Publications by authors named "Stefan Fernandez"

96 Publications

Coding-Complete Genome Sequences of 11 SARS-CoV-2 B.1.1.7 and B.1.351 Variants from Metro Manila, Philippines.

Microbiol Resour Announc 2021 Jul 15;10(28):e0049821. Epub 2021 Jul 15.

U.S. Army Medical Directorate-Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.

Here, we report the complete genome sequences of 11 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants from the Philippines. Lineage analysis showed 3 B.1.1.7 and 8 B.1.351 sequences. One B.1.1.7 sequence contained two additional mutations, F318N and V320F, with V320F located in the receptor binding domain of the S1 subunit.
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http://dx.doi.org/10.1128/MRA.00498-21DOI Listing
July 2021

Evaluation of the extended efficacy of the Dengvaxia vaccine against symptomatic and subclinical dengue infection.

Nat Med 2021 Jun 24. Epub 2021 Jun 24.

Institute for Immunology and Informatics, Department of Cell and Molecular Biology, University of Rhode Island, Providence, RI, USA.

More than half of the world's population lives in areas at risk for dengue virus infection. A vaccine will be pivotal to controlling spread, however, the only licensed vaccine, Dengvaxia, has been shown to increase the risk of severe disease in a subset of individuals. Vaccine efforts are hampered by a poor understanding of antibody responses, including those generated by vaccines, and whether antibody titers can be used as a marker of protection from infection or disease. Here we present the results of an ancillary study to a phase III vaccine study (n = 611). All participants received three doses of either Dengvaxia or placebo and were followed for 6 years. We performed neutralization tests on annual samples and during confirmed dengue episodes (n = 16,508 total measurements). We use mathematical models to reconstruct long-term antibody responses to vaccination and natural infection, and to identify subclinical infections. There were 87 symptomatic infections reported, and we estimated that there were a further 351 subclinical infections. Cumulative vaccine efficacy was positive for both subclinical and symptomatic infection, although the protective effect of the vaccine was concentrated in the first 3 years following vaccination. Among individuals with the same antibody titer, we found no difference between the risk of subsequent infection or disease between placebo and vaccine recipients, suggesting that antibody titers are a good predictor of both protection and disease risk.
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http://dx.doi.org/10.1038/s41591-021-01392-9DOI Listing
June 2021

Correlation between reported dengue illness history and seropositivity in rural Thailand.

PLoS Negl Trop Dis 2021 Jun 15;15(6):e0009459. Epub 2021 Jun 15.

State University of New York Upstate Medical University, Syracuse, New York, United States of America.

In the latest World Health Organization (WHO) recommendation for Dengvaxia implementation, either serological testing or a person's history of prior dengue illness may be used as supporting evidence to identify dengue virus (DENV)-immune individuals eligible for vaccination, in areas with limited capacity for laboratory confirmation. This analysis aimed to estimate the concordance between self-reported dengue illness histories and seropositivity in a prospective cohort study for dengue virus infection in Kamphaeng Phet province, a dengue-endemic area in northern Thailand. The study enrolled 2,076 subjects from 516 multigenerational families, with a median age of 30.6 years (range 0-90 years). Individual and family member dengue illness histories were obtained by questionnaire. Seropositivity was defined based on hemagglutination inhibition (HAI) assays. Overall seropositivity for DENV was 86.5% among those aged 9-45 years, which increased with age. 18.5% of participants reported a history of dengue illness prior to enrollment; 30.1% reported a previous DENV infection in the family, and 40.1% reported DENV infection in either themselves or a family member. Relative to seropositivity by HAI in the vaccine candidate group, the sensitivity and specificity of individual prior dengue illness history were 18.5% and 81.6%, respectively; sensitivity and specificity of reported dengue illness in a family member were 29.8% and 68.0%, and of either the individual or a family member were 40.1% and 60.5%. Notably, 13.4% of individuals reporting prior dengue illness were seronegative. Given the high occurrence of asymptomatic and mild DENV infection, self-reported dengue illness history is poorly sensitive for prior exposure and may misclassify individuals as 'exposed' when they were not. This analysis highlights that a simple, highly sensitive, and highly specific test for determining serostatus prior to Dengvaxia vaccination is urgently needed.
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http://dx.doi.org/10.1371/journal.pntd.0009459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232416PMC
June 2021

Reconstructing unseen transmission events to infer dengue dynamics from viral sequences.

Nat Commun 2021 03 22;12(1):1810. Epub 2021 Mar 22.

Department of Biology, University of Florida, Gainesville, FL, USA.

For most pathogens, transmission is driven by interactions between the behaviours of infectious individuals, the behaviours of the wider population, the local environment, and immunity. Phylogeographic approaches are currently unable to disentangle the relative effects of these competing factors. We develop a spatiotemporally structured phylogenetic framework that addresses these limitations by considering individual transmission events, reconstructed across spatial scales. We apply it to geocoded dengue virus sequences from Thailand (N = 726 over 18 years). We find infected individuals spend 96% of their time in their home community compared to 76% for the susceptible population (mainly children) and 42% for adults. Dynamic pockets of local immunity make transmission more likely in places with high heterotypic immunity and less likely where high homotypic immunity exists. Age-dependent mixing of individuals and vector distributions are not important in determining spread. This approach provides previously unknown insights into one of the most complex disease systems known and will be applicable to other pathogens.
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http://dx.doi.org/10.1038/s41467-021-21888-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985522PMC
March 2021

Effect of low-passage number on dengue consensus genomes and intra-host variant frequencies.

J Gen Virol 2021 03 16;102(3). Epub 2021 Feb 16.

Walter Reed Army Institute of Research, Silver Spring, MD, USA.

