Thesis Outline: Chapter 1: :Introduction and Research Question: I describe the evidence base on the transmission of respiratory pathogens within households using SARS-CoV2 and MDR TB as exemplars. I discuss the similarities and differences between the two pathogens, and include exposure, infection, disease, and treatment for both pathogens whilst summarising current gaps in knowledge and differences in practice. The discussion covers how these knowledge gaps translate to problems in clinical care and management, and how respiratory pathogens spread in the household setting even in the context of high community transmission. Research Question: What drives the increased risk of infection with respiratory pathogens in households and close contacts? • What is the risk of progression to active SARS-CoV-2 in exposed household contacts? • What is the risk of progression to active MDR TB in exposed household contacts? • Are there identifiable predictors of increased or decreased risk to guide future targeting of surveillance and preventive interventions? Chapter 2: Prospective cohort study in MDR TB exposed household contacts: I completed a prospective cohort study in MDR TB exposed household contacts in Lima, Peru. I followed up contacts for 2 years from infectious MDR TB index case diagnosis. The primary objectives were to calculate cumulative incidence (CI) and temporal incidence of TB in MDR TB contacts, with a denominator of person-time-at-risk. The hypothesis was that almost all cumulative TB will occur within the first year of follow up and there will be limited benefit to follow-up beyond one year. The sample size required was 1500 MDR exposed contacts expecting 5% of household contacts (HHC) developing cumulative (incident and co-prevalent) TB. TB incidence in HHC in published data ranges between 3.3 – 7.8% in high prevalence settings, expecting a margin of error of 3.5-6.5%. Even if 30% were lost to follow-up, a sample size of 1050 would be expected to generate between 36 and 68 cumulative secondary cases. Cox proportional hazards were used to model incidence rates over time. A survival analysis will be used to identify covariates associated with changes in the hazards of developing TB. I describe the cumulative incidence of MDR TB over 2 years according to time of MDR TB diagnosis and control for possible confounding variables such as crowding, ventilation, and smear status. I investigate confounding caused by increased household exposure and transmission during lockdown and explore whether community influence was less than normal on transmission. Chapter 3: Transmission of SARS-CoV-2 in a UK Ultra-Orthodox Jewish population: I implemented a community led cross sectional serosurvey of SARS-CoV-2 prevalence in a religious minority with perceived higher rates of SARS-CoV-2 early in 2020. I used detailed data collection on households, their social interactions and serological testing of seasonal CoV and SARS-CoV-2 to describe the seroprevalence of SARS-CoV-2 and the proportion of the population reporting a COVID-19 like illness. Households were randomly selected from a community wide list held by community partners. The sample size assumed a minimum seropositivity of 10%, with a 2% absolute precision and design effect of 2 which is 1730 individuals, the average household size is 6, therefore we aimed for 300 households. The outcomes reported on include seroprevalence by age and gender, and a random effects logistic regression model of factors associated with seroprevalence. I explored household level risk factors for transmission and higher secondary attack rates in households. Chapter 4: Measuring markers of immune and endothelial activation in previously exposed SARSCoV-2 community samples with a very high seroprevalence of SARS-CoV-2: We aimed to understand if markers of immune and endothelial activation vary between symptomatic and asymptomatic SARS-CoV-2 seropositive and seronegative individuals from a community with 64.3% seroprevalence of SARS-CoV-2. Recent published and unpublished data identified markers of interest in severe COVID-19 disease as IL-6, IL-10, and IP-10. Using serology samples from the Ultra-Orthodox household survey we described cytokine profiles in>900 samples comparing profiles in symptomatic, asymptomatic, seropositive, and seronegative groups and interrogated the data between those with symptoms in wave 1 and wave 2 of the UK pandemic. We compared children’s cytokine profiles from groups of SARSCoV-2 negative, positive symptomatic and positive asymptomatic. Additionally, we explored the relationship between survey data on illness severity and mortality with cytokine profile. Chapter 5: Community transmission of emerging SARS-CoV-2 variant transmissibility through active contact tracing: Using a cross-sectional seroprevalence study we described the difference in secondary infection attack rates between households with PCR confirmed wild type (WT) SARS-CoV-2 and households with the Alpha variant of concern (VOC) SARS-CoV-2. All individuals diagnosed with PCR confirmed SARS-CoV-2 at two London Hospitals between November 2020 and January 2021 and their household contacts were eligible. The outcome measured was the prevalence ratio for SARS-CoV-2 seropositivity between household contacts exposed to the alpha VOC SARS-CoV-2 and WT SARS-CoV-2. The sample size was 350 households with a ratio of 4:1 VOC: WT, 3 people per household assuming the seroprevalence in WT households is 0.3 gives a 90% power to detect an increase in seroprevalence to 0.42. Chapter 6: Discussion and Conclusion: I review the results from all the chapters within this thesis. Reflecting on the similarities and differences in themes, scientific findings, difficulties, and outcomes. I explore the key findings in each chapter, the similarities, differences, and difficulties. I review the methods used in this thesis, in particular the household transmission model and progressive models for developing research in unison with communities. I explore the strengths and weaknesses of transmission studies within households and the importance of the socioeconomic context of this research. I critically appraise the areas of weakness within this research, discuss policy impact and future work.