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, Agnès L. Chénine, Ashley N. Turonis, Jack Greenhouse, Rebecca Stone, Jaclyn Wear, Swagata Kar, Hanné Andersen, Yan‐Jang S. Huang, Dana L. Vanlandingham, Stephen Higgs, Rena G. Lapidus, Thomas R. Fuerst, David J. Weber, Richard T. Wyatt, Christel Iffland, Theodore C. Pierson, Alexander K. Andrianov, Edwin Pozharski, Yuxing Li
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.