Intra-host single nucleotide variants (iSNVs) have been increasingly used in genomic epidemiology to increase phylogenetic resolution and reconstruct fine-scale outbreak dynamics. These analyses are preferably done on sequence data from direct clinical samples, but in many cases due to low viral loads, there might not be enough genetic material for deep sequencing and iSNV determination. Isolation of the virus from clinical samples with low-passage number increases viral load, but few studies have investigated how dengue virus (DENV) culture isolation from a clinical sample impacts the consensus sequence and the intra-host virus population frequencies. In this study, we investigate consensus and iSNV frequency differences between DENV sequenced directly from clinical samples and their corresponding low-passage isolates. Twenty five DENV1 and DENV2 positive sera and their corresponding viral isolates ( inoculation and C6/36 passage) were obtained from a prospective cohort study in the Philippines. These were sequenced on MiSeq with minimum nucleotide depth of coverage of 500×, and iSNVs were detected using LoFreq. For both DENV1 and DENV2, we found a maximum of one consensus nucleotide difference between clinical sample and isolate. Interestingly, we found that iSNVs with frequencies ≥5 % were often preserved between the samples, and that the number of iSNV positions, and sample diversity, at this frequency cutoff did not differ significantly between the sample pairs (clinical sample and isolate) in either DENV1 or DENV2 data. Our results show that low-passage DENV isolate consensus genomes are largely representative of their direct sample parental viruses, and that low-passage isolates often mirror high frequency within-host variants from direct samples.
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http://dx.doi.org/10.1099/jgv.0.001553DOI Listing
March 2021

Temporally integrated single cell RNA sequencing analysis of PBMC from experimental and natural primary human DENV-1 infections.

PLoS Pathog 2021 01 29;17(1):e1009240. Epub 2021 Jan 29.

Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.

Dengue human infection studies present an opportunity to address many longstanding questions in the field of flavivirus biology. However, limited data are available on how the immunological and transcriptional response elicited by an attenuated challenge virus compares to that associated with a wild-type DENV infection. To determine the kinetic transcriptional signature associated with experimental primary DENV-1 infection and to assess how closely this profile correlates with the transcriptional signature accompanying natural primary DENV-1 infection, we utilized scRNAseq to analyze PBMC from individuals enrolled in a DENV-1 human challenge study and from individuals experiencing a natural primary DENV-1 infection. While both experimental and natural primary DENV-1 infection resulted in overlapping patterns of inflammatory gene upregulation, natural primary DENV-1 infection was accompanied with a more pronounced suppression in gene products associated with protein translation and mitochondrial function, principally in monocytes. This suggests that the immune response elicited by experimental and natural primary DENV infection are similar, but that natural primary DENV-1 infection has a more pronounced impact on basic cellular processes to induce a multi-layered anti-viral state.
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http://dx.doi.org/10.1371/journal.ppat.1009240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875406PMC
January 2021

Performance of a Rapid Diagnostic Test for Influenza in a Tertiary Military Hospital, Philippines.

Mil Med 2021 Jan 22. Epub 2021 Jan 22.

Department of Virology, U.S. Army Medical Directorate-Armed Forces Research Institute of Medical Sciences, Bangkok, 10400, Thailand.

Introduction: It is important to evaluate the performance of existing rapid influenza diagnostic tests (RIDTs) and the factors that can affect performance especially when the circulation dynamics of influenza strains change such as the displacement and replacement of the circulating seasonal influenza strains.

Materials And Methods: Nasal swabs were collected from patients presenting at V Luna Medical Center, Armed Forces of the Philippines Health Service Command, with influenza-like illness (ILI) with one swab tested using Quickvue (QV) influenza A+B RIDT (Quidel) and the other swab tested using the ABI 7500 (Applied Biosystems) real-time reverse transcriptase-polymerase chain reaction. Sensitivity, specificity, positive predictive value, and negative predictive value were estimated. We identified clinical symptoms predictive of influenza subtype and evaluated the independence of QV sensitivity on (1) Cycle threshold (Ct) value, controlling for timing of collection; (2) timing of collection, controlling for Ct value; and (3) Ct value and timing of collection taken together.

Results: Between August 2011 and October 2016, patients presenting with ILI (n = 2333) underwent testing. Quickvue sensitivity across all subtypes was significantly correlated with lower Ct values (higher virus titers) (P <.001) and, except for flu A/H3 (P = .974), was also significantly associated with timing of specimen collection (P <.05). No statistically significant difference was noted in QV sensitivity for Flu A/H3 (P = .130), pandemic H1/N1 (P = .207), Flu A/H3 + pandemic H1/N1 (P = .341), and Flu B (P = .103) across different age groups but sensitivity of QV significantly differed (P <.001) across the different influenza subtypes.

Conclusion: Overall specificity of QV was high across all flu subtypes, but overall sensitivity was low (Flu A/pdm H1) to moderate (Flu A/H3 and Flu B). The findings highlight the need to develop more sensitive influenza RDTs to detect circulating influenza strains and the use of the quadrivalent flu vaccine during the annual influenza vaccination.
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http://dx.doi.org/10.1093/milmed/usab006DOI Listing
January 2021

The feasibility and performance of participant-collected mid-turbinate nasal swabs for detection of influenza virus, respiratory syncytial virus, and human metapneumovirus infections among pregnant women.

J Infect Dis 2021 Jan 18. Epub 2021 Jan 18.

Influenza Program, Thailand Ministry of Public Health - U.S. Centers for Disease Control and Prevention Collaboration, Nonthaburi, Thailand.

Background: We assessed performance of participant-collected mid-turbinate nasal swabs compared to study staff-collected mid-turbinate nasal swabs for the detection of respiratory viruses among pregnant women in Bangkok, Thailand.

Methods: We enrolled pregnant women aged ≥18 years and followed them throughout the 2018 influenza season. Women with acute respiratory illness (ARI) self-collected mid-turbinate nasal swabs at homes for influenza viruses, RSV, and hMPV real-time RT-PCR testing while the study nurse collected a second mid-turbinate nasal swab during home visits. Paired specimens were processed and tested on the same day.

Results: The majority (109, 60%) of 182 participants were 20-30 years old. All 200 paired swabs had optimal specimen quality. The median time from symptom onsets to participant-collected swabs was two days and to staff-collected swabs was also two days. The median time difference between the two swabs was two hours. Compared to staff-collected swabs, the participant-collected swabs were 93% sensitive and 99% specific for influenza virus detection, 94% sensitive and 99% specific for RSV detection, and 100% sensitive and 100% specific for hMPV detection.

Conclusions: Participant-collected mid-turbinate nasal swabs were a valid alternative approach for laboratory confirmation of influenza-, RSV-, and hMPV-associated illnesses among pregnant women in a community setting.
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http://dx.doi.org/10.1093/infdis/jiab023DOI Listing
January 2021

Comparative Analyses of Historical Trends in Confirmed Dengue Illnesses Detected at Public Hospitals in Bangkok and Northern Thailand, 2002-2018.

