Background: The human noroviruses are a highly diverse group of diarrheagenic RNA viruses which are globally distributed, and a cause of acute gastroenteritis in all age groups with the elderly and young children usually experiencing severe clinical outcomes. To date, at least 40 different genotypes of noroviruses belonging to two major genogroups have been observed in humans. These different genotypes have been suggested to be associated with different transmission patterns and disease severity in humans. Also, host genetic factors including the presence of ABO antigens and mutations in the fucosyltransferase (FUT2 and FUT3) genes affect the susceptibility of individuals to infection with these diverse norovirus genotypes. This has raised questions on whether the prevalence, as well as the percentage of circulating Histo-Blood Group Antigen (HBGA) mutations within a population, would influence the prevalence of specific norovirus genotypes as a function of their ability to infect certain HBGA types. Moreover, the continuous changes observed in the genetic diversity of the noroviruses highlight the need for sustained surveillance to provide a full overview of norovirus epidemiology for future vaccine policy decisions. The overall aim of this thesis was to get a better understanding of norovirus infection dynamics, strain diversity, evolutionary dynamics, and the host genetic factors associated with the risk of norovirus infection in the Ghanaian pediatric population. Methods: A chronologically comprehensive 10-year study was conducted with diarrheic stool samples collected during active surveillance for diarrhoea in Ghanaian children between January 2008 and December 2017. A total of 1,337 stool specimens were obtained and subjected to RT-PCR and partial nucleotide sequencing for the typing of the polymerase and capsid genes of the norovirus genome. Phylodynamic and evolutionary relationships were performed using MEGA 6.0 and BEAST software, respectively, to analyze sequences that overlapped at open reading frame (ORF) 1 and ORF2 regions. The entire coding region of the FUT2 gene was also amplified from saliva samples collected from a cohort of the study population and genotyped using RLFP. Results: Overall positivity for norovirus infection among the Ghanaian pediatric population was 36.2%. Infection was most commonly (82.7%) observed in children aged between 6-24 months, suggesting that 0-6 months would be the most appropriate age range for effective norovirus vaccination, as early prevention is critical. Results from this thesis showed broad norovirus genotype diversity characterized by the circulation of both GII.4, and non-GII.4 strains. The evolution of these norovirus strains was usually a result of both intra- and intergenic recombination that occurred within the capsid and polymerase genes. A total of 25 capsid/RdRP combinations were detected with GII.4[P4] (25.9%); GII.4[P16] (9.2%); GII.3[P21] (6.3%); GII.4[P31] (4.6%) and GII.6P[7] (4.0%) being the most common norovirus strains. Children infected with non-GII.4 norovirus strains recorded equally severe clinical illness comparable to that caused by GII.4 norovirus strains. Data from this thesis also suggest that most norovirus strains circulated at low prevalence within the population before their recognition as epidemic and pandemic strains associated with increased norovirus outbreaks. The study results further indicate that neither secretor status nor genotype difference affects the susceptibility of an individual to norovirus infection in Ghana. More than half (62.0%; 8/13) of symptomatic patients were found to be carriers of the G428A mutation for inactivation of the FUT2 enzyme. Comparing norovirus genotype GII.4 with non-GII.4 genotypes, we observed that GII. 4norovirus strains infected more secretor-positive children who possessed heterozygous allele of the FUT2 gene than non-GII.4 strains (60.0% vs 40.0%, p=0.035) whereas non-GII.4 norovirus strains had a preference for secretor-positive children with the homozygous allele of the gene (62.5% vs 37.5%, p<0.05) in the study population. Conclusions: In summary, the study confirmed the significant role that noroviruses play in the cause of acute gastroenteritis among Ghanaian children and further contributes to our understanding of the epidemiology and evolution of the virus which hopefully can lead to better preventive measures for norovirus disease as well as baseline data for vaccine policy decisions. Since the epidemiology of norovirus changes rapidly, the establishment of systematic surveillance within sentinel sites across the country would enhance the monitoring of circulating norovirus strains and allow us to have a continuous understanding of the current state of norovirus infection within our settings.

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