Improvement of the Dengue Virus (DENV) Nonhuman Primate Model via a Reverse Translational Approach Based on Dengue Vaccine Clinical Efficacy Data against DENV-2 and -4.

Recent data obtained with the live-attenuated tetravalent dengue CYD-TDV vaccine showed higher protective efficacy against dengue virus type 4 (DENV-4) than against DENV-2. In contrast, results from previous studies in nonhuman primates predicted comparable high levels of protection against each serotype. Maximum viral loads achieved in macaques by subcutaneous inoculation of DENV are generally much lower than those observed in naturally dengue virus-infected humans. This may contribute to an overestimation of vaccine efficacy. Using more-stringent DENV infection conditions consisting of the intravenous inoculation of 107 50% cell culture infectious doses (CCID50) in CYD-TDV-vaccinated macaques, complete protection (i.e., undetectable viral RNA) was achieved in all 6 monkeys challenged with DENV-4 and in 6/18 of those challenged with DENV-2, including transiently positive animals. All other infected macaques (12/18) developed sustained DENV-2 RNAemia (defined as detection of viral RNA in serum samples) although 1 to 3 log10 units below the levels achieved in control animals. Similar results were obtained with macaques immunized with either CYD-TDV or monovalent (MV) CYD-2. This suggests that partial protection against DENV-2 was mediated mainly by CYD-2 and not by the other CYDs. Postchallenge induction of strong anamnestic responses, suggesting efficient vaccine priming, likely contributed to the reduction of DENV-2 RNAemia. Finally, an inverse correlation between DENV RNA titers postchallenge and vaccine-induced homotypic neutralizing antibody titers prechallenge was found, emphasizing the key role of these antibodies in controlling DENV infection. Collectively, these data show better agreement with reported data on CYD-TDV clinical vaccine efficacy against DENV-2 and DENV-4. Despite inherent limitations of the nonhuman primate model, these results reinforce its value in assessing the efficacy of dengue vaccines.IMPORTANCE The nonhuman primate (NHP) model is the most widely recognized tool for assessing the protective activity of dengue vaccine candidates, based on the prevention of postinfection DENV viremia. However, its use has been questioned after the recent CYD vaccine phase III trials, in which moderate protective efficacy against DENV-2 was reported, despite full protection against DENV-2 viremia previously being demonstrated in CYD-vaccinated monkeys. Using a reverse translational approach, we show here that the NHP model can be improved to achieve DENV-2 protection levels that show better agreement with clinical efficacy. With this new model, we demonstrate that the injection of the CYD-2 component of the vaccine, in either a monovalent or a tetravalent formulation, is able to reduce DENV-2 viremia in all immunized animals, and we provide clear statistical evidence that DENV-2-neutralizing antibodies are able to reduce viremia in a dose-dependent manner.

Vaccination Against Dengue: Challenges and Current Developments.

Dengue is a growing threat worldwide, and the development of a vaccine is a public health priority. The completion of the active phase of two pivotal efficacy studies conducted in Asia and Latin America by Sanofi Pasteur has constituted an important step. Several other approaches are under development, and whichever technology is used, vaccine developers face several challenges linked to the particular nature and etiology of dengue disease. We start our review by defining questions and potential issues linked to dengue pathology and presenting the main types of vaccine approaches that have explored these questions; some of these candidates are in a late stage of clinical development. In the second part of the review, we focus on the Sanofi Pasteur dengue vaccine candidate, describing the steps from research to phase III efficacy studies. Finally, we discuss what could be the next steps, before and after vaccine introduction, to ensure that the vaccine will provide the best benefit with an acceptable safety profile to the identified target populations.

Experience of the use of Ketamine to manage opioid withdrawal in an addicted woman: a case report.

