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Protective B-cell responses in chikungunya virus infection

Award Number: R01AI119056
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: 03/01/2016
PERIOD OF PERFORMANCE END DATE: 02/28/2021

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Protective B-cell responses in chikungunya virus infection - ¿ DESCRIPTION (provided by applicant): Chikungunya virus (CHIKV) has the potential to create a major public health impact should it be introduced into the United States, as seems likely following a large and sustained outbreak, first in the Caribbean and then into the mainland Americas. CHIKV causes extensive human and economic damage, partially due to acute fever and arthralgia, but primarily because of post-viral chronic joint pain/arthritis. Currently no licensed therapeutic treatments or vaccines exist for CHIKV. We will address the important public health threat posed by CHIKV by identifying lead candidate monoclonal antibodies (mAbs) for development into treatments capable of being used both prophylactically and therapeutically. Importantly, we have demonstrated the ability of mAbs directed against CHIKV to block viral assembly/budding - probably by preventing the envelope glycoprotein-driven membrane curvature required to form particles. We will characterize new antibodies targeting this mechanism, as well as describe the full B-cell repertoire in response to infection - both in acutely infected patients and recovered individuals. Finally, we will characterize CHIKV genetic diversity and evolution with emphasis on detecting variation and signatures of selection at B-cell epitopes. In order to achieve these goals we will perform three Specific Aims: Aim 1. Identification and characterization of potent human monoclonals capable of budding inhibition. We will derive and screen B-cell clones from recovered CHIKV patients specifically for inhibition of CHIKV virus release/budding. Resulting mAbs will be characterized for in vitro and in vivo potency, and their epitopes will be mapped using escape mutants and mutagenesis. Aim 2. Characterize acute and memory B-cell responses to CHIKV infection. Using Immune Repertoire Capture (IRCTM) technology, we will fully map B-cell repertoires during CHIKV infection. Common epitopes will be identified by looking for convergent evolution of B-cell paratopes in multiple individuals, and the relationship between entry neutralization and budding inhibition will be characterized in acutely infected and recovered individuals. Aim 3. Characterization of CHIKV envelope glycoprotein diversity and evolution. In order to assess the potential for the antibodies derived in Aims 1 and 2 to be broadly cross reactive, we will characterize the nature and extent of CHIKV envelope sequence variation in viral isolates derived from individuals enrolled in the study (over three years) together with CHIKV sequences from the wider global population. Data sets will be screened for signatures of selective pressure, particularly from the humoral response. In summary, we hope to develop novel mAbs, targeting specific stages of the viral lifecycle. The humoral responses during infection will be mapped and related to viral diversity and evolution.


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: 2022 ( Subtotal = -$68,112 )
2022	2019	VITALANT	6210 E OAK ST	SCOTTSDALE	AZ	85257	MARICOPA	USA	Allergy and Infectious Diseases Research	000	4	10/14/2021	NON-COMPETING CONTINUATION	-$68,112
														Subtotal = -$68,112

Issue Date FY: 2019 ( Subtotal = $450,038 )
2019	2019	BLOOD SYSTEMS, INC.	6210 E OAK ST	SCOTTSDALE	AZ	85257	MARICOPA	USA	Allergy and Infectious Diseases Research	000	4	2/19/2019	NON-COMPETING CONTINUATION	$450,038
														Subtotal = $450,038

Issue Date FY: 2018 ( Subtotal = $559,024 )
2018	2018	BLOOD SYSTEMS, INC.	6210 E OAK ST	SCOTTSDALE	AZ	85257	MARICOPA	USA	Allergy and Infectious Diseases Research	000	3	2/15/2018	NON-COMPETING CONTINUATION	$559,024
														Subtotal = $559,024

Issue Date FY: 2017 ( Subtotal = $510,584 )
2017	2017	BLOOD SYSTEMS, INC.	6210 E OAK ST	SCOTTSDALE	AZ	85257	MARICOPA	USA	Allergy and Infectious Diseases Research	000	2	2/24/2017	NON-COMPETING CONTINUATION	$510,584
														Subtotal = $510,584

Issue Date FY: 2016 ( Subtotal = $334,094 )
2016	2016	BLOOD SYSTEMS INC	6210 EAST OAK STREET	TEMPE	AZ	85257		USA	Allergy and Infectious Diseases Research	000	1	2/29/2016	NEW	$334,094
														Subtotal = $334,094

Grand Total All Awards = $1,785,628

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Protective B-cell responses in chikungunya virus infection

Award Number: R01AI119056

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: 03/01/2016

PERIOD OF PERFORMANCE END DATE: 02/28/2021

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