Polyfunctional immunity and transcriptional imprint associated with protection by chimeric live-attenuated Zika virus vaccine in non-human primates

Though generally mild in humans, Zika virus (ZIKV) frequently causes severe disease and congenital defects in children born to mothers infected during pregnancy (Musso et al. NEJM 2019 PMID: 31597021; Shan et al. Cell Host Microbe 2018 PMID: 30008291). Previously, chimeric candidate vaccine YF-ZIK was shown to protect mice against lethal ZIKV infection and congenital malformations after single-dose immunization (Kum et al. npj Vaccines 2018 PMID: 30564463; Kum et al. Emerg. Microbes Infect. 2020 PMID: 32116148). Here we demonstrate that YF-ZIK is safe, induces strong antiviral immunity, and protects rhesus macaques against vigorous experimental challenge. YF-ZIK triggered within 7-14 days after a single subcutaneous dose high levels of neutralizing antibodies, which could significantly be boosted by a second immunization 4 weeks later. Passively transferred immune serum protects AG129 mice from lethal ZIKV challenge, supporting neutralizing antibodies as major correlate of protection. Humoral immunity is complemented by ZIKV-specific cellular responses, characterized by a balanced Th1/Th2 cytokine production. Transcriptional analyses demonstrate the induction of a gene expression profile that is comparable to that of the original yellow fever YF17D vaccine, involving multiple pathways favoring polyvalent immunity. When YF-ZIK vaccinated macaques were challenged with a high intradermal dose of ZIKV, viral RNA remains undetectable in most animals. Immunity may be sterilizing immunity as no elevation of ZIKV neutralizing antibodies, nor seroconversion to anti-ZIKV NS1 antibodies was evident. Protection is associated with an activation of innate and adaptive immunity early after challenge. Systems analysis unveils B-cell receptor TNFRSF17 as predictor for strong antibody responses to YF-ZIK vaccination in common with YF17D (Gaucher et al. J. Exp. Med. 2008 PMID: 19047440; Querec et al. Nat. Immunol. 2009 PMID: 19029902; Fourati et al. Nat. Immunol. 2022 PMID: 36316476 ), along with GNAS and CD207 (Langerin) as novel biomarkers predicting clinical outcomes. The favorable preclinical safety, immunogenicity and efficacy of YF-ZIK justifies future evaluation in humans.