Publications by authors named "Robert V Gibbons"

125 Publications

Cell-mediated immune responses to different formulations of a live-attenuated tetravalent dengue vaccine candidate in subjects living in dengue endemic and non-endemic regions.

Hum Vaccin Immunother 2019 15;15(9):2090-2105. Epub 2019 Apr 15.

Department of Pediatrics, Phramongkutklao Hospital , Bangkok , Thailand.

Three phase II randomized trials evaluated the safety/immunogenicity of two formulations of live-attenuated tetravalent dengue virus (TDEN) vaccine in dengue-endemic (Puerto Rico, Thailand) and non-endemic (US) regions (NCT00350337/NCT00370682/NCT00468858). We describe cell-mediated immune (CMI) responses; safety and humoral responses were reported previously. Participants received two doses of vaccine or control (placebo or the precursor live-attenuated TDEN vaccine) 6 months apart. Selected US participants received a booster 5-12 months post-dose 2. Evaluated subsets of the per-protocol cohorts included 75 primarily dengue virus (DENV)-unprimed US adults, 69 primarily flavivirus-primed Thai adults, and 100 DENV-primed or DENV-unprimed Puerto Rican adults/adolescents/children. T-cell responses were quantified using intracellular cytokine staining (ICS; DENV-infected cell-lysate or DENV-1/DENV-2 peptide-pool stimulation) or IFN-γ ELISPOT (DENV-2 peptide-pool stimulation). Memory B-cell responses were quantified using B-cell ELISPOT. Across populations and age strata, DENV serotype-specific CD4 T-cell responses were slightly to moderately increased (medians ≤0.18% [ICS]), DENV-2-biased, and variable for both formulations. Responses in unprimed subjects were primarily detected post-dose 1. Response magnitudes in primed subjects were similar between doses. Multifunctional CD8 T-cell responses were detected after peptide-pool stimulation. T-cell responses were mostly directed to DENV nonstructural proteins 3 and 5. Memory B-cell responses were tetravalent, of low-to-moderate magnitudes (medians ≤0.25%), and mainly observed post-dose 2 in unprimed subjects and post-dose 1 in primed subjects. A third dose did not boost CMI responses. In conclusion, both formulations of the live-attenuated TDEN vaccine candidate were poorly to moderately immunogenic with respect to B-cell and T-cell responses, irrespective of the priming status of the participants. ATP: according-to-protocol; ICS: Intracellular Cytokine Staining; NS3: Nonstructural protein 3; ELISPOT: Enzyme-Linked ImmunoSpot; JEV: Japanese encephalitis virus; PBMC: peripheral blood mononuclear cells.
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http://dx.doi.org/10.1080/21645515.2019.1581536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773406PMC
March 2020

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

A Survey of Wilderness Medicine Analgesia Practice Patterns.

Wilderness Environ Med 2018 06 22;29(2):211-214. Epub 2018 Mar 22.

University of Colorado School of Medicine, Aurora, CO (Dr Cushing).

Introduction: In 2014, the Wilderness Medical Society (WMS) published guidelines for the treatment of acute pain in remote settings. We surveyed wilderness medicine providers on self-reported analgesia prescribing practices.

Methods: We conducted a prospective, anonymous survey. Respondents were recruited from the WMS annual symposium in 2016. All willing attendees were included.

Results: During the symposium, we collected a total of 124 surveys (68% response rate). Respondent age was 42±12 (24-79) years (mean±SD with range), 58% were male, and 69% reported physician-level training. All respondents had medical training of varying levels. Of the physicians reporting a specialty, emergency medicine (59%, n=51), family medicine (13%, n=11), and internal medicine (8%, n=7) were reported most frequently. Eighty-one (65%) respondents indicated they prefer a standardized pain assessment tool, with the 10-point numerical rating scale being the most common (54%, n=67). Most participants reported preferring oral acetaminophen (81%, n=101) or nonsteroidal anti-inflammatory drugs (NSAID) (91%, n=113). Of those preferring NSAID, most reported administering acetaminophen as an adjunct (82%, n=101). Ibuprofen was the most frequently cited NSAID (71%, n=88). Of respondents who preferred opioids, the most frequently preferred opioid was oxycodone (26%, n=32); a lower proportion of respondents reported preferring oral transmucosal fentanyl citrate (9%, n=11). Twenty-five (20%, n=25) respondents preferred ketamine.

Conclusions: Wilderness medicine practitioners prefer analgesic agents recommended by the WMS for the treatment of acute pain. Respondents most frequently preferred acetaminophen and NSAIDs.
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http://dx.doi.org/10.1016/j.wem.2018.01.009DOI Listing
June 2018

Clinical and laboratory predictors of influenza infection among individuals with influenza-like illness presenting to an urban Thai hospital over a five-year period.

PLoS One 2018 7;13(3):e0193050. Epub 2018 Mar 7.

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

Early diagnosis of influenza infection maximizes the effectiveness of antiviral medicines. Here, we assess the ability for clinical characteristics and rapid influenza tests to predict PCR-confirmed influenza infection in a sentinel, cross-sectional study for influenza-like illness (ILI) in Thailand. Participants meeting criteria for acute ILI (fever > 38°C and cough or sore throat) were recruited from inpatient and outpatient departments in Bangkok, Thailand, from 2009-2014. The primary endpoint for the study was the occurrence of virologically-confirmed influenza infection (based upon detection of viral RNA by RT-PCR) among individuals presenting for care with ILI. Nasal and throat swabs were tested by rapid influenza test (QuickVue) and by RT-PCR. Vaccine effectiveness (VE) was calculated using the case test-negative method. Classification and Regression Tree (CART) analysis was used to predict influenza RT-PCR positivity based upon symptoms reported. We enrolled 4572 individuals with ILI; 32.7% had detectable influenza RNA by RT-PCR. Influenza cases were attributable to influenza B (38.6%), A(H1N1)pdm09 (35.1%), and A(H3N2) (26.3%) viruses. VE was highest against influenza A(H1N1)pdm09 virus and among adults. The most important symptoms for predicting influenza PCR-positivity among patients with ILI were cough, runny nose, chills, and body aches. The accuracy of the CART predictive model was 72.8%, with an NPV of 78.1% and a PPV of 59.7%. During epidemic periods, PPV improved to 68.5%. The PPV of the QuickVue assay relative to RT-PCR was 93.0% overall, with peak performance during epidemic periods and in the absence of oseltamivir treatment. Clinical criteria demonstrated poor predictive capability outside of epidemic periods while rapid tests were reasonably accurate and may provide an acceptable alternative to RT-PCR testing in resource-limited areas.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193050PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841736PMC
June 2018

Polytopic vaccination with a live-attenuated dengue vaccine enhances B-cell and T-cell activation, but not neutralizing antibodies.

