Immune Imprinting Drives Human Norovirus Potential for Global Spread

Lisa C. Lindesmith; Florencia A.T. Boshier; Paul D. Brewer-Jensen; Sunando Roy; Veronica Costantini; Michael L. Mallory; Mark Zweigart; Samantha R. May; Helen Conrad; Kathleen M. O’Reilly; Daniel Kelly; Cristina C. Celma; Stuart Beard; Rachel Williams; Helena J. Tutill; Sylvia Becker Dreps; Filemón Bucardo; David J. Allen; Jan Vinjé; Richard A. Goldstein; Judith Breuer; Ralph S. Baric

doi:10.1128/mbio.01861-22

Immune Imprinting Drives Human Norovirus Potential for Global Spread

Lisa C. Lindesmith^*, Florencia A.T. Boshier, Paul D. Brewer-Jensen, Sunando Roy, Veronica Costantini, Michael L. Mallory, Mark Zweigart, Samantha R. May, Helen Conrad, Kathleen M. O’Reilly, Daniel Kelly, Cristina C. Celma, Stuart Beard, Rachel Williams, Helena J. Tutill, Sylvia Becker Dreps, Filemón Bucardo, David J. Allen, Jan Vinjé, Richard A. GoldsteinJudith Breuer, Ralph S. Baric

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

Understanding the complex interactions between virus and host that drive new strain evolution is key to predicting the emergence potential of variants and informing vaccine development. Under our hypothesis, future dominant human norovirus GII.4 variants with critical antigenic properties that allow them to spread are currently circulating undetected, having diverged years earlier. Through large-scale sequencing of GII.4 surveillance samples, we identified two variants with extensive divergence within domains that mediate neutralizing antibody binding. Subsequent serological characterization of these strains using temporally resolved adult and child sera suggests that neither candidate could spread globally in adults with multiple GII.4 exposures, yet young children with minimal GII.4 exposure appear susceptible. Antigenic cartography of surveillance and outbreak sera indicates that continued population exposure to GII.4 Sydney 2012 and antigenically related variants over a 6-year period resulted in a broadening of immunity to heterogeneous GII.4 variants, including those identified here. We show that the strongest antibody responses in adults exposed to GII.4 Sydney 2012 are directed to previously circulating GII.4 viruses. Our data suggest that the broadening of antibody responses compromises establishment of strong GII.4 Sydney 2012 immunity, thereby allowing the continued persistence of GII.4 Sydney 2012 and modulating the cycle of norovirus GII.4 variant replacement. Our results indicate a cycle of norovirus GII.4 variant replacement dependent upon population immunity. Young children are susceptible to divergent variants; therefore, emergence of these strains worldwide is driven proximally by changes in adult serological immunity and distally by viral evolution that confers fitness in the context of immunity.

Original language	English
Journal	mBio
Volume	13
Issue number	5
DOIs	https://doi.org/10.1128/mbio.01861-22
Publication status	Published - Sept 2022
Externally published	Yes

Bibliographical note

Funding Information:
We thank the Microscopy Services Laboratory, Department of Pathology and Laboratory Medicine, University of North Carolina Chapel Hill, and Shilpi Sheth, LSHTM, for her support of the genomics work through retrieval of specimens and preparation and testing of nucleic acid extracts. The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Funding was provided by the Wellcome Trust [203268/Z/16/Z], and the National Institute of Allergy and Infectious Disease R01 AI148260 and R01AI127845.

Funding Information:
Funding was provided by the Wellcome Trust [203268/Z/16/Z], and the National Institute of Allergy and Infectious Disease R01 AI148260 and R01AI127845.

Publisher Copyright:
Copyright © 2022 Lindesmith et al.

Keywords

antigenic cartography
antigenic seniority
epidemic
histo-blood group antigens
immune imprinting
neutralizing antibodies
norovirus
sequencing
surveillance
variant persistence
variants of concern

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1128/mbio.01861-22

Cite this

Lindesmith, L. C., Boshier, F. A. T., Brewer-Jensen, P. D., Roy, S., Costantini, V., Mallory, M. L., Zweigart, M., May, S. R., Conrad, H., O’Reilly, K. M., Kelly, D., Celma, C. C., Beard, S., Williams, R., Tutill, H. J., Dreps, S. B., Bucardo, F., Allen, D. J., Vinjé, J., ... Baric, R. S. (2022). Immune Imprinting Drives Human Norovirus Potential for Global Spread. mBio, 13(5). https://doi.org/10.1128/mbio.01861-22

