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
Affiliations
Lisa C. Lindesmith
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
Florencia A. T. Boshier
Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
Paul D. Brewer-Jensen
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
Sunando Roy
Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
Veronica Costantini
Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
Michael L. Mallory
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
Mark Zweigart
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
Samantha R. May
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
Helen Conrad
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
Kathleen M. O’Reilly
Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
Daniel Kelly
Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
Cristina C. Celma
Enteric Virus Unit, The Virus Reference Department, UK Health Security Agency, London, United Kingdom
Stuart Beard
Enteric Virus Unit, The Virus Reference Department, UK Health Security Agency, London, United Kingdom
Rachel Williams
Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
Helena J. Tutill
Department of Genetics & Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
Sylvia Becker Dreps
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
Filemón Bucardo
Department of Microbiology, National Autonomous University of Nicaragua, León, León, Nicaragua
David J. Allen
Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
Jan Vinjé
Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
Richard A. Goldstein
Division of Infection and Immunity, University College London, London, United Kingdom
Judith Breuer
Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
Ralph S. Baric
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
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. IMPORTANCE In our model, preepidemic human norovirus variants harbor genetic diversification that translates into novel antigenic features without compromising viral fitness. Through surveillance, we identified two viruses fitting this profile, forming long branches on a phylogenetic tree. Neither evades current adult immunity, yet young children are likely susceptible. By comparing serological responses, we demonstrate that population immunity varies by age/exposure, impacting predicted susceptibility to variants. Repeat exposure to antigenically similar variants broadens antibody responses, providing immunological coverage of diverse variants but compromising response to the infecting variant, allowing continued circulation. These data indicate norovirus GII.4 variant replacement is driven distally by virus evolution and proximally by immunity in adults.