BACKGROUND: Opioids are good painkillers, but many patients treated with opioids as painkillers developed a secondary addiction. These patients need to stop misusing opioids, but the mild-to-severe clinical symptoms associated with opioid withdrawal risk increasing their existing pain. In such cases, ketamine, which is used by anaesthetists and pain physicians to reduce opioid medication, may be an effective agent for managing opioid withdrawal. CASE PRESENTATION: We describe the case of a woman who developed a severe secondary addiction to opioids in the context of lombo-sciatic pain. She presented a severe opioid addiction, and her physicians refused to prescribe such high doses of opioid treatment (oxycontin® extended-release 120 mg daily, oxycodone 60 mg daily, and acetaminophen/codeine 300 mg/25 mg 6 times per day). To assist her with her opioid withdrawal which risked increasing her existing pain, she received 1 mg/kg ketamine oral solution, and two days after ketamine initiation her opioid treatment was gradually reduced. The patient dramatically reduced the dosage of opioid painkillers and ketamine was withdrawn without any withdrawal symptoms. CONCLUSION: Ketamine displays many interesting qualities for dealing with all symptoms relating to opioid withdrawal. Accordingly, it could be used instead of many psychotropic treatments, which interact with each other, to help with opioid withdrawal. However, the literature describes addiction to ketamine. All in all, although potentially addictive, ketamine could be a good candidate for the pharmacological management of opioid withdrawal.

AI algorithm combined with RNA editing-based blood biomarkers to discriminate bipolar from major depressive disorders in an external validation multicentric cohort.

Bipolar disorder (BD) is a leading cause of disability worldwide, as it can lead to cognitive and functional impairment and premature mortality. The first episode of BD is usually a depressive episode and is often misdiagnosed as major depressive disorder (MDD). Growing evidence indicates that peripheral immune activation and inflammation are involved in the pathophysiology of BD and MDD. Recently, by developing a panel of RNA editing-based blood biomarkers able to discriminate MDD from depressive BD, we have provided clinicians a new tool to reduce the misdiagnosis delay observed in patients suffering from BD. The present study aimed at validating the diagnostic value of this panel in an external independent multicentric Switzerland-based cohort of 143 patients suffering from moderate to major depression. The RNA-editing based blood biomarker (BMK) algorithm developped allowed to accurately discriminate MDD from depressive BD in an external cohort, with high accuracy, sensitivity and specificity values (82.5 %, 86.4 % and 80.8 %, respectively). These findings further confirm the important role of RNA editing in the physiopathology of mental disorders and emphasize the possible clinical usefulness of the biomarker panel for optimization treatment delay in patients suffering from BD.

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. Randomisation was by computer-generated permuted blocks of six and participants were assigned with an interactive response system. Participants were actively followed up until month 25. All acute febrile illnesses were investigated. Dengue viraemia was confirmed by serotype-specific RT-PCR and non-structural protein 1 ELISA. The primary objective was to assess protective efficacy against virologically confirmed, symptomatic dengue, irrespective of severity or serotype, occurring 1 month or longer after the third injection (per-protocol analysis). This trial is registered at ClinicalTrials.gov, NCT00842530. FINDINGS: 4002 participants were assigned to vaccine (n=2669) or control (n=1333). 3673 were included in the primary analysis (2452 vaccine, 1221 control). 134 cases of virologically confirmed dengue occurred during the study. Efficacy was 30·2% (95% CI -13·4 to 56·6), and differed by serotype. Dengue vaccine was well tolerated, with no safety signals after 2 years of follow-up after the first dose. INTERPRETATION: These data show for the first time that a safe vaccine against dengue is possible. Ongoing large-scale phase 3 studies in various epidemiological settings will provide pivotal data for the CYD dengue vaccine candidate. FUNDING: Sanofi Pasteur.

Different innate signatures induced in human monocyte-derived dendritic cells by wild-type dengue 3 virus, attenuated but reactogenic dengue 3 vaccine virus, or attenuated nonreactogenic dengue 1-4 vaccine virus strains.

DNA microarrays were used to assess the innate gene signature in human myeloid dendritic cells infected with chimeric dengue 1-4 vaccines, a wild-type dengue 3 virus, or a classically attenuated serotype 3 vaccine shown to be reactogenic in humans. We observed a very reproducible signature for each of the 4 chimeric dengue vaccines, involving stimulation of type I interferon and associated genes, together with genes encoding chemokines and other mediators involved in the initiation of adaptive responses. In contrast, wild-typeDEN3 virus induced a predominantly inflammatory profile, while the reactogenic attenuated serotype 3 vaccine appeared to induce a blunted response.

