Norovirus is a leading cause of viral acute gastroenteritis (AGE), responsible for substantial morbidity and societal costs every year. Further, human noroviruses primarily span two genogroups (GI and GII) and at least 49 genotypes. The GII.4 genotype is unique with regular emergence of pandemic variants every 2-8 years. Despite this burden, questions remain regarding this antigenic diversity and the effects of infection on the gut. The goal of this research is to observe individual and population level effects of norovirus infection in order to make inferences about norovirus infection natural history.
Noroviruses cases and outbreaks are most common in the winter months, but it remains unclear if this pattern extends to all genogroups or across multiple geographic areas. In Aim 1, we compared periodicity, peak timing, and seasonal strength of GI, GII non-4, and GII.4 time series from several countries. We found that GII.4 had an annual 12-month period in nearly all countries as well as higher seasonal strength during seasons with new variant emergence. In contrast, GII non-4 did not always have an annual period and had a higher seasonal strength in non-emergence seasons.
The impact of GII.4’s evolution on immunity within broader genogroup antigenic diversity is not well understood. In Aim 2, we assessed the importance of antigenic diversity and estimated duration of immunity to GI, GII non-4, and GII.4, through a series of Susceptible-Infected-Recovered dynamic models, comparing simulations to observed monthly cases in Japan. A model including waning but without antigenic diversity was best able to explain dynamics, but had long immunity duration estimates.
Norovirus AGE has a profound effect on the gut environment, including the bacteria living there. For Aim 3, we assessed gut microbiome diversity in VA patients, comparing recent norovirus AGE patients to non-norovirus AGE patients or to those without recent AGE. We found that patients with recent AGE had an average of 216.2 species detected compared to 270.2 in those without.
Norovirus seasonality differs by genogroup, but this antigenic diversity alone may not explain long-term norovirus dynamics. Norovirus alone does not appear to independently affect microbiome diversity.
Table of Contents
1 – Background. 1
1.1 – Norovirus morbidity and mortality. 1
1.2 – Basic norovirus virology and clinical presentation. 2
1.3 – International surveillance systems: monitoring norovirus diversity and seasonal dynamics. 5
1.4 – Prospects for prevention: vaccine candidates in clinical trials. 9
1.5 – Norovirus immunity following experimental or natural infection and implications for norovirus models. 10
1.6 – The gut microbiome and the effects of norovirus infection. 13
1.7 – Summary. 15
2 – Study rationale and specific aims. 17
2.1 – Study rationale. 17
2.2 – Aims overview.. 19
3 – Data sources. 21
3.1 – Data set 1: International genotyped cases and outbreak data. 21
3.2 – Data set 2: The SUPERNOVA study and microbiome sequencing. 24
4 – Aim 1: Global patterns and seasonality. 31
5 – Aim 2: Immune structures and norovirus dynamic modeling. 69
6 – Aim 3: Norovirus, secretor status, and the microbiome. 103
7 – Public Health Impact 129
7.1 – Overview.. 129
7.2 – Contribution of each specific aim and future directions. 129
7.2.1 – Aim 1: Global patterns and seasonality. 129
7.2.2 – Aim 2: Immune structures and norovirus dynamic modeling. 132
7.2.3 – Aim 3: Norovirus, secretor status, and the microbiome. 134
7.3 – Summary. 135
8 – References. 137
About this Dissertation
|Committee Chair / Thesis Advisor|
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