Age-time-specific transmission of hand-foot-and-mouth disease enterovirus serotypes in Vietnam: A catalytic model with maternal immunity.

Hand, foot and mouth disease (HFMD) is highly prevalent in the Asia Pacific region, particularly in Vietnam. To develop effective interventions and efficient vaccination programs, we inferred the age-time-specific transmission patterns of HFMD serotypes enterovirus A71 (EV-A71), coxsackievirus A6 (CV-A6), coxsackievirus A10 (CV-A10), coxsackievirus A16 (CV-A16) in Ho Chi Minh City, Vietnam from a case data collected during 2013-2018 and a serological survey data collected in 2015 and 2017. We proposed a catalytic model framework with good adaptability to incorporate maternal immunity using various mathematical functions. Our results indicate the high-level transmission of CV-A6 and CV-A10 which is not obvious in the case data, due to the variation of disease severity across serotypes. Our results provide statistical evidence supporting the strong association between severe illness and CV-A6 and EV-A71 infections. The HFMD dynamic pattern presents a cyclical pattern with large outbreaks followed by a decline in subsequent years. Additionally, we identify the age group with highest risk of infection as 1-2 years and emphasise the risk of future outbreaks as over 50% of children aged 6-7 years were estimated to be susceptible to CV-A16 and EV-A71. Our study highlights the importance of multivalent vaccines and active surveillance for different serotypes, supports early vaccination prior to 1 year old, and points out the potential utility for vaccinating children older than 5 years old in Vietnam.

Emerging Enterovirus A71 Subgenogroup B5 Causing Severe Hand, Foot, and Mouth Disease, Vietnam, 2023.

We report on a 2023 outbreak of severe hand, foot, and mouth disease in southern Vietnam caused by an emerging lineage of enterovirus A71 subgenogroup B5. Affected children were significantly older than those reported during previous outbreaks. The virus should be closely monitored to assess its potential for global dispersal.

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.

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.

Monkeypox Virus Infection in 2 Female Travelers Returning to Vietnam from Dubai, United Arab Emirates, 2022.

Mpox was diagnosed in 2 women returning to Vietnam from the United Arab Emirates. The monkeypox viruses belonged to an emerging sublineage, A.2.1, distinct from B.1, which is responsible for the ongoing multicountry outbreak. Women could contribute to mpox transmission, and enhanced genomic surveillance is needed to clarify pathogen evolution.

Kinetics of Neutralizing Antibodies against Omicron Variant in Vietnamese Healthcare Workers after Primary Immunization with ChAdOx1-S and Booster Immunization with BNT162b2.

We studied the development and persistence of neutralizing antibodies against SARS-CoV-2 ancestral strain, and Delta and Omicron (BA.1 and BA.2) variants in Vietnamese healthcare workers (HCWs) up to 15 weeks after booster vaccination. We included 47 HCWs, including group 1 (G1, N = 21) and group 2 (G2; N = 26) without and with breakthrough Delta variant infection before booster immunization, respectively). The study participants had completed primary immunization with ChAdOx1-S and booster vaccination with BNT162b2. Neutralizing antibodies were measured using a surrogate virus neutralization assay. Of the 21 study participants in G1, neutralizing antibodies against ancestral strain, Delta variant, BA.1, and BA.2 were (almost) abolished at month 8 after the second dose, but all had detectable neutralizing antibodies to the study viruses at week 2 post booster dose. Of the 26 study participants in G2, neutralizing antibody levels to BA.1 and BA.2 were significantly higher than those to the corresponding viruses measured at week 2 post breakthrough infection and before the booster dose. At week 15 post booster vaccination, neutralizing antibodies to BA.1 and BA.2 dropped significantly, with more profound changes observed in those without breakthrough Delta variant infection. Booster vaccination enhanced neutralizing activities against ancestral strain and Delta variant compared with those induced by primary vaccination. These responses were maintained at high levels for at least 15 weeks. Our findings emphasize the importance of the first booster dose in producing cross-neutralizing antibodies against Omicron variant. A second booster to maintain long-term vaccine effectiveness against the currently circulating variants merits further research.

Age-dependent heterogeneity in the antigenic effects of mutations to influenza hemagglutinin.

