Epidemiological, clinical, and public health response characteristics of a large outbreak of diphtheria among the Rohingya population in Cox's Bazar, Bangladesh, 2017 to 2019: A retrospective study.

BACKGROUND: Unrest in Myanmar in August 2017 resulted in the movement of over 700,000 Rohingya refugees to overcrowded camps in Cox's Bazar, Bangladesh. A large outbreak of diphtheria subsequently began in this population. METHODS AND FINDINGS: Data were collected during mass vaccination campaigns (MVCs), contact tracing activities, and from 9 Diphtheria Treatment Centers (DTCs) operated by national and international organizations. These data were used to describe the epidemiological and clinical features and the control measures to prevent transmission, during the first 2 years of the outbreak. Between November 10, 2017 and November 9, 2019, 7,064 cases were reported: 285 (4.0%) laboratory-confirmed, 3,610 (51.1%) probable, and 3,169 (44.9%) suspected cases. The crude attack rate was 51.5 cases per 10,000 person-years, and epidemic doubling time was 4.4 days (95% confidence interval [CI] 4.2-4.7) during the exponential growth phase. The median age was 10 years (range 0-85), and 3,126 (44.3%) were male. The typical symptoms were sore throat (93.5%), fever (86.0%), pseudomembrane (34.7%), and gross cervical lymphadenopathy (GCL; 30.6%). Diphtheria antitoxin (DAT) was administered to 1,062 (89.0%) out of 1,193 eligible patients, with adverse reactions following among 229 (21.6%). There were 45 deaths (case fatality ratio [CFR] 0.6%). Household contacts for 5,702 (80.7%) of 7,064 cases were successfully traced. A total of 41,452 contacts were identified, of whom 40,364 (97.4%) consented to begin chemoprophylaxis; adherence was 55.0% (N = 22,218) at 3-day follow-up. Unvaccinated household contacts were vaccinated with 3 doses (with 4-week interval), while a booster dose was administered if the primary vaccination schedule had been completed. The proportion of contacts vaccinated was 64.7% overall. Three MVC rounds were conducted, with administrative coverage varying between 88.5% and 110.4%. Pentavalent vaccine was administered to those aged 6 weeks to 6 years, while tetanus and diphtheria (Td) vaccine was administered to those aged 7 years and older. Lack of adequate diagnostic capacity to confirm cases was the main limitation, with a majority of cases unconfirmed and the proportion of true diphtheria cases unknown. CONCLUSIONS: To our knowledge, this is the largest reported diphtheria outbreak in refugee settings. We observed that high population density, poor living conditions, and fast growth rate were associated with explosive expansion of the outbreak during the initial exponential growth phase. Three rounds of mass vaccinations targeting those aged 6 weeks to 14 years were associated with only modestly reduced transmission, and additional public health measures were necessary to end the outbreak. This outbreak has a long-lasting tail, with Rt oscillating at around 1 for an extended period. An adequate global DAT stockpile needs to be maintained. All populations must have access to health services and routine vaccination, and this access must be maintained during humanitarian crises

Understanding factors contributing to outbreaks of diphtheria and implications for vaccination policy in Vietnam

Background: Diphtheria is a severe, acute infectious disease caused by toxin-producing Corynebacterium species, mainly C. diphtheriae. The diphtheria toxoid vaccine successfully reduced global diphtheria incidence. However, diphtheria remains endemic in many countries. Currently, the World Health Organization recommends three primary doses during infancy and three booster doses until the adolescent period; however, many low- and middle-income countries have not introduced all booster doses. Vietnam experienced several outbreaks of diphtheria in the last decade. This thesis aims to elucidate the mechanism of diphtheria outbreaks and appropriate vaccination strategies in Vietnam. Methods: This thesis consists of five components: first, the diphtheria outbreak in Vietnam is described with the available data (Chapter 3); second, a systematic review was conducted with age-specific seroprevalence data from 15 countries to estimate the optimal booster dose interval (Chapter 4); third, a cross-sectional and cohort study was conducted in a well-vaccinated community in Vietnam with no reported cases to assess population immunity and the waning of vaccine-derived immunity (Chapter 5); fourth, another cross-sectional carriage prevalence and seroprevalence survey was conducted in an epidemic-prone area (Chapter 6); and finally, a validation study for enzyme-linked immunosorbent assay (ELISA) was conducted via parallel comparison of ELISA and neutralising test measurements (Chapter 7). Results: In Chapter 3, we found that 73% of diphtheria cases reported in Central Vietnam between 2015 and 2018 were in school-age children. While this finding indicated that there is an immunity gap in school aged children, Chapter 5 confirmed the low seroprevalence in the age group of 6-15 years (7%). In Chapter 3, we identified two fatal cases (7 and 13 years old) who had received three or more doses of the diphtheria-tetanus-pertussis (DTP) vaccine, indicating that vaccine-derived immunity waned or vaccine was not effective. The findings in Chapter 5 suggested that the duration of protection of vaccine-derived immunity was 4.3 years after four doses of DTP, which was much shorter than the commonly perceive 10 years. In contrast, the systematic review in Chapter 4 suggested that the interval between the fourth and fifth doses could be up to 10.3 years. In Chapter 3, strains of the same genetic type were shared by all epidemiologically linked cases; however, it was often impossible to track the transmission chains. The findings indicated that local transmission of C. diphtheriae was attributed to multiple strains with asymptomatic carriers. In Chapter 6, we identified that 1.4% of the population were asymptomatic carriers; the highest carriage prevalence was observed in individuals aged 1–5 years (4.5%), which was much higher than the recently reported carriage prevalence in Europe. Furthermore, 67% of carriers harboured a non-toxigenic strain. Seroprevalence identified in epidemic and non-epidemic settings varied. Seroprevalence among 1–5-year-old in the epidemic-prone area was low due to the limited vaccination history and low seroconversion rate, probably derived from the children’s poor nutrition status. These children (asymptomatic carriers) might maintain transmission of C. diphtheriae in their communities. When the bacteria reaches susceptible hosts, likely school-age children, they are detected as symptomatic cases. This is likely the mechanism of the current diphtheria outbreak in Vietnam. Chapter 7 confirmed that the ELISA method used for the study showed appropriate protection levels in the population when a cut-off value of 0.1 IU/ml was used. Conclusions: The most susceptible age group in Vietnam was school-age children due to the waning of vaccine-derived immunity. In addition, the recent diphtheria epidemic in Vietnam might be attributed to the low vaccine coverage due to limited healthcare access and the low seroconversion rate due to child malnutrition. Based on these findings, it was concluded that improved DTP3 coverage and a school-entry booster dose are essential to control the transmission of C. diphtheriae in Vietnam. In the long term, multiple booster doses will be required to reduce the susceptible population

