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

Award Number: R01AI124690
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2016
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Unraveling yellow fever 17D vaccine attenuation: The role of type I interferon and innate immunity - 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 and mutational approaches. These studies will uncover critical host-pathogen interactions that can be exploited to develop safer vaccines, SAE treatment or prevention approaches, and new drug targets. The information gained can also be broadly applied to vaccine development for other flaviviruses.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $846,776 )
2026	2026	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	10	7/23/2026	NON-COMPETING CONTINUATION	$846,776
														Subtotal = $846,776

Issue Date FY: 2025 ( Subtotal = $846,776 )
2025	2025	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	9	7/15/2025	NON-COMPETING CONTINUATION	$846,776
														Subtotal = $846,776

Issue Date FY: 2024 ( Subtotal = $846,776 )
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	8	7/15/2024	NON-COMPETING CONTINUATION	$846,776
														Subtotal = $846,776

Issue Date FY: 2023 ( Subtotal = $846,776 )
2023	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	7	7/11/2023	NON-COMPETING CONTINUATION	$846,776
														Subtotal = $846,776

Issue Date FY: 2022 ( Subtotal = $881,526 )
2022	2022	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	6	9/19/2022	COMPETING CONTINUATION	$881,526
2022	2020	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	5	8/25/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $881,526

Issue Date FY: 2020 ( Subtotal = $741,079 )
2020	2020	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	5	1/16/2020	NON-COMPETING CONTINUATION	$741,079
														Subtotal = $741,079

Issue Date FY: 2019 ( Subtotal = $939,659 )
2019	2019	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	4	8/21/2019	NON-COMPETING CONTINUATION	$166,798
2019	2019	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	4	1/14/2019	NON-COMPETING CONTINUATION	$772,861
														Subtotal = $939,659

Issue Date FY: 2018 ( Subtotal = $772,861 )
2018	2018	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	1/24/2018	NON-COMPETING CONTINUATION	$772,861
														Subtotal = $772,861

Issue Date FY: 2017 ( Subtotal = $798,777 )
2017	2017	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	1/6/2017	NON-COMPETING CONTINUATION	$798,777
														Subtotal = $798,777

Issue Date FY: 2016 ( Subtotal = $790,963 )
2016	2016	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	2/15/2016	NEW	$790,963
														Subtotal = $790,963

Grand Total All Awards = $8,311,969

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

Award Number: R01AI124690

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/15/2016

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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