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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.

Objectives Central nervous system (CNS) infections are common causes of morbidity and mortality worldwide. We aimed to discover protein biomarkers that could rapidly and accurately identify the likely cause of the infections, essential for clinical management and improving outcome. Methods We applied liquid chromatography tandem mass spectrometry on 45 cerebrospinal fluid (CSF) samples from a cohort of adults with and without CNS infections to discover potential diagnostic biomarkers. We then validated the diagnostic performance of a selected biomarker candidate in an independent cohort of 364 consecutively treated adults with CNS infections admitted to a referral hospital in Vietnam. Results In the discovery cohort, we identified lipocalin 2 (LCN2) as a potential biomarker of bacterial meningitis (BM) other than tuberculous meningitis. The analysis of the validation cohort showed that LCN2 could discriminate BM from other CNS infections (including tuberculous meningitis, cryptococcal meningitis and virus/antibody-mediated encephalitis), with sensitivity of 0.88 (95% confident interval (CI), 0.77–0.94), specificity of 0.91 (95% CI, 0.88–0.94) and diagnostic odds ratio of 73.8 (95% CI, 31.8–171.4). LCN2 outperformed other CSF markers (leukocytes, glucose, protein and lactate) commonly used in routine care worldwide. The combination of LCN2, CSF leukocytes, glucose, protein and lactate resulted in the highest diagnostic performance for BM (area under the receiver operating characteristics curve, 0.96; 95% CI, 0.93–0.99). Data are available via ProteomeXchange with identifier PXD020510. Conclusions LCN2 is a sensitive and specific biomarker for discriminating BM from a broad spectrum of other CNS infections. A prospective study is needed to assess the diagnostic utility of LCN2 in the diagnosis and management of CNS infections.

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 that there was no evidence of prior serological cross-reactivity with SARS-CoV-2 that might explain the low numbers of COVID-19 in Vietnam. Future studies should look at pre-existing B cell and T cell memory in pre-pandemic samples in Vietnam, which might further shed light on the pathogenesis of the infection.

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.

Hand, foot and mouth disease (HFMD) is an emerging infection with pandemic potential. Knowledge of neutralizing antibody responses among its pathogens is essential to inform vaccine development and epidemiologic research. We used 120 paired-plasma samples collected at enrollment and >7 days after the onset of illness from HFMD patients infected with enterovirus A71 (EV-A71), coxsackievirus A (CVA) 6, CVA10, and CVA16 to study cross neutralization. For homotypic viruses, seropositivity increased from

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, indicating no prior serological cross-reactivity with SARS-CoV-2 that might explain the low numbers of COVID-19 in Vietnam.

We studied the immunogenicity of Oxford-AstraZeneca vaccine in Vietnamese healthcare workers. We collected blood samples before each dose, at 14 days after each dose, and month 1 and 3 after dose 1 from each participant alongside demographics data. We measured neutralizing antibodies using a surrogate virus neutralization assay. The 554 study participants (136 males and 418 females) were aged between 22-71 years (median: 36 years). 104 and 94 out of 144 selected participants were successfully followed up at 14 days after dose 2 and 3 months after dose 1, respectively. Neutralizing antibodies increased after each dose, with the sero-conversion rate reaching 98.1% (102/104) at 14 days after dose 2. At month 3 after dose 1, neutralizing antibody levels decreased, while 94.7% (89/94) of the study participants remained seropositive. Oxford-AstraZeneca COVID-19 vaccine is immunogenic in Vietnamese healthcare workers. The requirement for a third dose warrants further research.

We investigated enterovirus A71–associated hand, foot and mouth disease in Vietnam and found that, after replacing subgenogroup C4 in 2013, B5 remained the leading cause of this disease. In contrast with previous observations, this switch did not result in an explosive outbreak, and B5 evolution was driven by negative selection.

Background: Data on breakthrough SARS-CoV-2 Delta variant infections are limited. Methods: We studied breakthrough infections among healthcare workers of a major infectious diseases hospital in Vietnam. We collected demographics, vaccination history and results of PCR diagnosis alongside clinical data. We measured SARS-CoV-2 (neutralizing) antibodies at diagnosis, and at week 1, 2 and 3 after diagnosis. We sequenced the viruses using ARTIC protocol. Findings: Between 11th–25th June 2021 (week 7–8 after dose 2), 69 healthcare workers were tested positive for SARS-CoV-2. 62 participated in the clinical study. 49 were (pre)symptomatic with one requiring oxygen supplementation. All recovered uneventfully. 23 complete-genome sequences were obtained. They all belonged to the Delta variant, and were phylogenetically distinct from the contemporary Delta variant sequences obtained from community transmission cases, suggestive of ongoing transmission between the workers. Viral loads of breakthrough Delta variant infection cases were 251 times higher than those of cases infected with old strains detected between March-April 2020. Time from diagnosis to PCR negative was 8–33 days (median: 21). Neutralizing antibody levels after vaccination and at diagnosis of the cases were lower than those in the matched uninfected controls. There was no correlation between vaccine-induced neutralizing antibody levels and viral loads or the development of symptoms. Interpretation: Breakthrough Delta variant infections are associated with high viral loads, prolonged PCR positivity, and low levels of vaccine-induced neutralizing antibodies, explaining the transmission between the vaccinated people. Physical distancing measures remain critical to reduce SARS-CoV-2 Delta variant transmission. Funding: Wellcome (106680/B/14/Z and 204904/Z/16/Z). Declaration of Interest: None to declare. Ethical Approval: The study was approved by the Institutional Review Board of HTD and the Oxford Tropical Research Ethics Committee, University of Oxford, UK.

