Differential human antibody repertoires following Zika infection and the implications for serodiagnostics and disease outcome

Supriya Ravichandran,José Ramos-Castañeda,Pablo F Belaunzarán-Zamudio,Sandra Caballero-Sosa,Hana Golding,John H Beigel,Guillermo Ruiz-Palacios,Surender Khurana,Megan Hahn,Gabriel Nájera-Cancino,Karla R Navarro-Fuentes

doi:10.1038/s41467-019-09914-3

Abstract

Zika virus (ZIKV) outbreak in Americas led to extensive efforts to develop vaccines and ZIKV-specific diagnostics. In the current study, we use whole genome phage display library spanning the entire ZIKV genome (ZIKV-GFPDL) for in-depth immune profiling of IgG and IgM antibody repertoires in serum and urine longitudinal samples from individuals acutely infected with ZIKV. We observe a very diverse IgM immune repertoire encompassing the entire ZIKV polyprotein on day 0 in both serum and urine. ZIKV-specific IgG antibodies increase 10-fold between day 0 and day 7 in serum, but not in urine; these are highly focused on prM/E, NS1 and NS2B. Differential antibody affinity maturation is observed against ZIKV structural E protein compared with nonstructural protein NS1. Serum antibody affinity to ZIKV-E protein inversely correlates with ZIKV disease symptoms. Our study provides insight into unlinked evolution of immune response to ZIKV infection and identified unique targets for ZIKV serodiagnostics.

Highlights

Zika virus (ZIKV) outbreak in Americas led to extensive efforts to develop vaccines and ZIKV-specific diagnostics
Protection against ZIKV disease is at least partially attributed to the humoral immune response, since strong correlation was demonstrated between ZIKV-specific antibody responses and protective efficacy after vaccination of mice and nonhuman primates (NHPs)
The only region not recognized by serum antibodies was the NS2A protein, even though it was well represented in the ZIKV-GFPDL (Supplementary Figs. 1 and 2)

Summary

Introduction

Zika virus (ZIKV) outbreak in Americas led to extensive efforts to develop vaccines and ZIKV-specific diagnostics. “Whole-Genome-Fragment-Phage-Display-Libraries” (GFPDL) has been previously used for an unbiased comprehensive analysis of the antibody repertoires in individuals infected with viruses, either early or during recovery[23,24] They can help to determine the diversity of epitopes bound by post-vaccination sera and decipher the impact of novel adjuvants[25,26,27,28]. GFPDL spanning the entire genome of ZIKV was constructed and used for in-depth immune profiling of IgG and IgM antibody repertoires in both serum and urine body fluids from individuals acutely infected with ZIKV. The results showed unlinked evolution of antibody responses in terms of antibody epitope repertoire and affinity maturation against structural and non-structural proteins following ZIKV infection in humans, suggesting differential recognition of various ZIKV proteins by the human immune system

Methods

Results

Conclusion