4CMenB Vaccination to Prevent Meningococcal B Disease in Vietnam: Expert Review and Opinion.

An advisory board meeting was held with experts in Vietnam (Hanoi, August 2022), to review the evidence on invasive meningococcal disease (IMD) epidemiology, clinical management, and meningococcal vaccines to reach a consensus on recommendations for meningococcal vaccination in Vietnam. IMD is a severe disease, with the highest burden in infants and children. IMD presents as meningitis and/or meningococcemia and can progress extremely rapidly. Almost 90% of deaths in children occur within the first 24 h, and disabling sequelae (e.g., limb amputations and neurological damage) occur in up to 20% of survivors. IMD patients are often hospitalized late, due to mild and nonspecific early symptoms and misdiagnosis. Difficulties related to diagnosis and antibiotic misuse mean that the number of reported IMD cases in Vietnam is likely to be underestimated. Serogroup B IMD is predominant in many regions of the world, including Vietnam, where 82% of IMD cases were due to serogroup B (surveillance data from 2012 to 2021). Four component meningococcal B vaccine (4CMenB) is used in many countries (and is part of the pediatric National Immunization Program in 13 countries), with infant vaccination starting from two months of age, and a 2 + 1 dosing schedule. Experts recommend 4CMenB vaccination as soon as possible in Vietnam, starting from two months of age, with a 2 + 1 dosing schedule, and at least completing one dose before 6 months of age.

Influenza vaccination allocation in tropical settings under constrained resources.

Influenza virus seasonality, synchronicity, and vaccine supply differ substantially between temperate and tropical settings, and optimal vaccination strategy may differ on this basis. Most national vaccine recommendations focus on high-risk groups, elderly populations, and healthcare workers despite previous analyses demonstrating broad benefits to vaccinating younger high-contact age groups. Here, we parameterized an age-structured non-seasonal asynchronous epidemiological model of influenza virus transmission for a tropical low-income setting. We evaluated timing and age allocation of vaccines across vaccine supplies ranging from 10% to 90% using decade-based age groups. Year-round vaccination was beneficial when comparing to vaccination strategies focused on a particular time of year. When targeting a single age-group for vaccine prioritization, maximum vaccine allocation to the 10-19 high-contact age group minimized annual influenza mortality for all but one vaccine supply. When evaluating across all possible age allocations, optimal strategies always allocated a plurality of vaccines to school-age children (10-19). The converse however was not true as not all strategies allocating a plurality to children aged 10-19 minimized mortality. Allocating a high proportion of vaccine supply to the 10-19 age group is necessary but not sufficient to minimize annual mortality as distribution of remaining vaccine doses to other age groups also needs to be optimized. Strategies focusing on indirect benefits (vaccinating children) showed higher variance in mortality outcomes than strategies focusing on direct benefits (vaccinating the elderly). However, the indirect benefit approaches showed lower mean mortality and lower minimum mortality than vaccination focused on the elderly.

A combination of annual and nonannual forces drive respiratory disease in the tropics.

INTRODUCTION: It is well known that influenza and other respiratory viruses are wintertime-seasonal in temperate regions. However, respiratory disease seasonality in the tropics is less well understood. In this study, we aimed to characterise the seasonality of influenza-like illness (ILI) and influenza virus in Ho Chi Minh City, Vietnam. METHODS: We monitored the daily number of ILI patients in 89 outpatient clinics from January 2010 to December 2019. We collected nasal swabs and tested for influenza from a subset of clinics from May 2012 to December 2019. We used spectral analysis to describe the periodic signals in the system. We evaluated the contribution of these periodic signals to predicting ILI and influenza patterns through lognormal and gamma hurdle models. RESULTS: During 10 years of community surveillance, 66 799 ILI reports were collected covering 2.9 million patient visits; 2604 nasal swabs were collected, 559 of which were PCR-positive for influenza virus. Both annual and nonannual cycles were detected in the ILI time series, with the annual cycle showing 8.9% lower ILI activity (95% CI 8.8% to 9.0%) from February 24 to May 15. Nonannual cycles had substantial explanatory power for ILI trends (ΔAIC=183) compared with all annual covariates (ΔAIC=263) in lognormal regression. Near-annual signals were observed for PCR-confirmed influenza but were not consistent over time or across influenza (sub)types. The explanatory power of climate factors for ILI and influenza virus trends was weak. CONCLUSION: Our study reveals a unique pattern of respiratory disease dynamics in a tropical setting influenced by both annual and nonannual drivers, with influenza dynamics showing near-annual periodicities. Timing of vaccination campaigns and hospital capacity planning may require a complex forecasting approach.