A game changer for bipolar disorder diagnosis using RNA editing-based biomarkers.

In clinical practice, differentiating Bipolar Disorder (BD) from unipolar depression is a challenge due to the depressive symptoms, which are the core presentations of both disorders. This misdiagnosis during depressive episodes results in a delay in proper treatment and a poor management of their condition. In a first step, using A-to-I RNA editome analysis, we discovered 646 variants (366 genes) differentially edited between depressed patients and healthy volunteers in a discovery cohort of 57 participants. After using stringent criteria and biological pathway analysis, candidate biomarkers from 8 genes were singled out and tested in a validation cohort of 410 participants. Combining the selected biomarkers with a machine learning approach achieved to discriminate depressed patients (n = 267) versus controls (n = 143) with an AUC of 0.930 (CI 95% [0.879-0.982]), a sensitivity of 84.0% and a specificity of 87.1%. In a second step by selecting among the depressed patients those with unipolar depression (n = 160) or BD (n = 95), we identified a combination of 6 biomarkers which allowed a differential diagnosis of bipolar disorder with an AUC of 0.935 and high specificity (Sp = 84.6%) and sensitivity (Se = 90.9%). The association of RNA editing variants modifications with depression subtypes and the use of artificial intelligence allowed developing a new tool to identify, among depressed patients, those suffering from BD. This test will help to reduce the misdiagnosis delay of bipolar patients, leading to an earlier implementation of a proper treatment.

Characteristics and care of chronic hepatitis C treated with direct-acting antivirals in migrants.

BACKGROUND AND AIMS: Hepatitis C is poorly documented in migrants. The published studies mainly concern the screening in this population and are limited to some countries in Europe and North America. This study aimed to evaluate the characteristics and care of chronic hepatitis C in this population compared to the nonmigrant population, in the era of direct-acting antivirals (DAAs). METHOD: We performed a retrospective analysis based on data presented at the multidisciplinary team meetings of our tertiary care center between 2015 and 2019. RESULTS: We included 277 migrant- and 1390 nonmigrant patients mono-infected with hepatitis C virus (HCV) and treated with DAAs. The majority of the migrants were from Eastern European countries. In multivariable analysis, BMI classes associated with more obesity (OR = 1.84; 95% CI, 1.37-2.49; P < 0.001) and therapeutic patient education (OR = 3.91; 95% CI, 2.38-6.49; P < 0.001) were positively associated with migrant status, whereas age (OR = 0.92; 95% CI, 0.90-0.94; P < 0.001), female gender (OR = 0.46; 95% CI, 0.28-0.74; P = 0.002), modes of contamination with less drug use, transfusion history or nosocomial risk, as well more unknown mode (OR = 0.70; 95% CI, 0.50-0.96; P = 0.031), alcohol consumption (OR = 0.48; 95% CI, 0.29-0.73; P = 0.001), types of structures with less care in a general hospital or health network of general practitioners and more care in a university hospital or primary addictology center (OR = 0.78; 95% CI, 0.60-0.99; P = 0.046) and opioid substitution therapy (OR = 0.25; 95% CI, 0.08-0.68; P = 0.008) were negatively associated with migrant status. The substained virologic response 12 was close to 97% in both groups. CONCLUSION: Despite multiple differences in characteristics and therapeutic care between the two populations, the chances of healing hepatitis C were the same among migrant- compared with nonmigrant patients.

Changes in the profile and therapeutic care of people who use drugs with HCV mono-infection: a retrospective study between 2015 and 2019 from a monocentric tertiary referent center in France.