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title = "Immune Imprinting Drives Human Norovirus Potential for Global Spread",

abstract = "Understanding the complex interactions between virus and host that drive new strain evolution is key to predicting the emergence potential of variants and informing vaccine development. Under our hypothesis, future dominant human norovirus GII.4 variants with critical antigenic properties that allow them to spread are currently circulating undetected, having diverged years earlier. Through large-scale sequencing of GII.4 surveillance samples, we identified two variants with extensive divergence within domains that mediate neutralizing antibody binding. Subsequent serological characterization of these strains using temporally resolved adult and child sera suggests that neither candidate could spread globally in adults with multiple GII.4 exposures, yet young children with minimal GII.4 exposure appear susceptible. Antigenic cartography of surveillance and outbreak sera indicates that continued population exposure to GII.4 Sydney 2012 and antigenically related variants over a 6-year period resulted in a broadening of immunity to heterogeneous GII.4 variants, including those identified here. We show that the strongest antibody responses in adults exposed to GII.4 Sydney 2012 are directed to previously circulating GII.4 viruses. Our data suggest that the broadening of antibody responses compromises establishment of strong GII.4 Sydney 2012 immunity, thereby allowing the continued persistence of GII.4 Sydney 2012 and modulating the cycle of norovirus GII.4 variant replacement. Our results indicate a cycle of norovirus GII.4 variant replacement dependent upon population immunity. Young children are susceptible to divergent variants; therefore, emergence of these strains worldwide is driven proximally by changes in adult serological immunity and distally by viral evolution that confers fitness in the context of immunity.",

keywords = "antigenic cartography, antigenic seniority, epidemic, histo-blood group antigens, immune imprinting, neutralizing antibodies, norovirus, sequencing, surveillance, variant persistence, variants of concern",

author = "Lindesmith, {Lisa C.} and Boshier, {Florencia A.T.} and Brewer-Jensen, {Paul D.} and Sunando Roy and Veronica Costantini and Mallory, {Michael L.} and Mark Zweigart and May, {Samantha R.} and Helen Conrad and O{\textquoteright}Reilly, {Kathleen M.} and Daniel Kelly and Celma, {Cristina C.} and Stuart Beard and Rachel Williams and Tutill, {Helena J.} and Dreps, {Sylvia Becker} and Filem{\'o}n Bucardo and Allen, {David J.} and Jan Vinj{\'e} and Goldstein, {Richard A.} and Judith Breuer and Baric, {Ralph S.}",

note = "Funding Information: We thank the Microscopy Services Laboratory, Department of Pathology and Laboratory Medicine, University of North Carolina Chapel Hill, and Shilpi Sheth, LSHTM, for her support of the genomics work through retrieval of specimens and preparation and testing of nucleic acid extracts. The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Funding was provided by the Wellcome Trust [203268/Z/16/Z], and the National Institute of Allergy and Infectious Disease R01 AI148260 and R01AI127845. Funding Information: Funding was provided by the Wellcome Trust [203268/Z/16/Z], and the National Institute of Allergy and Infectious Disease R01 AI148260 and R01AI127845. Publisher Copyright: Copyright {\textcopyright} 2022 Lindesmith et al.",

year = "2022",

month = sep,

doi = "10.1128/mbio.01861-22",

language = "English",

volume = "13",

journal = "mBio",

issn = "2161-2129",

publisher = "American Society for Microbiology",

number = "5",

}

Lindesmith, LC, Boshier, FAT, Brewer-Jensen, PD, Roy, S, Costantini, V, Mallory, ML, Zweigart, M, May, SR, Conrad, H, O’Reilly, KM, Kelly, D, Celma, CC , Beard, S, Williams, R, Tutill, HJ, Dreps, SB, Bucardo, F, Allen, DJ, Vinjé, J, Goldstein, RA, Breuer, J & Baric, RS 2022, 'Immune Imprinting Drives Human Norovirus Potential for Global Spread', mBio, vol. 13, no. 5. https://doi.org/10.1128/mbio.01861-22

TY - JOUR

T1 - Immune Imprinting Drives Human Norovirus Potential for Global Spread

AU - Lindesmith, Lisa C.

AU - Boshier, Florencia A.T.

AU - Brewer-Jensen, Paul D.

AU - Roy, Sunando

AU - Costantini, Veronica

AU - Mallory, Michael L.

AU - Zweigart, Mark

AU - May, Samantha R.

AU - Conrad, Helen

AU - O’Reilly, Kathleen M.

AU - Kelly, Daniel

AU - Celma, Cristina C.

AU - Beard, Stuart

AU - Williams, Rachel

AU - Tutill, Helena J.

