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.