Repeatability and timing of tropical influenza epidemics.

Much of the world experiences influenza in yearly recurring seasons, particularly in temperate areas. These patterns can be considered repeatable if they occur predictably and consistently at the same time of year. In tropical areas, including southeast Asia, timing of influenza epidemics is less consistent, leading to a lack of consensus regarding whether influenza is repeatable. This study aimed to assess repeatability of influenza in Vietnam, with repeatability defined as seasonality that occurs at a consistent time of year with low variation. We developed a mathematical model incorporating parameters to represent periods of increased transmission and then fitted the model to data collected from sentinel hospitals throughout Vietnam as well as four temperate locations. We fitted the model for individual (sub)types of influenza as well as all combined influenza throughout northern, central, and southern Vietnam. Repeatability was evaluated through the variance of the timings of peak transmission. Model fits from Vietnam show high variance (sd = 64-179 days) in peak transmission timing, with peaks occurring at irregular intervals and throughout different times of year. Fits from temperate locations showed regular, annual epidemics in winter months, with low variance in peak timings (sd = 32-57 days). This suggests that influenza patterns are not repeatable or seasonal in Vietnam. Influenza prevention in Vietnam therefore cannot rely on anticipation of regularly occurring outbreaks.

The spatio-temporal distribution of acute encephalitis syndrome and its association with climate and landcover in Vietnam.

BACKGROUND: Acute encephalitis syndrome (AES) differs in its spatio-temporal distribution in Vietnam with the highest incidence seen during the summer months in the northern provinces. AES has multiple aetiologies, and the cause remains unknown in many cases. While vector-borne disease such as Japanese encephalitis and dengue virus and non-vector-borne diseases such as influenza and enterovirus show evidence of seasonality, associations with climate variables and the spatio-temporal distribution in Vietnam differs between these. The aim of this study was therefore to understand the spatio-temporal distribution of, and risk factors for AES in Vietnam to help hypothesise the aetiology. METHODS: The number of monthly cases per province for AES, meningitis and diseases including dengue fever; influenza-like-illness (ILI); hand, foot, and mouth disease (HFMD); and Streptococcus suis were obtained from the General Department for Preventive Medicine (GDPM) from 1998-2016. Covariates including climate, normalized difference vegetation index (NDVI), elevation, the number of pigs, socio-demographics, JEV vaccination coverage and the number of hospitals were also collected. Spatio-temporal multivariable mixed-effects negative binomial Bayesian models with an outcome of the number of cases of AES, a combination of the covariates and harmonic terms to determine the magnitude of seasonality were developed. RESULTS: The national monthly incidence of AES declined by 63.3% over the study period. However, incidence increased in some provinces, particularly in the Northwest region. In northern Vietnam, the incidence peaked in the summer months in contrast to the southern provinces where incidence remained relatively constant throughout the year. The incidence of meningitis, ILI and S. suis infection; temperature, relative humidity with no lag, NDVI at a lag of one month, and the number of pigs per 100,000 population were positively associated with the number of cases of AES in all models in which these covariates were included. CONCLUSIONS: The positive correlation of AES with temperature and humidity suggest that a number of cases may be due to vector-borne diseases, suggesting a need to focus on vaccination campaigns. However, further surveillance and research are recommended to investigate other possible aetiologies such as S. suis or Orientia tsutsugamushi.

A combination of annual and nonannual forces drive respiratory disease in the tropics.

