Enterovirus interference with rotavirus vaccine replication and immunity

Active Project Grant Awarded Last action

Award ID
R01AI173360
Recipient
Awarding agency
Obligated
$4,916,370

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 68% complete
Place of performance
University City, MO 63130, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Rotavirus (RV) is the leading cause of diarrhea-associated morbidity and mortality in children younger than five worldwide. While RV vaccines have substantially decreased RV deaths, children in low- and middle- income countries remain at risk of life-threatening RV disease because of significantly lower vaccine effectiveness compared to high-income countries. We recently identified a potential role for enterovirus b (EV- b) infection in reducing oral RV vaccine (ORV) performance. Specifically, EV-b infection at the time of vaccination is associated with a lack of seroconversion to ORV in a cohort of infants from ghana. However, the signaling pathways and mechanisms associated with this interference have not yet been defined. We hypothesize that EV-BS induce epithelial-derived antiviral cytokines to limit both ORV replication and anti-RV immune responses. Determination of the mechanisms underlying EV-b-mediated interference with ORV will leverage complementary analyses in EX vivo human intestinal organoids, in vivo mouse models, and non-invasive fecal analyses from a human clinical trial cohort of infants receiving RV vaccines. Representative EV-b strains consistent with those identified in the ghanaian infant cohort and which are prevalent in countries with reduced vaccine efficacy have been selected for these studies. We will interrogate the innate antiviral signaling pathways induced by EV-b infection, as well as test whether they are required to limit ORV or RV replication, in both pediatric human organoids, including isogenic lines where key innate immune genes are knocked-out, and wild- type, transgenic or knock-out mouse lines. EV-b CO-infection effects on development of adaptive immune responses to RV will also be evaluated in murine models. Additionally, fecal samples from an ongoing clinical trial evaluating ORV and non-replicating RV vaccine clinical efficacy will be used to validate EV-b interference with ORV, define EV-b-associated antiviral cytokines, and assess whether EV-b also interferes with non- replicating RV vaccines. We have assembled a team of investigators with extensive expertise in the experimental RV systems, clinical vaccinology, and virome analyses required to define the molecular mechanisms underlying the important and persistent clinical challenge of low ORV performance in low- and middle-income countries. Completion of this proposal will provide key insights into EV-b-mediated interference with ORV, as well as broadly into virus-virus interactions in the intestinal environment and their consequences for development of immune responses. By identifying key factors that regulate vaccine responsiveness, we aim to facilitate development and testing of evidence-based interventions to improve RV vaccine performance.

Transactions

Action Obligated Date
Amendment $126,597
Amendment $560,480
Amendment $560,480
Amendment $145,693
Amendment $145,693
Amendment $546,268
Amendment $546,268
Amendment $723,555
Amendment $780,668
Original award $780,668

Subawards

Subrecipient Amount Awarded
Stichting Amsterdam UMC Enterovirus interference with rotavirus vaccine replication and immunity. SubPI will be specifically responsible for conducting the studies described in Aim… $126,597
Baylor College Of Medicine Examination of the interactions between live, attenuated rotavirus vaccines and specific enteroviruses that are associated with diminished response to ORVs in… $257,032
Stichting Amsterdam UMC Scope of Work Dr. Vanessa Harris of S/ch/ng Amsterdam UMC is a world expert in rotavirus vaccine and microbiome interac/ons, and was the lead inves/gator in the… $145,693
Stichting Amsterdam UMC $167,749
Baylor College Of Medicine Scope of Work Sasirekha Ramani, Ph.D. will be responsible for the execution of the experiments proposed in Aim 1 of the application, including (Subaim 1a)… $268,474
The General Hospital Corporation Type I IFN-dependent and independent contributions to the outcomes of early innate immune cell interactions during HIV/TB co-infection Statement of Work… $266,151
University Of Pittsburgh - Of The Commonwealth System Of Higher Education Statement of work at the University of Pittsburgh The Mattila Lab at the University of Pittsburgh will perform studies investigating early events in granuloma… $131,171
Academisch Medisch Centrum Scope of Work Dr. Vanessa Harris of Amsterdam University Medical Center (AUMC) is a world expert in rotavirus vaccine and microbiome interactions, and was the… $71,714
Baylor College Of Medicine Scope of Work Sasirekha Ramani, Ph.D. will be responsible for the execution of the experiments proposed in Aim 1 of the application, including (Subaim 1a)… $798,393

Quick answers

Who received award R01AI173360?

R01AI173360 was awarded to The Washington University by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on June 12, 2023.

How much is award R01AI173360 worth?

$4,916,370 has been obligated on R01AI173360.

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