Rational design of flavivirus E protein vaccine optimizes immunogenicity and mitigates antibody dependent enhancement risk
- Yimeng Wang
- Andrey Galkin
- Xiaoran Shang
- Alexander Marin
- Shaohua Jin
- Ting-Juan Ye
- Shridhar Bale
- Chi-I Chiang
- Ananda Chowdhury
- Agnes L. Chenine
- Ashley Turonis
- Jack Greenhouse
- Rebecca Stone
- Jaclyn Wear
- Swagata Kar
- Hanne Andersen
- Yan-Jang S. Huang
- Dana L. Vanlandingham
- Stephen Higgs
- Rena G. Lapidus
- Thomas Fuerst
- David J. Weber
- Richard T. Wyatt
- Christel Iffland
- Theodore C. Pierson
- Alexander K. Andrianov
- Edwin Pozharski
- Yuxing Li
2025-12-22
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.