Background: It is well known that influenza and other respiratory viruses are wintertime-seasonal in temperate regions. However, respiratory disease seasonality in the tropics remains elusive. In this study, we aimed to characterize the seasonality of influenza-like illness (ILI) and influenza virus in Ho Chi Minh City (HCMC), Vietnam. Methods: We monitored the daily number of ILI patients in 89 outpatient clinics from January 2010 to December 2019. We collected nasal swabs and tested for influenza from a subset of clinics from May 2012 to December 2019. We used spectral analysis to describe the periodicities in the system. We evaluated the contribution of these periodicities to predicting ILI and influenza patterns through lognormal and gamma hurdle models. Findings: During ten years of community surveillance, 66,799 ILI reports were collected covering 2.9 million patient visits; 2604 nasal swabs were collected 559 of which were PCR-positive for influenza virus. Both annual and nonannual cycles were detected in the ILI time series, with the annual cycle showing 8.9% lower ILI activity (95% CI: 8.8%-9.0%) from February 24 to May 15. Nonannual cycles had substantial explanatory power for ILI trends (ΔAIC = 183) compared to all annual covariates (ΔAIC = 263). Near-annual signals were observed for PCR-confirmed influenza but were not consistent along in time or across influenza (sub)types. Interpretation: Our study reveals a unique pattern of respiratory disease dynamics in a tropical setting influenced by both annual and nonannual drivers. Timing of vaccination campaigns and hospital capacity planning may require a complex forecasting approach.

Spatiotemporal Evolution of SARS-CoV-2 Alpha and Delta Variants during Large Nationwide Outbreak of COVID-19, Vietnam, 2021.

We analyzed 1,303 SARS-CoV-2 whole-genome sequences from Vietnam, and found the Alpha and Delta variants were responsible for a large nationwide outbreak of COVID-19 in 2021. The Delta variant was confined to the AY.57 lineage and caused >1.7 million infections and >32,000 deaths. Viral transmission was strongly affected by nonpharmaceutical interventions.

Seroprotection against tetanus in southern Vietnam.

BACKGROUND: Ongoing tetanus cases and sporadic outbreaks of vaccine-preventable diseases associated with routine vaccination programmes remain problems in many low and middle-income countries, including Vietnam. With no human-to-human transmission or natural immunity, tetanus antibody levels indicate both individual risk of tetanus and gaps in vaccination programmes. METHODS: To investigate gaps in immunity to tetanus in Vietnam, a country with a historically high level of tetanus vaccination coverage, tetanus antibodies were measure by ELISA from samples selected from a long-term serum bank, established for the purposes of general-population seroepidemiological investigations in southern Vietnam. Samples were selected from 10 provinces, focussing on age-groups targeted by national vaccination programmes for infants and pregnant women (Expanded Programme on Immunization, EPI, and Maternal and Neonatal Tetanus, MNT). RESULTS: Antibodies were measured from a total of 3864 samples. Highest tetanus antibody concentrations occurred in children under 4 years old, over 90 % of whom had protective levels. Approximately 70 % of children aged 7-12 years had protective antibody concentrations although there was variation among provinces. For infants and children, there were no significant differences in tetanus protection between males and females, but for adults aged 20-35 years, in five of the ten provinces surveyed, protection against tetanus was higher in females (p < 0.05) who are eligible for booster doses under the MNT programme. In seven of ten provinces, antibody concentrations were inversely related to age (p < 0.01) and protection of older individuals was generally low. CONCLUSION: Widespread immunity to tetanus toxoid is seen in infants and young children consistent with the high coverage rates reported for diptheria tetanus toxoid and pertussis (DTP) in Vietnam. However, the lower antibody concentrations seen in older children and men suggest reduced immunity to tetanus in populations not targeted by EPI and MNT programmes.

Spatial analysis of human and livestock anthrax in Dien Bien province, Vietnam (2010-2019) and the significance of anthrax vaccination in livestock.

