[R01] Enterovirus interference with rotavirus vaccine replication and immunity
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2028-05-31
Importo max: 126.597 EUR
Paese: US
Descrizione
PROJECT SUMMARY/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, many children remain at risk of life-threatening RV disease because of inadequate response to vaccination. 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 was associated with a lack of seroconversion to ORV in a previously studied cohort of infants from Ghana. However, the signaling pathways and mechanisms associated with this interference have not yet been defined.
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 fecal analyses from a human clinical trial cohort of infants receiving RV vaccines. Representative EV-B strains which are prevalent in settings with reduced vaccine efficacy have been selected for these studies. We will interrogate the 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 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 mouse models. Additionally, a distinctive collection of fecal samples from a clinical trial evaluating ORV and non-replicating RV vaccine clinical efficacy will be used to confirm EV-B interference with ORV, define EV-B-associated antiviral cytokines, and assess whether EV-B also interferes with non-replicating RV vaccines. Because these samples were already collected from infants in Ghana, where a larger percentage of infants fail to develop strong protection after vaccination compared with infants in the United States, they provide a rare opportunity to directly compare babies who developed protection after vaccination with those who did not. Such studies would not be feasible in other settings like the US, because with lower rates of infants failing to respond to vaccines at these sites, there would not be enough data to draw statistically valid conclusions. The Ghanaian cohort includes many more non-responders, making it possible to more clearly identify the biological factors, like viral interference, that limit vaccine effectiveness and drive poor vaccine responses across settings.
Completion of this proposal will provide key insights into EV-B-mediated interference with ORV, as well as broadly into virus-virus interactions and their consequences for development of immune responses. RV continues to cause nearly 3 million cases of diarrheal illness per year in the United States. The outcomes from this study will help to develop evidence-based interventions to help to mitigate these diarrheal illnesses affecting infants in the
Istituzione: WASHINGTON UNIVERSITY
PI: Megan T Baldridge, Vanessa Catherine HARRIS, Sasirekha Ramani
Progetto: 3R01AI173360-04S1
Settori: National Institute of Allergy and Infectious Diseases
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