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<p>Zika virus (ZIKV) vaccine candidates developed through Phase I clinical trials are based on the full-length envelope glycoprotein (E), which presents both desirable and undesirable antigenic determinants. Among the latter, the conserved fusion loop epitope (FLE) within domain II is a major target for flavivirus cross-reactive and poorly neutralizing responses. To eliminate unwanted FLE targeting, we redesigned ZIKV E using a reverse vaccinology approach, excising domain II and allowing domains I and III (DI-DIII) to fold into an independent subunit harboring key neutralizing epitopes. <i>Ifnar1</i><sup><i>-/-</i></sup> mice vaccinated with ZIKV DI-DIII elicited high ZIKV neutralizing antibodies and were protected from weight loss and death. In addition, sera from DI-DIII vaccinated mice demonstrated a reduced capacity to enhance DENV 1-4 infection in vitro, compared to mice vaccinated with full-length E. This study identifies DI-DIII as a promising immunogen, focusing antibody responses to protective epitopes on ZIKV and minimizing the elicitation of unwanted responses.</p>

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Targeting the Zika virus envelope domains I and III as a recombinant vaccine protects mice from lethal challenge

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月14日

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  • Vincent Dussupt,
  • Jaime L. Jensen,
  • Angélica Peña Rosado,
  • Marissa Donofrio,
  • Jill Pflugheber,
  • Letzibeth Mendez-Rivera,
  • Rajeshwer S. Sankhala,
  • Wei-Hung Chen,
  • Bonnie M. Slike,
  • Annika Schmid,
  • Ursula Tran,
  • Lily Metzger,
  • Caroline E. Peterson,
  • Amelia K. Pinto,
  • Sandhya Vasan,
  • Natalie D. Collins,
  • Aaron Farmer,
  • Nelson L. Michael,
  • M. Gordon Joyce,
  • James D. Brien,
  • Shelly J. Krebs

摘要

Zika virus (ZIKV) vaccine candidates developed through Phase I clinical trials are based on the full-length envelope glycoprotein (E), which presents both desirable and undesirable antigenic determinants. Among the latter, the conserved fusion loop epitope (FLE) within domain II is a major target for flavivirus cross-reactive and poorly neutralizing responses. To eliminate unwanted FLE targeting, we redesigned ZIKV E using a reverse vaccinology approach, excising domain II and allowing domains I and III (DI-DIII) to fold into an independent subunit harboring key neutralizing epitopes. Ifnar1-/- mice vaccinated with ZIKV DI-DIII elicited high ZIKV neutralizing antibodies and were protected from weight loss and death. In addition, sera from DI-DIII vaccinated mice demonstrated a reduced capacity to enhance DENV 1-4 infection in vitro, compared to mice vaccinated with full-length E. This study identifies DI-DIII as a promising immunogen, focusing antibody responses to protective epitopes on ZIKV and minimizing the elicitation of unwanted responses.