Heliyon 2017 Mar 21;3(3):e00271. Epub 2017 Mar 21.

The United States Army Medical Materiel Development Activity, Fort Detrick, MD, USA.

Dengue, caused by dengue viruses (DENVs), is the most common arboviral disease of humans. Several dengue vaccine candidates are at different stages of clinical development and one has been licensed. Inoculation with live-attenuated DENV constructs is an approach that has been used by vaccine developers. Unfortunately, the simultaneous injection of all four attenuated DENV serotypes (DENV1-4) into a single injection site (monotopic vaccination) has been postulated to result in interference in the replication of some serotypes in favor of others, an important obstacle in obtaining a balanced immune response against all serotypes. Here, we demonstrate the virus replicative and immunostimulatory effects of polytopic monovalent dengue vaccination (PV) in which, each of the four components of the tetravalent vaccine is simultaneously delivered to four different sites versus the more traditional monotopic tetravalent vaccination (MV) in a non-human primate (NHP) model. With the exception of DENV-2, there was no significant difference in detectable viral RNA levels between PV and MV inoculation. Interestingly, longer periods of detection and higher viral RNA levels were seen in the lymph nodes of NHPs inoculated PV compared to MV. Induction of lymph node dendritic cell maturation and of blood T- and B-cell activation showed different kinetics in PV inoculated NHPs compared to MV. The MV inoculated group showed earlier maturation of dendritic cells and activation of B and T cells compared to PV inoculated NHPs. A similar kinetic difference was also observed in the cytokine response: MV induced earlier cytokine responses compared to PV. However, similar levels of DENV neutralizing antibodies were observed in PV and MV NHPs. These findings indicate that cellular immune response after vaccination may be affected by the location of inoculation. Design of vaccine delivery may need to take into account the effects of locations of vaccine delivery of multiples serotype live viral vaccine on the induction of immune response.
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http://dx.doi.org/10.1016/j.heliyon.2017.e00271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367862PMC
March 2017

Dengue diversity across spatial and temporal scales: Local structure and the effect of host population size.

Science 2017 03;355(6331):1302-1306

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.

A fundamental mystery for dengue and other infectious pathogens is how observed patterns of cases relate to actual chains of individual transmission events. These pathways are intimately tied to the mechanisms by which strains interact and compete across spatial scales. Phylogeographic methods have been used to characterize pathogen dispersal at global and regional scales but have yielded few insights into the local spatiotemporal structure of endemic transmission. Using geolocated genotype (800 cases) and serotype (17,291 cases) data, we show that in Bangkok, Thailand, 60% of dengue cases living <200 meters apart come from the same transmission chain, as opposed to 3% of cases separated by 1 to 5 kilometers. At distances <200 meters from a case (encompassing an average of 1300 people in Bangkok), the effective number of chains is 1.7. This number rises by a factor of 7 for each 10-fold increase in the population of the "enclosed" region. This trend is observed regardless of whether population density or area increases, though increases in density over 7000 people per square kilometer do not lead to additional chains. Within Thailand these chains quickly mix, and by the next dengue season viral lineages are no longer highly spatially structured within the country. In contrast, viral flow to neighboring countries is limited. These findings are consistent with local, density-dependent transmission and implicate densely populated communities as key sources of viral diversity, with home location the focal point of transmission. These findings have important implications for targeted vector control and active surveillance.
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http://dx.doi.org/10.1126/science.aaj9384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777672PMC
March 2017

State-of-the-art monitoring in treatment of dengue shock syndrome: a case series.

J Med Case Rep 2016 Aug 24;10(1):233. Epub 2016 Aug 24.

US Army Institute of Surgical Research, 3698 Chambers Pass, JBSA Fort Sam Houston, TX, 78234-7549, USA.

Background: Early recognition and treatment of circulatory volume loss is essential in the clinical management of dengue viral infection. We hypothesized that a novel computational algorithm, originally developed for noninvasive monitoring of blood loss in combat casualties, could: (1) indicate the central volume status of children with dengue during the early stages of "shock"; and (2) track fluid resuscitation status.

Methods: Continuous noninvasive photoplethysmographic waveforms were collected over a 5-month period from three children of Thai ethnicity with clinical suspicion of dengue. Waveform data were processed by the algorithm to calculate each child's Compensatory Reserve Index, where 1 represents supine normovolemia and 0 represents the circulatory volume at which hemodynamic decompensation occurs. Values between 1 and 0 indicate the proportion of reserve remaining before hemodynamic decompensation.

Results: This case report describes a 7-year-old Thai boy, another 7-year-old Thai boy, and a 9-year-old Thai boy who exhibited signs and symptoms of dengue shock syndrome; all the children had secondary dengue virus infections, documented by serology and reverse transcriptase polymerase chain reaction. The three boys experienced substantial plasma leakage demonstrated by pleural effusion index >25, ascites, and >20 % hemoconcentration. They received fluid administered intravenously; one received a blood transfusion. All three boys showed a significantly low initial Compensatory Reserve Index (≥0.20), indicating a clinical diagnosis of "near shock". Following 5 days with fluid resuscitation treatment, their Compensatory Reserve Index increased towards "normovolemia" (that is, Compensatory Reserve Index >0.75).

Conclusions: The results from these cases demonstrate a new variation in the diagnostic capability to manage patients with dengue shock syndrome. The findings shed new light on a method that can avoid possible adverse effects of shock by noninvasive measurement of a patient's compensatory reserve rather than standard vital signs or invasive diagnostic methods.
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http://dx.doi.org/10.1186/s13256-016-1019-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995799PMC
August 2016

Long-Term Safety and Immunogenicity of a Tetravalent Live-Attenuated Dengue Vaccine and Evaluation of a Booster Dose Administered to Healthy Thai Children.

Am J Trop Med Hyg 2016 06 28;94(6):1348-1358. Epub 2016 Mar 28.