Am J Trop Med Hyg 2020 Dec 14. Epub 2020 Dec 14.

Department of Virology, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.

Dengue is a re-emerging global public health problem, the most common arbovirus causing human disease in the world, and a major cause of hospitalization in endemic countries causing significant economic burden. Data were analyzed from passive surveillance of hospital-attended dengue cases from 2002 to 2018 at Phramongkutklao Hospital (PMKH) located in Bangkok, Thailand, and Kamphaeng Phet Provincial Hospital (KPPH) located in the lower northern region of Thailand. At PMKH, serotype 1 proved to be the most common strain of the virus, whereas at KPPH, serotypes 1, 2, and 3 were the most common strains from 2006 to 2008, 2009 to 2012, and 2013 to 2015, respectively. The 11-17 years age-group made up the largest proportion of patients impacted by dengue illnesses during the study period at both sites. At KPPH, dengue virus (DENV)-3 was responsible for most cases of dengue fever (DF), whereas it was DENV-1 at PMKH. In cases where dengue hemorrhagic fever was the clinical diagnosis, DENV-2 was the predominant serotype at KPPH, whereas at PMKH, it was DENV-1. The overall disease prevalence remained consistent across the two study sites with DF being the predominant clinical diagnosis as the result of an acute secondary dengue infection, representing 40.7% of overall cases at KPPH and 56.8% at PMKH. The differences seen between these sites could be a result of climate change increasing the length of dengue season and shifts in migration patterns of these populations from rural to urban areas and vice versa.
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http://dx.doi.org/10.4269/ajtmh.20-0396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941814PMC
December 2020

A multi-country field validation of the FluChip-8G Insight Assay.

J Virol Methods 2021 03 30;289:114029. Epub 2020 Nov 30.

U.S. Army Medical Directorate - Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand. Electronic address:

Introduction: It is critical to rapidly detect novel and non-seasonal influenza strains. Currently available assays have limited sensitivity in detecting novel influenza subtypes. We performed a multi-country field validation of the FluChip-8G Insight, an assay able to detect and characterize influenza A/B viruses and non-seasonal influenza viruses.

Materials And Methods: We evaluated the performance of the FluChip-8G Insight on nasal and throat swab clinical samples from Thailand, Philippines and Nepal. Influenza PCR positive and negative samples tested using the US CDC Human Influenza Dx Panel reference standard were selected for testing using the FluChip-8G Influenza Insight.

Results: A total of 909 specimens were included in the analysis. The overall sensitivity and specificity of the FluChip-8G Insight to detect combined influenza A+B was 86 % and 100%, respectively. PPV and NPV were estimated at 100 % (95 % CI 99-100) and 73 % (95 % CI 68-78), respectively. Sensitivity across all influenza subtypes was 100% for specimens with <20 and 20-25 Ct values, respectively, but as Ct values increased, sensitivity across all influenza subtypes decreased significantly (p < 0.001) for specimens with Ct values ≥32.

Conclusion: The FluChip-8G Insight showed good precision and reproducibility among all 3 sites with robust identification of both influenza A and B targets with Ct values <32 and in the absence of co-infection. Positioning this platform in countries considered as hotspots for the emergence of novel/zoonotic influenza strains can increase the lead time in detecting and containing novel influenza strains with pandemic potential.
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http://dx.doi.org/10.1016/j.jviromet.2020.114029DOI Listing
March 2021

SARS-CoV-2 Among Military and Civilian Patients, Metro Manila, Philippines.

Mil Med 2021 07;186(7-8):e760-e766

Department of Virology, U.S. Army Medical Directorate, Armed Forces Research Institute of Medical Sciences, Bangkok 10400, Thailand.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belonging to the family Coronaviridae and genus Betacoronavirus is the causative agent of COVID-19 disease and was first identified in Wuhan, China. SARS-CoV-2 spread globally with >28 million cases and 911,000 deaths recorded worldwide as of September 12, 2020. The Philippines reported the first case of community transmission on March 5, 2020, and despite the government imposing one of the longest and strictest lockdowns in Southeast Asia, the number of confirmed COVID-19 cases still surged with >250,000 cases and 4,000 deaths reported as of September 12, 2020. It is important to estimate the burden and impact of SARS-CoV-2 on the military population since this can affect the military readiness.

Materials And Methods: Nasopharyngeal and oropharyngeal swabs were collected and SARS-CoV-2 real-time RT-PCR testing was performed on the samples. Phylogenetic analysis was performed using sequences from 23 SARS-CoV-2-positive specimens from this study and sequences retrieved from GenBank and GISAID databases.

Results: From April 14 to August 15, 2020, a total of 12,432 specimens were tested with 763 (6%) unique individuals testing positive for SARS-CoV-2 by rRT-PCR. In the military population, majority of the patients who were tested (80%) and those who tested positive for SARS-CoV-2 (86%) were male. Military and civilian status was available for 7,672 patients with 515/5,042 (10%) positive among military patients and 248/2,630 (9%) positive among civilian patients. Both military and civilian populations had the highest case counts of SARS-CoV-2-positive cases in the 21- to 30- and 31- to 40-year-old age groups, while the 71- to 80-year-old age group had the highest proportion (18%) of SARS-CoV-2-positive cases. Sequencing analysis showed 19 different variants in the 23 genomes. Twenty of the 23 genomes were classified under clade GR/B1.1, 2 genomes were classified under clade GR/B1.1.28, and 1 genome was classified under Clade O/B.6. Twenty-two of the 23 sequences collected after June 25, 2020, contained the D614G mutation.

Conclusion: We describe here the results of SARS-CoV-2 testing for military and civilian patients and personnel. The 21- to 30- and 31- to 40-year-old age groups had the highest case counts of SARS-CoV-2-positive cases. Sequencing results showed the presence of the D614G mutation in the spike protein in a majority of specimens collected from the end of June to July 2020.
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http://dx.doi.org/10.1093/milmed/usaa525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798984PMC
July 2021

Genomic surveillance of SARS-CoV-2 in Thailand reveals mixed imported populations, a local lineage expansion and a virus with truncated ORF7a.

