Engineered dengue virus domain III proteins elicit cross-neutralizing antibody responses in mice

Julia C. Frei, Ariel S. Wirchnianski, Jennifer Govero, Olivia Vergnolle, Kimberly A. Dowd, Theodore C. Pierson, Margaret Kielian, Mark E. Girvin, Michael S. Diamond, Jonathan R. Lai

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8 Scopus citations

Abstract

Dengue virus is the most globally prevalent mosquito-transmitted virus. Primary infection with one of four cocirculating serotypes (DENV-1 to -4) causes a febrile illness, but secondary infection with a heterologous serotype can result in severe disease, due in part to antibody-dependent enhancement of infection (ADE). In ADE, cross-reactive but nonneutralizing antibodies, or subprotective levels of neutralizing antibodies, promote uptake of antibody-opsonized virus in Fc-γ receptor-positive cells. Thus, elicitation of broadly neutralizing antibodies (bNAbs), but not nonneutralizing antibodies, is desirable for dengue vaccine development. Domain III of the envelope glycoprotein (EDIII) is targeted by bNAbs and thus is an attractive immunogen. However, immunization with EDIII results in sera with limited neutralization breadth. We developed "resurfaced" EDIII immunogens (rsDIIIs) in which the A/G strand epitope that is targeted by bNAb 4E11 is maintained but less desirable epitopes are masked. RsDIIIs bound 4E11, but not serotype-specific or nonneutralizing antibodies. One rsDIII and, unexpectedly, wild-type (WT) DENV-2 EDIII elicited cross-neutralizing antibody responses against DENV-1 to -3 in mice. While these sera were cross-neutralizing, they were not sufficiently potent to protect AG129 immunocompromised mice at a dose of 200 μl (50% focus reduction neutralization titer [FRNT50], ∼1:60 to 1:130) against mouse-adapted DENV-2. Our results provide insight into immunogen design strategies based on EDIII.

Original languageEnglish (US)
Article numbere01023
JournalJournal of virology
Volume92
Issue number18
DOIs
StatePublished - Sep 1 2018

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Keywords

  • Dengue virus
  • Domain IIII
  • Immunogen
  • Phage display
  • Protein engineering
  • Vaccine

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Frei, J. C., Wirchnianski, A. S., Govero, J., Vergnolle, O., Dowd, K. A., Pierson, T. C., Kielian, M., Girvin, M. E., Diamond, M. S., & Lai, J. R. (2018). Engineered dengue virus domain III proteins elicit cross-neutralizing antibody responses in mice. Journal of virology, 92(18), [e01023]. https://doi.org/10.1128/JVI.01023-18