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Globally, an estimated 11 to 21 million cases of febrile illness and 117,000 to 161,000 deaths are attributed to typhoid fever each year. Typhoid fever is prevalent mainly in low-resource settings with poor water, and inadequate sanitation and hygiene facilities, with South Asia accounting for a large proportion of the burden. Children bear a substantial burden of the disease. Increasing antimicrobial resistance threatens to limit treatment options for typhoid fever. The WHO, in 2018, recommended the use of a new generation vaccine, typhoid conjugate vaccine (TCV), for the control of typhoid fever in endemic regions; however, data from typhoid-endemic settings were lacking. A randomized controlled trial was therefore conducted in Lalitpur, Nepal, to assess the impact of TCV. In this phase III participant-observer-blind randomized controlled trial, children aged 9 months to under-16 years old, were individually randomized (1:1) to either receive the TCV (Typbar-TCV, Bharat Biotech) or a capsular group A meningococcal conjugate vaccine (MenA) as control, and were followed-up for two years. The protective efficacy of TCV against blood culture-confirmed typhoid fever at two years was 79.0% (95% confidence interval (CI): 61.9%, 88.5%; P The results of this trial represent one of the first findings confirming that TCV is efficacious in a setting of high endemicity. As a direct result of the findings of this trial and with GAVI support, TCV introduction has been implemented in policy in Nepal. TCV is now routinely administered to children at 15 months of age as part of the national immunization schedule. In this thesis, I describe the design, implementation and results of the trial conducted in Nepal.

BACKGROUND Salmonella Typhi is a major cause of fever in children in low- and middle-income countries. A typhoid conjugate vaccine (TCV) that was recently prequalified by the World Health Organization was shown to be efficacious in a human challenge model, but data from efficacy trials in areas where typhoid is endemic are lacking. METHODS In this phase 3, randomized, controlled trial in Lalitpur, Nepal, in which both the participants and observers were unaware of the trial-group assignments, we randomly assigned children who were between 9 months and 16 years of age, in a 1:1 ratio, to receive either a TCV or a capsular group A meningococcal conjugate vaccine (MenA) as a control. The primary outcome was typhoid fever confirmed by blood culture. We present the prespecified analysis of the primary and main secondary outcomes (including an immunogenicity subgroup); the 2-year trial follow-up is ongoing. RESULTS A total of 10,005 participants received the TCV and 10,014 received the MenA vaccine. Blood culture–confirmed typhoid fever occurred in 7 participants who received TCV (79 cases per 100,000 person-years) and in 38 who received MenA vaccine (428 cases per 100,000 person-years) (vaccine efficacy, 81.6%; 95% confidence interval, 58.8 to 91.8; P CONCLUSIONS A single dose of TCV was immunogenic and effective in reducing S. Typhi bacteremia in children 9 months to 16 years of age. (Funded by the Bill and Melinda Gates Foundation; Current Controlled Trials number, ISRCTN43385161. opens in new tab.)

Introduction Invasive infections caused by Salmonella enterica serovar Typhi and Paratyphi A are estimated to account for 12–27 million febrile illness episodes worldwide annually. Determining the true burden of typhoidal Salmonellae infections is hindered by lack of population-based studies and adequate laboratory diagnostics.\ud \ud The Strategic Typhoid alliance across Africa and Asia study takes a systematic approach to measuring the age-stratified burden of clinical and subclinical disease caused by typhoidal Salmonellae infections at three high-incidence urban sites in Africa and Asia. We aim to explore the natural history of Salmonella transmission in endemic settings, addressing key uncertainties relating to the epidemiology of enteric fever identified through mathematical models, and enabling optimisation of vaccine strategies.\ud \ud Methods/design Using census-defined denominator populations of ≥100 000 individuals at sites in Malawi, Bangladesh and Nepal, the primary outcome is to characterise the burden of enteric fever in these populations over a 24-month period. During passive surveillance, clinical and household data, and laboratory samples will be collected from febrile individuals. In parallel, healthcare utilisation and water, sanitation and hygiene surveys will be performed to characterise healthcare-seeking behaviour and assess potential routes of transmission. The rates of both undiagnosed and subclinical exposure to typhoidal Salmonellae (seroincidence), identification of chronic carriage and population seroprevalence of typhoid infection will be assessed through age-stratified serosurveys performed at each site. Secondary attack rates will be estimated among household contacts of acute enteric fever cases and possible chronic carriers.\ud \ud Ethics and dissemination This protocol has been ethically approved by the Oxford Tropical Research Ethics Committee, the icddr,b Institutional Review Board, the Malawian National Health Sciences Research Committee and College of Medicine Research Ethics Committee and Nepal Health Research Council. The study is being conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Informed consent was obtained before study enrolment. Results will be submitted to international peer-reviewed journals and presented at international conferences.\ud \ud Trial registration number ISRCTN 12131979.\ud \ud Ethics references Oxford (Oxford Tropical Research Ethics Committee 39-15).\ud \ud Bangladesh (icddr,b Institutional Review Board PR-15119).\ud \ud Malawi (National Health Sciences Research Committee 15/5/1599).\ud \ud Nepal (Nepal Health Research Council 306/2015).