Virus Res 2021 01 21;292:198233. Epub 2020 Nov 21.

COVID-19 Network Investigations Alliance (CONI), Bangkok, Thailand; Center for Medical Genomics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. Electronic address:

Coronavirus Disease 2019 (COVID-19) is a global public health threat. Genomic surveillance of SARS-CoV-2 was implemented in March of 2020 at a major diagnostic hub in Bangkok, Thailand. Several virus lineages supposedly originated in many countries were found, and a Thai-specific lineage, designated A/Thai-1, has expanded to be predominant in Thailand. A virus sample in the SARS-CoV-2 A/Thai-1 lineage contains a frame-shift deletion at ORF7a, encoding a putative host antagonizing factor of the virus.
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http://dx.doi.org/10.1016/j.virusres.2020.198233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679658PMC
January 2021

Coding-Complete Genome Sequences of 23 SARS-CoV-2 Samples from the Philippines.

Microbiol Resour Announc 2020 Oct 22;9(43). Epub 2020 Oct 22.

Department of Virology, U.S. Army Medical Directorate-Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.

Here, we report the coding-complete genome sequences of 23 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) samples from the Philippines. Sequences were obtained from nasopharyngeal and oropharyngeal swabs from coronavirus disease 2019 (COVID-19)-positive patients. Mutation analysis showed the presence of the D614G mutation in the spike protein in 22 of 23 genomes.
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http://dx.doi.org/10.1128/MRA.01031-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585851PMC
October 2020

Complete Coding Sequences of 22 East/Central/South African Genotype Chikungunya Virus Isolates from Thailand (2018 to 2019).

Microbiol Resour Announc 2020 Oct 15;9(42). Epub 2020 Oct 15.

Department of Virology, U.S. Army Medical Directorate-Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.

The coding-complete genome sequences of 22 chikungunya virus strains collected from the 2018-2019 outbreak in Thailand are reported. All sequences belong to the East/Central/South African (ECSA) genotype and contain two mutations, E1:K211E and E2:V264A, which were previously shown to be associated with increased viral infectivity, dissemination, and transmission in .
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http://dx.doi.org/10.1128/MRA.00438-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561681PMC
October 2020

Development of an adjuvanted nanoparticle vaccine against influenza virus, an in vitro study.

PLoS One 2020 6;15(8):e0237218. Epub 2020 Aug 6.

Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand.

Influenza is an infectious respiratory illness caused by influenza viruses. Despite yearly updates, the efficacy of influenza vaccines is significantly curtailed by the virus antigenic drift and antigenic shift. These constant changes to the influenza virus make-up also challenge the development of a universal flu vaccine, which requires conserved antigenic regions shared by influenza viruses of different subtypes. We propose that it is possible to bypass these challenges by the development of an influenza vaccine based on conserved proteins delivered in an adjuvanted nanoparticle system. In this study, we generated influenza nanoparticle constructs using trimethyl chitosan nanoparticles (TMC nPs) as the carrier of recombinant influenza hemagglutinin subunit 2 (HA2) and nucleoprotein (NP). The purified HA2 and NP recombinant proteins were encapsulated into TMC nPs to form HA2-TMC nPs and NP-TMC nPs, respectively. Primary human intranasal epithelium cells (HNEpCs) were used as an in vitro model to measure immunity responses. HA2-TMC nPs, NP-TMC nPs, and HA2-NP-TMC nPs (influenza nanoparticle constructs) showed no toxicity in HNEpCs. The loading efficiency of HA2 and NP into the TMC nPs was 97.9% and 98.5%, respectively. HA2-TMC nPs and NP-TMC nPs more efficiently delivered HA2 and NP proteins to HNEpCs than soluble HA2 and NP proteins alone. The induction of various cytokines and chemokines was more evident in influenza nanoparticle construct-treated HNEpCs than in soluble protein-treated HNEpCs. In addition, soluble factors secreted by influenza nanoparticle construct-treated HNEpCs significantly induced MoDCs maturation markers (CD80, CD83, CD86 and HLA-DR), as compared to soluble factors secreted by protein-treated HNEpCs. HNEpCs treated with the influenza nanoparticle constructs significantly reduced influenza virus replication in an in vitro challenge assay. The results indicate that TMC nPs can be used as influenza vaccine adjuvants and carriers capable of delivering HA2 and NP proteins to HNEpCs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237218PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410248PMC
October 2020

Major Histocompatibility Complex Class I Chain-Related A and B (MICA and MICB) Gene, Allele, and Haplotype Associations With Dengue Infections in Ethnic Thais.

J Infect Dis 2020 08;222(5):840-846

Department of Transfusion Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Background: Major histocompatibility complex class I chain-related (MIC) A and B (MICA and MICB) are polymorphic stress molecules recognized by natural killer cells. This study was performed to analyze MIC gene profiles in hospitalized Thai children with acute dengue illness.

Methods: MIC allele profiles were determined in a discovery cohort of patients with dengue fever or dengue hemorrhagic fever (DHF) (n = 166) and controls (n = 149). A replication cohort of patients with dengue (n = 222) was used to confirm specific MICB associations with disease.

Results: MICA*045 and MICB*004 associated with susceptibility to DHF in secondary dengue virus (DENV) infections (odds ratio [OR], 3.22; [95% confidence interval (CI), 1.18-8.84] and 1.99 [1.07-2.13], respectively), and MICB*002 with protection from DHF in secondary DENV infections (OR, 0.41; 95% CI, .21-.68). The protective effect of MICB*002 against secondary DHF was confirmed in the replication cohort (OR, 0.43; 95% CI, .22-.82) and was stronger when MICB*002 is present in individuals also carrying HLA-B*18, B*40, and B*44 alleles which form the B44 supertype of functionally related alleles (0.29, 95% CI, .14-.60).

Conclusions: Given that MICB*002 is a low expresser of soluble proteins, these data indicate that surface expression of MICB*002 with B44 supertype alleles on DENV-infected cells confer a protective advantage in controlling DENV infection using natural killer cells.
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http://dx.doi.org/10.1093/infdis/jiaa134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399699PMC
August 2020

Analysis of cell-associated DENV RNA by oligo(dT) primed 5' capture scRNAseq.

