# Identifying genetic determinants of Rotavirus Vaccine Failure in Malawian Children

> **NIH NIH K01** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2022 · $135,351

## Abstract

Project Summary
 Rotavirus is the leading cause of severe childhood gastroenteritis, resulting in over 215,000 deaths per
year. The recently introduced live, oral rotavirus vaccine (RVV) demonstrated 90-95% protection in Europe and
the US, but is less than 50% in low-income countries, where the disease burden is highest. The biological
basis of rotavirus vaccine failure remains unknown but likely includes both microbial and host factors.
In Malawi there is a high prevalence of rotavirus disease and after a pivotal placebo-controlled clinical
trial there was modest seroconversion, only 40%-50%. Despite high vaccine coverage rotavirus remains the
leading cause of diarrhea hospitalization among infants in Malawi. There is no evidence of vaccine escape
however potential explanations for RVV failure include: effects of gut/systemic infection, variation in the
microbiome, interference from passively acquired maternal antibodies, and/or genetic predisposition but
evidence for each of these is limited. Preliminary data suggest that mutations in blood group antigens may
influence rotavirus vaccine failure, but this hypothesis has not been well characterized in African populations.
There is additional evidence that the high pathogen burden in low-income countries may be reducing infants'
response to live vaccines. To fully understand the causes of RVV failure a robust investigation of host and
microbial genetic factors is needed.
 To elucidate genetic variants linked to low rotavirus vaccine immunogenicity and clinical vaccine failure,
this study will utilize a genome wide association study (GWAS) and transcriptomic analysis. Detailed infant
health will be collected at baseline and established diagnostic assays will be used to characterize serological
response to RVV. To assess whether concurrent infection at the time of vaccination is correlated with RVV
failure, common pathogens will be screened for – using commercially available diagnostics, novel CRISPR-
Cas13a assays, and metagenomic sequencing . This study will leverage prospective and retrospective
collections combined with a GWAS and transcriptomic profiling of infants pre vs. post-vaccination to identify
genetic variants that are associated with and predictive of RVV failure.
 The genetic variants identified in the GWAS will undergo improved signal resolution and functional
analysis through Composite of Multiple Signals, Massively Parallel Report Assay, In vitro analysis, and gene
editing using CRISPR. This study will produce the first GWAS of a viral diarrheal illness in Africa and may
uncover mechanisms of defense to rotavirus.
 Despite widespread vaccination, rotavirus remains the main cause of severe life threatening diarrhea in
Malawian infants. This study has the potential to identify host-derived signatures that can be used as early
predictors of RVV failure, inform immunization strategies and the future of vaccine development.

## Key facts

- **NIH application ID:** 10322365
- **Project number:** 5K01TW010853-05
- **Recipient organization:** HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** KAYLA G BARNES
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $135,351
- **Award type:** 5
- **Project period:** 2018-09-24 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322365

## Citation

> US National Institutes of Health, RePORTER application 10322365, Identifying genetic determinants of Rotavirus Vaccine Failure in Malawian Children (5K01TW010853-05). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10322365. Licensed CC0.

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