BACKGROUND AND AIMS: People who use drugs (PWUDs) are the main group at risk for hepatitis C virus (HCV) transmission and a key population for hepatitis C elimination. Multidisciplinary team (MDT) meetings were set up in France in December 2014 within regional reference centers to supervise the prescriptions and delivery of direct-acting antivirals (DAAs) to optimize the management of HCV infection. The aim of this retrospective study was to analyze the changes in the profile and therapeutic care of PWUDs with HCV mono-infection according to the evolution of MDT meetings in a regional tertiary reference center. METHODS: Between 2015 and 2019, overall 1912 HCV-infected patients presented at the MDT meetings, 547 were PWUDs with HCV mono-infection treated with DAAs. Five periods were defined according to the evolution of MDT meetings. The profile and management of PWUDs were compared among these five periods. RESULTS: Over time, the frequency of advanced stage of fibrosis decreased from 90.8 to 36.3% (P < 0.001), whereas the therapeutic care of the patients in primary addictology centers and networks of general practitioners increased from 17.4 to 55% (P < 0.001). The frequency of excessive alcohol consumption varied between 9.1 and 30% (P = 0.003) and that of opioid substitution therapy between 42.5 and 70% (P < 0.001). The Sustained virologic response assessed 12 weeks after the end of treatment rate was above 95% for the five periods. CONCLUSION: Between 2015 and 2019, the changes in the profile and management of PWUDs have followed the evolution of MDT meetings concerning patients with less advanced fibrosis and more therapeutic hepatitis C care made by the primary care centers.

Adherence to treatment and quality of life during hepatitis C therapy: a prospective, real-life, observational study.

BACKGROUND: Adherence is important for therapy of chronic diseases, but has still not been well studied in real life in chronic hepatitis C. AIMS: To assess adherence to hepatitis C combination therapy in routine clinical practice and to identify factors associated with imperfect adherence. METHODS: This cohort study included unselected chronic hepatitis C patients initiating peginterferon α-2b plus ribavirin. 100% adherence was defined by taking all the prescribed doses of both drugs for the full initially intended duration, as declared by the patient or believed by the physician. Quality of life was assessed using the short-form health survey (SF-36) questionnaire. RESULTS: 1860 patients were analysed, including 72% treatment-naive, 36% genotype 2/3, 23% psychiatric, 44% drug addicts and 3% human immunodeficiency virus (HIV)-positive patients. Early treatment discontinuation occurred in 30% of patients. Overall, 38% of patients reported 100% adherence. Patient- and physician-reported adherences were discordant, with a 20-30% overestimation by physicians. HIV co-infection [odds ratio (OR) 2.52, 95% confidence interval (CI) 1.36-4.67], no drug use during follow-up (2.37, 1.30-4.31), genotype 3 (1.55, 1.20-2.00) and treatment-naive (1.32, 1.03-1.69) were associated with 100% adherence. Quality of life worsened during treatment but returned to baseline after the end of treatment. CONCLUSIONS: Imperfect adherence to combination therapy is common in routine patients. Adherence is markedly overestimated by physicians and is associated with some patient's baseline characteristics. Knowledge of these factors might help identify patients who are most in need of intervention and plan more frequent and accurate follow-up.

A novel tetravalent dengue vaccine is well tolerated and immunogenic against all 4 serotypes in flavivirus-naive adults.

BACKGROUND. Sanofi Pasteur has developed a tetravalent dengue vaccine (TDV) against the world's most common arbovirus infection. METHODS. We assessed the safety and immunogenicity of the TDV in healthy adults randomized into 2 groups. Group 1 received 3 TDV injections at months 0, 4, and 12-15; group 2 received saline placebo at month 0 and then 2 TDV injections at months 4 and 12-15. Adverse events were recorded, and biological parameters and viremia levels were measured. Neutralizing antibodies against 4 World Health Organization (WHO) reference strains were measured before and after vaccinations. RESULTS. A total of 33 participants were enrolled in each group. Demographic characteristics were comparable. No vaccine-related serious adverse event was reported. The most common systemic reactions were headache, malaise, and myalgia. Low viremia levels were detected, mainly of serotype 4. Immune response increased with successive vaccine doses. All participants seroconverted against all 4 serotypes after receiving 3 doses at 0, 4, and 12-15-months, and almost all seroconverted after 2 doses given 8-11 months apart. CONCLUSIONS. Sanofi Pasteur's TDV was well tolerated and induced full seroconversion against all WHO reference strain serotypes after 3 doses.