Anthrax is a serious zoonosis caused by Bacillus anthracis, which primarily affects wild herbivorous animals with spillover into humans. The disease occurs nearly worldwide but is poorly reported in Southeast Asian countries. In Vietnam, anthrax is underreported, and little is known about its temporal and spatial distributions. This paper examines the spatio-temporal distribution and epidemiological characteristics of human and livestock anthrax from Dien Bien province, Vietnam from 2010 to 2019. We also aim to define the role of livestock vaccination in reducing human cases. Historical anthrax data were collected by local human and animal health sectors in the province. Spatial rate smoothing and spatial clustering analysis, using Local Moran's I in GeoDa and space-time scan statistic in SaTScan, were employed to address these objectives. We found temporal and spatial overlap of anthrax incidence in humans and livestock with hotspots of human anthrax in the east. We identified three significant space-time clusters of human anthrax persisting from 2010 to 2014 in the east and southeast, each with high relative risk. Most of the human cases were male (69%), aged 15-59 years (80%), involved in processing, slaughtering, or eating meat of sick or dead livestock (96.9%) but environmental and unknown exposure were reported. Animal reports were limited compared to humans and at coarser spatial scale, but in areas with human case clusters. In years when livestock vaccination was high (>~25%), human incidence was reduced, with the opposite effect when vaccine rates dropped. This indicates livestock vaccination campaigns reduce anthrax burden in both humans and livestock in Vietnam, though livestock surveillance needs immediate improvement. These findings suggest further investigation and measures to strengthen the surveillance of human and animal anthrax for other provinces of Vietnam, as well as in other countries with similar disease context.

Spatiotemporal Patterns of Anthrax, Vietnam, 1990-2015.

Anthrax is a priority zoonosis for control in Vietnam. The geographic distribution of anthrax remains to be defined, challenging our ability to target areas for control. We analyzed human anthrax cases in Vietnam to obtain anthrax incidence at the national and provincial level. Nationally, the trendline for cases remained at ≈61 cases/year throughout the 26 years of available data, indicating control efforts are not effectively reducing disease burden over time. Most anthrax cases occurred in the Northern Midlands and Mountainous regions, and the provinces of Lai Chau, Dien Bien, Lao Cai, Ha Giang, Cao Bang, and Son La experienced some of the highest incidence rates. Based on spatial Bayes smoothed maps, every region of Vietnam experienced human anthrax cases during the study period. Clarifying the distribution of anthrax in Vietnam will enable us to better identify risk areas for improved surveillance, rapid clinical care, and livestock vaccination campaigns.

Opposing Effects of Prior Infection versus Prior Vaccination on Vaccine Immunogenicity against Influenza A(H3N2) Viruses.

Prior vaccination can alternately enhance or attenuate influenza vaccine immunogenicity and effectiveness. Analogously, we found that vaccine immunogenicity was enhanced by prior A(H3N2) virus infection among participants of the Ha Nam Cohort, Viet Nam, but was attenuated by prior vaccination among Australian Health Care Workers (HCWs) vaccinated in the same year. Here, we combined these studies to directly compare antibody titers against 35 A(H3N2) viruses spanning 1968-2018. Participants received licensed inactivated vaccines containing A/HongKong/4801/2014 (H3N2). The analysis was limited to participants aged 18-65 Y, and compared those exposed to A(H3N2) viruses circulating since 2009 by infection (Ha Nam) or vaccination (HCWs) to a reference group who had no recent A(H3N2) infection or vaccination (Ha Nam). Antibody responses were compared by fitting titer/titer-rise landscapes across strains, and by estimating titer ratios to the reference group of 2009-2018 viruses. Pre-vaccination, titers were lowest against 2009-2014 viruses among the reference (no recent exposure) group. Post-vaccination, titers were, on average, two-fold higher among participants with prior infection and two-fold lower among participants with 3-5 prior vaccinations compared to the reference group. Titer rise was negligible among participants with 3-5 prior vaccinations, poor among participants with 1-2 prior vaccinations, and equivalent or better among those with prior infection compared to the reference group. The enhancing effect of prior infection versus the incrementally attenuating effect of prior vaccinations suggests that these exposures may alternately promote and constrain the generation of memory that can be recalled by a new vaccine strain.

Influenza virus infection history shapes antibody responses to influenza vaccination.