Introduction Invasive infections caused by Salmonella enterica serovar Typhi and Paratyphi A are estimated to account for 12–27 million febrile illness episodes worldwide annually. Determining the true burden of typhoidal Salmonellae infections is hindered by lack of population-based studies and adequate laboratory diagnostics. The Strategic Typhoid alliance across Africa and Asia study takes a systematic approach to measuring the age-stratified burden of clinical and subclinical disease caused by typhoidal Salmonellae infections at three high-incidence urban sites in Africa and Asia. We aim to explore the natural history of Salmonella transmission in endemic settings, addressing key uncertainties relating to the epidemiology of enteric fever identified through mathematical models, and enabling optimisation of vaccine strategies. Methods/design Using census-defined denominator populations of ≥100 000 individuals at sites in Malawi, Bangladesh and Nepal, the primary outcome is to characterise the burden of enteric fever in these populations over a 24-month period. During passive surveillance, clinical and household data, and laboratory samples will be collected from febrile individuals. In parallel, healthcare utilisation and water, sanitation and hygiene surveys will be performed to characterise healthcare-seeking behaviour and assess potential routes of transmission. The rates of both undiagnosed and subclinical exposure to typhoidal Salmonellae (seroincidence), identification of chronic carriage and population seroprevalence of typhoid infection will be assessed through age-stratified serosurveys performed at each site. Secondary attack rates will be estimated among household contacts of acute enteric fever cases and possible chronic carriers. Ethics and dissemination This protocol has been ethically approved by the Oxford Tropical Research Ethics Committee, the icddr,b Institutional Review Board, the Malawian National Health Sciences Research Committee and College of Medicine Research Ethics Committee and Nepal Health Research Council. The study is being conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Informed consent was obtained before study enrolment. Results will be submitted to international peer-reviewed journals and presented at international conferences.

NDM-producing Klebsiella pneumoniae strains represent major clinical and infection control challenges, particularly in resource-limited settings with high rates of antimicrobial resistance. Determining whether transmission occurs at a gene, plasmid, or bacterial strain level and within hospital and/or the community has implications for monitoring and controlling spread. Whole-genome sequencing (WGS) is the highest-resolution typing method available for transmission epidemiology. We sequenced carbapenem-resistant K. pneumoniae isolates from 26 individuals involved in several infection case clusters in a Nepali neonatal unit and 68 other clinical Gram-negative isolates from a similar time frame, using Illumina and PacBio technologies. Within-outbreak chromosomal and closed-plasmid structures were generated and used as data set-specific references. Three temporally separated case clusters were caused by a single NDM K. pneumoniae strain with a conserved set of four plasmids, one being a 304,526-bp plasmid carrying bla(NDM-1). The plasmids contained a large number of antimicrobial/heavy metal resistance and plasmid maintenance genes, which may have explained their persistence. No obvious environmental/human reservoir was found. There was no evidence of transmission of outbreak plasmids to other Gram-negative clinical isolates, although bla(NDM) variants were present in other isolates in different genetic contexts. WGS can effectively define complex antimicrobial resistance epidemiology. Wider sampling frames are required to contextualize outbreaks. Infection control may be effective in terminating outbreaks caused by particular strains, even in areas with widespread resistance, although this study could not demonstrate evidence supporting specific interventions. Larger, detailed studies are needed to characterize resistance genes, vectors, and host strains involved in disease, to enable effective intervention.

Nepal is located in one of the most severe earthquake prone areas of the world, lying between collisions of Indian to the Eurasian plate, moving continuously, resulting in frequent devastating earthquakes within this region. Moreover, different authors refer mention that the accumulated slip deficit (central seismic gap) is likely to produce large earthquakes in the future. Also, the analysis of the available information of previous earthquakes indicates the potential damage that can occurs in unreinforced traditional masonry structures in future earthquakes. Most of the Nepalese pagoda temples were erected following very simple rules and construction details to accomplish with seismic resistance requirement, or even without any consideration for seismic resistance, during the period of Malla dynasty (1200-1768). Presently, conservation and restoration of ancient monuments are one of the major concerns in order to preserve our built heritage, transferring it to the future generations. The present paper is devoted to outline particular structural fragility characteristics in the historic Nepalese pagoda temples which affect their seismic performance. Moreover, based on the parametric analysis identified structural weaknesses/fragilities of pagoda topology, the associated traditional building technology and constructional details.