Phosphodiesterase 8A to discriminate in blood samples depressed patients and suicide attempters from healthy controls based on A-to-I RNA editing modifications.

Mental health issues, including major depressive disorder, which can lead to suicidal behavior, are considered by the World Health Organization as a major threat to global health. Alterations in neurotransmitter signaling, e.g., serotonin and glutamate, or inflammatory response have been linked to both MDD and suicide. Phosphodiesterase 8A (PDE8A) gene expression is significantly decreased in the temporal cortex of major depressive disorder (MDD) patients. PDE8A specifically hydrolyzes adenosine 3',5'-cyclic monophosphate (cAMP), which is a key second messenger involved in inflammation, cognition, and chronic antidepressant treatment. Moreover, alterations of RNA editing in PDE8A mRNA has been described in the brain of depressed suicide decedents. Here, we investigated PDE8A A-to-I RNA editing-related modifications in whole blood of depressed patients and suicide attempters compared to age-matched and sex-matched healthy controls. We report significant alterations of RNA editing of PDE8A in the blood of depressed patients and suicide attempters with major depression, for which the suicide attempt took place during the last month before sample collection. The reported RNA editing modifications in whole blood were similar to the changes observed in the brain of suicide decedents. Furthermore, analysis and combinations of different edited isoforms allowed us to discriminate between suicide attempters and control groups. Altogether, our results identify PDE8A as an immune response-related marker whose RNA editing modifications translate from brain to blood, suggesting that monitoring RNA editing in PDE8A in blood samples could help to evaluate depressive state and suicide risk.

[Tetravalent dengue vaccine development]. / Développement d'un vaccin tétravalent contre la dengue.

The Sanofi Pasteur tetravalent dengue vaccine candidate (TV) is composed of four recombinant live attenuated vaccines based on a yellow fever virus vaccine 17D (YFV 17D) backbone, each expressing the prM and envelope genes of one of the four dengue virus serotypes. Pre-clinical studies have demonstrated that the TV dengue vaccine is genetically and phenotypi- cally stable, non-hepatotropic, less neurovirulent than YFV 17D and does not infect mosquitoes by the oral route. In clinics, TV dengue vaccine reactogeni- city, viraemia induction and antibody responses were investigated in three Phase II trials in endemic and non-endemic countries, which demonstrated its good safety and immunogenicity. An extensive clinical development program for dengue TV is underway including an efficacy trial in Thailand, in an area of high dengue incidence. Assuming continued successful outcomes, initial submissions to regulatory authorities are envisaged within a 5-year period.

Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study.