We evaluated the safety and immunogenicity of two doses of a live-attenuated, tetravalent dengue virus vaccine (F17/Pre formulation) and a booster dose in a dengue endemic setting in two studies. Seven children (7- to 8-year-olds) were followed for 1 year after dose 2 and then given a booster dose (F17/Pre formulation), and followed for four more years (Child study). In the Infant study, 49 2-year-olds, vaccinated as infants, were followed for approximately 3.5 years after dose 2 and then given a booster dose (F17) and followed for one additional year. Two clinically notable events were observed, both in dengue vaccine recipients in the Infant study: 1 case of dengue approximately 2.7 years after dose 2 and 1 case of suspected dengue after booster vaccinations. The booster vaccinations had a favorable safety profile in terms of reactogenicity and adverse events reported during the 1-month follow-up periods. No vaccine-related serious adverse events were reported during the studies. Neutralizing antibodies against dengue viruses 1-4 waned during the 1-3 years before boosting, which elicited a short-lived booster response but did not provide a long-lived, multivalent antibody response in most subjects. Overall, this candidate vaccine did not elicit a durable humoral immune response.
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http://dx.doi.org/10.4269/ajtmh.15-0659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889756PMC
June 2016

Dengue Virus (DENV) Neutralizing Antibody Kinetics in Children After Symptomatic Primary and Postprimary DENV Infection.

J Infect Dis 2016 May 23;213(9):1428-35. Epub 2015 Dec 23.

Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland Department of Biology, University of Florida, Gainesville Emerging Pathogens Institute, University of Florida, Gainesville.

The immune response to dengue virus (DENV) infection is complex and not fully understood. Using longitudinal data from 181 children with dengue in Thailand who were followed for up to 3 years, we describe neutralizing antibody kinetics following symptomatic DENV infection. We observed that antibody titers varied by serotype, homotypic vs heterotypic responses, and primary versus postprimary infections. The rates of change in antibody titers over time varied between primary and postprimary responses. For primary infections, titers increased from convalescence to 6 months. By comparing homotypic and heterotypic antibody titers, we saw an increase in type specificity from convalescence to 6 months for primary DENV3 infections but not primary DENV1 infections. In postprimary cases, there was a decrease in titers from convalescence up until 6 months after infection. Beginning 1 year after both primary and postprimary infections, there was evidence of increasing antibody titers, with greater increases in children with lower titers, suggesting that antibody titers were boosted due to infection and that higher levels of neutralizing antibody may be more likely to confer a sterilizing immune response. These findings may help to model virus transmission dynamics and provide baseline data to support the development of vaccines and therapeutics.
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http://dx.doi.org/10.1093/infdis/jiv759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4813744PMC
May 2016

Randomized Controlled Trial to Compare Immunogenicity of Standard-Dose Intramuscular Versus Intradermal Trivalent Inactivated Influenza Vaccine in HIV-Infected Men Who Have Sex With Men in Bangkok, Thailand.

Clin Infect Dis 2016 Feb 20;62(3):383-391. Epub 2015 Oct 20.

Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia.

Background: Individuals infected with human immunodeficiency virus (HIV) are at increased risk for severe influenza, yet immune responses to standard-dose intramuscular (IM) influenza vaccine are suboptimal in this population. Intradermal (ID) delivery of influenza vaccine might improve immune response through enhanced stimulation of dendritic cells.

Methods: We conducted a randomized, double-blind, controlled trial to compare the immunogenicity of off-label standard-dose (15 µg) ID vs standard-dose (15 µg) IM inactive influenza vaccine in HIV-infected men in Bangkok, Thailand. The primary study outcome was seroconversion (minimum titer of 1:40 and ≥4-fold rise in antibody titer) at 1 month postvaccination based on serum hemagglutination inhibition antibody titers against each vaccine strain. Adverse events (AEs) in the 7 days following vaccination were also assessed.

Results: We enrolled 400 HIV-infected participants; 200 were randomly assigned to receive IM and 200 ID vaccine. Vaccine arms were well-balanced with respect to age, CD4 cell count, HIV RNA load, and antiretroviral treatment. Percentage of seroconversion to all (ID 14% vs IM 15%; P = .8) or at least 1 (ID 69% vs IM 68%; P = .7) of the 3 vaccine strains did not differ significantly between ID vs IM vaccine recipients. A higher proportion of participants who received ID vaccine had mild injection-site AEs compared with participants who received IM vaccine (77% vs 27%).

Conclusions: There were no significant differences in the immunogenicity of standard-dose ID vs IM influenza vaccine in this HIV-infected population in Thailand. Additional strategies to enhance immune responses to influenza vaccine among HIV-infected persons are needed.

Clinical Trials Registration: NCT01538940.
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http://dx.doi.org/10.1093/cid/civ884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707082PMC
February 2016

Region-wide synchrony and traveling waves of dengue across eight countries in Southeast Asia.

Proc Natl Acad Sci U S A 2015 Oct 5;112(42):13069-74. Epub 2015 Oct 5.

Department of Biology, University of Florida, Gainesville, FL 32610; Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610.

Dengue is a mosquito-transmitted virus infection that causes epidemics of febrile illness and hemorrhagic fever across the tropics and subtropics worldwide. Annual epidemics are commonly observed, but there is substantial spatiotemporal heterogeneity in intensity. A better understanding of this heterogeneity in dengue transmission could lead to improved epidemic prediction and disease control. Time series decomposition methods enable the isolation and study of temporal epidemic dynamics with a specific periodicity (e.g., annual cycles related to climatic drivers and multiannual cycles caused by dynamics in population immunity). We collected and analyzed up to 18 y of monthly dengue surveillance reports on a total of 3.5 million reported dengue cases from 273 provinces in eight countries in Southeast Asia, covering ∼ 10(7) km(2). We detected strong patterns of synchronous dengue transmission across the entire region, most markedly during a period of high incidence in 1997-1998, which was followed by a period of extremely low incidence in 2001-2002. This synchrony in dengue incidence coincided with elevated temperatures throughout the region in 1997-1998 and the strongest El Niño episode of the century. Multiannual dengue cycles (2-5 y) were highly coherent with the Oceanic Niño Index, and synchrony of these cycles increased with temperature. We also detected localized traveling waves of multiannual dengue epidemic cycles in Thailand, Laos, and the Philippines that were dependent on temperature. This study reveals forcing mechanisms that drive synchronization of dengue epidemics on a continental scale across Southeast Asia.
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http://dx.doi.org/10.1073/pnas.1501375112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620875PMC
October 2015

Dengue viruses cluster antigenically but not as discrete serotypes.

