Epidemiological conditions to support dengue vaccine introduction in Asia using data from traditional and novel sources

Dengue, an Aedes mosquito-borne flavivirus, is the most common vector-borne viral infection worldwide. Infections result in around 100 million (95% credible interval: 67 - 136 million) clinical episodes and 10.5 million (95% uncertainty intervals: 4.1 – 22.7 million) hospitalizations annually, mostly within the Asia Pacific region. There are four closely related viral serotypes, all of which cause severe disease. First infections are often mild/asymptomatic but subsequent infections with heterologous serotypes more frequently result in severe episodes and hospitalisations. National surveillance systems are not designed to estimate the full disease burden and the value of preventive measures is therefore poorly defined. In 2014 the first dengue vaccine, CYD-TDV, was licensed having demonstrated significant efficacy against all four serotypes in study participants aged 2 – 16 years. Subsequent analyses after 5 years’ follow-up revealed a more complex vaccine profile with superior protection in individuals seropositive for dengue, but an elevated risk of hospitalized dengue in seronegative vaccine recipients. Population-level benefit-risk is therefore dependent on epidemiological criteria and WHO recommends its use only under certain conditions or following confirmation of individual serostatus. This thesis describes a body of epidemiological research designed to improve understanding of these conditions. Studies were intended to fill important knowledge gaps identified following discussions with local vaccine policymakers and experts. My role, working within a multidisciplinary team, was to understand identified gaps and develop and implement a corresponding research agenda to fill them. I designed and contributed to protocols, provided oversight to their implementation working with local research teams, analysed and interpreted the resulting data and drafted the manuscripts included in this thesis which were published between 2016 and 2020. These studies used different methods: we analysed existing data sources to improve estimates of symptomatic dengue disease burden; measured age-stratified dengue seroprevalence in children in India and Indonesia; estimated force-of-infection (the annual rate at which seronegative individuals acquire infection) as an indicator of endemicity in seven Asian countries; and conducted a prospective surveillance study to plan future dengue vaccine effectiveness research. After refining these methods for dengue, we extended them to Japanese encephalitis, another mosquito-borne flavivirus. Using data derived from active case ascertainment from the placebo arm of a paediatric clinical trial, wherein parents were contacted weekly and reminded to report to study sites in case of febrile illness in their children, we identified a crude dengue attack rate of 4.6%/year. Only 29% of these events were clinically diagnosed as dengue by study investigators, indicating that most symptomatic disease fails to satisfy existing case definitions. This active case ascertainment captured a greater proportion of symptomatic dengue than national passive surveillance systems. The ratio between these two rates (“expansion factor”) can be used to estimate the full disease burden from passive surveillance reports and we calculated factors ranging from 0.5 – 31.7, depending on country and case definition. Large seroprevalence surveys in India and Indonesia confirmed very high rates of paediatric infection: by the age of 10 years, 73% of children in India and 79% in Indonesia had been infected at least once. We also identified serological evidence for circulation of multiple dengue serotypes in both countries. We used these and other serological data to estimate force-of-infection which varied widely between countries from 1.7% (Singapore) to 24.1% (the Philippines), with significant heterogeneity within countries. The force of infection of Japanese encephalitis was much lower (varying from 0.8% in Malaysia to 5.2% in Vietnam) but this demonstration of transmission in urban areas was an important finding in areas where Japanese encephalitis vaccination is not routine. After conducting a hospital-based surveillance study to plan future dengue vaccine effectiveness studies in Malaysia, we concluded that test-negative case control studies are not feasible due to small numbers of test-negative controls; and that case control studies for dengue vaccines could be significantly biased by underlying differences between cases and controls. In summary, these studies demonstrated intense but heterogeneous dengue transmission across multiple Asia-pacific countries. These levels of transmission are broadly compatible with recommendations for dengue vaccine introduction at the national level but, due to heterogeneity in endemicity, more local approaches would likely be needed before implementation of mass vaccination programmes

Methods to account for measured and unmeasured confounders in influenza relative vaccine effectiveness studies:A brief review of the literature

Observational seasonal influenza relative vaccine effectiveness (rVE) studies employ a variety of statistical methods to account for confounding and biases. To better understand the range of methods employed and implications for policy, we conducted a brief literature review. Across 37 included rVE studies, 10 different types of statistical methods were identified, and only eight studies reported methods to detect residual confounding, highlighting the heterogeneous state of the literature. To improve the comparability and credibility of future rVE research, researchers should clearly explain methods and design choices and implement methods to detect and quantify residual confounding

Looking Back on 50 Years of Literature to Understand the Potential Impact of Influenza on Extrapulmonary Medical Outcomes