Human influenza virus evolves to escape neutralization by polyclonal antibodies. However, we have a limited understanding of how the antigenic effects of viral mutations vary across the human population, and how this heterogeneity affects virus evolution. Here we use deep mutational scanning to map how mutations to the hemagglutinin (HA) proteins of the A/Hong Kong/45/2019 (H3N2) and A/Perth/16/2009 (H3N2) strains affect neutralization by serum from individuals of a variety of ages. The effects of HA mutations on serum neutralization differ across age groups in ways that can be partially rationalized in terms of exposure histories. Mutations that fixed in influenza variants after 2020 cause the greatest escape from sera from younger individuals. Overall, these results demonstrate that influenza faces distinct antigenic selection regimes from different age groups, and suggest approaches to understand how this heterogeneous selection shapes viral evolution.

Balancing uncertainty and proactivity in care seeking for hepatitis C: qualitative research with participants enrolled in a treatment trial in Ho Chi Minh City, Vietnam.

PURPOSE: Direct acting antiviral treatment to cure hepatitis C virus (HCV) is becoming more accessible yet the experiences of those accessing care and treatment and the contexts under which care seeking takes place are largely unknown in low- and middle-income countries. These experiences are important for insight into the challenges people encounter and the support/structures they utilize. The study objective was to explore the experiences of care seeking and treatment for participants enrolled in a clinical trial in Ho Chi Minh City, Vietnam. METHODS: We used in-depth interviews, home visits, mobile interviews, at both the clinic and in the home as we explored how participants experienced health and illness within their social worlds over time. RESULTS: We enrolled 20 participants, of whom 20 completed the first interview, 16 the second, and 18 completed the last interview. Findings explore four themes: (1) navigating uncertainty, (2) proactivity in the face of challenges, (3) living in fear with faith, and (4) dynamic support systems. CONCLUSIONS: Understanding how participants envision and act upon their lived experiences can help to develop public health programmes that effectively address barriers and promote access to care and treatment for people with HCV in Vietnam.

Enhanced bedside mortality prediction combining point-of-care lactate and the quick Sequential Organ Failure Assessment (qSOFA) score in patients hospitalised with suspected infection in southeast Asia: a cohort study.

BACKGROUND: Simple, bedside prediction of infection-related mortality in low-resource settings is crucial for triage and resource-utilisation decisions. We aimed to evaluate mortality prediction by combining point-of-care venous lactate with the quick Sequential Organ Failure Assessment (qSOFA) score in adult patients admitted to hospital with suspected infection in southeast Asia. METHODS: We performed a cohort study by prospectively enrolling patients aged 18 years or older who had been admitted to hospital within the previous 24 h for suspected infection (with at least three documented systemic manifestations of infection according to the 2012 Surviving Sepsis Campaign) at Sunpasitthiprasong Hospital in Ubon Ratchathani, Thailand (derivation cohort). Venous lactate concentration was determined by a point-of-care device and multiple scores were developed. We then evaluated candidate 28-day mortality prediction models combining qSOFA and the lactate scores. A final model was compared with the qSOFA score, a lactate score, and a modified Sequential Organ Failure Assessment (SOFA) score for mortality discrimination using the area under the receiver operating characteristic curve (AUROC). Mortality discrimination of the qSOFA-lactate score was then verified in an external, prospectively enrolled, multinational cohort in southeast Asia. FINDINGS: Between March 1, 2013, and Jan 26, 2017, 5001 patients were enrolled in the derivation cohort; 4980 had point-of-care lactate data available and were eligible for analysis, and 816 died within 28 days of enrolment. The discrimination for 28-day mortality prediction of a qSOFA-lactate score combining the qSOFA score and a lactate score was superior to that of the qSOFA score alone (AUROC 0·78 [95% CI 0·76-0·80] vs 0·68 [0·67-0·70]; p<0·0001) and similar to a modified SOFA score (0·77 [0·75-0·78]; p=0·088). A lactate score alone had superior discrimination compared with the qSOFA score (AUROC 0·76 [95% CI 0·74-0·78]; p<0·0001). 815 patients were enrolled in the external validation cohort and 792 had point-of-care lactate data and were included in the analysis; the qSOFA-lactate score (AUROC 0·77 [95% CI 0·73-0·82]) showed significantly improved 28-day mortality discrimination compared with the qSOFA score alone (0·69 [0·63-0·74]; p<0·0001). INTERPRETATION: In southeast Asia, rapid, bedside assessments based on point-of-care lactate concentration combined with the qSOFA score can identify patients at risk of sepsis-related mortality with greater accuracy than the qSOFA score alone, and with similar accuracy to a modified SOFA score. FUNDING: National Institutes of Health, Wellcome Trust.