Studies of successive vaccination suggest that immunological memory against past influenza viruses may limit responses to vaccines containing current strains. The impact of memory induced by prior infection is rarely considered and is difficult to ascertain, because infections are often subclinical. This study investigated influenza vaccination among adults from the Ha Nam cohort (Vietnam), who were purposefully selected to include 72 with and 28 without documented influenza A(H3N2) infection during the preceding 9 years (Australian New Zealand Clinical Trials Registry 12621000110886). The primary outcome was the effect of prior influenza A(H3N2) infection on hemagglutinin-inhibiting antibody responses induced by a locally available influenza vaccine administered in November 2016. Baseline and postvaccination sera were titrated against 40 influenza A(H3N2) strains spanning 1968-2018. At each time point (baseline, day 14 and day 280), geometric mean antibody titers against 2008-2018 strains were higher among participants with recent infection (34 (29-40), 187 (154-227) and 86 (72-103)) than among participants without recent infection (19 (17-22), 91 (64-130) and 38 (30-49)). On days 14 and 280, mean titer rises against 2014-2018 strains were 6.1-fold (5.0- to 7.4-fold) and 2.6-fold (2.2- to 3.1-fold) for participants with recent infection versus 4.8-fold (3.5- to 6.7-fold) and 1.9-fold (1.5- to 2.3-fold) for those without. One of 72 vaccinees with recent infection versus 4 of 28 without developed symptomatic A(H3N2) infection in the season after vaccination (P = 0.021). The range of A(H3N2) viruses recognized by vaccine-induced antibodies was associated with the prior infection strain. These results suggest that recall of immunological memory induced by prior infection enhances antibody responses to inactivated influenza vaccine and is important to attain protective antibody titers.

Influenza A(H1N1)pdm09 But Not A(H3N2) Virus Infection Induces Durable Seroprotection: Results From the Ha Nam Cohort.

BACKGROUND: The extent to which influenza recurrence depends upon waning immunity from prior infection is undefined. We used antibody titers of Ha-Nam cohort participants to estimate protection curves and decay trajectories. METHODS: Households (270) participated in influenza-like-illness (ILI) surveillance and provided blood at intervals spanning laboratory-confirmed virus transmission. Sera were tested in hemagglutination inhibition assay. Infection was defined as influenza virus-positive ILI and/or seroconversion. Median protective titers were estimated using scaled-logistic regression to model pretransmission titer against infection status in that season, limiting analysis to households with infection(s). Titers were modelled against month since infection using mixed-effects linear regression to estimate decay and when titers fell below protection thresholds. RESULTS: From December 2008-2012, 295 and 314 participants were infected with H1N1pdm09-like and A/Perth/16/09-like (H3N2Pe09) viruses, respectively. The proportion protected rose more steeply with titer for H1N1pdm09 than for H3N2Pe09, and estimated 50% protection titers were 19.6 and 37.3, respectively. Postinfection titers started higher against H3N2Pe09 but decayed more steeply than against H1N1pdm09. Seroprotection was estimated to be sustained against H1N1pdm09 but to wane by 8-months for H3N2Pe09. CONCLUSIONS: Estimates indicate that infection induces durable seroprotection against H1N1pdm09 but not H3N2Pe09, which could in part account for the younger age of A(H1N1) versus A(H3N2) cases.

Age-seroprevalence curves for the multi-strain structure of influenza A virus.

The relationship between age and seroprevalence can be used to estimate the annual attack rate of an infectious disease. For pathogens with multiple serologically distinct strains, there is a need to describe composite exposure to an antigenically variable group of pathogens. In this study, we assay 24,402 general-population serum samples, collected in Vietnam between 2009 to 2015, for antibodies to eleven human influenza A strains. We report that a principal components decomposition of antibody titer data gives the first principal component as an appropriate surrogate for seroprevalence; this results in annual attack rate estimates of 25.6% (95% CI: 24.1% - 27.1%) for subtype H3 and 16.0% (95% CI: 14.7% - 17.3%) for subtype H1. The remaining principal components separate the strains by serological similarity and associate birth cohorts with their particular influenza histories. Our work shows that dimensionality reduction can be used on human antibody profiles to construct an age-seroprevalence relationship for antigenically variable pathogens.

The First 100 Days of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Control in Vietnam.

