TY - JOUR
T1 - Sera Antibody Repertoire Analyses Reveal Mechanisms of Broad and Pandemic Strain Neutralizing Responses after Human Norovirus Vaccination
AU - Lindesmith, Lisa C.
AU - McDaniel, Jonathan R.
AU - Changela, Anita
AU - Verardi, Raffaello
AU - Kerr, Scott A.
AU - Costantini, Veronica
AU - Brewer-Jensen, Paul D.
AU - Mallory, Michael L.
AU - Voss, William N.
AU - Boutz, Daniel R.
AU - Blazeck, John J.
AU - Ippolito, Gregory C.
AU - Vinje, Jan
AU - Kwong, Peter D.
AU - Georgiou, George
AU - Baric, Ralph S.
N1 - Funding Information:
The authors would like to thank Takeda Vaccines for provision of human samples; the Genome Sequencing and Analysis Facility at the University of Texas at Austin for performing Illumina next-generation sequencing; the Center for Biomedical Research Support Proteomics Facility at the University of Texas at Austin for providing mass spectrometry analysis; and Victoria Madden of Microscopy Services Laboratory, Department of Pathology and Laboratory Medicine, University of North Carolina–Chapel Hill for expert technical support. Support for this work was provided by the Intramural Research Program of” the Vaccine Research Center, NIAID, NIH, and the intramural food safety program at CDC and by grants from the NIH (R56AI106006, G.G. and R.S.B. and U19 AI109761 CETR, R.S.B.), Defense Threat Reduction Agency (DTRA) (contract HDTRA1-12-C-0105, G.G.), and the Wellcome Trust [203268/Z/16/Z] (R.S.B.). Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38. 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. Conceptualization: R.S.B. G.G. L.C.L. J.R.M. A.C. R.V. S.A.K. and P.D.K. Investigation and Formal Analysis: L.C.L. J.R.M. A.C. R.V. S.A.K. V.C. P.D.J.B. M.L.M. W.N.V. D.R.B. J.J.B. G.C.I. and J.V. Writing, All Drafts: L.C.L. J.R.M. A.C. R.V. P.D.K. G.G. and R.S.B. with input from all authors. Funding Acquisition and Supervision: R.S.B. G.G. and P.D.K. J.R.M. S.A.K. A.C. R.V. V.C. P.D.B.J. M.L.M. W.N.V. D.R.B. J.J.B. G.C.I. J.V. P.D.K. and G.G. declare no competing interests. L.C.L. and R.S.B. have consulted and collaborated with Takeda on norovirus vaccines. They are also inventors on patents filed on issues relevant to noroviruses. G.G. is an inventor on patents related to the analysis of the serological antibody repertoire.
Funding Information:
The authors would like to thank Takeda Vaccines for provision of human samples; the Genome Sequencing and Analysis Facility at the University of Texas at Austin for performing Illumina next-generation sequencing; the Center for Biomedical Research Support Proteomics Facility at the University of Texas at Austin for providing mass spectrometry analysis; and Victoria Madden of Microscopy Services Laboratory, Department of Pathology and Laboratory Medicine, University of North Carolina–Chapel Hill for expert technical support. Support for this work was provided by the Intramural Research Program of” the Vaccine Research Center , NIAID, NIH , and the intramural food safety program at CDC and by grants from the NIH ( R56AI106006 , G.G. and R.S.B. and U19 AI109761 CETR , R.S.B.), Defense Threat Reduction Agency ( DTRA ) (contract HDTRA1-12-C-0105 , G.G.), and the Wellcome Trust [ 203268/Z/16/Z ] (R.S.B.). Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the U.S. Department of Energy , Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38 . 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.
Publisher Copyright:
© 2019 The Author(s)
PY - 2019/6/18
Y1 - 2019/6/18
N2 - Rapidly evolving RNA viruses, such as the GII.4 strain of human norovirus (HuNoV), and their vaccines elicit complex serological responses associated with previous exposure. Specific correlates of protection, moreover, remain poorly understood. Here, we report the GII.4-serological antibody repertoire—pre- and post-vaccination—and select several antibody clonotypes for epitope and structural analysis. The humoral response was dominated by GII.4-specific antibodies that blocked ancestral strains or by antibodies that bound to divergent genotypes and did not block viral-entry-ligand interactions. However, one antibody, A1431, showed broad blockade toward tested GII.4 strains and neutralized the pandemic GII.P16-GII.4 Sydney strain. Structural mapping revealed conserved epitopes, which were occluded on the virion or partially exposed, allowing for broad blockade with neutralizing activity. Overall, our results provide high-resolution molecular information on humoral immune responses after HuNoV vaccination and demonstrate that infection-derived and vaccine-elicited antibodies can exhibit broad blockade and neutralization against this prevalent human pathogen. Human norovirus (HuNoV) is a leading cause of gastroenteritis. Lindesmith et al. identify circulating serum antibodies following experimental HuNoV vaccination in humans and map them to viral epitopes. One antibody recognizes a neutralizing epitope conserved across three decades of pandemic strains and neutralizes virus in vitro, demonstrating that vaccination can elicit pandemic-strain neutralizing antibody responses in some individuals.
AB - Rapidly evolving RNA viruses, such as the GII.4 strain of human norovirus (HuNoV), and their vaccines elicit complex serological responses associated with previous exposure. Specific correlates of protection, moreover, remain poorly understood. Here, we report the GII.4-serological antibody repertoire—pre- and post-vaccination—and select several antibody clonotypes for epitope and structural analysis. The humoral response was dominated by GII.4-specific antibodies that blocked ancestral strains or by antibodies that bound to divergent genotypes and did not block viral-entry-ligand interactions. However, one antibody, A1431, showed broad blockade toward tested GII.4 strains and neutralized the pandemic GII.P16-GII.4 Sydney strain. Structural mapping revealed conserved epitopes, which were occluded on the virion or partially exposed, allowing for broad blockade with neutralizing activity. Overall, our results provide high-resolution molecular information on humoral immune responses after HuNoV vaccination and demonstrate that infection-derived and vaccine-elicited antibodies can exhibit broad blockade and neutralization against this prevalent human pathogen. Human norovirus (HuNoV) is a leading cause of gastroenteritis. Lindesmith et al. identify circulating serum antibodies following experimental HuNoV vaccination in humans and map them to viral epitopes. One antibody recognizes a neutralizing epitope conserved across three decades of pandemic strains and neutralizes virus in vitro, demonstrating that vaccination can elicit pandemic-strain neutralizing antibody responses in some individuals.
KW - antigenic seniority
KW - epitope mapping
KW - human monoclonal antibodies
KW - imprinting
KW - neutralizing antibodies
KW - norovirus
KW - original antigen sin
KW - serological repertoire
KW - vaccination
KW - x-ray crystallography
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U2 - 10.1016/j.immuni.2019.05.007
DO - 10.1016/j.immuni.2019.05.007
M3 - Article
C2 - 31216462
AN - SCOPUS:85066877707
VL - 50
SP - 1530-1541.e8
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 6
ER -