Immunogenicity of Oxford-AstraZeneca COVID-19 Vaccine in Vietnamese Health-Care Workers.

We studied the immunogenicity of the Oxford-AstraZeneca vaccine in health-care workers of a major infectious diseases hospital in Vietnam. We measured neutralizing antibodies before and 14 days after each dose, and at day 28 and month 3 after dose 1. A total of 554 workers (136 men and 418 women; age range, 22-71 years; median age, 36 years) participated with the study. Of the 144 participants selected for follow-up after dose 1, 104 and 94 gave blood for antibody measurement at weeks 6 and 8, and at month 3 after dose 1, respectively. The window time between the two doses was 6 weeks. At baseline, none had detectable neutralizing antibodies. After dose 1, the proportion of participants with detectable neutralizing antibodies increased from 27.3% (151 of 554) at day 14 to 78.0% (432 of 554) at day 28. Age correlated negatively with the development and the levels of neutralizing antibodies. However, at day 28, these differences were less profound, and women had a greater seroconversion rate and greater levels of neutralizing antibodies than men. After dose 2, these age and gender associations were not observable. In addition, the proportion of study participants with detectable neutralizing antibodies increased from 70.2% (73 of 104) before dose 2 (week 6, after dose 1) to 98.1% (102 of 104) 14 days later. At month 3, neutralizing antibodies decreased and 94.7% (89 of 94) of the study participants remained seropositive. The Oxford-AstraZeneca COVID-19 vaccine is immunogenic in Vietnamese health-care workers. These data are critical to informing the deployment of the COVID-19 vaccine in Vietnam and in Southeast Asia, where vaccination coverage remains inadequate.

Applied machine learning for the risk-stratification and clinical decision support of hospitalised patients with dengue in Vietnam.

BACKGROUND: Identifying patients at risk of dengue shock syndrome (DSS) is vital for effective healthcare delivery. This can be challenging in endemic settings because of high caseloads and limited resources. Machine learning models trained using clinical data could support decision-making in this context. METHODS: We developed supervised machine learning prediction models using pooled data from adult and paediatric patients hospitalised with dengue. Individuals from 5 prospective clinical studies in Ho Chi Minh City, Vietnam conducted between 12th April 2001 and 30th January 2018 were included. The outcome was onset of dengue shock syndrome during hospitalisation. Data underwent random stratified splitting at 80:20 ratio with the former used only for model development. Ten-fold cross-validation was used for hyperparameter optimisation and confidence intervals derived from percentile bootstrapping. Optimised models were evaluated against the hold-out set. FINDINGS: The final dataset included 4,131 patients (477 adults and 3,654 children). DSS was experienced by 222 (5.4%) of individuals. Predictors were age, sex, weight, day of illness at hospitalisation, indices of haematocrit and platelets over first 48 hours of admission and before the onset of DSS. An artificial neural network model (ANN) model had best performance with an area under receiver operator curve (AUROC) of 0.83 (95% confidence interval [CI], 0.76-0.85) in predicting DSS. When evaluated against the independent hold-out set this calibrated model exhibited an AUROC of 0.82, specificity of 0.84, sensitivity of 0.66, positive predictive value of 0.18 and negative predictive value of 0.98. INTERPRETATION: The study demonstrates additional insights can be obtained from basic healthcare data, when applied through a machine learning framework. The high negative predictive value could support interventions such as early discharge or ambulatory patient management in this population. Work is underway to incorporate these findings into an electronic clinical decision support system to guide individual patient management.

Wearable devices for remote monitoring of hospitalized patients with COVID-19 in Vietnam.

