Associations of human leukocyte antigen with neutralizing antibody titers in a tetravalent dengue vaccine phase 2 efficacy trial in Thailand.

The recombinant, live, attenuated, tetravalent dengue vaccine CYD-TDV has shown efficacy against all four dengue serotypes. In this exploratory study (CYD59, NCT02827162), we evaluated potential associations of host human leukocyte antigen (HLA) alleles with dengue antibody responses, CYD-TDV vaccine efficacy, and virologically-confirmed dengue (VCD) cases. Children 4-11 years old, who previously completed a phase 2b efficacy study of CYD-TDV in a single center in Thailand, were included in the study.

Monoclonal antibody-based capture ELISA in the diagnosis of previous dengue infection.

Background: Dengue is an important mosquito-borne disease. There is currently only one licensed vaccine for dengue prevention. The vaccine provides higher efficacy in pre-vaccination dengue-seropositive persons but a higher risk of subsequent more severe dengue in dengue-seronegative persons.

Serodiagnosis of asymptomatic dengue infection.

Dengue virus (DENV) is a mosquito-transmitted virus that is expanding across the world. The incidence of dengue infection, especially severe disease, has been increasing. DENV consist of 4 serotypes of single stranded RNA viruses (D1-D4) in the genus Flavivirus, family Flaviviridae.

Detection of dengue cases by serological testing in a dengue vaccine efficacy trial: Utility for efficacy evaluation and impact of future vaccine introduction.

Background: Dengue diagnosis confirmation and surveillance are widely based on serological assays to detect anti-dengue IgM or IgG antibodies since such tests are affordable/user-friendly. The World Health Organization identified serological based diagnosis as a potential tool to define probable dengue cases in the context of vaccine trials, while acknowledging that this may have to be interpreted with caution.

Methods: In a phase IIb randomized, placebo-controlled trial assessing the efficacy of a tetravalent dengue vaccine (CYD-TDV) in Thai schoolchildren, case definition was based on virological confirmation by either serotype-specific RT-PCRs or by NS1-antigen ELISA (Clinicaltrials.

Plaque reduction neutralization antibody test does not accurately predict protection against dengue infection in Ratchaburi cohort, Thailand.

Background: The plaque reduction neutralization test (PRNT) is currently the best and most widely accepted approach to measuring virus-neutralizing and protective antibodies to dengue virus, and in assessing the immunogenicity of a dengue vaccine. However, the correlation between presence of dengue-neutralizing antibody and protection from infection is not absolute.

Findings: In a cohort study in Ratchaburi Province, Thailand, 48 subjects with serologically confirmed symptomatic dengue infection were tested for pre-existing dengue neutralizing antibody using PRNT.

Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial.

Background: Roughly half the world's population live in dengue-endemic countries, but no vaccine is licensed. We investigated the efficacy of a recombinant, live, attenuated tetravalent dengue vaccine.

Methods: In this observer-masked, randomised, controlled, monocentre, phase 2b, proof-of-concept trial, healthy Thai schoolchildren aged 4-11 years were randomly assigned (2:1) to receive three injections of dengue vaccine or control (rabies vaccine or placebo) at months 0, 6, and 12.

Dengue infection in children in Ratchaburi, Thailand: a cohort study. I. Epidemiology of symptomatic acute dengue infection in children, 2006-2009.

Background: There is an urgent need to field test dengue vaccines to determine their role in the control of the disease. Our aims were to study dengue epidemiology and prepare the site for a dengue vaccine efficacy trial.

Methods And Findings: We performed a prospective cohort study of children in primary schools in central Thailand from 2006 through 2009.

Dengue infection in children in Ratchaburi, Thailand: a cohort study. II. Clinical manifestations.

Background: Dengue infection is one of the most important mosquito-borne diseases. More data regarding the disease burden and the prevalence of each clinical spectrum among symptomatic infections and the clinical manifestations are needed. This study aims to describe the incidence and clinical manifestations of symptomatic dengue infection in Thai children during 2006 through 2008.

Decay and persistence of maternal dengue antibodies among infants in Bangkok.

Abstract. Maternal dengue antibodies are important in determining the optimal age of dengue vaccination, but no study has quantified the heterogeneity of antibody decay and persistence in infants. We used longitudinal regression methods and survival analysis to measure decay and persistence times of serotype-specific neutralizing antibodies in 139 infants in Bangkok.

Dengue antibody in Thai children from maternally transferred antibody to acquired infection.