BACKGROUND: One hundred days after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Vietnam on 23 January, 270 cases were confirmed, with no deaths. We describe the control measures used by the government and their relationship with imported and domestically acquired case numbers, with the aim of identifying the measures associated with successful SARS-CoV-2 control. METHODS: Clinical and demographic data on the first 270 SARS-CoV-2 infected cases and the timing and nature of government control measures, including numbers of tests and quarantined individuals, were analyzed. Apple and Google mobility data provided proxies for population movement. Serial intervals were calculated from 33 infector-infectee pairs and used to estimate the proportion of presymptomatic transmission events and time-varying reproduction numbers. RESULTS: A national lockdown was implemented between 1 and 22 April. Around 200 000 people were quarantined and 266 122 reverse transcription polymerase chain reaction (RT-PCR) tests conducted. Population mobility decreased progressively before lockdown. In total, 60% (163/270) of cases were imported; 43% (89/208) of resolved infections remained asymptomatic for the duration of infection. The serial interval was 3.24 days, and 27.5% (95% confidence interval [CI], 15.7%-40.0%) of transmissions occurred presymptomatically. Limited transmission amounted to a maximum reproduction number of 1.15 (95% CI, .·37-2.·36). No community transmission has been detected since 15 April. CONCLUSIONS: Vietnam has controlled SARS-CoV-2 spread through the early introduction of mass communication, meticulous contact tracing with strict quarantine, and international travel restrictions. The value of these interventions is supported by the high proportion of asymptomatic and imported cases, and evidence for substantial presymptomatic transmission.

Transmission of SARS-CoV 2 During Long-Haul Flight.

To assess the role of in-flight transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we investigated a cluster of cases among passengers on a 10-hour commercial flight. Affected persons were passengers, crew, and their close contacts. We traced 217 passengers and crew to their final destinations and interviewed, tested, and quarantined them. Among the 16 persons in whom SARS-CoV-2 infection was detected, 12 (75%) were passengers seated in business class along with the only symptomatic person (attack rate 62%). Seating proximity was strongly associated with increased infection risk (risk ratio 7.3, 95% CI 1.2-46.2). We found no strong evidence supporting alternative transmission scenarios. In-flight transmission that probably originated from 1 symptomatic passenger caused a large cluster of cases during a long flight. Guidelines for preventing SARS-CoV-2 infection among air passengers should consider individual passengers' risk for infection, the number of passengers traveling, and flight duration.

Factors associated with the duration of hospitalisation among COVID-19 patients in Vietnam: A survival analysis.

BACKGROUND: The median duration of hospital stays due to COVID-19 has been reported in several studies on China as 10-13 days. Global studies have indicated that the length of hospitalisation depends on different factors, such as the time elapsed from exposure to symptom onset, and from symptom onset to hospital admission, as well as specificities of the country under study. The goal of this paper is to identify factors associated with the median duration of hospital stays of COVID-19 patients during the second COVID-19 wave that hit Vietnam from 5 March to 8 April 2020. METHOD: We used retrospective data on 133 hospitalised patients with COVID-19 recorded over at least two weeks during the study period. The Cox proportional-hazards regression model was applied to determine the potential risk factors associated with length of hospital stay. RESULTS: There were 65 (48.9%) females, 98 (73.7%) patients 48 years old or younger, 15 (11.3%) persons with comorbidities, 21 (16.0%) severely ill patients and 5 (3.8%) individuals with life-threatening conditions. Eighty-two (61.7%) patients were discharged after testing negative for the SARS-CoV-2 virus, 51 were still in the hospital at the end of the study period and none died. The median duration of stay in a hospital was 21 (IQR: 16-34) days. The multivariable Cox regression model showed that age, residence and sources of contamination were significantly associated with longer duration of hospitalisation. CONCLUSION: A close look at how long COVID-19 patients stayed in the hospital could provide an overview of their treatment process in Vietnam, and support the country's National Steering Committee on COVID-19 Prevention and Control in the efficient allocation of resources over the next stages of the COVID-19 prevention period.

Combating the COVID-19 Epidemic: Experiences from Vietnam.

The COVID-19 pandemic is spreading fast globally. Vietnam's strict containment measures have significantly reduced the spread of the epidemic in the country. This was achieved through the use of emergency control measures in the epidemic areas and integration of resources from multiple sectors including health, mass media, transportation, education, public affairs, and defense. This paper reviews and shares specific measures for successful prevention and control of COVID-19 in Vietnam, which could provide useful learning for other countries.