We conducted a scoping review of the epidemiological literature from the past 50 years to document the contribution of influenza virus infection to extrapulmonary clinical outcomes. We identified 99 publications reporting 243 associations using many study designs, exposure and outcome definitions, and methods. Laboratory confirmation of influenza was used in only 28 (12%) estimates, mostly in case-control and self-controlled case series study designs. We identified 50 individual clinical conditions associated with influenza. The most numerous estimates were of cardiocirculatory diseases, neurological/neuromuscular diseases, and fetal/newborn disorders, with myocardial infarction the most common individual outcome. Due to heterogeneity, we could not generate summary estimates of effect size, but of 130 relative effect estimates, 105 (81%) indicated an elevated risk of extrapulmonary outcome with influenza exposure. The literature is indicative of systemic complications of influenza virus infection, the requirement for more effective influenza control, and a need for robust confirmatory studies

Influenza vaccine in chronic obstructive pulmonary disease among elderly male veterans

BACKGROUND: Prior studies have established those elderly patients with chronic obstructive pulmonary disease (COPD) are at elevated risk for developing influenza-associated complications such as hospitalization, intensive-care admission, and death. This study sought to determine whether influenza vaccination could improve survival among elderly patients with COPD. MATERIALS/METHODS: This study included Veterans (age ≥ 65 years) diagnosed with COPD that received care at the United States Veterans Health Administration (VHA) during four influenza seasons, from 2012–2013 to 2015–2016. We linked VHA electronic medical records and Medicare administrative files to Centers for Disease Control and Prevention National Death Index cause of death records as well as influenza surveillance data. A multivariable time-dependent Cox proportional hazards model was used to compare rates of mortality of recipients of influenza vaccination to those who did not have records of influenza vaccination. We estimated hazard ratios (HRs) adjusted for age, gender, race, socioeconomic status, comorbidities, and healthcare utilization. RESULTS: Over a span of four influenza seasons, we included 1,856,970 person-seasons of observation where 1,199,275 (65%) had a record of influenza vaccination and 657,695 (35%) did not have a record of influenza vaccination. After adjusting for comorbidities, demographic and socioeconomic characteristics, influenza vaccination was associated with reduced risk of death during the most severe periods of influenza seasons: 75% all-cause (HR = 0.25; 95% CI: 0.24–0.26), 76% respiratory causes (HR = 0.24; 95% CI: 0.21–0.26), and 82% pneumonia/influenza cause (HR = 0.18; 95% CI: 0.13–0.26). A significant part of the effect could be attributed to “healthy vaccinee” bias as reduced risk of mortality was also found during the periods when there was no influenza activity and before patients received vaccination: 30% all-cause (HR = 0.70; 95% CI: 0.65–0.75), 32% respiratory causes (HR = 0.68; 95% CI: 0.60–0.78), and 51% pneumonia/influenza cause (HR = 0.49; 95% CI: 0.31–0.78). However, as a falsification study, we found that influenza vaccination had no impact on hospitalization due to urinary tract infection (HR = 0.97; 95% CI: 0.80–1.18). CONCLUSIONS: Among elderly patients with COPD, influenza vaccination was associated with reduced risk for all-cause and cause-specific mortality

Effectiveness of a single-dose mass dengue vaccination in Cebu, Philippines: A case-control study.

BACKGROUND: Dengue fever is an important public health problem in the Philippines. In April 2016, the Department of Health launched a three-dose school based dengue vaccination program of nine- to fourteen-year-old children in three regions with the highest number of dengue cases using CYD-TDV (Dengvaxia, Sanofi Pasteur). In July 2017, a community-based dengue vaccination program was implemented in Cebu province. The program was discontinued in December 2017 amidst public controversy, after the first dose had been administered. We assessed the effectiveness of a single dose of CYD-TDV against hospitalized virologically confirmed dengue (VCD). METHODS: We conducted a case-control study in Cebu province following the dengue mass vaccination. Children who were nine to fourteen years of age during the mass vaccination and subsequently admitted to any of four participating public hospitals with suspected dengue were enrolled in the study as cases. Blood for RT-PCR and clinical and socio-demographic information were obtained. To estimate the level of vaccine protection, vaccination status was compared between children with hospitalized virologically confirmed dengue and controls of the same six-year age-group as the cases, matched on sex, neighborhood and time of occurrence of cases. FINDINGS: We enrolled 490 cases and 980 controls. Receipt of one dose of CYD-TDV was associated with 26% (95 % CI, -2 to 47%; p = 0 0675) overall protection against hospitalized virologically confirmed dengue and 51% (95 % CI, 23 to 68; p = 0 0016) protection against dengue with warning signs. INTERPRETATION: A single dose of CYD-TDV given to nine to fourteen-year-old children through a community-based mass vaccination program conferred protection against dengue with warning signs and severe dengue but we were unable to conclude on protection against milder illness