Science 2015 Sep;349(6254):1338-43

Center for Pathogen Evolution, Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ, UK. World Health Organization (WHO) Collaborating Center for Modeling, Evolution, and Control of Emerging Infectious Diseases, Cambridge CB2 3EJ, UK. Department of Viroscience, Erasmus MC, Rotterdam 3015 GE, Netherlands.

The four genetically divergent dengue virus (DENV) types are traditionally classified as serotypes. Antigenic and genetic differences among the DENV types influence disease outcome, vaccine-induced protection, epidemic magnitude, and viral evolution. We characterized antigenic diversity in the DENV types by antigenic maps constructed from neutralizing antibody titers obtained from African green monkeys and after human vaccination and natural infections. Genetically, geographically, and temporally, diverse DENV isolates clustered loosely by type, but we found that many are as similar antigenically to a virus of a different type as to some viruses of the same type. Primary infection antisera did not neutralize all viruses of the same DENV type any better than other types did up to 2 years after infection and did not show improved neutralization to homologous type isolates. That the canonical DENV types are not antigenically homogeneous has implications for vaccination and research on the dynamics of immunity, disease, and the evolution of DENV.
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http://dx.doi.org/10.1126/science.aac5017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876809PMC
September 2015

Patterns of Flavivirus Seroprevalence in the Human Population of Northern Laos.

Am J Trop Med Hyg 2015 Nov 24;93(5):1010-1013. Epub 2015 Aug 24.

A total of 1,136 samples from 289 households in four provinces in northern Laos were subjected to Japanese encephalitis virus (JEV) and dengue virus hemagglutination inhibition (DENV HI). Overall, antibodies to JEV were detected by HI in 620 (54.6%) of 1,136 people; of which 217 (19.1%) had HI activity against JEV only. Antibodies to DENV4 were detected by HI in 526 (46.3%) of 1,136 people; of which 124 (10.9%) had HI activity against DENV4 only. Antibodies to DENV1-3 were detected by HI in 296 (26.1%), 274 (24.1%), and 283 (24.9) of 1,136 people, respectively; of which 7, 1, and 0, respectively, had HI activity against DENV1-3 only. JEV was the most prevalent Flavivirus in Oudomxay, Luangprabang, and Huaphan provinces and DENV4 was the most prevalent in Xiengkhouang province. Seroprevalence for JEV increased with increasing age and wealth and was higher in villages where rice was cultivated in paddy fields and highest for people of Lao-Tai ethnicity.
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http://dx.doi.org/10.4269/ajtmh.15-0072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703266PMC
November 2015

Elevated transmission of upper respiratory illness among new recruits in military barracks in Thailand.

Influenza Other Respir Viruses 2015 Nov;9(6):308-314

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

Background: New recruits within military barracks present conditions favorable for the spread of respiratory pathogens. However, respiratory pathogen transmission in such confined settings in the tropics has not been well studied.

Methods: Recruits in four successive Royal Thai Army basic training classes living in military barracks were monitored for the symptoms of influenza-like illness (ILI) or upper respiratory illness (URI). Classes 1 and 2 were also monitored after basic training. Nasal/throat swabs from acute illnesses were collected and tested by influenza RT-PCR (all four classes). In addition, class 1 had multiplex PCR performed along with the analysis of bed locations within the barracks.

Results: Influenza-like illness/upper respiratory illness rates ranged from 4·7 to 6·9 per 100 recruit-weeks in the four classes and generally decreased during the course of basic training (P < 0·05 in three of four classes). Rates during basic training were 1·7 (95% CI: 1·29, 2·29) and 2·5 (95% CI: 1·5, 4·1) times higher than after basic training (classes 1 and 2, respectively). In class 1, coronavirus, parainfluenza virus, and rhinovirus were the most commonly identified respiratory pathogens; only one influenza PCR-positive infection was detected in all four classes. Bed locations of URI/ILI cases in class 1 tended to be in closer proximity to each other.

Conclusion: Basic training recruits in military barracks in the tropics had high rates of acute respiratory illnesses with illness patterns consistent with external seeding followed by substantial internal transmission. Our findings may contribute to control measures in similar confined settings both within and outside the military.
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http://dx.doi.org/10.1111/irv.12345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605412PMC
November 2015

Influenza vaccine effectiveness in the tropics: moderate protection in a case test-negative analysis of a hospital-based surveillance population in Bangkok between August 2009 and January 2013.

PLoS One 2015 12;10(8):e0134318. Epub 2015 Aug 12.

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

Influenza in the tropics occurs year round with peaks that correspond variably to temperate regions. However, data on influenza vaccine effectiveness (VE) in the tropics is sparse. We report on the effectiveness of influenza vaccine to prevent medically attended laboratory confirmed influenza from sentinel surveillance conducted at a Thai military medical facility in Bangkok, Thailand from August 2009 to January 2013. Patients ≥6 months old presenting with influenza-like illness underwent combined nasal/throat swabs which were tested by influenza RT-PCR. A case test-negative study design was used to evaluate VE. Of 2999 samples available for analysis,1059 (35.3%) were PCR-positive (cases) and 1940 (64.6%) were PCR-negative (test-negative controls). Five hundred and seven (16.9%) of these patients reported being vaccinated within the previous 12 months. Periods of high and low influenza activity were defined based on publicly available Thai Ministry of Public Health data. Overall VE adjusted for age and epiweek was found to be 50.1% (95%CI: 35.0, 61.9%). The May to April adjusted VE for year 2010, 2011 and 2012 was 57.7% (95%CI: 33.7, 73.8%), 57.1% (95% CI: 35.2, 68.3%) and 37.6% (95% CI: 3.5, 62.9%).During high influenza activity in years with the same vaccine formulation, the adjusted VE was 54.9% (95%CI: 38.9, 66.9%). VE appeared to be much higher during high versus low influenza activity periods. The adjusted point estimate for VE was highest in the 18-49 year age group (76.6%) followed by 6-23 months (58.1%) and 2-17 years (52.5%). Adjusted estimates were not done for those ≥50 years of age due to small numbers. VE in patients with underlying disease was 75.5% compared to 48.0% in those without. Our findings demonstrate moderate protection by influenza vaccination and support the utility of influenza vaccination in the tropics including in very young children and those with underlying disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0134318PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534293PMC
May 2016

Evaluation of Cardiac Involvement in Children with Dengue by Serial Echocardiographic Studies.