Patients with severe COVID-19 disease require monitoring with pulse oximetry as a minimal requirement. In many low- and middle- income countries, this has been challenging due to lack of staff and equipment. Wearable pulse oximeters potentially offer an attractive means to address this need, due to their low cost, battery operability and capacity for remote monitoring. Between July and October 2021, Ho Chi Minh City experienced its first major wave of SARS-CoV-2 infection, leading to an unprecedented demand for monitoring in hospitalized patients. We assess the feasibility of a continuous remote monitoring system for patients with COVID-19 under these circumstances as we implemented 2 different systems using wearable pulse oximeter devices in a stepwise manner across 4 departments.

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.

An observational study of breakthrough SARS-CoV-2 Delta variant infections among vaccinated healthcare workers in Vietnam.

BACKGROUND: Data on breakthrough SARS-CoV-2 Delta variant infections in vaccinated individuals are limited. METHODS: We studied breakthrough infections among Oxford-AstraZeneca vaccinated healthcare workers in an infectious diseases hospital in Vietnam. We collected demographic and clinical data alongside serial PCR testing, measurement of SARS-CoV-2 antibodies, and viral whole-genome sequencing. FINDINGS: Between 11th-25th June 2021 (7-8 weeks after the second dose), 69 staff tested positive for SARS-CoV-2. 62 participated in the study. Most were asymptomatic or mildly symptomatic and all recovered. Twenty-two complete-genome sequences were obtained; all were Delta variant and were phylogenetically distinct from contemporary viruses obtained from the community or from hospital patients admitted prior to the outbreak. Viral loads inferred from Ct values were 251 times higher than in cases infected with the original strain in March/April 2020. Median time from diagnosis to negative PCR was 21 days (range 8-33). Neutralizing antibodies (expressed as percentage of inhibition) measured after the second vaccine dose, or at diagnosis, were lower in cases than in uninfected, fully vaccinated controls (median (IQR): 69.4 (50.7-89.1) vs. 91.3 (79.6-94.9), p=0.005 and 59.4 (32.5-73.1) vs. 91.1 (77.3-94.2), p=0.002). There was no correlation between vaccine-induced neutralizing antibody levels and peak viral loads or the development of symptoms. INTERPRETATION: Breakthrough Delta variant infections following Oxford-AstraZeneca vaccination may cause asymptomatic or mild disease, but are associated with high viral loads, prolonged PCR positivity and low levels of vaccine-induced neutralizing antibodies. Epidemiological and sequence data suggested ongoing transmission had occurred between fully vaccinated individuals. FUNDING: Wellcome and NIH/NIAID.

An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis.

Background: Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anticancer agent tamoxifen has synergistic anti-cryptococcal activity with amphotericin in vitro. It is off-patent, cheap, and widely available. We performed a trial to determine its therapeutic potential. Methods: Open label randomized controlled trial. Participants received standard care - amphotericin combined with fluconazole for the first 2 weeks - or standard care plus tamoxifen 300 mg/day. The primary end point was Early Fungicidal Activity (EFA) - the rate of yeast clearance from cerebrospinal fluid (CSF). Trial registration https://clinicaltrials.gov/ct2/show/NCT03112031. Results: Fifty patients were enrolled (median age 34 years, 35 male). Tamoxifen had no effect on EFA (-0.48log10 colony-forming units/mL/CSF control arm versus -0.49 tamoxifen arm, difference -0.005log10CFU/ml/day, 95% CI: -0.16, 0.15, p=0.95). Tamoxifen caused QTc prolongation. Conclusions: High-dose tamoxifen does not increase the clearance rate of Cryptococcus from CSF. Novel, affordable therapies are needed. Funding: The trial was funded through the Wellcome Trust Asia Programme Vietnam Core Grant 106680 and a Wellcome Trust Intermediate Fellowship to JND grant number WT097147MA.

Absence of SARS-CoV-2 antibodies in pre-pandemic plasma from children and adults in Vietnam.

We tested pre-pandemic (2015--2019) plasma samples from 148 Vietnamese children and 100 Vietnamese adults at high risk of zoonotic infections for antibodies against SARS-CoV-2 nucleocapsid and spike proteins. None was positive. The data thus demonstrated no evidence of prior serological cross-reactivity with SARS-CoV-2 that might explain the low numbers of COVID-19 in Vietnam. No pre-existing cross-reactivity might explain Vietnam success of COVID-19 control.