Hand, foot and mouth disease (HFMD) continues to challenge Asia with pandemic potential. In Vietnam, there have been two major outbreaks occurring during 2011–2012 (>200,000 hospitalizations and >200 deaths) and more recently in 2018 (>130,000 hospitalizations and 17 deaths). Given the high burden and the complex epidemic dynamics of HFMD, synthesizing its clinical and epidemiological data remains essential to inform the development of appropriate interventions and design public health measures. We report the results of a hospital-based study conducted during 2015–2018, covering the severe HFMD outbreak recently documented in Vietnam in 2018. The study was conducted at three major hospitals responsible for receiving HFMD patients from southern Vietnam with a population of over 40 million. A total of 19 enterovirus serotypes were detected in 1196 HFMD patients enrolled in the clinical study during 2015–2018, with enterovirus A71 (EV-A71), coxsackievirus A6 (CV-A6), CV-A10 and CV-A16 being the major causes. Despite the emergence of coxsackieviruses, EV-A71 remains the leading cause of severe HFMD in Vietnam. EV-A71 was consistently detected at a higher frequency during the second half of the years. The emergence of EV-A71 subgenogroup C4 in late 2018 was preceded by its low activity during 2017–early 2018. Compared with EV-A71 subgenogroup B5, C4 was more likely to be associated with severe HFMD, representing the first report demonstrating the difference in clinical severity between subgenogroup C4 and B5, the two predominant EV-A71 subgenogroups causing HFMD worldwide. Our data have provided significant insights into important aspects of HFMD over four years (2015–2018) in Vietnam, and emphasize active surveillance for pathogen circulation remains essential to inform the local public health authorities in the development of appropriate intervention strategies to reduce the burden of this emerging infections. Multivalent vaccines are urgently needed to control HFMD., Author summary Hand, foot and mouth disease (HFMD) continues to challenge Asia with pandemic potential. Synthesizing epidemiological data remains essential to inform the development of appropriate interventions. We report the results of a comprehensive hospital-based study conducted in southern Vietnam during 2015–2018. A total of 19 different viruses were detected in 1196 HFMD patients enrolled in the study, with enterovirus A71 (EV-A71), coxsackievirus A6 (CV-A6), CV-A10 and CV-A16 being the major causes. EV-A71 was associated with severe HFMD and consistently detected at a higher frequency during the second half of the years. The emergence of EV-A71 subgenogroup C4 in late 2018 was preceded by its low activity during 2017–early 2018. Compared with subgenogroup B5, C4 was more likely to be associated with severe HFMD. Collectively, despite the emergence of coxsackieviruses, EV-A71 remains the major cause of severe HFMD, and multivalent vaccines are urgently needed to control the ongoing HFMD challenge.

Background Meningoencephalitis is a devastating disease worldwide. Current diagnosis fails to establish the cause in ≥50% of patients. Metagenomic next-generation sequencing (mNGS) has emerged as pan-pathogen assays for infectious diseases diagnosis, but few studies have been conducted in resource-limited settings. Methods We assessed the performance of mNGS in the cerebrospinal fluid (CSF) of 66 consecutively treated adults with meningoencephalitis in a tertiary referral hospital for infectious diseases in Vietnam, a resource-limited setting. All mNGS results were confirmed by viral-specific polymerase chain reaction (PCR). As a complementary analysis, 6 viral PCR-positive samples were analyzed using MinION-based metagenomics. Results Routine diagnosis could identify a virus in 15 (22.7%) patients, including herpes simplex virus (HSV; n = 7) and varicella zoster virus (VZV; n = 1) by PCR, and mumps virus (n = 4), dengue virus (DENV; n = 2), and Japanese encephalitis virus (JEV; n = 1) by serological diagnosis. mNGS detected HSV, VZV, and mumps virus in 5/7, 1/1, and 1/4 of the CSF positive by routine assays, respectively, but it detected DENV and JEV in none of the positive CSF. Additionally, mNGS detected enteroviruses in 7 patients of unknown cause. Metagenomic MinION-Nanopore sequencing could detect a virus in 5/6 PCR-positive CSF samples, including HSV in 1 CSF sample that was negative by mNGS, suggesting that the sensitivity of MinION is comparable with that of mNGS/PCR. Conclusions In a single assay, metagenomics could accurately detect a wide spectrum of neurotropic viruses in the CSF of meningoencephalitis patients. Further studies are needed to determine the value that real-time sequencing may contribute to the diagnosis and management of meningoencephalitis patients, especially in resource-limited settings where pathogen-specific assays are limited in number.