PLoS Negl Trop Dis 2015 30;9(7):e0003943. Epub 2015 Jul 30.

Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.

Background: Infection with dengue virus results in a wide range of clinical manifestations from dengue fever (DF), a self-limited febrile illness, to dengue hemorrhagic fever (DHF) which is characterized by plasma leakage and bleeding tendency. Although cardiac involvement has been reported in dengue, the incidence and the extent of cardiac involvement are not well defined.

Methods And Principal Findings: We characterized the incidence and changes in cardiac function in a prospective in-patient cohort of suspected dengue cases by serial echocardiography. Plasma leakage was detected by serial chest and abdominal ultrasonography. Daily cardiac troponin-T levels were measured. One hundred and eighty one dengue cases were enrolled. On the day of enrollment, dengue cases that already developed plasma leakage had lower cardiac index (2695 (127) vs 3188 (75) (L/min/m2), p = .003) and higher left ventricular myocardial performance index (.413 (.021) vs .328 (.026), p = .021) and systemic vascular resistance (2478 (184) vs 1820 (133) (dynes·s/cm5), p = .005) compared to those without plasma leakage. Early diastolic wall motion of the left ventricle was decreased in dengue cases with plasma leakage compared to those without. Decreased left ventricular wall motility was more common in dengue patients compared to non-dengue cases particularly in cases with plasma leakage. Differences in cardiac function between DF and DHF were most pronounced around the time of plasma leakage. Cardiac dysfunction was transient and did not require treatment. Transient elevated troponin-T levels were more common in DHF cases compared to DF (14.5% vs 5%, p = 0.028).

Conclusions: Transient left ventricular systolic and diastolic dysfunction was common in children hospitalized with dengue and related to severity of plasma leakage. The functional abnormality spontaneously resolved without specific treatment. Cardiac structural changes including myocarditis were uncommon.
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http://dx.doi.org/10.1371/journal.pntd.0003943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520477PMC
April 2016

Absence of neutralizing antibodies against influenza A/H5N1 virus among children in Kamphaeng Phet, Thailand.

J Clin Virol 2015 Aug 3;69:78-80. Epub 2015 Jun 3.

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

Background: Influenza A/H5N1 actively circulated in Kamphaeng Phet (KPP), Thailand from 2004 to 2006. A prospective longitudinal cohort study of influenza virus infection in 800 adults conducted during 2008-2010 in KPP suggested that subclinical or mild H5N1 infections had occurred among this adult cohort. However, this study was conducted after the peak of H5N1 activity in KPP. Coincidentally, banked serum samples were available from a prospective longitudinal cohort study of primary school children who had undergone active surveillance for febrile illnesses from 2004 to 2007 and lived in the same district of KPP as the adult cohort.

Objectives: We sought to investigate whether subclinical or mild H5N1 infections had occurred among KPP residents during the peak of H5N1 activity from 2004 to 2006.

Study Design: H5N1 microneutralization (MN) assay was performed on banked serum samples from a prospective longitudinal cohort study of primary school children who had undergone active surveillance for febrile illnesses in KPP. Annual blood samples collected from 2004 to 2006 from 251 children were selected based on the criteria that they lived in villages with documented H5N1 infection.

Result: No H5N1 neutralizing antibodies were detected in 753 annual blood samples from 251 children.

Conclusion: During 2004-2006, very few subclinical or mild H5N1 infections occurred in KPP. Elevated H5N1 MN titers found in the adult cohort in 2008 were likely due to cross-reactivity from other influenza virus subtypes highlighting the complexities in interpreting influenza serological data.
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http://dx.doi.org/10.1016/j.jcv.2015.05.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515272PMC
August 2015

A model immunization programme to control Japanese encephalitis in Viet Nam.

J Health Popul Nutr 2015 Mar;33(1):207-13

International Vaccine Institute, San 4-8, Bongcheon-7 dong, Kwanak-ku, Seoul 151-818, Republic of Korea ; Department of Epidemiology, Fudan University School of Public Health, Shanghai, China.

In Viet Nam, an inactivated, mouse brain-derived vaccine for Japanese encephalitis (JE) has been given exclusively to ≤ 5 years old children in 3 paediatric doses since 1997. However, JE incidence remained high, especially among children aged 5-9 years. We conducted a model JE immunization programme to assess the feasibility and impact of JE vaccine administered to 1-9 year(s) children in 3 standard-dose regimen: paediatric doses for children aged <3 years and adult doses for those aged ≥ 3 years. Of the targeted children, 96.2% were immunized with ≥ 2 doses of the vaccine. Compared to the national immunization programme, JE incidence rate declined sharply in districts with the model programme (11.32 to 0.87 per 100,000 in pre-versus post-vaccination period). The rate of reduction was most significant in the 5-9 years age-group. We recommend a policy change to include 5-9 years old children in the catch-up immunization campaign and administer a 4th dose to those aged 5-9 years, who had received 3 doses of the vaccine during the first 2-3 years of life.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438663PMC
March 2015

Improving dengue virus capture rates in humans and vectors in Kamphaeng Phet Province, Thailand, using an enhanced spatiotemporal surveillance strategy.

Am J Trop Med Hyg 2015 Jul 18;93(1):24-32. Epub 2015 May 18.

Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland; Department of Virology, United States Army Medical Component, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand; Department of Geography, University at Buffalo, Buffalo, New York; Department of Entomology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand; Bureau of Epidemiology, Department of Disease Control Sciences, Ministry of Public Health, Nonthaburi, Thailand; Department of Entomology, University of California, Davis, Davis, California; Institute for Immunology and Informatics, University of Rhode Island, Providence, Rhode Island; Insect-Virus Interactions Group, Department of Genomes and Genetics, Institut Pasteur, Centre National de la Recherche Scientifique, Paris, France; Department of Infectious Diseases, State University of New York, Syracuse, New York; Fogarty International Center, National Institutes of Health, Bethesda, Maryland.

