# Unraveling yellow fever 17D vaccine attenuation: The role of type I interferon and innate immunity

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2022 · $881,526

## Abstract

Project Summary
 The yellow fever 17D live-attenuated vaccine has been administered to millions of people and is a highly
successful and safe vaccine providing essentially life-long protection. However, the mechanisms of attenuation
are poorly understood, and rare individuals suffer from sometimes fatal severe adverse events (SAEs) including
yellow fever-like viscerotropic disease, or neurologic disease. Epidemics of this mosquito-borne disease continue
to occur in tropical and sub-tropical regions of South America and Africa, so understanding the mechanisms of
17D attenuation and the factors predisposing to SAEs is critical for development of safer vaccines and SAE
prevention or treatment strategies. Work of others and of ours in the prior funding period determined that type I
interferon (IFN) responses are greater after infection of cells with 17D compared to the virulent Asibi parental
strain. New preliminary data demonstrate that the prophylactic IFN-induced antiviral state is also more effective
at controlling 17D. Importantly, our work uncovered mutations in genes encoding type I IFN receptor chains
(IFNAR1 and IFNAR2) and autoantibodies against type I IFNs as factors causing SAEs after 17D vaccination,
thus linking the observed IFN phenotype with 17D attenuation in vivo. We also discovered a differential
requirement between 17D and Asibi, mediated by the viral NS4B protein, for the host factor TMEM41B, with
increased innate immune responses to 17D in TMEM41B KO cells. Prior studies have been hampered by the
disparate specific infectivities of 17D and Asibi, precluding meaningful comparisons in bulk cell-based assays.
New preliminary data demonstrates that 17D and Asibi harboring the 17D E protein (Asibi+17D E) have similar
specific infectivities, replicate with similar kinetics in the HepG2 hepatocyte cell line, and maintain previously
described differences in IFN transcription and secretion. Unexpectedly, levels of phosphorylated STAT1 are
similar in 17D- and Asibi+17D E-infected cells. In this project continuation, in Aim 1 17D and Asibi+17D E will be
used to examine pattern recognition receptor activation, including kinase activation and downstream
transcriptional responses using phosphoproteomics and RNASeq. The mechanism by which Asibi+17D E blocks
IFN secretion, the process by which STAT1 phosphorylation occurs and the consequences to infection and role
of individual ISGs in controlling 17D and Asibi infection will be elucidated. In Aim 2 interactions of Asibi and 17D
with both pro- and anti-viral host factors will be characterized through imaging-based methods allowing single
cell resolution. We will examine responses in the infected cell and the influence of individual genes (at genome
scale) on innate immunity and infection. Patient-specific mutations associated with SAEs will be functionally
interrogated as we have done previously. In Aim 3 the role of NS4B in differential TMEM41B requirements will
be elucidated using proteomic a...

## Key facts

- **NIH application ID:** 10587153
- **Project number:** 2R01AI124690-06A1
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Charles M Rice
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $881,526
- **Award type:** 2
- **Project period:** 2016-02-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10587153

## Citation

> US National Institutes of Health, RePORTER application 10587153, Unraveling yellow fever 17D vaccine attenuation: The role of type I interferon and innate immunity (2R01AI124690-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10587153. Licensed CC0.

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