Sci Rep 2020 06 3;10(1):9047. Epub 2020 Jun 3.

Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.

Dengue is one of the most widespread vector-borne viral diseases in the world. However, the size, heterogeneity, and temporal dynamics of the cell-associated viral reservoir during acute dengue virus (DENV) infection remains unclear. In this study, we analyzed cells infected in vitro with DENV and PBMC from an individual experiencing a natural DENV infection utilizing 5' capture single cell RNA sequencing (scRNAseq). Both positive- and negative-sense DENV RNA was detected in reactions containing either an oligo(dT) primer alone, or in reactions supplemented with a DENV-specific primer. The addition of a DENV-specific primer did not increase the total amount of DENV RNA captured or the fraction of cells identified as containing DENV RNA. However, inclusion of a DENV-specific cDNA primer did increase the viral genome coverage immediately 5' to the primer binding site. Furthermore, while the majority of intracellular DENV sequence captured in this analysis mapped to the 5' end of the viral genome, distinct patterns of enhanced coverage within the DENV polyprotein coding region were observed. The 5' capture scRNAseq analysis of PBMC not only recapitulated previously published reports by detecting virally infected memory and naïve B cells, but also identified cell-associated genomic variants not observed in contemporaneous serum samples. These results demonstrate that oligo(dT) primed 5' capture scRNAseq can detect DENV RNA and quantify virus-infected cells in physiologically relevant conditions, and provides insight into viral sequence variability within infected cells.
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http://dx.doi.org/10.1038/s41598-020-65939-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270085PMC
June 2020

Molecular epidemiology of dengue fever outbreaks in Bhutan, 2016-2017.

PLoS Negl Trop Dis 2020 04 22;14(4):e0008165. Epub 2020 Apr 22.

Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.

Dengue continues to pose a significant public health problem in tropical and subtropical countries. In Bhutan, first outbreak of dengue fever (DF) was reported in 2004 in a southern border town, followed by sporadic cases over the years. In this study, we analysed DF outbreaks that occurred in 3 different places during the years 2016 and 2017. A total of 533 cases in 2016 and 163 in 2017 were suspected of having of DF, where young adults were mostly affected. A total of 240 acute serum specimens collected and analyzed for serotype by nested RT-PCR revealed predominance of serotypes 1 and 2 (DENV-1 and 2). Phylogenetic analysis using envelope gene for both the serotypes demonstrated cosmopolitan genotype which were closely related to strains from India, indicating that they were probably imported from the neighboring country over the past few years.
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http://dx.doi.org/10.1371/journal.pntd.0008165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176082PMC
April 2020

Transcriptional and clonal characterization of B cell plasmablast diversity following primary and secondary natural DENV infection.

EBioMedicine 2020 Apr 18;54:102733. Epub 2020 Apr 18.

Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States.

Antibody-mediated humoral immunity is thought to play a central role in mediating the immunopathogenesis of acute DENV infection, but limited data are available on the diversity, specificity, and functionality of the antibody response at the molecular level elicited by primary or secondary DENV infection. In order to close this functional gap in our understanding of DENV-specific humoral immunity, we utilized high-throughput single cell RNA sequencing to investigate B cells circulating in both primary and secondary natural DENV infections. We captured full-length paired immunoglobulin receptor sequence data from 9,027 B cells from a total of 6 subjects, including 2,717 plasmablasts. In addition to IgG and IgM class-switched cells, we unexpectedly found a high proportion of the DENV-elicited plasmablasts expressing IgA, principally in individuals with primary DENV infections. These IgA class-switched cells were extensively hypermutated even in individuals with a serologically confirmed primary DENV infection. Utilizing a combination of conventional biochemical assays and high-throughput shotgun mutagenesis, we determined that DENV-reactive IgA class-switched antibodies represent a significant fraction of DENV-reactive Igs generated in response to DENV infection, and that they exhibit a comparable epitope specificity to DENV-reactive IgG antibodies. These results provide insight into the molecular-level diversity of DENV-elicited humoral immunity and identify a heretofore unappreciated IgA plasmablast response to DENV infection.
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http://dx.doi.org/10.1016/j.ebiom.2020.102733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170960PMC
April 2020

Pre-existing chikungunya virus neutralizing antibodies correlate with risk of symptomatic infection and subclinical seroconversion in a Philippine cohort.

Int J Infect Dis 2020 Jun 1;95:167-173. Epub 2020 Apr 1.

Department of Genetics, University of Cambridge, Cambridge, UK.

Background: A longitudinal cohort study performed in Cebu City, Philippines found that the presence of pre-existing chikungunya virus (CHIKV) neutralizing antibodies (NAb) was associated with a decreased risk of symptomatic CHIKV infection. However, the relationship between pre-existing NAb and the risk of subclinical seroconversion has not been well described.

Methods: Data were analyzed from a longitudinal cohort aged 6 months to 83 years who underwent active fever surveillance in Cebu City, Philippines from 2012 to 2014. Participants with a history of fever underwent acute and 3-week convalescent visits with blood collection, and annual visits at baseline, 12 months, and 24 months. Symptomatic CHIKV infections were detected by PCR of acute illness sera. Subclinical seroconversion was defined as a ≥8-fold rise in 80% plaque reduction neutralization test (PRNT80) titer between annual visits without intervening symptomatic infection.

Results: Among 854 participants who completed the 12-month visit (year 1) and 765 who completed the 24-month visit (year 2), 25 symptomatic CHIKV infections and 104 subclinical seroconversions occurred among 615 individuals with no detectable pre-year NAb in year 1 and 444 in year 2, while no symptomatic infections and one subclinical seroconversion occurred in those with a pre-year PRNT80 titer ≥1:10. Pre-year PRNT80 titer ≥1:10 was associated with zero relative risk of symptomatic CHIKV infection and 0.018 risk of subclinical seroconversion.

Conclusions: The presence of detectable pre-existing CHIKV NAb correlated with a decreased risk of both symptomatic CHIKV infection and subclinical seroconversion. These findings support the potential use of CHIKV NAb titer as a surrogate endpoint of protection from infection for vaccine development.
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http://dx.doi.org/10.1016/j.ijid.2020.03.073DOI Listing
June 2020

Key Findings and Comparisons From Analogous Case-Cluster Studies for Dengue Virus Infection Conducted in Machala, Ecuador, and Kamphaeng Phet, Thailand.

