Research ArticleEMERGING INFECTIONS

Durability and correlates of vaccine protection against Zika virus in rhesus monkeys

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Science Translational Medicine  13 Dec 2017:
Vol. 9, Issue 420, eaao4163
DOI: 10.1126/scitranslmed.aao4163
  • Fig. 1 ZIKV prM-Env antigen development.

    (A) Zika virus (ZIKV) prM-Env antigens tested: cleavage peptide–deleted prM-Env (amino acids 216 to 794; also termed M-Env), full-length prM-Env, and full-length prM-Env with the stem and transmembrane (TM) region of Japanese encephalitis virus (JEV). CAP, capsid. (B) Expression from DNA vaccines expressing these three antigens by Western blot and immunogenicity in Balb/c mice (n = 5 per group) by Env-specific enzyme-linked immunosorbent assay (ELISA) after a single immunization of 50-μg DNA vaccines expressing M-Env, prM-Env (full-length), or prM-Env (JEV stem). P values were determined by t test. The dotted line reflects log ELISA titers of 2.0. Red lines reflect medians. (C) Mice were challenged by the intravenous route with 105 viral particles (VP) [102 plaque-forming units (PFU)] ZIKV-BR. Viral loads were determined in serum on days 0, 1, 2, 3, 4, and 6.

  • Fig. 2 Long-term immunogenicity and protective efficacy of ZIKV vaccines in Balb/c mice.

    (A) Balb/c mice (n = 5 per group) were immunized once by the intramuscular route with 109 VP Ad26-M-Env, 109 VP RhAd52-M-Env, 1-μg purified inactivated virus (PIV) with alum, 50-μg DNA-M-Env, 50-μg DNA-prM-Env, or sham vaccine. Median Env-specific ELISA titers are shown. Error bars reflect SEM. The dotted line reflects log ELISA titers of 2.0. (B and C) Mice were challenged 20 weeks later by the intravenous route with 105 VP (102 PFU) ZIKV-BR. Viral loads were determined in serum on days 0, 1, 2, 3, 4, and 6.

  • Fig. 3 Long-term immunogenicity and protective efficacy of the ZIKV PIV vaccine in rhesus monkeys.

    (A) Log ZIKV-specific microneutralization (MN50) titers after immunization of rhesus monkeys by the subcutaneous route with 5-μg ZIKV PIV vaccine (n = 8) at weeks 0 and 4 (red arrows). The dotted line reflects log MN50 titers of 2.0. Red bars reflect medians. PIV-vaccinated and sham control rhesus monkeys (n = 8 per group) were challenged by the subcutaneous route with 106 VP (103 PFU) ZIKV-BR. Viral loads are shown in (B) plasma, (C) cerebrospinal fluid (CSF), and (D) lymph nodes (LN). Viral loads were determined on days 0, 1, 2, 3, 4, 5, and 7 for the plasma samples and on days 0, 3, 14, and 35 for the other samples. P value determined by Fisher’s exact test. NAb, neutralizing antibody.

  • Fig. 4 Long-term immunogenicity and protective efficacy of the ZIKV DNA-M-Env and RhAd52-M-Env vaccines in rhesus monkeys.

    (A) Log ZIKV-specific microneutralization (MN50) titers after immunization of rhesus monkeys by intramuscular with two immunizations of 5-mg DNA-M-Env (n = 7) at weeks 0 and 4 (red arrows) or a single-shot immunization of 1011 VP RhAd52-M-Env (n = 4) at week 0 (red arrow). The dotted lines reflect log MN50 titers of 2.0. Red bars reflect medians. Vaccinated and sham control rhesus monkeys were challenged by the subcutaneous route with 106 VP (103 PFU) ZIKV-BR. Viral loads are shown in (B) plasma, (C) CSF, and (D) LN. Viral loads were determined on days 0, 1, 2, 3, 4, 5, and 7 for the plasma samples and on days 0, 3, 14, and 35 for the other samples. P values determined by Fisher’s exact tests. NS, not significant.