This prospective cohort study examined serotype-specific neutralizing serum antibodies to dengue in 55 maternal-newborn pairs, at 3, 6, 9, 12, 18, and 24 months, and again at 4 to 8 years of age. In all, 95% of the mothers had neutralizing antibody to at least one dengue serotype, and 92.7% of the maternally transferred antibody had disappeared in 12-month-old infants.

Dengue in Thailand and Cambodia: an assessment of the degree of underrecognized disease burden based on reported cases.

Background: Disease incidence data are needed to guide decision-making for public health interventions. Although dengue is a reportable disease in Thailand and Cambodia, the degree that reported incidence underrecognizes true disease burden is unknown. We utilized dengue incidence calculated from laboratory-confirmed outpatient and inpatient cases in prospective cohort studies to estimate the magnitude of dengue underrecognition and to establish more accurate disease burden estimates for these countries.

Safety and immunogenicity of a single administration of live-attenuated Japanese encephalitis vaccine in previously primed 2- to 5-year-olds and naive 12- to 24-month-olds: multicenter randomized controlled trial.

Background: Safe and effective Japanese encephalitis (JE) vaccines are needed to protect populations living in or visiting endemic areas. A live-attenuated JE-chimeric virus vaccine (JE-CV) has been developed with a single-dose regimen.

Methods: In an open-label, crossover study, 100 children aged 2 to 5 years with a history of 2-dose primary vaccination with mouse-brain derived inactivated JE vaccine according to the Thai Expanded Program for Immunization schedule, and 200 JE vaccination-naive 12- to 24-month-old toddlers were randomized 1:1 to receive JE-CV, containing ≥4 log10 plaque forming units, 1 month before or after hepatitis A control vaccine.

A three-year clinical study on immunogenicity, safety, and booster response of purified chick embryo cell rabies vaccine administered intramuscularly or intradermally to 12- to 18-month-old Thai children, concomitantly with Japanese encephalitis vaccine.

After concomitant administration of purified chick embryo cell rabies vaccine and Japanese encephalitis vaccine to toddlers, adequate rabies and Japanese encephalitis virus neutralizing antibodies concentrations were demonstrated by day 49, 7 days after a booster at 1 year, and in the majorly at 3 years postvaccination. The inclusion of rabies vaccine in the expanded program on immunization should be considered in rabies endemic countries.

Age-specific prevalence of dengue antibodies in Bangkok infants and children.

Seroprevalence of dengue antibodies were determined in healthy children in Bangkok. At 9, 12, and 18 months of age 23%, 9%, and 17% of children respectively had neutralizing antibodies against one or more serotypes. DEN1 was the most prevalent, followed by DEN3, DEN2, and DEN4.

Comparative study of the effectiveness and pharmacokinetics of two rectal artesunate/oral mefloquine combination regimens for the treatment of uncomplicated childhood falciparum malaria.

Background: Rectal artesunate has been shown to be an effective treatment for falciparum malaria and is useful in patients who cannot take medicine orally or when parenteral medication is inconvenient. A combination with mefloquine can decrease the duration of treatment, increase compliance and delay development of resistance. There are no clear data on whether a higher dosage of rectal artesunate results in a better clinical response.

Scientific consultation on immunological correlates of protection induced by dengue vaccines report from a meeting held at the World Health Organization 17-18 November 2005.

Several dengue vaccine candidates have been evaluated in early clinical phase, and some are scheduled for efficacy testing in population-based studies. Given the advancements in dengue vaccine development, there is an increased interest in identifying immunological correlates of protection for these vaccines in order to facilitate their evaluation, further refinement, production and registration. To this end, the WHO Initiative for Vaccine Research (IVR) convened a consultation on primary and secondary immunological correlates of protection induced by dengue vaccines.

Dengue virus infections in the first 2 years of life and the kinetics of transplacentally transferred dengue neutralizing antibodies in thai children.

Background: Understanding dengue virus infection in children and the kinetics of maternal dengue neutralizing antibodies is essential for effective dengue immunization of children in endemic areas.

Methods: Serum samples from 219 mother-child pairs and 140 children at 3, 6, 9, 12, 18, and 24 months of age from Bangkok, Thailand, were tested for serotype-specific dengue antibodies. Febrile episodes in the children were recorded.

Short report: immune response and occurrence of dengue infection in thai children three to eight years after vaccination with live attenuated tetravalent dengue vaccine.

