Distinct Patterns of B-Cell Activation and Priming by Natural Influenza Virus Infection Versus Inactivated Influenza Vaccination

ABSTRACTMemory 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.IMPORTANCERapid 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.

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Requirement for memory B-cell activation in protection from heterologous influenza virus reinfection

International Immunology ◽

10.1093/intimm/dxz049 ◽

2019 ◽

Vol 31 (12) ◽

pp. 771-779 ◽

Cited By ~ 8

Author(s):

Sarah Leach ◽

Ryo Shinnakasu ◽

Yu Adachi ◽

Masatoshi Momota ◽

Chieko Makino-Okamura ◽

...

Keyword(s):

Influenza Virus ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Influenza Infection ◽

Memory B Cells ◽

B Cell Activation ◽

Memory B Cell

Memory B cells protect against heterologous influenza infection

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Influenza Virus-Induced Type I Interferon Leads to Polyclonal B-Cell Activation but Does Not Break Down B-Cell Tolerance

Journal of Virology ◽

10.1128/jvi.00839-07 ◽

2007 ◽

Vol 81 (22) ◽

pp. 12525-12534 ◽

Cited By ~ 10

Author(s):

Anne Woods ◽

Fanny Monneaux ◽

Pauline Soulas-Sprauel ◽

Sylviane Muller ◽

Thierry Martin ◽

...

Keyword(s):

Influenza Virus ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Type I Interferon ◽

Type I ◽

Interferon Production ◽

B Cell Activation ◽

B Cell Tolerance

ABSTRACT The link between infection and autoimmunity is not yet well understood. This study was designed to evaluate if an acute viral infection known to induce type I interferon production, like influenza, can by itself be responsible for the breakdown of immune tolerance and for autoimmunity. We first tested the effects of influenza virus on B cells in vitro. We then infected different transgenic mice expressing human rheumatoid factors (RF) in the absence or in the constitutive presence of the autoantigen (human immunoglobulin G [IgG]) and young lupus-prone mice [(NZB × NZW)F1] with influenza virus and looked for B-cell activation. In vitro, the virus induces B-cell activation through type I interferon production by non-B cells but does not directly stimulate purified B cells. In vivo, both RF and non-RF B cells were activated in an autoantigen-independent manner. This activation was abortive since IgM and IgM-RF production levels were not increased in infected mice compared to uninfected controls, whether or not anti-influenza virus human IgG was detected and even after viral rechallenge. As in RF transgenic mice, acute viral infection of (NZB × NZW)F1 mice induced only an abortive activation of B cells and no increase in autoantibody production compared to uninfected animals. Taken together, these experiments show that virus-induced acute type I interferon production is not able by itself to break down B-cell tolerance in both normal and autoimmune genetic backgrounds.

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Dendritic Cell-Independent B Cell Activation During Acute Virus Infection: A Role for Early CCR7-Driven B-T Helper Cell Collaboration

The Journal of Immunology ◽

10.4049/jimmunol.178.3.1468 ◽

2007 ◽

Vol 178 (3) ◽

pp. 1468-1476 ◽

Cited By ~ 34

Author(s):

Elke Scandella ◽

Katja Fink ◽

Tobias Junt ◽

Beatrice M. Senn ◽

Evelyn Lattmann ◽

...

Keyword(s):

Dendritic Cell ◽

Virus Infection ◽

B Cell ◽

Cell Activation ◽

T Helper Cell ◽

Helper Cell ◽

B Cell Activation ◽

T Helper

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Maternal Influenza Vaccination and Effect on Influenza Virus Infection in Young Infants

Yearbook of Neonatal and Perinatal Medicine ◽

10.1016/j.ynpm.2011.04.011 ◽

2011 ◽

Vol 2011 ◽

pp. 165-166

Author(s):

W.E. Benitz

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Influenza Vaccination ◽

Influenza Virus Infection ◽

Young Infants ◽

Maternal Influenza

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Residual Antigen Presentation after Influenza Virus Infection Affects CD8 T Cell Activation and Migration

Immunity ◽

10.1016/j.immuni.2006.01.015 ◽

2006 ◽

Vol 24 (4) ◽

pp. 439-449 ◽

Cited By ~ 183

Author(s):