Front Public Health 2020 12;8. Epub 2020 Feb 12.

Department of Medicine, SUNY Upstate Medical University, Syracuse, NY, United States.

Dengue viruses (DENV) pose a significant and increasing threat to human health across broad regions of the globe. Currently, prevention, control, and treatment strategies are limited. Promising interventions are on the horizon, including multiple vaccine candidates under development and a renewed and innovative focus on controlling the vector, . However, significant gaps persist in our understanding of the similarities and differences in DENV epidemiology across regions of potential implementation and evaluation. In this manuscript, we highlight and compare findings from two analogous cluster-based studies for DENV transmission and pathogenesis conducted in Thailand and Ecuador to identify key features and questions for further pursuit. Despite a remarkably similar incidence of DENV infection among enrolled neighborhood contacts at the two sites, we note a higher occurrence of secondary infection and severe illness in Thailand compared to Ecuador. A higher force of infection in Thailand, defined as the incidence of infection among susceptible individuals, is suggested by the higher number of captured mosquitoes per household, the increasing proportion of asymptomatic infections with advancing age, and the high proportion of infections identified as secondary-type infections by serology. These observations should be confirmed in long-term, parallel prospective cohort studies conducted across regions, which would advantageously permit characterization of baseline immune status (susceptibility) and contemporaneous assessment of risks and risk factors for dengue illness.
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http://dx.doi.org/10.3389/fpubh.2020.00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028768PMC
May 2021

An Innovative, Prospective, Hybrid Cohort-Cluster Study Design to Characterize Dengue Virus Transmission in Multigenerational Households in Kamphaeng Phet, Thailand.

Am J Epidemiol 2020 07;189(7):648-659

Difficulties inherent in the identification of immune correlates of protection or severe disease have challenged the development and evaluation of dengue vaccines. There persist substantial gaps in knowledge about the complex effects of age and sequential dengue virus (DENV) exposures on these correlations. To address these gaps, we were conducting a novel family-based cohort-cluster study for DENV transmission in Kamphaeng Phet, Thailand. The study began in 2015 and is funded until at least 2023. As of May 2019, 2,870 individuals in 485 families were actively enrolled. The families comprise at least 1 child born into the study as a newborn, 1 other child, a parent, and a grandparent. The median age of enrolled participants is 21 years (range 0-93 years). Active surveillance is performed to detect acute dengue illnesses, and annual blood testing identifies subclinical seroconversions. Extended follow-up of this cohort will detect sequential infections and correlate antibody kinetics and sequence of infections with disease outcomes. The central goal of this prospective study is to characterize how different DENV exposure histories within multigenerational family units, from DENV-naive infants to grandparents with multiple prior DENV exposures, affect transmission, disease, and protection at the level of the individual, household, and community.
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http://dx.doi.org/10.1093/aje/kwaa008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393304PMC
July 2020

First report of the mcr-1 colistin resistance gene identified in two Escherichia coli isolates from clinical samples, Philippines, 2018.

J Glob Antimicrob Resist 2020 06 9;21:291-293. Epub 2020 Jan 9.

Walter Reed Army Institute of Research, Silver Spring, MD, USA.

Objectives: The first report of a plasmid-borne colistin resistance gene (mcr-1) detected in an Escherichia coli isolate from China heralded the emergence of pandrug-resistant bacteria. Since then, the mcr-1 gene has been detected worldwide, but to date it has not been reported in the Philippines.

Methods: In this study, 123 antimicrobial-resistant isolates collected from January-June 2018 from patients admitted to a tertiary hospital in Manila, Philippines, were characterised. Biochemical identification and antimicrobial susceptibility testing were performed using a BD Phoenix™ M50 system with NMIC/ID-95 panel. Conventional PCR was performed to detect the genes mcr-1 to mcr-5, and short- and long-read whole-genome sequencing was performed.

Results: Two mcr-1-positive E. coli clinical isolates from separate patients harboured mcr-1 on an IncI2 plasmid. One isolate was shown to carry 12 antimicrobial resistance genes (ARGs) in addition to mcr-1, including the extended-spectrum β-lactamase bla, whilst the other E. coli isolate carried 6 ARGs in addition to mcr-1.

Conclusion: Both patients had no prior colistin treatment recorded in their medical history and no travel history outside of the country within the past 6 months from the date of hospital admission, indicating local transmission and acquisition of the colistin-resistant strain from either community or hospital settings within the Philippines. This report should serve as a signal to local public-health officials of the need to intensify surveillance efforts and to increase vigilance and implementation of antimicrobial stewardship programmes to contain and slow the spread of antimicrobial resistance.
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http://dx.doi.org/10.1016/j.jgar.2019.12.018DOI Listing
June 2020

Multidrug Resistant Mycobacterium tuberculosis Among Military and Civilian Personnel seen at a Tertiary Military Hospital, Manila, Philippines (2015-2018).

Mil Med 2020 08;185(7-8):e1106-e1111

Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Springs, MD, USA.

Introduction: About one third of the world population is estimated to be infected with Mycobacterium tuberculosis (MTB), and this proportion is expected to be higher in countries with a high tuberculosis (TB) burden. The Philippines is both a high tuberculosis burden and a high multidrug resistant tuberculosis (MDR-TB) burden country. Though TB has been extensively described in the civilian population, there is limited data on TB in the military population. The objectives are: (1) To determine MTB/MDR-TB prevalence among military and civilian patients in the Philippines presenting with clinically suspected TB in a tertiary military hospital and (2) To determine performance of direct sputum smear microscopy (DSSM) using Ziehl-Neelsen (ZN) staining compared to Xpert MTB/RIF real-time reverse transcriptase polymerase chain reaction.

Materials And Methods: Sputum samples were obtained from patients, clinically suspected with TB, and/or with TB associated signs/symptoms. Sputum specimens were tested using DSSM with ZN staining and Xpert MTB/RIF assay (Cepheid, Sunnyvale, California) and patient demographic and clinical data were collected.