  • Fig. 5 Immune correlates analysis in vaccinated rhesus monkeys.

    Correlation of maximum log viral loads after ZIKV-BR challenge with log MN50 titers at week 52 before challenge (left). P value determined by Spearman rank correlation test. Comparison of log MN50 titers at week 52 in protected versus infected animals (right). P value determined by Wilcoxon rank-sum test. The dotted lines reflect log MN50 titers of 2.0 and 2.1. Red lines reflect medians.

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/9/420/eaao4163/DC1

    Fig. S1. Immune correlates analysis in mice.

    Fig. S2. Cellular immune responses in the ZIKV PIV vaccine study.

    Fig. S3. Cellular immune responses in the ZIKV DNA-M-Env and RhAd52-M-Env vaccine study.

    Fig. S4. Cross-strain neutralization of a panel of ZIKV strains.

    Fig. S5. Antibody-dependent enhancement assays in the ZIKV PIV vaccine study.

    Fig. S6. Antibody-dependent enhancement assays in the ZIKV DNA-M-Env and RhAd52-M-Env vaccine study after challenge.

    Fig. S7. MN50 titers in the ZIKV PIV vaccine study after challenge.

    Fig. S8. MN50 titers in the ZIKV DNA-M-Env and RhAd52-M-Env vaccine study after challenge.

    Fig. S9. Cellular immune responses in the ZIKV DNA-M-Env and RhAd52-M-Env vaccine study after challenge.

    Fig. S10. Immune correlates analysis in vaccinated and sham control rhesus monkeys.

    Fig. S11. Adoptive transfer studies of rhesus monkey IgG in mice.

    Primary data

  • Supplementary Material for:

    Durability and correlates of vaccine protection against Zika virus in rhesus monkeys

    Peter Abbink, Rafael A. Larocca, Kittipos Visitsunthorn, Michael Boyd, Rafael A. De La Barrera, Gregory D. Gromowski, Marinela Kirilova, Rebecca Peterson, Zhenfeng Li, Ovini Nanayakkara, Ramya Nityanandam, Noe B. Mercado, Erica N. Borducchi, Abishek Chandrashekar, David Jetton, Shanell Mojta, Priya Gandhi, Jake LeSuer, Shreeya Khatiwada, Mark G. Lewis, Kayvon Modjarrad, Richard G. Jarman, Kenneth H. Eckels, Stephen J. Thomas, Nelson L. Michael, Dan H. Barouch*

    *Corresponding author. Email: dbarouch{at}bidmc.harvard.edu

    Published 13 December 2017, Sci. Transl. Med. 9, eaao4163 (2017)
    DOI: 10.1126/scitranslmed.aao4163

    This PDF file includes:

    • Fig. S1. Immune correlates analysis in mice.
    • Fig. S2. Cellular immune responses in the ZIKV PIV vaccine study.
    • Fig. S3. Cellular immune responses in the ZIKV DNA-M-Env and RhAd52-MEnv vaccine study.
    • Fig. S4. Cross-strain neutralization of a panel of ZIKV strains.
    • Fig. S5. Antibody-dependent enhancement assays in the ZIKV PIV vaccine study.
    • Fig. S6. Antibody-dependent enhancement assays in the ZIKV DNA-M-Env and RhAd52-M-Env vaccine study after challenge.
    • Fig. S7. MN50 titers in the ZIKV PIV vaccine study after challenge.
    • Fig. S8. MN50 titers in the ZIKV DNA-M-Env and RhAd52-M-Env vaccine study after challenge.
    • Fig. S9. Cellular immune responses in the ZIKV DNA-M-Env and RhAd52-MEnv vaccine study after challenge.
    • Fig. S10. Immune correlates analysis in vaccinated and sham control rhesus monkeys.
    • Fig. S11. Adoptive transfer studies of rhesus monkey IgG in mice.

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    Other Supplementary Material for this manuscript includes the following:

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