From 1992 to 1997, 140 Thai children 4-15 years of age received an investigational live attenuated tetravalent dengue vaccine (LATDV). These children were contacted 3-8 years later in 2001 to assess humoral immunity and investigate whether they were subsequently at higher risk of developing severe dengue. One hundred thirteen were successfully contacted and participated in this retrospective cohort study with two age- and address-matched controls per vaccinee.

Life-saving rectal artesunate for complicated malaria in children.

We report the effectiveness of two regimens of rectal artesunate formulation in treating 13 Thai children with cerebral/complicated falciparum malaria. The drug was given at an initial dose of 40 mg/kg bodyweight, in 3 or 4 divided doses in the first 24 hours, followed by 10 mg/kg bodyweight once daily for three consecutive days. Mefloquine, at a dose of 15 mg/kg bodyweight was given orally at 72 hours after the initial dose of artesunate, followed by 10 mg/kg bodyweight 6 hours later.

Review on flavivirus vaccine development. Proceedings of a meeting jointly organised by the World Health Organization and the Thai Ministry of Public Health, 26-27 April 2004, Bangkok, Thailand.

In light of the continuous spread of human pathogenic flaviviruses, in particular the mosquito-transmitted species, vaccine development remains a high priority on the public health agenda. On 26-27 April 2004, a conference was held in Bangkok, Thailand, to review current status of flavivirus vaccine development and related issues, focussing on dengue (DEN) and Japanese encephalitis (JE). This event, co-sponsored by the World Health Organization (WHO) and the Thai Ministry of Public Health, reviewed the progress made with vaccine development, sero-epidemiological studies and other accompanying activities critical for vaccine development and vaccination.

Evaluation by flow cytometry of antibody-dependent enhancement (ADE) of dengue infection by sera from Thai children immunized with a live-attenuated tetravalent dengue vaccine.

Sera from Thai children immunized with a live-attenuated tetravalent dengue virus vaccine or from naturally infected age-matched site-control subjects were examined for immune enhancement capacity by a highly reproducible flow cytometric assay in Fc receptor-bearing K562 human cells. None of the sera under study corresponded to cases of severe dengue disease. In parallel assays employing each dengue virus serotype, we found no or only minimal antibody-dependent enhancement (ADE) when sera from vaccinated or control subjects were used at a low serum dilution [1/12] that approximated the in vivo condition.

Safety and immunogenicity of a three dose regimen of two tetravalent live-attenuated dengue vaccines in five- to twelve-year-old Thai children.

Objective: The safety and immunogenicity of tetravalent live-attenuated dengue vaccines after a three dose vaccination series were evaluated in Thai children.

Method: One hundred three healthy flavivirus-seronegative schoolchildren ages 5 to 12 years were randomized to receive either dengue vaccine containing 3, 2, 1 and 2 log10 of the 50% cell culture infective dose, respectively, of the live-attenuated dengue vaccine serotypes 1, 2, 3 and 4 per dose (F3212; n = 40) or 3, 3, 1 and 3 log10 of the 50% cell culture infective dose (F3313; n = 42) or purified Vero cell rabies vaccine (control group; n = 21) given in a two dose schedule (3 to 5 months apart). A third dose was administered 8 to 12 months after the second dose to 90 subjects.

Maternally transferred neutralising dengue antibodies in Thai infants: a pilot study.

In a dengue-endemic area, sera from 42 mother-infant pairs and sera collected from the infants at follow-up at the ages of 3 months (n =27), 6 months (n =34), 9 months (n =23) and 12 months (n =8) were tested for antibodies to four dengue serotypes using a plaque reduction neutralisation test (PRNT(50)), IgG ELISA and haemagglutination inhibition assay (HAI). The IgG ELISA and HAI tests were less sensitive than PRNT(50) in detecting low levels of antibodies. Levels of maternally transferred dengue neutralising antibodies in the cord sera were very high and identical to those in the mothers.

Safety and immunogenicity of tetravalent live-attenuated dengue vaccines in Thai adult volunteers: role of serotype concentration, ratio, and multiple doses.

Dengue fever, caused by four serotypes of a mosquito-borne virus, is a growing problem in tropical countries. Currently, there is no treatment or vaccine. We evaluated safety and immunogenicity of two doses, given six months apart, of seven formulations of dengue tetravalent live-attenuated vaccine (containing different concentrations of the component viruses) versus placebo in 59 flavivirus-seronegative Thai adults.