Rational design of flavivirus E protein vaccine optimizes immunogenicity and mitigates antibody dependent enhancement risk

Flaviviruses are a family of related viruses that cause substantial global morbidity and mortality. Vaccination against one flavivirus can sometimes exacerbate disease caused by related viruses through antibody-dependent enhancement (ADE) or interfere with the efficacy of subsequent vaccines. To address this challenge, we develop a vaccine strategy by introducing G5C/G102C mutations into the flavivirus envelope (E) glycoprotein. These mutations promote E dimerization through the formation of an inter-chain disulfide bond that conceals the immunodominant and ADE-prone fusion loop epitope (FLE). We validate this design on E proteins from multiple flaviviruses through biochemical, antigenic, and structural analyses. The resulting vaccine candidate, CC_FLE sE, derived from the Zika virus (ZIKV) and formulated with an advanced supramolecular adjuvant, provides significant protection in female mice challenged with ZIKV and prevents ADE caused by a related flavivirus, Dengue virus. In genetically modified mice expressing diverse human immunoglobulin loci, ZIKV CC_FLE sE induces robust neutralizing antibody responses targeting key ZIKV E protein epitopes, including the E-dimer-dependent epitope (EDE), indicating that ZIKV CC_FLE sE can elicit protective antibody responses within the human naïve B cell repertoire. Therefore, CC_FLE sE represents a promising strategy for developing flavivirus vaccines that minimize ADE risk while maintaining high protective efficacy.

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Publication Details

Journal
Nature Communications
Published
2025-12-22
DOI
https://doi.org/10.1038/s41467-025-67447-4
Citations
4
Primary Topic
Mosquito-borne diseases and control
Type
article
Field-Weighted Citation Impact
7.51

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article

Rational design of flavivirus E protein vaccine optimizes immunogenicity and mitigates antibody dependent enhancement risk

Shridhar Bale, Alexander K. Andrianov, Ashley N. Turonis, Edwin Pozharski et al.
4 citations
Nature Communications
Mosquito-borne diseases and control
7.51
article

Rational design of flavivirus E protein vaccine optimizes immunogenicity and mitigates antibody dependent enhancement risk

Shridhar Bale, Alexander K. Andrianov, Ashley N. Turonis, Edwin Pozharski, Dana L. Vanlandingham, David J. Weber, Richard T. Wyatt, Thomas R. Fuerst, Theodore C. Pierson, Christel Iffland, Swagata Kar, Rebecca Stone, Jack Greenhouse, Jaclyn Wear, Hanné Andersen, Andrey Galkin, Agnès L. Chénine, Yimeng Wang, Stephen Higgs, Ananda Chowdhury, Yan-Jang S. Huang, Ting-Juan Ye, Alexander Marin, Xiaoran Shang, Yuxing Li, Chi-I Chiang, Shaohua Jin, Rena G. Lapidus
article en
4 citations

Abstract

Flaviviruses are a family of related viruses that cause substantial global morbidity and mortality. Vaccination against one flavivirus can sometimes exacerbate disease caused by related viruses through antibody-dependent enhancement (ADE) or interfere with the efficacy of subsequent vaccines. To address this challenge, we develop a vaccine strategy by introducing G5C/G102C mutations into the flavivirus envelope (E) glycoprotein. These mutations promote E dimerization through the formation of an inter-chain disulfide bond that conceals the immunodominant and ADE-prone fusion loop epitope (FLE). We validate this design on E proteins from multiple flaviviruses through biochemical, antigenic, and structural analyses. The resulting vaccine candidate, CC_FLE sE, derived from the Zika virus (ZIKV) and formulated with an advanced supramolecular adjuvant, provides significant protection in female mice challenged with ZIKV and prevents ADE caused by a related flavivirus, Dengue virus. In genetically modified mice expressing diverse human immunoglobulin loci, ZIKV CC_FLE sE induces robust neutralizing antibody responses targeting key ZIKV E protein epitopes, including the E-dimer-dependent epitope (EDE), indicating that ZIKV CC_FLE sE can elicit protective antibody responses within the human naïve B cell repertoire. Therefore, CC_FLE sE represents a promising strategy for developing flavivirus vaccines that minimize ADE risk while maintaining high protective efficacy.

Nature CommunicationsVol. 16(1)
Scripps Research Institute (US), University of Maryland, Baltimore (US), Kansas State University (US), Center for Medical Technology Policy (US), Bioqual (US), Integrated BioTherapeutics (United States) (US), University of Maryland Extension (US), National Institute of Allergy and Infectious Diseases (US), United Therapeutics (United States) (US), Research Institute for Bioscience and Biotechnology (NP), Adamas Pharmaceuticals (United States) (US), Io Therapeutics (United States) (US), Advanced Bioscience Laboratories (United States) (US), Institute for Bioscience and Biotechnology Research, University of Maryland, College Park (US), REVA University (IN)
National Institutes of Health, National Institute of Standards and Technology, National Cancer Institute, National Institute of Allergy and Infectious Diseases
Good health and well-being
Openalex Percentile: Top 3%
Mosquito-borne diseases and control
7.51
DOIOpen Access PDFOpenAlex
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