Type-I IFN promotes humoral immunity in viral vector vaccination.

Recombinant viral vectors are an important platform for vaccine delivery. Our recent study has demonstrated distinct innate immune profiles in responding to viral vectors of different families (e.g., adenovirus vs. poxvirus): while human Ad5 vector is minimally innate immune stimulatory, the poxviral vector ALVAC induces strong innate response and stimulates type-I IFN and inflammasome activation. However, impact of the innate immune signaling on vaccine-induced adaptive immunity in viral vector vaccination is less clear. Here, we showed that Modified Vaccinia Ankara (MVA), another poxviral vector, stimulated type-I IFN response in innate immune cells through cGAS-STING. Using MVA-HIV vaccine as a model, we found that type-I IFN signaling promoted the generation of humoral immunity in MVA-HIV vaccination in vivo. Following vaccination, type-I IFN receptor knockout (IFNAR1-/-) mice produced significantly lower levels of total and HIV gp120-specific antibodies compared to the wild-type (WT) mice. Consistent with the antibody response, type-I IFN signaling deficiency also led to reduced levels of plasma cells and memory-like B cells compared to those in WT mice. Furthermore, analysis of vaccine-induced CD4 T cells showed that type-I IFN signaling also promoted the generation of vaccine-specific CD4 T-cell response and T follicular helper (Tfh) response in mice. Together, our data indicate a role of type-I IFN signaling in promoting humoral immunity in poxviral vector vaccination. The study suggests that modulating type-I IFN and its associated innate immune pathways will likely affect vaccine efficacy. IMPORTANCE Viral vectors, including MVA, are an important antigen delivery platform and have been commonly used in vaccine development. Understanding the innate host-viral vector interactions and its impact on vaccine-induced immunity is critical but understudied. Using MVA-HIV vaccination of WT and IFNAR1-/- mice as a model, our study reports that type-I IFN signaling promotes humoral immunity in MVA vaccination, including vaccine-induced antibody, B-cell, and Tfh responses. Findings of the present study provide insights not only for basic understanding of host-viral vector interactions, but also for improving vaccine design by potentially modulating type-I IFN and its associated innate immune pathways in viral vector vaccination.