The Beat Generation

Program for the tenth annual RISD Cabaret held in the Waterman Building, top floor coinciding with the fiftieth anniversary of the year when Allen Ginsburg, William Burroughs and Jack Kerouac first met and started a movement which changed the face of postwar American and influenced the 1960s as well as the subculture of the \u2770s and \u2780s. Program, poster and tickets designed by Antoinette le Vaillant.https://digitalcommons.risd.edu/liberalarts_cabaret_programs/1012/thumbnail.jp

Associations between malaria and local and global climate variability in five regions in Papua New Guinea

Background: Malaria is a significant public health issue in Papua New Guinea (PNG) as the burden is among the highest in Asia and the Pacific region. Though PNG’s vulnerability to climate change and sensitivity of malaria mosquitoes to weather are well-documented, there are few in-depth epidemiological studies conducted on the potential impacts of climate on malaria incidence in the country. Methods: This study explored what and how local weather and global climate variability impact on malaria incidence in five regions of PNG. Time series methods were applied to evaluate the associations of malaria incidence with weather and climate factors, respectively. Local weather factors including precipitation and temperature and global climate phenomena such as El Nino-Southern Oscillation (ENSO), the ENSO Modoki, the Southern Annular Mode, and the Indian Ocean Dipole were considered in analyses. Results: The results showed that malaria incidence was associated with local weather factors in most regions but at the different lag times and in directions. Meanwhile, there were trends in associations with global climate factors by geographical locations of study sites. Conclusions: Overall heterogeneous associations suggest the importance of location-specific approaches in PNG not only for further investigations but also public health interventions in repose to the potential impacts arising from climate change

Geographic variation in dengue seroprevalence and force of infection in the urban paediatric population of Indonesia

Understanding the heterogeneous nature of dengue transmission is important for prioritizing and guiding the implementation of prevention strategies. However, passive surveillance data in endemic countries are rarely adequately informative. We analyzed data from a cluster-sample, cross-sectional seroprevalence study in 1-18 year-olds to investigate geographic differences in dengue seroprevalence and force of infection in Indonesia. We used catalytic models to estimate the force of infection in each of the 30 randomly selected sub-districts. Based on these estimates, we determined the proportion of sub-districts expected to reach seroprevalence levels of 50%, 70% and 90% by year of age. We used population averaged generalized estimating equation models to investigate individual- and cluster-level determinants of dengue seropositivity. Dengue force of infection varied substantially across Indonesia, ranging from 4.3% to 30.0% between sub-districts. By age nine, 60% of sub-districts are expected to have a seroprevalence ≥70%, rising to 83% by age 11. Higher odds of seropositivity were associated with higher population density (OR = 1.54 per 10-fold rise in population density, 95% CI: 1.03-2.32) and with City (relative to Regency) administrative status (OR = 1.92, 95% CI: 1.32-2.79). Our findings highlight the substantial variation in dengue endemicity within Indonesia and the importance of understanding spatial heterogeneity in dengue transmission intensity for optimal dengue prevention strategies including future implementation of dengue vaccination programmes

Changing sero-epidemiology of hepatitis A in Asia Pacific countries: A systematic review

Objectives: Hepatitis A is a viral liver disease whose prevalence is associated with low socio-economic and hygiene levels due to its faecal–oral transmission. Severity increases with age, and immunity is life-long. Decreased endemicity could result in increased age and severity of cases. A literature review was conducted to describe changes in age-stratified hepatitis A seroprevalence in Asia Pacific countries from 1980 to 2016, and to identify gaps in the literature. The PRISMA guidelines were followed. Methods: The PubMed database was searched for studies on age-specific hepatitis A seroprevalence in 17 Asia Pacific countries. All studies published in the English language, reporting human hepatitis A seroprevalence levels in any age group, were included. Results: Seventy-three publications from 11 countries were identified. A trend of increasing age at first exposure over time was observed, particularly in developed countries such as Japan, Taiwan, Thailand, and Korea, suggesting a transition in terms of endemicity. Conclusions: Extensive gaps in the literature were identified between countries and year of publication, indicating the need for further research. Decreasing hepatitis A exposure and thus immunity conferred during childhood, may render older populations susceptible to infection. The public health and economic value of vaccination against hepatitis A should be assessed within this changing epidemiological context. Keywords: Hepatitis A, Seroprevalence, Asia Pacific, Epidemiolog