Coxsackievirus A16 in Southern Vietnam.

Background: Hand, Foot and Mouth Disease (HFMD) is a major public health concern in the Asia-Pacific region. Most recent HFMD outbreaks have been caused by enterovirus A71 (EV-A71), coxsackievirus A16 (CVA16), CVA10, and CVA6. There has been no report regarding the epidemiology and genetic diversity of CVA16 in Vietnam. Such knowledge is critical to inform the development of intervention strategies. Materials and Methods: From 2011 to 2017, clinical samples were collected from in- and outpatients enrolled in a HFMD research program conducted at three referral hospitals in Ho Chi Minh City (HCMC), Vietnam. Throat or rectal swabs positive for CVA16 with sufficient viral load were selected for whole genome sequencing and evolutionary analysis. Results: Throughout the study period, 320 CVA16 positive samples were collected from 2808 HFMD patients (11.4%). 59.4% of patients were male. The median age was 20.8 months (IQR, 14.96-31.41). Patients resided in HCMC (55.3%), Mekong Delta (22.2%), and South East Vietnam (22.5%). 10% of CVA16 infected patients had moderately severe or severe HFMD. CVA16 positive samples from 153 patients were selected for whole genome sequencing, and 66 complete genomes were obtained. Phylogenetic analysis demonstrated that Vietnamese CVA16 strains belong to a single genogroup B1a that clusters together with isolates from China, Japan, Thailand, Malaysia, France and Australia. The CVA16 strains of the present study were circulating in Vietnam some 4 years prior to its detection in HFMD cases. Conclusion: We report for the first time on the molecular epidemiology of CVA16 in Vietnam. Unlike EV-A71, which showed frequent replacement between subgenogroups B5 and C4 every 2-3 years in Vietnam, CVA16 displays a less pronounced genetic alternation with only subgenogroup B1a circulating in Vietnam since 2011. Our collective findings emphasize the importance of active surveillance for viral circulation in HFMD endemic countries, critical to informing outbreak response and vaccine development.

Neurocognitive Trajectories After 72 Weeks of First-Line Anti-retroviral Therapy in Vietnamese Adults With HIV-HCV Co-infection.

Background: Long-term neurocognitive outcomes following first-line suppressive anti-retroviral therapy (ART) remain uncertain for individuals with HIV and hepatitis C (HCV) co-infection. The study examined neurocognitive performance before and after 72 weeks of ART using repeated multivariate analyses and latent trajectory models. Methods: One hundred and sixty adults with chronic, untreated HIV infection (n = 80 with HCV co-infection and n = 80 HIV mono-infected) and 80 demographically similar healthy controls were recruited from the Hospital for Tropical Diseases in Ho Chi Minh City and the surrounding community, respectively. Neurocognitive measures (adapted for use in Vietnam) and liver enzyme tests were compared across groups at baseline. Repeated multivariate and group-based trajectory analyses (GBTA) examined neurocognitive subgroup profiles of the co-infected individuals after 72 weeks of de novo efavirenz- (n = 41) or raltegravir-based (n = 39) ART. Results: Baseline analyses revealed worse motor function in HIV-HCV co-infected individuals compared to both comparison groups. Longitudinal analyses revealed improved neurocognitive performance by week 48 for most participants regardless of treatment arm. GBTA identified a subgroup (35% of HIV-HCV sample) with persistent motor impairment despite otherwise successful ART. Higher HIV viral load and lower CD4+ T cell count at baseline predicted persistent motor dysfunction. Liver indices and ART regimen did not predict neurocognitive outcomes in HIV-HCV co-infected individuals. Conclusions: Most HIV-HCV co-infected individuals achieve normative neurocognitive performance after 48 weeks of de novo suppressive ART. However, individuals with more severe HIV disease prior to ART exhibited motor impairment at baseline and 72 weeks after otherwise successful treatment. Interventions aimed at improving motor symptoms at the time of HIV treatment onset may improve long-term clinical outcomes in HIV-HCV co-infected adults.