman, Jason M. Brenchley

Salim Abdool Karim, Editor

DOI: 10.1128/mBio.02790-19



Flaviviruses are controlled by adaptive immune responses but are exquisitely sensitive to interferon-stimulated genes (ISGs). How coinfections, particularly simian immunodeficiency viruses (SIVs), that induce robust ISG signatures influence flavivirus clearance and pathogenesis is unclear. Here, we studied how Zika virus (ZIKV) infection is modulated in SIV-infected nonhuman primates. We measured ZIKV replication, cellular ZIKV RNA levels, and immune responses in non-SIV-infected and SIV-infected rhesus macaques (RMs), which we infected with ZIKV. Coinfected animals had a 1- to 2-day delay in peak ZIKV viremia, which was 30% of that in non-SIV-infected animals. However, ZIKV viremia was significantly prolonged in SIV-positive (SIV+) RMs. ISG levels at the time of ZIKV infection were predictive for lower ZIKV viremia in the SIV+ RMs, while prolonged ZIKV viremia was associated with muted and delayed adaptive responses in SIV+ RMs.



Immunocompromised individuals often become symptomatic with infections which are normally fairly asymptomatic in healthy individuals. The particular mechanisms that underlie susceptibility to coinfections in human immunodeficiency virus (HIV)-infected individuals are multifaceted. ZIKV and other flaviviruses are sensitive to neutralizing antibodies, whose production can be limited in HIV-infected individuals but are also sensitive to type I interferons, which are expressed at high levels in HIV-infected individuals. Data in this study highlight how individual components of the innate and adaptive immune responses which become perturbed in HIV-infected individuals influence ZIKV infection.

Keywords: HIV/AIDS; Zika Virus; SIV; Immunology; Animal models.


#Circadian control of #lung #inflammation in #influenza #infection (Nat Commun., abstract)

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

Article / Open Access / Published: 11 September 2019

Circadian control of lung inflammation in influenza infection

Shaon Sengupta, Soon Y. Tang, Jill C. Devine, Seán T. Anderson, Soumyashant Nayak, Shirley L. Zhang, Alex Valenzuela, Devin G. Fisher, Gregory R. Grant, Carolina B. López & Garret A. FitzGerald

Nature Communications, volume 10, Article number: 4107 (2019)



Influenza is a leading cause of respiratory mortality and morbidity. While inflammation is essential for fighting infection, a balance of anti-viral defense and host tolerance is necessary for recovery. Circadian rhythms have been shown to modulate inflammation. However, the importance of diurnal variability in the timing of influenza infection is not well understood. Here we demonstrate that endogenous rhythms affect survival in influenza infection. Circadian control of influenza infection is mediated by enhanced inflammation as proven by increased cellularity in bronchoalveolar lavage (BAL), pulmonary transcriptomic profile and histology and is not attributable to viral burden. Better survival is associated with a time dependent preponderance of NK and NKT cells and lower proportion of inflammatory monocytes in the lung. Further, using a series of genetic mouse mutants, we elucidate cellular mechanisms underlying circadian gating of influenza infection.

Keywords: Influenza A; Immunology; Animal models.