Results: From March 2015 to December 2018, a total of 795 (173 military personnel [164 active duty and 9 retired]; 618 civilians; and 4 with no data on military/civilian status) patients with TB associated symptoms or clinically suspected with TB were tested. Overall, MTB prevalence was 81/795 (10%). MTB prevalence among active duty and retired military personnel were 27/164 (16%) and 4/9 (44%), respectively while MTB prevalence for civilian patients was 50/618 (8%) (p value = 0.0003; OR = 2.48 [95% C.I. 1.5-4]). Among active and retired military personnel who tested positive for MTB, rifampin resistance was 4/27 (15%) and 1/4 (25%), respectively, while rifampin resistance for civilian patients was 9/50 (18%) (p value = 1; OR = 0.88 [95% C.I. 0.26-2.90]). For active duty military personnel, average MTB prevalence (based on Xpert MTB/RIF) covering years 2015-2018 was 21% and ranged from 13% to 35%, while average rifampin resistance among MTB positive active duty military personnel was 15% and ranged from 0% to 25%. Overall sensitivity and specificity of DSSM compared to Xpert MTB/RIF were 70% and 96%, respectively. Positive and negative predictive values of DSSM to accurately categorize MTB in symptomatic cases (with Xpert MTB/RIF as "true positive" reference) were 74% and 95%, respectively. Performance of DSSM varied according to MTB load detected by Xpert MTB/RIF with increasing DSSM sensitivity observed as the MTB load detected by Xpert MTB/RIF increased (p = 0.02).

Conclusion: This report describes high MTB and MDR-TB prevalence rates among symptomatic military patients with military personnel having higher odds of MTB infection compared to the civilian patients in the study. Since DSSM (ZN) sensitivity greatly varied depending on MTB load, the Xpert MTB/RIF should be used as a first-line diagnostic tool to identify MTB and detect rifampin resistance among presumptive TB cases instead of DSSM (ZN) microscopy.
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http://dx.doi.org/10.1093/milmed/usz456DOI Listing
August 2020

Influenza virus seroincidence in a cohort of healthy and high-risk children enrolled in infancy, Bangkok, Thailand.

Int J Infect Dis 2019 Dec 27;89:21-26. Epub 2019 Aug 27.

Influenza Program, Thailand Ministry of Public Health - U.S. Centers for Disease Control and Prevention Collaboration, Nonthaburi, Thailand; Influenza Division, U.S. Centers for Disease Control and Prevention, Georgia, USA.

Background: We measured seroconversion to influenza viruses and incidence of symptomatic influenza virus infection in a cohort of children in Bangkok, Thailand.

Methods: Children aged ≤6 months were followed for two years for acute respiratory illness (ARI) and had serum specimens taken at 6-month intervals and tested by hemagglutination inhibition (HI) assay. Seroconversion was defined as a >4-fold rise in the HI titers between time points with a titer of >40 in the second specimen. Respiratory swabs were tested by rRT-PCR for influenza. Data were analyzed using generalized linear models.

Results: Of 350 children, 266 (76%, 147 were healthy and 119 were high-risk) had ≥2 serum specimens collected before influenza vaccination. During the 2-year follow-up, 266 children contributed 370 person-years of observation, excluding post-vaccination periods. We identified 32 ARI cases with rRT-PCR-confirmed influenza virus infection (7 infections/100 person-years, 95% confidence interval [CI], 4-11). There were 126 episodes of influenza virus infection, resulting in a seroconversion rate of 35 infections/100 person-years (95% CI, 30-42). Rates in healthy and high-risk children did not differ.

Conclusions: Influenza virus infection is common during the first two years of life among Thai children. A large proportion of infections may not be detected using the ARI case definition.
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http://dx.doi.org/10.1016/j.ijid.2019.08.022DOI Listing
December 2019

Standard-Dose Intradermal Influenza Vaccine Elicits Cellular Immune Responses Similar to Those of Intramuscular Vaccine in Men With and Those Without HIV Infection.

J Infect Dis 2019 07;220(5):743-751

Influenza Division, National Center for Immunization and Respiratory Diseases, Atlanta, Georgia.

Background: Human immunodeficiency virus (HIV)-infected persons are at a higher risk of severe influenza. Although we have shown that a standard-dose intradermal influenza vaccine versus a standard-dose intramuscular influenza vaccine does not result in differences in hemagglutination-inhibition titers in this population, a comprehensive examination of cell-mediated immune responses remains lacking.

Methods: Serological, antigen-specific B-cell, and interleukin 2-, interferon γ-, and tumor necrosis factor α-secreting T-cell responses were assessed in 79 HIV-infected men and 79 HIV-uninfected men.

Results: The route of vaccination did not affect the immunoglobulin A and immunoglobulin G (IgG) plasmablast or memory B-cell response, although these were severely impaired in the group with a CD4+ T-cell count of <200 cells/μL. The frequencies of IgG memory B cells measured on day 28 after vaccination were highest in the HIV-uninfected group, followed by the group with a CD4+ T-cell count of ≥200 cells/μL and the group with a CD4+ T-cell count of <200 cells/μL. The route of vaccination did not affect the CD4+ or CD8+ T-cell responses measured at various times after vaccination.

Conclusions: The route of vaccination had no effect on antibody responses, antibody avidity, T-cell responses, or B-cell responses in HIV-infected or HIV-uninfected subjects. With the serological and cellular immune responses to influenza vaccination being impaired in HIV-infected individuals with a CD4+ T-cell count of <200 cells/μL, passive immunization strategies need to be explored to protect this population.

Clinical Trials Registration: NCT01538940.
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http://dx.doi.org/10.1093/infdis/jiz205DOI Listing
July 2019

Impact of Dengue Virus Serotype 2 Strain Diversity on Serological Immune Responses to Dengue.

ACS Infect Dis 2018 12 5;4(12):1705-1717. Epub 2018 Nov 5.

Molecular and Translational Sciences Division , U.S. Army Medical Research Institute of Infectious Diseases , 1425 Porter Street , Frederick , Maryland 21702 , United States.