Dengue is of public health importance in tropical and sub-tropical regions. Dengue virus (DENV) transmission dynamics was studied in Kamphaeng Phet Province, Thailand, using an enhanced spatiotemporal surveillance of 93 hospitalized subjects with confirmed dengue (initiates) and associated cluster individuals (associates) with entomologic sampling. A total of 438 associates were enrolled from 208 houses with household members with a history of fever, located within a 200-m radius of an initiate case. Of 409 associates, 86 (21%) had laboratory-confirmed DENV infection. A total of 63 (1.8%) of the 3,565 mosquitoes collected were dengue polymerase chain reaction positive (PCR+). There was a significant relationship between spatial proximity to the initiate case and likelihood of detecting DENV from associate cases and Aedes mosquitoes. The viral detection rate from human hosts and mosquito vectors in this study was higher than previously observed by the study team in the same geographic area using different methodologies. We propose that the sampling strategy used in this study could support surveillance of DENV transmission and vector interactions.
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http://dx.doi.org/10.4269/ajtmh.14-0242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497898PMC
July 2015

Sequential dengue virus infections detected in active and passive surveillance programs in Thailand, 1994-2010.

BMC Public Health 2015 Mar 14;15:250. Epub 2015 Mar 14.

US Army Institute of Surgical Research, San Antonio, TX, USA.

Background: The effect of prior dengue virus (DENV) exposure on subsequent heterologous infection can be beneficial or detrimental depending on many factors including timing of infection. We sought to evaluate this effect by examining a large database of DENV infections captured by both active and passive surveillance encompassing a wide clinical spectrum of disease.

Methods: We evaluated datasets from 17 years of hospital-based passive surveillance and nine years of cohort studies, including clinical and subclinical DENV infections, to assess the outcomes of sequential heterologous infections. Chi square or Fisher's exact test was used to compare proportions of infection outcomes such as disease severity; ANOVA was used for continuous variables. Multivariate logistic regression was used to assess risk factors for infection outcomes.

Results: Of 38,740 DENV infections, two or more infections were detected in 502 individuals; 14 had three infections. The mean ages at the time of the first and second detected infections were 7.6 ± 3.0 and 11.2 ± 3.0 years. The shortest time between sequential infections was 66 days. A longer time interval between sequential infections was associated with dengue hemorrhagic fever (DHF) in the second detected infection (OR 1.3, 95% CI 1.2-1.4). All possible sequential serotype pairs were observed among 201 subjects with DHF at the second detected infection, except DENV-4 followed by DENV-3. Among DENV infections detected in cohort subjects by active study surveillance and subsequent non-study hospital-based passive surveillance, hospitalization at the first detected infection increased the likelihood of hospitalization at the second detected infection.

Conclusions: Increasing time between sequential DENV infections was associated with greater severity of the second detected infection, supporting the role of heterotypic immunity in both protection and enhancement. Hospitalization was positively associated between the first and second detected infections, suggesting a possible predisposition in some individuals to more severe dengue disease.
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http://dx.doi.org/10.1186/s12889-015-1590-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371716PMC
March 2015

HLA Class I Supertype Associations With Clinical Outcome of Secondary Dengue Virus Infections in Ethnic Thais.

J Infect Dis 2015 Sep 4;212(6):939-47. Epub 2015 Mar 4.

Department of Transfusion Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University UCL Centre for Nephrology and Anthony Nolan Laboratories, Royal Free NHS Foundation Trust, Royal Free Hospital, London, United Kingdom.

Background: Human leukocyte antigen (HLA) supertypes are groups of functionally related alleles that present structurally similar antigens to the immune system.

Objectives: To analyze HLA class I supertype associations with clinical outcome in hospitalized Thai children with acute dengue illness.

Methods: Seven hundred sixty-two patients and population-matched controls recruited predominantly in Bangkok were HLA-A and -B typed. HLA supertype frequencies were compared and tested for significant dengue disease associations using logistic regression analyses. Multivariable models were built by conducting forward stepwise selection procedures.

Results: In the final logistic regression model, the HLA-B44 supertype was protective against dengue hemorrhagic fever (DHF) in secondary infections (odds ratio [OR] = 0.46, 95% confidence interval [CI], .30-.72), while the HLA-A02 supertype (OR = 1.92, 95% CI, 1.30-2.83) and the HLA-A01/03 supertype (OR = 3.01, 95% CI, 1.01-8.92) were associated with susceptibility to secondary dengue fever. The B07 supertype was associated with susceptibility to secondary DHF in the univariate analysis (OR = 1.60, 95% CI, 1.05-2.46), whereas that was not retained in the final model.

Conclusions: As the HLA-B44 supertype is predicted to target conserved epitopes in dengue, our results suggest that B44 supertype-restricted immune responses to highly conserved regions of the dengue proteome may protect against secondary DHF.
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http://dx.doi.org/10.1093/infdis/jiv127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548457PMC
September 2015

Seroincidence of Influenza Among HIV-infected and HIV-uninfected Men During the 2009 H1N1 Influenza Pandemic, Bangkok, Thailand.

Open Forum Infect Dis 2014 Dec 10;1(3):ofu082. Epub 2014 Oct 10.

Influenza Division , Centers for Disease Control and Prevention , Atlanta, Georgia.

Among 368 Thai men who have sex with men with paired serum samples collected before and during the 2009 H1N1 influenza pandemic, we determined influenza A (H1N1)pdm09 seroconversion rates (≥4-fold rise in antibody titers by hemagglutination inhibition or microneutralization assays). Overall, 66 of 232 (28%) participants seroconverted after the first year of A(H1N1)pdm09 activity, and 83 of 234 (35%) participants seroconverted after the second year. Influenza A(H1N1)pdm09 seroconversion did not differ between human immunodeficiency virus (HIV)-infected (55 of 2157 [35%]) and HIV-uninfected (71 of 2211 [34%]) participants (P = .78). Influenza A(H1N1)pdm09 seroconversion occurred in approximately one third of our Thai study population and was similar among HIV-infected and HIV-uninfected participants.
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http://dx.doi.org/10.1093/ofid/ofu082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324228PMC
December 2014

Monitoring and improving the sensitivity of dengue nested RT-PCR used in longitudinal surveillance in Thailand.

J Clin Virol 2015 Feb 12;63:25-31. Epub 2014 Dec 12.

Department of Virology, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, Bangkok, Thailand.

