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Immune competence as a factor of treatment efficacy in human Trypanosoma cruzi in

Award Number: R01AI110346
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: 03/11/2014
PERIOD OF PERFORMANCE END DATE: 02/29/2020

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Immune competence as a factor of treatment efficacy in human Trypanosoma cruzi in - DESCRIPTION (provided by applicant): Immune competence as a factor of treatment efficacy in Trypanosoma cruzi infection. The main drawbacks for a wider application of treatment of long-term T. cruzi infections include the difficulty of assessing treatment efficacy and the potential adverse effects of these therapeutics. Likewise, treatment regimens in terms of doses and duration in chronically T. cruzi-infected subjects are still debated. Conversely, drug therapy in T. cruzi-infected children is considered to be more effective than in adult patients. The aim of this application is to determine the association between the immunological status prior to treatment and the rate of cure following either complete treatment with benznidazole or interrupted treatment due to adverse effects. The prediction is that subjects with polyfunctional T cell responses to T. cruzi pre-therapy have higher chances to achieve cure compared with those displaying a narrower range of T cell functions. Furthermore, shortened treatment regimens are predicted to be effective in cases where immune responses are strong prior to treatment. Based on extensive preliminary data produced in the applicants' laboratories, these hypotheses will be tested by pursuing two specific aims: 1) Determine the association between the quality of T cell responses prior to drug therapy and success of treatment with benznidazole, and further validate non-conventional parameters as markers of treatment efficacy in T. cruzi-infected children; and 2) Compare treatment outcomes between complete and incomplete treatment schedules in T. cruzi-infected adults and children treated with benznidazole. Under Aim1, pretreatment immune responses specific for T. cruzi will be determined in infected children and stratified based on the capacity of T cells to exert monofunctional or polyfunctional T cell responses as determined by ELISPOT and flow cytometric assays. Then, treatment efficacy after benznidazole administration will be assessed by the achievement of complete seronegative conversion by conventional serological tests (i.e. the accepted standard of treatment success and cure in Chagas disease) and determine if treatment success is associated with a highly functional T cell profile prior to treatment compared with patients in which treatment fails. In addition, we will follow these treated subjects (irrespective of prior quality in T cell responses) with our previously reported surrogate parameters of treatment efficacy (i.e. T cell cytokine ELISPOT technique and multiplex serological assay) to determine whether patients who achieve cure show changes in immune responses post-treatment considered to reflect parasite clearance; as well as to identify the earliest changes that can be associated with cure. An observation of such association would further validate these metrics for monitoring treatment outcomes. Under the second aim, we will assess whether an incomplete course of treatment preferentially provide cure in those individuals who had more highly functional parasite specific T cell responses prior to therapy. Changes in T and B cell responses by non-conventional measures of treatment efficacy will be also compared between patients receiving full doses of benznidazole vs. those who received incomplete treatment regimens to evaluate the usefulness of these parameters to measure efficacy in cases of interrupted treatment. The proposed study is innovative in that it represents a departure from the current therapeutic approaches, namely the notion that improving host immune responses to T. cruzi could enhance treatment efficacy. These contributions will be significant because it will expand our understanding of how drug treatment works and provide guidance on how to most effectively treat and monitor therapy outcomes in chronically infected individuals.


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: 2020 ( Subtotal = $0 )
2020	2018	MINISTERIO DE SALUD DE LA PROVINCIA DE BUENOS AIRES	AVENIDA DOCTOR RICARDO BALBIN 3170	SAN MARTIN		B1650NBN		ARG	Allergy and Infectious Diseases Research	000	5	4/24/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $135,756 )
2018	2018	MINISTERIO DE SALUD DE LA PROVINCIA DE BUENOS AIRES	AVENIDA DOCTOR RICARDO BALBIN 3170	SAN MARTIN		B1650NBN		ARG	Allergy and Infectious Diseases Research	000	5	2/16/2018	NON-COMPETING CONTINUATION	$135,756
														Subtotal = $135,756

Issue Date FY: 2017 ( Subtotal = $129,631 )
2017	2017	MINISTERIO DE SALUD DE LA PROVINCIA DE BUENOS AIRES	AVENIDA DOCTOR RICARDO BALBIN 3170	SAN MARTIN		B1650NBN		ARG	Allergy and Infectious Diseases Research	000	4	3/10/2017	NON-COMPETING CONTINUATION	$129,631
														Subtotal = $129,631

Issue Date FY: 2016 ( Subtotal = $130,684 )
2016	2016	ASOCIACION COOPERADORA DEL HOSP INTERZONAL DE AGUDOS EV	AVENIDA DR RICARDO BALDIN 3170	BUENOS AIRES				ARG	Allergy and Infectious Diseases Research	000	3	2/25/2016	NON-COMPETING CONTINUATION	$130,684
														Subtotal = $130,684

Issue Date FY: 2015 ( Subtotal = $132,732 )
2015	2015	ASOCIACION COOPERADORA DEL HOSP INTERZONAL DE AGUDOS EV	AVENIDA DR RICARDO BALDIN 3170	BUENOS AIRES				ARG	Allergy and Infectious Diseases Research	000	2	2/13/2015	NON-COMPETING CONTINUATION	$132,732
														Subtotal = $132,732

Issue Date FY: 2014 ( Subtotal = $132,922 )
2014	2014	ASOCIACION COOPERADORA DEL HOSP INTERZONAL DE AGUDOS EV	AVENIDA DR RICARDO BALDIN 3170	BUENOS AIRES				ARG	Allergy and Infectious Diseases Research	000	1	3/11/2014	NEW	$132,922
														Subtotal = $132,922

Grand Total All Awards = $661,725

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Immune competence as a factor of treatment efficacy in human Trypanosoma cruzi in

Award Number: R01AI110346

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: 03/11/2014

PERIOD OF PERFORMANCE END DATE: 02/29/2020

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