Dengue is a mosquito-borne disease caused by four dengue virus serotypes (DENV1-4) that are loosely categorized by sequence commonalities and antibody recognition profiles. The highly variable envelope protein (E) that is prominently displayed on the surface of DENV is an essential component of vaccines currently under development, yet the impact of using single strains to represent each serotype in tetravalent vaccines has not been adequately studied. We synthesized chimeric E by replacing highly variable residues from a dengue virus serotype 2 vaccine strain (PUO-218) with those from 16 DENV2 lineages spanning 60 years of antigen evolution. Examining sera from human and rhesus macaques challenged with single strains of DENV2, antibody-E interactions were markedly inhibited or enhanced by residues mainly focused within a 480 Å footprint displayed on the E backbone. The striking impact of E diversity on polyclonal immune responses suggests that frequent antigen updates may be necessary for vaccines to counter shifts in circulating strains.
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http://dx.doi.org/10.1021/acsinfecdis.8b00185DOI Listing
December 2018

Association between semi-quantitative microbial load and respiratory symptoms among Thai military recruits: a prospective cohort study.

BMC Infect Dis 2018 Sep 14;18(1):462. Epub 2018 Sep 14.

Phramongkutklao Hospital, Bangkok, 10400, Thailand.

Background: Multiplex real-time polymerase chain reaction assays have improved diagnostic sensitivity for a wide range of pathogens. However, co-detection of multiple agents and bacterial colonization make it difficult to distinguish between asymptomatic infection or illness aetiology. We assessed whether semi-quantitative microbial load data can differentiate between symptomatic and asymptomatic states for common respiratory pathogens.

Methods: We obtained throat and nasal swab samples from military trainees at two Thai Army barracks. Specimens were collected at the start and end of 10-week training periods (non-acute samples), and from individuals who developed upper respiratory tract infection during training (acute samples). We analysed the samples using a commercial multiplex respiratory panel comprising 33 bacterial, viral and fungal targets. We used random effects tobit models to compare cycle threshold (Ct) value distributions from non-acute and acute samples.

Results: We analysed 341 non-acute and 145 acute swab samples from 274 participants. Haemophilus influenzae type B was the most commonly detected microbe (77.4% of non-acute and 64.8% of acute samples). In acute samples, nine specific microbe pairs were detected more frequently than expected by chance. Regression models indicated significantly lower microbial load in non-acute relative to acute samples for H. influenzae non-type B, Streptococcus pneumoniae and rhinovirus, although it was not possible to identify a Ct-value threshold indicating causal etiology for any of these organisms.

Conclusions: Semi-quantitative measures of microbial concentration did not reliably differentiate between illness and asymptomatic colonization, suggesting that clinical symptoms may not always be directly related to microbial load for common respiratory infections.
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http://dx.doi.org/10.1186/s12879-018-3358-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137728PMC
September 2018

Epidemiology and Transmission of Respiratory Infections in Thai Army Recruits: A Prospective Cohort Study.

Am J Trop Med Hyg 2018 10;99(4):1089-1095

Phramongkutklao Hospital, Bangkok, Thailand.

Military recruits are at high risk of respiratory infections. However, limited data exist on military populations in tropical settings, where the epidemiology of respiratory infections differs substantially from temperate settings. We enrolled recruits undertaking a 10-week military training at two Royal Thai Army barracks between May 2014 and July 2015. We used a multiplex respiratory panel to analyze nose and throat swabs collected at the start and end of the training period, and from participants experiencing respiratory symptoms during follow-up. Paired sera were tested for influenza seroconversion using a hemagglutinin inhibition assay. Overall rates of upper respiratory illness and influenza-like illness were 3.1 and 2.0 episodes per 100 person-weeks, respectively. A pathogen was detected in 96% of samples. The most commonly detected microbes were type B (62.7%) or non-type B (58.2%) and rhinovirus (22.4%). At baseline, bacterial colonization was high and included type B (82.3%), non-type B (31.5%), (14.6%), (8.5%), and (8.5%). At the end of follow-up, colonization with non-type B had increased to 74.1%, and to 33.6%. In the serology subset, the rate of influenza infection was 3.4 per 100 person-months; 58% of influenza infections resulted in clinical disease. Our study provides key data on the epidemiology and transmission of respiratory pathogens in tropical settings. Our results emphasize the need for improved infection prevention and control in military environments, given the high burden of illness and potential for intense transmission of respiratory pathogens.
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http://dx.doi.org/10.4269/ajtmh.18-0219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159564PMC
October 2018

Comparison of incidence and cost of influenza between healthy and high-risk children <60 months old in Thailand, 2011-2015.

PLoS One 2018 17;13(5):e0197207. Epub 2018 May 17.

Influenza Division, U.S. Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.

Introduction: Thailand recommends influenza vaccination for children aged 6 months to <36 months, but investment in vaccine purchase is limited. To inform policy decision with respect to influenza disease burden and associated cost in young children and to support the continued inclusion of children as the recommended group for influenza vaccination, we conducted a prospective cohort study of children in Bangkok hospital to estimate and compare influenza incidence and cost between healthy and high-risk children.

Methods: Caregivers of healthy children and children with medical conditions ('high-risk') aged <36 months were called weekly for two years to identify acute respiratory illness (ARI) episodes and collect illness-associated costs. Children with ARI were tested for influenza viruses by polymerase chain reaction. Illnesses were categorized as mild or severe depending on whether children were hospitalized. Population-averaged Poisson models were used to compare influenza incidence by risk group. Quantile regression was used to examine differences in the median illness expenses.

Results: During August 2011-September 2015, 659 healthy and 490 high-risk children were enrolled; median age was 10 months. Incidence of mild influenza-associated ARI was higher among healthy than high-risk children (incidence rate ratio [IRR]: 1.67; 95% confidence interval [CI]: 1.13-2.48). Incidence of severe influenza-associated ARI did not differ (IRR: 0.40; 95% CI: 0.11-1.38). The median cost per mild influenza-associated ARI episode was $22 among healthy and $25 among high-risk children (3-4% of monthly household income; difference in medians: -$1; 95% CI for difference in medians: -$9 to $6). The median cost per severe influenza-associated ARI episode was $232 among healthy and $318 among high-risk children (26-40% and 36-54% of monthly household income, respectively; difference in medians: 110; 95% CI for difference in medians: -$352 to $571).

Conclusions: Compared to high-risk children, healthy children had higher incidence of mild influenza-associated ARI but not severe influenza-associated ARI. Costs of severe influenza-associated ARI were substantial. These findings support the benefit of annual influenza vaccination in reducing the burden of influenza and associated cost in young children.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197207PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957403PMC
August 2018
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