Background: AFRIMS longitudinal dengue surveillance in Thailand depends on the nested RT-PCR and the dengue IgM/IgG ELISA.

Objective: To examine and improve the sensitivity of the nested RT-PCR using a panel of archived samples collected during dengue surveillance.

Study Design: A retrospective analysis of 16,454 dengue IgM/IgG ELISA positive cases collected between 2000 and 2013 was done to investigate the sensitivity of the nested RT-PCR. From these cases, 318 acute serum specimens or extracted RNA, previously found to be negative by the nested RT-PCR, were tested using TaqMan real-time RT-PCR (TaqMan rRT-PCR). To improve the sensitivity of nested RT-PCR, we designed a new primer based on nucleotide sequences from contemporary strains found to be positive by the TaqMan rRT-PCR. Sensitivity of the new nested PCR was calculated using a panel of 87 samples collected during 2011-2013.

Results And Conclusion: The percentage of dengue IgM/IgG ELISA positive cases that were negative by the nested RT-PCR varied from 17% to 42% for all serotypes depending on the year. Using TaqMan rRT-PCR, dengue RNA was detected in 194 (61%) of the 318 acute sera or extracted RNA previously found to be negative by the nested RT-PCR. The newly designed DENV-1 specific primer increased the sensitivity of DENV-1 detection by the nested RT-PCR from 48% to 88%, and of all 4 serotypes from 73% to 87%. These findings demonstrate the impact of genetic diversity and signal erosion on the sensitivity of PCR-based methods.
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http://dx.doi.org/10.1016/j.jcv.2014.12.009DOI Listing
February 2015

Advances in the understanding, management, and prevention of dengue.

J Clin Virol 2015 Mar 20;64:153-9. Epub 2014 Oct 20.

Merck and Company, 351 North Sumneytown Pike, North Wales, PA 19454, United States. Electronic address:

Dengue causes more human morbidity globally than any other vector-borne viral disease. Recent research has led to improved epidemiological methods that predict disease burden and factors involved in transmission, a better understanding of immune responses in infection, and enhanced animal models. In addition, a number of control measures, including preventative vaccines, are in clinical trials. However, significant gaps remain, including the need for better surveillance in large parts of the world, methods to predict which individuals will develop severe disease, and immunologic correlates of protection against dengue illness. During the next decade, dengue will likely expand its geographic reach and become an increasing burden on health resources in affected areas. Licensed vaccines and antiviral agents are needed in order to effectively control dengue and limit disease.
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http://dx.doi.org/10.1016/j.jcv.2014.08.031DOI Listing
March 2015

The spatial dynamics of dengue virus in Kamphaeng Phet, Thailand.

PLoS Negl Trop Dis 2014 Sep 11;8(9):e3138. Epub 2014 Sep 11.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.

Background: Dengue is endemic to the rural province of Kamphaeng Phet, Northern Thailand. A decade of prospective cohort studies has provided important insights into the dengue viruses and their generated disease. However, as elsewhere, spatial dynamics of the pathogen remain poorly understood. In particular, the spatial scale of transmission and the scale of clustering are poorly characterized. This information is critical for effective deployment of spatially targeted interventions and for understanding the mechanisms that drive the dispersal of the virus.

Methodology/principal Findings: We geocoded the home locations of 4,768 confirmed dengue cases admitted to the main hospital in Kamphaeng Phet province between 1994 and 2008. We used the phi clustering statistic to characterize short-term spatial dependence between cases. Further, to see if clustering of cases led to similar temporal patterns of disease across villages, we calculated the correlation in the long-term epidemic curves between communities. We found that cases were 2.9 times (95% confidence interval 2.7-3.2) more likely to live in the same village and be infected within the same month than expected given the underlying spatial and temporal distribution of cases. This fell to 1.4 times (1.2-1.7) for individuals living in villages 1 km apart. Significant clustering was observed up to 5 km. We found a steadily decreasing trend in the correlation in epidemics curves by distance: communities separated by up to 5 km had a mean correlation of 0.28 falling to 0.16 for communities separated between 20 km and 25 km. A potential explanation for these patterns is a role for human movement in spreading the pathogen between communities. Gravity style models, which attempt to capture population movement, outperformed competing models in describing the observed correlations.

Conclusions: There exists significant short-term clustering of cases within individual villages. Effective spatially and temporally targeted interventions deployed within villages may target ongoing transmission and reduce infection risk.
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http://dx.doi.org/10.1371/journal.pntd.0003138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161352PMC
September 2014

High rate of A(H1N1)pdm09 infections among rural Thai villagers, 2009-2010.

PLoS One 2014 4;9(9):e106751. Epub 2014 Sep 4.

College of Public Health and Health Professions and Emerging Pathogens Institute, University of Florida, Gainesville, Florida, United States of America.

Background: Pandemic influenza A(H1N1)pdm09 emerged in Thailand in 2009. A prospective longitudinal adult cohort and household transmission study of influenza-like illness (ILI) was ongoing in rural Thailand at the time of emergence. Symptomatic and subclinical A(H1N1)pdm09 infection rates in the cohort and among household members were evaluated.

Methods: A cohort of 800 Thai adults underwent active community-based surveillance for ILI from 2008-2010. Acute respiratory samples from ILI episodes were tested for A(H1N1)pdm09 by qRT-PCR; acute and 60-day convalescent blood samples were tested by A(H1N1)pdm09 hemagglutination inhibition assay (HI). Enrollment, 12-month and 24-month follow-up blood samples were tested for A(H1N1)pdm09 seroconversion by HI. Household members of influenza A-infected cohort subjects with ILI were enrolled in household transmission investigations in which day 0 and 60 blood samples and acute respiratory samples were tested by either qRT-PCR or HI for A(H1N1)pdm09. Seroconversion between annual blood samples without A(H1N1)pdm09-positive ILI was considered as subclinical infection.

Results: The 2-yr cumulative incidence of A(H1N1)pdm09 infection in the cohort in 2009/2010 was 10.8% (84/781) with an annual incidence of 1.2% in 2009 and 9.7% in 2010; 83.3% of infections were subclinical (50% in 2009 and 85.9% in 2010). The 2-yr cumulative incidence was lowest (5%) in adults born ≤ 1957. The A(H1N1)pdm09 secondary attack rate among household contacts was 47.2% (17/36); 47.1% of these infections were subclinical. The highest A(H1N1)pdm09 secondary attack rate among household contacts (70.6%, 12/17) occurred among children born between 1990 and 2003.