Does sunlight drive seasonality of TB in Vietnam? A retrospective environmental ecological study of tuberculosis seasonality in Vietnam from 2010 to 2015.

BACKGROUND: Tuberculosis (TB) is a major global health burden, with an estimated quarter of the world's population being infected. The World Health Organization (WHO) launched the "End TB Strategy" in 2014 emphasising knowing the epidemic. WHO ranks Vietnam 12th in the world of high burden countries. TB spatial and temporal patterns have been observed globally with evidence of Vitamin D playing a role in seasonality. We explored the presence of temporal and spatial clustering of TB in Vietnam and their determinants to aid public health measures. METHODS: Data were collected by the National TB program of Vietnam from 2010 to 2015 and linked to the following datasets: socio-demographic characteristics; climatic variables; influenza-like-illness (ILI) incidence; geospatial data. The TB dataset was aggregated by province and quarter. Descriptive time series analyses using LOESS regression were completed per province to determine seasonality and trend. Harmonic regression was used to determine the amplitude of seasonality by province. A mixed-effect linear model was used with province and year as random effects and all other variables as fixed effects. RESULTS: There were 610,676 cases of TB notified between 2010 and 2015 in Vietnam. Heat maps of TB incidence per quarter per province showed substantial temporal and geospatial variation. Time series analysis demonstrated seasonality throughout the country, with peaks in spring/summer and troughs in autumn/winter. Incidence was consistently higher in the south, the three provinces with the highest incidence per 100,000 population were Tay Ninh, An Giang and Ho Chi Minh City. However, relative seasonal amplitude was more pronounced in the north. Mixed-effect linear model confirmed that TB incidence was associated with time and latitude. Of the demographic, socio-economic and health related variables, population density, percentage of those under 15 years of age, and HIV infection prevalence per province were associated with TB incidence. Of the climate variables, absolute humidity, average temperature and sunlight were associated with TB incidence. CONCLUSION: Preventative public health measures should be focused in the south of Viet Nam where incidence is highest. Vitamin D is unlikely to be a strong driver of seasonality but supplementation may play a role in a package of interventions.

Heatwaves and dengue outbreaks in Hanoi, Vietnam: New evidence on early warning.

BACKGROUND: Many studies have shown associations between rising temperatures, El Niño events and dengue incidence, but the effect of sustained periods of extreme high temperatures (i.e., heatwaves) on dengue outbreaks has not yet been investigated. This study aimed to compare the short-term temperature-dengue associations during different dengue outbreak periods, estimate the dengue cases attributable to temperature, and ascertain if there was an association between heatwaves and dengue outbreaks in Hanoi, Vietnam. METHODOLOGY/PRINCIPAL FINDINGS: Dengue outbreaks were assigned to one of three categories (small, medium and large) based on the 50th, 75th, and 90th percentiles of distribution of weekly dengue cases during 2008-2016. Using a generalised linear regression model with a negative binomial link that controlled for temporal trends, temperature variation, rainfall and population size over time, we examined and compared associations between weekly average temperature and weekly dengue incidence for different outbreak categories. The same model using weeks with or without heatwaves as binary variables was applied to examine the potential effects of extreme heatwaves, defined as seven or more days with temperatures above the 95th percentile of daily temperature distribution during the study period. This study included 55,801 dengue cases, with an average of 119 (range: 0 to 1454) cases per week. The exposure-response relationship between temperature and dengue risk was non-linear and differed with dengue category. After considering the delayed effects of temperature (one week lag), we estimated that 4.6%, 11.6%, and 21.9% of incident cases during small, medium, and large outbreaks were attributable to temperature. We found evidence of an association between heatwaves and dengue outbreaks, with longer delayed effects on large outbreaks (around 14 weeks later) than small and medium outbreaks (4 to 9 weeks later). Compared with non-heatwave years, dengue outbreaks (i.e., small, moderate and large outbreaks combined) in heatwave years had higher weekly number of dengue cases (p<0.05). Findings were robust under different sensitivity analyses. CONCLUSIONS: The short-term association between temperature and dengue risk varied by the level of outbreaks and temperature seems more likely affect large outbreaks. Moreover, heatwaves may delay the timing and increase the magnitude of dengue outbreaks.