David J. Zammit ◽

Damian L. Turner ◽

Kimberly D. Klonowski ◽

Leo Lefrançois ◽

Linda S. Cauley

Keyword(s):

Influenza Virus ◽

T Cell ◽

Virus Infection ◽

Antigen Presentation ◽

T Cell Activation ◽

Cell Activation ◽

Influenza Virus Infection ◽

Cd8 T Cell ◽

And Migration

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CD4 T Cell Help Is Limiting and Selective during the Primary B Cell Response to Influenza Virus Infection

Journal of Virology ◽

10.1128/jvi.02077-13 ◽

2013 ◽

Vol 88 (1) ◽

pp. 314-324 ◽

Cited By ~ 44

Author(s):

S. Alam ◽

Z. A. G. Knowlden ◽

M. Y. Sangster ◽

A. J. Sant

Keyword(s):

Influenza Virus ◽

T Cell ◽

Virus Infection ◽

B Cell ◽

Cell Response ◽

Influenza Virus Infection ◽

Cd4 T Cell ◽

Cd4 T Cell Help ◽

T Cell Help ◽

B Cell Response

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Estimating Vaccine Effectiveness Against Hospitalized Influenza During Pregnancy: Multicountry Protocol for a Retrospective Cohort Study (Preprint)

10.2196/preprints.11333 ◽

2018 ◽

Author(s):

Allison L Naleway ◽

Sarah Ball ◽

Jeffrey C Kwong ◽

Brandy E Wyant ◽

Mark A Katz ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Influenza Vaccine ◽

Influenza Vaccination ◽

Pregnant Women ◽

Retrospective Cohort ◽

Clinical Course ◽

Influenza Virus Infection ◽

The United States ◽

Vaccine Effectiveness

BACKGROUND Although pregnant women are believed to have elevated risks of severe influenza infection and are targeted for influenza vaccination, no study to date has examined influenza vaccine effectiveness (IVE) against laboratory-confirmed influenza-associated hospitalizations during pregnancy, primarily because this outcome poses many methodological challenges. OBJECTIVE The Pregnancy Influenza Vaccine Effectiveness Network (PREVENT) was formed in 2016 as an international collaboration with the Centers for Disease Control and Prevention; Abt Associates; and study sites in Australia, Canada, Israel, and the United States. The primary goal of this collaboration is to estimate IVE in preventing acute respiratory or febrile illness (ARFI) hospitalizations associated with laboratory-confirmed influenza virus infection during pregnancy. Secondary aims include (1) describing the incidence, clinical course, and severity of influenza-associated ARFI hospitalization during pregnancy; (2) comparing the characteristics of ARFI-hospitalized pregnant women who were tested for influenza with those who were not tested; (3) describing influenza vaccination coverage in pregnant women; and (4) comparing birth outcomes among women with laboratory-confirmed influenza-associated hospitalization versus other noninfluenza ARFI hospitalizations. METHODS For an initial assessment of IVE, sites identified a retrospective cohort of pregnant women aged from 18 to 50 years whose pregnancies overlapped with local influenza seasons from 2010 to 2016. Pregnancies were defined as those that ended in a live birth or stillbirth of at least 20 weeks gestation. The analytic sample for the primary IVE analysis was restricted to pregnant women who were hospitalized for ARFI during site-specific influenza seasons and clinically tested for influenza virus infection using real-time reverse transcription polymerase chain reaction. RESULTS We identified approximately 2 million women whose pregnancies overlapped with influenza seasons; 550,344 had at least one hospitalization during this time. After restricting to women who were hospitalized for ARFI and tested for influenza, the IVE analytic sample included 1005 women. CONCLUSIONS In addition to addressing the primary question about the effectiveness of influenza vaccination, PREVENT data will address other important knowledge gaps including understanding the incidence, clinical course, and severity of influenza-related hospitalizations during pregnancy. The data infrastructure and international partnerships created for these analyses may be useful and informative for future influenza studies. INTERNATIONAL REGISTERED REPOR DERR1-10.2196/11333

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