BackgroundLittle is known about the natural history of asymptomatic SARS-CoV-2 infection or its contribution to infection transmission.MethodsWe conducted a prospective study at a quarantine centre for COVID-19 in Ho Chi Minh City, Vietnam. We enrolled quarantined people with RT-PCR-confirmed SARS-CoV-2 infection, collecting clinical data, travel and contact history, and saliva at enrolment and daily nasopharyngeal throat swabs (NTS) for RT-PCR testing. We compared the natural history and transmission potential of asymptomatic and symptomatic individuals.ResultsBetween March 10th and April 4th, 2020, 14,000 quarantined people were tested for SARS-CoV-2; 49 were positive. Of these, 30 participated in the study: 13(43%) never had symptoms and 17(57%) were symptomatic. 17(57%) participants acquired their infection outside Vietnam. Compared with symptomatic individuals, asymptomatic people were less likely to have detectable SARS-CoV-2 in NTS samples collected at enrolment (8/13 (62%) vs. 17/17 (100%) P=0.02). SARS-CoV-2 RNA was detected in 20/27 (74%) available saliva; 7/11 (64%) in the asymptomatic and 13/16 (81%) in the symptomatic group (P=0.56). Analysis of the probability of RT-PCR positivity showed asymptomatic participants had faster viral clearance than symptomatic participants (PConclusionsAsymptomatic SARS-CoV-2 infection is common and can be detected by analysis of saliva or NTS. NTS viral loads fall faster in asymptomatic individuals, but they appear able to transmit the virus to others.

The rapid spread of coronavirus disease 2019 (COVID-19) raises concern about a global pandemic. Knowledge about the duration of viral shedding remains important for patient management and infection control. We report the duration of viral detection in throat and rectum of a COVID-19 patient treated at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam. Despite clinical recovery, SARS-CoV-2 RNA remained detectable by real time RT-PCR in throat and rectal swabs until day 11 and 18 of hospitalization, respectively. Because live SARS-CoV-2 has been successfully isolated from a stool sample from a COVID-19 patient in China, the results demonstrate that COVID-19 patients may remain infectious for long periods, and fecal-oral transmission may be possible. Therefore, our finding has important implications for infection control.

Hand, Foot, and Mouth Disease (HFMD) is a major public health issue in the Asia-Pacific region. Our research program aims to address unanswered questions about clinical, epidemiology, pathogen evolution, cost of illness, and host-genetic makers associated with severe HFMD in Vietnam. A multi-hospital-based observational study has been conducted at three referral hospitals in Ho Chi Minh City, Vietnam since 2013. Demographic, clinical data, and cost of illness were collected alongside clinical specimens. Multiplex PCR and next-generation sequencing were employed to identify enterovirus serotypes and to study pathogen evolution, respectively. A genome-wide association-based approach was used to explore genetic markers of disease severity. From 2013 to 2017, 2,191 HFMD patients were enrolled. More than twenty enterovirus serotypes were detected in 84.3 per cent of patients. EV-A71 was the major cause, accounting for 22 per cent of total number of cases, followed by CV-A6 (21%), CV-A16 (13%), and CV-A10 (8%). Interestingly, these four common enteroviruses replaced each other during the study period. EV-A71 and CV-A6 were the two most predominant viruses detected in 2013 and 2014. However, CV-A6 was replaced by CV-A16 and CV-A10 in 2015 and 2016, respectively. A total of 396 whole-genome sequences (EV-A71 (n = 200), CV-A6 (n = 98), CV-A10 (n = 66), and CV-A16 (n = 32)) were obtained. Phylogenetic analysis showed that EV-A71 subgenogroup B5 has replaced C4 in 2012, and, since then, B5 has continued to circulate predominantly, while C4 has been sporadically detected. All Vietnamese CV-A6 isolates belonged to genogroup A, which has caused large outbreaks of HFMD worldwide. Costs of illness varied between disease severities, ranging from $USD 244 [95% confidence interval (95% CI): 230–258] per patient for grade 2A (mild) to $USD 1984 (95% CI: 1,752–2,227) for grade 3 (severe). The genome-wide association study identified two genetic markers potentially associated with severe HFMD. The results highlight that active surveillance and understanding pathogen evolution are essential to inform public health in prioritizing the development of intervention strategies. Efforts to unravel the evolutionary process of Vietnamese CV-A10 and CV-A16 in relation to global strains are ongoing. An independent cohort is needed to replicate the preliminary findings of the genome-wide association study.

