title: Integrating viral RNA sequence and epidemiological data to define transmission patterns for respiratory syncytial virus
Creators: name: Kombe, IK
Publisher: name: London School of Hygiene & Tropical Medicine
Year: 2020

description: The analyses contained herein focus on making comparisons between model inferences obtained using different scales of pathogen identification, with a particular focus on respiratory syncytial virus (RSV). A significant proportion of lower respiratory tract infections in children has been attributed to infection by RSV and as such, there has been global interest in understanding its transmission characteristics in order to plan for effective control. Mathematical models have often been used to explore potential mechanisms that drive the patterns observed in data collected at different scales. Several models have been used to explore how immunity to RSV is acquired and maintained, vaccination strategies and potential drivers of seasonality. However, most of these models do not make a distinction between the two antigenically and genetically distinct RSV groups (RSV A and RSV B), neither do they consider its ecological environment, in particular, potential interactions between RSV and other viral pathogens. This thesis therefore presents work done aimed at understanding the transmission characteristics of viral respiratory pathogens spreading in a group of households using a dynamic model of transmission The data analysed is cohort data collected between December 2009 and June 2010 from 493 individual distributed across 47 households from a rural coastal community in Kenya. Individuals in the study had nasopharyngeal swab samples collected twice weekly irrespective of symptom status. Infecting viral pathogens were identified using RT-PCR resulting in the identification of 4 main pathogens: RSV, human coronavirus, rhinovirus and adenovirus. RSV and coronavirus were further classified according to genetically distinct subgroups. Some of the RSV samples were sequenced to obtain whole genome sequences (WGS) and further classified into genetic clades/clusters. I first conducted a review of methods to identify the best way to integrate socialtemporal data and WGS genetic data into a single modelling framework for RSV. Given that the social-temporal data and genetic data were available at different sampling densities, I decided to use a model that focused on the data with the highest density. The results in this thesis are thus presented in three main chapters; the first focuses on analysing social-temporal shedding patterns of RSV identified at the group level (i.e. distinguish between RSV A and RSV B); the second incorporates the available genetic data into the model used to analyse the social-temporal data (i.e. separating RSV-A into 5 clusters, and RSV-B into 7 clusters); the third is an analysis of the interaction of two pathogens, RSV and coronavirus, identified at two different scales. One of the main findings in this thesis is that the household setting plays an important role in the spread of RSV, a finding that is made clearer with added detail on pathogen type. In the case of the data analysed here, and the social structuring from which it was collected, RSV clades appeared to mimic household structure as such identification at this level did not drastically change the transmission characteristic observed with identification at the group level. However, the combination of epidemiological and genetic data elucidated transmission chains within the household enabling the identification of the sources of infant RSV infections. For this particular study, it was inferred that the sources of infant RSV infections were both in the same household as the infant and from external sources. Where infant infections occurred in the household, the source of infection was often a child between the ages of 2-13 years. It was inferred that previous infection with one RSV group type reduced susceptibility to re-infection by heterologous group type within the same epidemic. Interactions were also observed between RSV and human coronavirus groups. In particular, previous infection with RSV B was estimated to increase susceptibility to corona OC43 by 81% (95% CrI: 40%, 134%). Detailed data of infection events in individual hosts can provide a wealth of knowledge. The inferences made from this study should be explored at larger spatial and temporal scales to determine the population level impact, and hence public-health significance, of pathogen interactions, whether these interactions are between strains of the same pathogen of between different pathogens. In planning for, and assessing the impact of, an intervention against a particular pathogen, investigators should not ignore the preexisting ecological balance and should make efforts to understand how this will be disrupted by an intervention against one or more pathogens.