Norovirus and rotavirus susceptibility : studies from a Nicaraguan birth cohort

Sammanfattning: Norovirus and rotavirus are major causes of pediatric acute gastroenteritis (AGE). It is estimated that norovirus is responsible for ~20% of all diarrheal diseases in children worldwide and causes approximately 200,000 deaths each year, mostly in young children and the elderly. Despite this vast disease burden, there is no licensed vaccine available. The introduction of universal infant rotavirus vaccination has led to marked reductions in diarrhea incidence and diarrhea-associated mortality in children. However, rotavirus continues to cause a high disease burden, particularly in low- and middle-income countries (LMIC), associated with an estimated 128,500 deaths in young children. Susceptibility to both norovirus and rotavirus AGE is strongly associated with the secretor phenotype (expression of specific glycans in mucosa and secretions). This, along with the Lewis phenotype and ABO group form the differential expression of histo-blood group antigens (HBGAs) in the mucosa. These HBGAs can act as putative receptors or attachment factors facilitating infection of these viruses.   The overall aim of this thesis was to address outstanding questions regarding susceptibility and immunity to norovirus and rotavirus infections in children. These questions are of relevance for understanding the effects of a future norovirus vaccine and factors influencing vaccine protection. Our questions were addressed by investigating norovirus and rotavirus disease burden, molecular epidemiology, and the role of HBGAs in susceptibility in children enrolled in a rotavirus-vaccinated birth cohort in Nicaragua. We further estimated the breadth and duration of immune response and protection after the first norovirus AGE episode.   Our results showed that the incidence of rotavirus and norovirus was 9.3 and 21.9 per 100 child-years, respectively. Several different norovirus genotypes were observed (n=13), the most common being GII.4 (42%), GI.3 (18%), GII.12 (9%) and GII.17 (9%). Genotype GII.4 was not only the most common genotype but also infected children earlier in life and caused more severe AGE episodes compared to other genotypes. In contrast, the distribution of rotavirus genotypes was limited and dominated by animal-derived strains and the absence of the wild-type G1P[8] genotype, which is the component of the Rotarix vaccine used in Nicaragua. Secretor children had the highest risk of norovirus AGE, with the predominant and clinically more severe GII.4 genotype only observed in secretors. Secretor children also had the highest risk for rotavirus AGE after vaccination. This is of particular interest since previous studies have observed that non-secretors have a less immune response after vaccination of the live oral rotavirus vaccines. Hence, the mediation of protection against rotavirus AGE for these children is likely due to genetic resistance to wild-type infections and not by vaccine-induced immune protection.  Using surrogate neutralization assays, we observed that the antibody-mediated immune response after the first AGE episode of norovirus GII.4 persisted for about 19 months, thus suggesting a relatively long-term protection. We further found that the immune response against GII.4 was genotype-specific in a significant proportion (60%) of children. The multitypic response exhibited in some children could be due to asymptomatic infections with two or more genotypes over the studied period. Using statistical models, we found that one episode of norovirus GI and norovirus GII conferred approximately 33% and 80% reduced hazard against future genogroup-specific episodes in the first 3 years of life, respectively.  In summary, the results presented in this thesis suggest that a pediatric norovirus vaccine including norovirus GII.4, and given early in life, would significantly reduce the high burden of diarrheal disease in young children, particularly for secretors.