Since the beginning of January 2018, there has been a significant increase in the number of hospitalisations (including cases with neurological symptoms) due to hand, foot and mouth disease (HFMD) across Vietnam. By the end of September more than 53,000 clinical cases were reported, of whom six died [1]. Our aim was to characterise the epidemiology, virology and clinical characteristics of patients, especially those with severe HFMD, through an ongoing clinical study conducted at a large tertiary referral hospital for children in Ho Chi Minh City, Vietnam from January to September 2018.

We report human pegivirus 2 (HPgV-2) infection in Vietnam. We detected HPgV-2 in some patients with hepatitis C virus/HIV co-infection but not in patients with HIV or hepatitis A, B, or C virus infection, nor in healthy controls. HPgV-2 strains in Vietnam are phylogenetically related to global strains.

Japanese encephalitis virus was detected by deep sequencing for the first time in urine of a 16-year-old boy with encephalitis. Seroconversion and polymerase chain reaction analysis confirmed the metagenomics finding. Urine is useful for diagnosis of flaviviral encephalitis, whereas deep sequencing can be a panpathogen assay for the diagnosis of life-threatening infectious diseases.

As part of an ongoing effort to generate complete genome sequences of hand, foot and mouth disease-causing enteroviruses directly from clinical specimens, two complete coding sequences and two partial genomic sequences of human bocavirus 1 (n=3) and 2 (n=1) were co-amplified and sequenced, representing the first genome sequences of human bocaviruses from Vietnam. The sequences may aid future study aiming at understanding the evolution of the pathogen.

As avian influenza A(H5N1) viruses continue to circulate in Asia and Africa, global concerns of an imminent pandemic persist. Recent experimental studies suggest that efficient transmission between humans of current H5N1 viruses only requires a few genetic changes. An essential step is alteration of the virus hemagglutinin from preferential binding to avian receptors for the recognition of human receptors present in the upper airway. We have identified receptor-binding changes which emerged during H5N1 infection of humans, due to single amino acid substitutions, Ala134Val and Ile151Phe, in the hemagglutinin. Detailed biological, receptor-binding, and structural analyses revealed reduced binding of the mutated viruses to avian-like receptors, but without commensurate increased binding to the human-like receptors investigated, possibly reflecting a receptor-binding phenotype intermediate in adaptation to more human-like characteristics. These observations emphasize that evolution in nature of avian H5N1 viruses to efficient binding of human receptors is a complex multistep process., Highlights • Changes in receptor binding of HA during H5N1 human infection were identified. • Single A134V and L151F substitutions caused reduced affinity for avian receptors. • Glycan array analyses were used to identify changes in receptor binding specificity. • Structural basis for altered receptor binding was examined by X-ray crystallography.

H5N1 adaptation process is thought to primarily involve in changes of the 2 main glycoproteins of influenza virus: hemagglutinin HA, responsible for viral entry via binding with host cell receptors, and neuraminidase NA, a receptor destroying enzyme, promoting release of newly formed virions and preventing their self-aggregation. With their opposing roles in viral replication cycle, one rational assumption is that influenza virus needs to maintain a balance between these 2 proteins activities to ensure productive infection. Because of their impacts on both viral evolution and drug susceptibility, it is necessary to gain insight into the interplay between HA and NA proteins as this will further our understanding of the cross-species A/H5N1 adaptation process, with or without selective pressure. One of the most suitable systems to study influenza adaptation is cultures of differentiated human epithelial cells; which have been used for more than 30 years in various types of research. This project aimed to set-up that system in our laboratory in Vietnam to passage H5N1 viruses in order to use in later studies monitoring the adaptive changes of those viruses, especially in the two major glycoproteins HA and NA. In parallel, H5N1 isolates with different oseltamivir susceptibility profile were investigated to gain clear insight on NA enzymatic properties as well as the underlying mechanism of resistance. Those H5N1 isolates were human clade 1 viruses from the period of 2004 - 2005 in south of Vietnam with different oseltamivir sensitivity. Recombinant variants, with NA derived from H5N1 viruses and other segments from laboratory adapted human seasonal strain WSN33, were generated by reverse genetic techniques and then characterized on NA enzymatic properties. We identified 2 NA mutations which were suspected to affect NA activity and/or expression. Further investigations are required to conclude whether these 2 substitutions might support or allow the virus(es) to overcome the deficiency caused by oseltamivir resistance mutation, resulting in adaptive evolution of influenza viruses.