Longitudinal dynamics and lineage cross-reactivity of the human antibody response to West Nile virus
11 affiliations
- 1Division of Infectious Disease, Department of Pediatrics, Center for Childhood Infections and Vaccines (CCIV), Emory University School of Medicine, Atlanta, Georgia, USA
- 2Department of Pediatrics, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
- 3Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA
- 4Microbiology and Virology Unit, Padova University Hospital, Padova, Italy
- 5Department of Molecular Medicine, University of Padova, Padova, Italy
- 6Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA
- 7Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
- 8Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, USA
- 9Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA
- 10Vitalant Research Institute, San Francisco, California, USA
- 11Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA
Abstract
West Nile virus (WNV) is an emerging/re-emerging flavivirus representing one of the major global causes of mosquito-borne encephalitis, yet no approved therapeutics or vaccines currently exist. To characterize the kinetics of WNV-specific immunity, we evaluated the humoral response in a longitudinal cohort of 55 WNV lineage 1-infected blood donors up to 1 year. We demonstrate that WNV infection elicits robust and durable binding and neutralizing antibodies. Using a biphasic decay model, we estimated the half-life of neutralizing antibodies to be 37 days during the rapid decay phase and 472 days during the extended slow decay phase. Notably, the magnitude and durability of these antibodies were largely independent of viral RNA persistence in the whole blood (WB) compartment. To assess the breadth of this response, we evaluated cross-reactivity against an emerging divergent WNV lineage 2 strain and observed that WNV lineage 1-immune sera exhibited reduced neutralizing activity with high variability between donors during both acute and convalescent phases. These deficits in heterologous neutralization were reciprocally confirmed using an independent WNV cohort from Italy. Together, our results establish that lineage-specific divergence results in antibodies with a highly variable reduction in neutralization, indicating that successful WNV vaccine candidates should overcome this variability to confer pan-lineage protection.
IMPORTANCE: West Nile virus (WNV) is a growing global health threat spread by mosquitoes that can cause severe disease, yet there are currently no approved vaccines or treatments available. We followed 55 WNV lineage 1-infected blood donors up to 1 year to study their antibody response to infection. We found that natural infection generates a long-lasting antibody response. Interestingly, the magnitude and durability of these antibodies were maintained regardless of viral RNA persistence in the whole blood compartment. However, a potential gap in cross-protective immunity emerged when we examined WNV lineage 1-specific antibodies against WNV lineage 2, a genetically distinct and divergent viral strain with over 25 mutations in the envelope protein. Sera from WNV lineage 1-infected donors showed a highly variable reduction in neutralizing activity against lineage 2 WNV during both the acute and convalescent phases of infection. We corroborated this observation using an independent cohort of patients from Italy, again demonstrating reduced cross-neutralization between the two viral lineages. Together, our results establish that lineage-specific divergence results in reduced cross-neutralization of heterologous strains, indicating that successful WNV vaccine candidates should overcome this barrier to confer pan-lineage protection.
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BibTeX
@article{leach2026longitudinal,
title = {{Longitudinal dynamics and lineage cross-reactivity of the human antibody response to West Nile virus}},
author = {Austin G. Leach and Lingling Xu and Shilu Malakar and Monia Pacenti and Stefania Vogiatzis and Sanjeev Kumar and Jacob Vander Velden and Meng Wang and Mitchell J. Kendzel and Veronika I. Zarnitsyna and Sean Hui and Michael N. Nguyen and Christopher A. Nelson and Tyshawn Ferrell and Christopher J. Neufeldt and Daved H. Fremont and Vineet D. Menachery and Michael P. Busch and Philip J. Norris and Marion Lanteri and Luisa Barzon and Jens Wrammert and Mehul S. Suthar},
journal = {mBio},
year = {2026},
month = sep,
doi = {10.1128/mbio.01766-26},
url = {https://doi.org/10.1128/mbio.01766-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Longitudinal dynamics and lineage cross-reactivity of the human antibody response to West Nile virus
AU - Austin G. Leach
AU - Lingling Xu
AU - Shilu Malakar
AU - Monia Pacenti
AU - Stefania Vogiatzis
AU - Sanjeev Kumar
AU - Jacob Vander Velden
AU - Meng Wang
AU - Mitchell J. Kendzel
AU - Veronika I. Zarnitsyna
AU - Sean Hui
AU - Michael N. Nguyen
AU - Christopher A. Nelson
AU - Tyshawn Ferrell
AU - Christopher J. Neufeldt
AU - Daved H. Fremont
AU - Vineet D. Menachery
AU - Michael P. Busch
AU - Philip J. Norris
AU - Marion Lanteri
AU - Luisa Barzon
AU - Jens Wrammert
AU - Mehul S. Suthar
PY - 2026
DA - 2026/09/17
JO - mBio
DO - 10.1128/mbio.01766-26
UR - https://doi.org/10.1128/mbio.01766-26
AB - West Nile virus (WNV) is an emerging/re-emerging flavivirus representing one of the major global causes of mosquito-borne encephalitis, yet no approved therapeutics or vaccines currently exist. To characterize the kinetics of WNV-specific immunity, we evaluated the humoral response in a longitudinal cohort of 55 WNV lineage 1-infected blood donors up to 1 year. We demonstrate that WNV infection elicits robust and durable binding and neutralizing antibodies. Using a biphasic decay model, we estimated the half-life of neutralizing antibodies to be 37 days during the rapid decay phase and 472 days during the extended slow decay phase. Notably, the magnitude and durability of these antibodies were largely independent of viral RNA persistence in the whole blood (WB) compartment. To assess the breadth of this response, we evaluated cross-reactivity against an emerging divergent WNV lineage 2 strain and observed that WNV lineage 1-immune sera exhibited reduced neutralizing activity with high variability between donors during both acute and convalescent phases. These deficits in heterologous neutralization were reciprocally confirmed using an independent WNV cohort from Italy. Together, our results establish that lineage-specific divergence results in antibodies with a highly variable reduction in neutralization, indicating that successful WNV vaccine candidates should overcome this variability to confer pan-lineage protection. IMPORTANCE: West Nile virus (WNV) is a growing global health threat spread by mosquitoes that can cause severe disease, yet there are currently no approved vaccines or treatments available. We followed 55 WNV lineage 1-infected blood donors up to 1 year to study their antibody response to infection. We found that natural infection generates a long-lasting antibody response. Interestingly, the magnitude and durability of these antibodies were maintained regardless of viral RNA persistence in the whole blood compartment. However, a potential gap in cross-protective immunity emerged when we examined WNV lineage 1-specific antibodies against WNV lineage 2, a genetically distinct and divergent viral strain with over 25 mutations in the envelope protein. Sera from WNV lineage 1-infected donors showed a highly variable reduction in neutralizing activity against lineage 2 WNV during both the acute and convalescent phases of infection. We corroborated this observation using an independent cohort of patients from Italy, again demonstrating reduced cross-neutralization between the two viral lineages. Together, our results establish that lineage-specific divergence results in reduced cross-neutralization of heterologous strains, indicating that successful WNV vaccine candidates should overcome this barrier to confer pan-lineage protection.
SN - 2150-7511
ER -