Investigating vaccine preventable diseases and the COVID-19 pandemic

Vaccination is widely regarded to be one of the greatest public health achievements of the 20th century. While 2020 was the Year of COVID-19, 2021 is being regarded as the Year of the Vaccine, with vaccinations in the public spotlight, serving as a cornerstone of global pandemic management. This thesis contains work undertaken for the Master of Philosophy in Applied Epidemiology (MAE) while on placement at the National Centre for Immunisation Research and Surveillance (NCIRS) in 2020 and 2021. The MAE core requirements presented in this thesis cover four pillars of epidemiology: investigation of an acute public health problem or threat (outbreak investigation), public health data analysis, epidemiological study, and the establishment or evaluation of a surveillance system. The outbreak investigation competency is fulfilled by my participation in the COVID-19 Schools Study, which ran across both 2020 and 2021. This was an active surveillance project carried out in all NSW schools and early childhood education and care (ECEC) services to quantify and characterise the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in these settings. I present some of the findings in Chapter 2, showing that while spread in educational settings was limited, a small number of outbreaks did occur and transmission within these outbreaks may have been facilitated by delayed outbreak recognition, very close or prolonged contact with a case, and specific high-risk transmission events. The risk of school and ECEC outbreaks may be mitigated by stay-at-home-if-sick messaging, school-based mitigation measures aimed at improving infection control, and restricting high-risk activities to times with low community incidence of disease. In Chapter 3, I present a detailed analysis of national measles notifications, hospitalisations, and deaths from 2012 to 2019 which fulfilled the competency for conducting an epidemiological study. Australia was verified as having eliminated measles in 2014, but incidence almost doubled in the 2012 to 2019 period compared with 2000 to 2011. While the data presented in Chapter 3 support Australia's continuing elimination status, global progress towards elimination has stalled, and a global resurgence is expected as a result of increased immunity gaps due to the COVID-19 pandemic. Australia will need to remain vigilant, maintaining robust surveillance and high coverage of measles vaccination. The MAE requirement of carrying out a public health data analysis project is demonstrated in Chapter 4, in which I report my analysis of two decades of national diphtheria notification, hospitalisation, and mortality data (1999-2019). Although still exceedingly rare, Australia has seen an increase in notified cases of diphtheria in the last decade, likely driven by a combination of a series of case definition changes occurring over the period and improvements in case ascertainment. It remains important to maintain high levels of vaccination coverage. In particular, pre-travel booster vaccination should continue to be encouraged. A surveillance system evaluation project is presented in Chapter 5, in which I evaluated the COVID-19 and Paediatric Multisystem Inflammatory Syndrome-Temporally Associated with SARS-CoV-2 (PIMS-TS) components of the Paediatric Active Enhanced Disease Surveillance (PAEDS) system. The evaluation followed the Centers for Disease Control and Prevention's Updated Guidelines for the Evaluation of Public Health Surveillance Systems using a mixed methods approach, and provided recommendations for ensuring PAEDS can continue to continue to support Australia's national surveillance goals into the future. Chapter 6 outlines teaching activities undertaken during my MAE and lessons learnt through such activities. The work presented in this thesis represents my MAE activities at NCIRS, and a contribution to public health in Australia