AU - Dreps, Sylvia Becker

AU - Bucardo, Filemón

AU - Allen, David J.

AU - Vinjé, Jan

AU - Goldstein, Richard A.

AU - Breuer, Judith

AU - Baric, Ralph S.

N1 - Funding Information: We thank the Microscopy Services Laboratory, Department of Pathology and Laboratory Medicine, University of North Carolina Chapel Hill, and Shilpi Sheth, LSHTM, for her support of the genomics work through retrieval of specimens and preparation and testing of nucleic acid extracts. The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Funding was provided by the Wellcome Trust [203268/Z/16/Z], and the National Institute of Allergy and Infectious Disease R01 AI148260 and R01AI127845. Funding Information: Funding was provided by the Wellcome Trust [203268/Z/16/Z], and the National Institute of Allergy and Infectious Disease R01 AI148260 and R01AI127845. Publisher Copyright: Copyright © 2022 Lindesmith et al.

PY - 2022/9

Y1 - 2022/9

N2 - Understanding the complex interactions between virus and host that drive new strain evolution is key to predicting the emergence potential of variants and informing vaccine development. Under our hypothesis, future dominant human norovirus GII.4 variants with critical antigenic properties that allow them to spread are currently circulating undetected, having diverged years earlier. Through large-scale sequencing of GII.4 surveillance samples, we identified two variants with extensive divergence within domains that mediate neutralizing antibody binding. Subsequent serological characterization of these strains using temporally resolved adult and child sera suggests that neither candidate could spread globally in adults with multiple GII.4 exposures, yet young children with minimal GII.4 exposure appear susceptible. Antigenic cartography of surveillance and outbreak sera indicates that continued population exposure to GII.4 Sydney 2012 and antigenically related variants over a 6-year period resulted in a broadening of immunity to heterogeneous GII.4 variants, including those identified here. We show that the strongest antibody responses in adults exposed to GII.4 Sydney 2012 are directed to previously circulating GII.4 viruses. Our data suggest that the broadening of antibody responses compromises establishment of strong GII.4 Sydney 2012 immunity, thereby allowing the continued persistence of GII.4 Sydney 2012 and modulating the cycle of norovirus GII.4 variant replacement. Our results indicate a cycle of norovirus GII.4 variant replacement dependent upon population immunity. Young children are susceptible to divergent variants; therefore, emergence of these strains worldwide is driven proximally by changes in adult serological immunity and distally by viral evolution that confers fitness in the context of immunity.

AB - Understanding the complex interactions between virus and host that drive new strain evolution is key to predicting the emergence potential of variants and informing vaccine development. Under our hypothesis, future dominant human norovirus GII.4 variants with critical antigenic properties that allow them to spread are currently circulating undetected, having diverged years earlier. Through large-scale sequencing of GII.4 surveillance samples, we identified two variants with extensive divergence within domains that mediate neutralizing antibody binding. Subsequent serological characterization of these strains using temporally resolved adult and child sera suggests that neither candidate could spread globally in adults with multiple GII.4 exposures, yet young children with minimal GII.4 exposure appear susceptible. Antigenic cartography of surveillance and outbreak sera indicates that continued population exposure to GII.4 Sydney 2012 and antigenically related variants over a 6-year period resulted in a broadening of immunity to heterogeneous GII.4 variants, including those identified here. We show that the strongest antibody responses in adults exposed to GII.4 Sydney 2012 are directed to previously circulating GII.4 viruses. Our data suggest that the broadening of antibody responses compromises establishment of strong GII.4 Sydney 2012 immunity, thereby allowing the continued persistence of GII.4 Sydney 2012 and modulating the cycle of norovirus GII.4 variant replacement. Our results indicate a cycle of norovirus GII.4 variant replacement dependent upon population immunity. Young children are susceptible to divergent variants; therefore, emergence of these strains worldwide is driven proximally by changes in adult serological immunity and distally by viral evolution that confers fitness in the context of immunity.

KW - antigenic cartography

KW - antigenic seniority

KW - epidemic

KW - histo-blood group antigens

KW - immune imprinting

KW - neutralizing antibodies

KW - norovirus

KW - sequencing

KW - surveillance

KW - variant persistence

KW - variants of concern

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DO - 10.1128/mbio.01861-22

M3 - Article

C2 - 36102514

AN - SCOPUS:85140856748

SN - 2161-2129

VL - 13

JO - mBio

JF - mBio

IS - 5

ER -

Immune Imprinting Drives Human Norovirus Potential for Global Spread

Abstract

Bibliographical note

Keywords

UN SDGs

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