Conclusion: Subclinical A(H1N1)pdm09 infections in Thai adults occurred frequently and accounted for a greater proportion of all A(H1N1)pdm09 infections than previously estimated. The role of subclinical infections in A(H1N1)pdm09 transmission has important implications in formulating strategies to predict and prevent the spread of A(H1N1)pdm09 and other influenza virus strains.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106751PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154756PMC
December 2015

Neuropathogenesis of Japanese encephalitis in a primate model.

PLoS Negl Trop Dis 2014 Aug 7;8(8):e2980. Epub 2014 Aug 7.

Brain Infections Group, Institute of Infection and Global Health, University of Liverpool, NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, and Walton Centre NHS Foundation Trust, Liverpool, United Kingdom.

Background: Japanese encephalitis (JE) is a major cause of mortality and morbidity for which there is no treatment. In addition to direct viral cytopathology, the inflammatory response is postulated to contribute to the pathogenesis. Our goal was to determine the contribution of bystander effects and inflammatory mediators to neuronal cell death.

Methodology/principal Findings: Material from a macaque model was used to characterize the inflammatory response and cytopathic effects of JE virus (JEV). Intranasal JEV infection induced a non-suppurative encephalitis, dominated by perivascular, infiltrates of mostly T cells, alongside endothelial cell activation, vascular damage and blood brain barrier (BBB) leakage; in the adjacent parenchyma there was macrophage infiltration, astrocyte and microglia activation. JEV antigen was mostly in neurons, but there was no correlation between intensity of viral infection and degree of inflammatory response. Apoptotic cell death occurred in both infected and non-infected neurons. Interferon-α, which is a microglial activator, was also expressed by both. Tumour Necrosis Factor-α, inducible nitric oxide synthase and nitrotyrosine were expressed by microglial cells, astrocytes and macrophages. The same cells expressed matrix metalloproteinase (MMP)-2 whilst MMP-9 was expressed by neurons.

Conclusions/significance: The results are consistent with JEV inducing neuronal apoptotic death and release of cytokines that initiate microglial activation and release of pro-inflammatory and apoptotic mediators with subsequent apoptotic death of both infected and uninfected neurons. Activation of astrocytes, microglial and endothelial cells likely contributes to inflammatory cell recruitment and BBB breakdown. It appears that neuronal apoptotic death and activation of microglial cells and astrocytes play a crucial role in the pathogenesis of JE.
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http://dx.doi.org/10.1371/journal.pntd.0002980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4125110PMC
August 2014

Preliminary evaluation of near infrared spectroscopy as a method to detect plasma leakage in children with dengue hemorrhagic fever.

BMC Infect Dis 2014 Jul 17;14:396. Epub 2014 Jul 17.

Reflectance Medical, Inc,, 116 Flanders Rd, Suite 1000, Westborough, MA 01581, USA.

Background: Dengue viral infections are prevalent in the tropical and sub-tropical regions of the world, resulting in substantial morbidity and mortality. Clinical manifestations range from a self-limited fever to a potential life-threatening plasma leakage syndrome (dengue hemorrhagic fever). The objective of this study was to assess the utility of near infrared spectroscopy (NIRS) measurements of muscle oxygen saturation (SmO2) as a possible continuous measure to detect plasma leakage in children with dengue.

Methods: Children ages 6 months to 15 years of age admitted with suspected dengue were enrolled from the dengue ward at Queen Sirikit National Institute for Child Health. Children were monitored daily until discharge. NIRS data were collected continuously using a prototype CareGuide Oximeter 1100 with sensors placed on the deltoid or thigh. Daily ultrasound of the chest and a right lateral decubitus chest x-ray the day after defervescence were performed to detect and quantitate plasma leakage in the pleural cavity.

Results: NIRS data were obtained from 19 children with laboratory-confirmed dengue. Average minimum SmO2 decreased for all subjects prior to defervescence. Average minimum SmO2 subsequently increased in children with no ultrasound evidence of pleural effusion but remained low in children with pleural effusion following defervescence. Average minimum SmO2 was inversely correlated with pleural space fluid volume. ROC analysis revealed a cut-off value for SmO2 which yielded high specificity and sensitivity.

Conclusions: SmO2 measured using NIRS may be a useful guide for real-time and non-invasive identification of plasma leakage in children with dengue. Further investigation of the utility of NIRS measurements for prediction and management of severe dengue syndromes is warranted.
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http://dx.doi.org/10.1186/1471-2334-14-396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223418PMC
July 2014

Safety and immunogenicity of a rederived, live-attenuated dengue virus vaccine in healthy adults living in Thailand: a randomized trial.

Am J Trop Med Hyg 2014 Jul 27;91(1):119-28. Epub 2014 May 27.

Department of Pediatrics, Phramongkutklao Hospital (PMK), Bangkok, Thailand; US Army Medical Component-Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand; Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland; GlaxoSmithKline Vaccines, Wavre, Belgium; Bioproduction Facility, Translational Medicine Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland; GlaxoSmithKline Vaccines, King of Prussia, Pennsylvania.

Safety and immunogenicity of two formulations of a live-attenuated tetravalent dengue virus (TDEN) vaccine produced using rederived master seeds from a precursor vaccine were tested against a placebo control in a phase II, randomized, double blind trial (NCT00370682). Two doses were administered 6 months apart to 120 healthy, predominantly flavivirus-primed adults (87.5% and 97.5% in the two vaccine groups and 92.5% in the placebo group). Symptoms and signs reported after vaccination were mild to moderate and transient. There were no vaccine-related serious adverse events or dengue cases reported. Asymptomatic, low-level viremia (dengue virus type 2 [DENV-2], DENV-3, or DENV-4) was detected in 5 of 80 vaccine recipients. One placebo recipient developed a subclinical natural DENV-1 infection. All flavivirus-unprimed subjects and at least 97.1% of flavivirus-primed subjects were seropositive to antibodies against all four DENV types 1 and 3 months post-TDEN dose 2. The TDEN vaccine was immunogenic with an acceptable safety profile in flavivirus-primed adults.
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http://dx.doi.org/10.4269/ajtmh.13-0452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080550PMC
July 2014
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