BACKGROUND: The relative roles of immunodeficiency, HIV viral load, and combination antiretroviral therapy (cART) in the onset of individual cancers have rarely been examined. We examined the effect of these factors on the risk of specific cancers in patients infected with HIV-1. METHODS: We investigated the incidence of both AIDS-defining cancers (Kaposi's sarcoma, non-Hodgkin lymphoma, and cervical cancer) and non-AIDS-defining cancers (Hodgkin's lymphoma, lung cancer, liver cancer, and anal cancer) in 52 278 patients followed up in the French Hospital Database on HIV cohort during 1998-2006 (median follow-up 4.9 years, IQR 2.1-7.9; 255 353 person-years). We tested 78 models with different classifications of immunodeficiency, viral load, and cART with Poisson regression. FINDINGS: Current CD4 cell count was the most predictive risk factor for all malignancies apart from anal cancer. Compared with patients with CD4 count greater than 500 cells per microL, rate ratios (RR) ranged from 1.9 (95% CI 1.3-2.7) for CD4 counts 350-499 cells per microL to 25.2 (17.1-37.0) for counts less than 50 cells per microL for Kaposi's sarcoma (p<0.0001), from 1.3 (0.9-2.0) to 14.8 (9.7-22.6) for non-Hodgkin lymphoma (p<0.0001), from 1.2 (0.7-2.2) to 5.4 (2.4-12.1) for Hodgkin's lymphoma (p<0.0001), from 2.2 (1.3-3.6) to 8.5 (4.3-16.7) for lung cancer (p<0.0001), and from 2.0 (0.9-4.5) to 7.6 (2.7-20.8) for liver cancer (p<0.0001). For cervical cancer, we noted a strong effect of current CD4 (RR 0.7 per log(2), 95% CI 0.6-0.8; p=0.0002). The risk of Kaposi's sarcoma and non-Hodgkin lymphoma increased for current plasma HIV RNA greater than 100 000 copies per mL compared with patients with controlled viral load (RR 3.1, 95% CI 2.3-4.2, p<0.0001; and 2.9, 2.1-3.9, p<0.0001, respectively), whereas cART was independently associated with a decreased incidence (0.3, 0.2-0.4, p<0.0001; and 0.8, 0.6-1.0, p=0.07, respectively). The RR of cervical cancer for those receiving cART was 0.5 (0.3-0.9; p=0.03). The risk of anal cancer increased with the time during which the CD4 count was less than 200 cells per microL (1.3 per year, 1.2-1.5; p=0.0001), and viral load was greater than 100 000 copies per mL (1.2 per year, 1.1-1.4, p=0.005). INTERPRETATION: cART would be most beneficial if it restores or maintains CD4 count above 500 cells per microL, thereby indicating an earlier diagnosis of HIV infection and an earlier treatment initiation. Cancer-specific screening programmes need to be assessed in patients with HIV. FUNDING: Agence Nationale de Recherches sur le SIDA et les hépatites (ANRS), INSERM, and the French Ministry of Health.

Precise predictions for double-Higgs production via vector-boson fusion.

Theoretical predictions with next-to-next-to-leading order (NNLO) QCD accuracy combined with the next-to-leading order (NLO) electroweak (EW) corrections are presented for differential observables of the double-Higgs production process via vector-boson fusion. While the QCD corrections were previously known, the EW ones are computed here for the first time. The numerical results are obtained for a realistic experimental set-up at the LHC and are presented in the form of fiducial cross sections and differential distributions. Within this setup we find that the VBF approximation employed in the NNLO QCD correction is accurate at the sub-percent level. We find that the NLO EW corrections within the fiducial volume are - 6.1 % , making them of almost the same order as the NLO QCD corrections. In some kinematic regions they can grow as large as - 30 % making them the dominant radiative corrections. When the EW corrections are combined with the NNLO QCD corrections we find a total correction of - 14.8 % . The results presented here thus comprise the state-of-the-art theoretical predicition for the double-Higgs production via vector-boson fusion, which will be of value to the high-luminosity programme at the LHC.

Pre-exposure purified vero cell rabies vaccine and concomitant routine childhood vaccinations: 5-year post-vaccination follow-up study of an infant cohort in Vietnam.

Children have a high risk of exposure to rabies in countries where the disease is endemic. This prospective, 5-year study followed two groups of children who had received diphtheria, tetanus, whole-cell pertussis and inactivated poliomyelitis vaccine (DTP-IPV) at 2, 3, 4 months and 1 year (Group B) or concomitant with three doses of purified Vero cell rabies vaccine (PVRV), given at 2, 4 months and 1 year (Group A). Antibody determinations were made annually for 5 years. Data were available from a total of 72 subjects; 30 in Group A and 32 in Group B. In Group A, the percentage of patients immunized against rabies (anti-rabies > or = 0.5 IU/ml) decreased from 100% after the third vaccination to 63%, 5 years later. After 5 years, 93.8% in Group A and 96.7% in Group B had seroprotective diphtheria antibody titers > or = 0.01 IU/ml, and all subjects had anti-polio (type 1, 2 and 3) seroprotective titers > or = 5 1:dil. We conclude that co-administration of PVRV with DTP-IPV elicited protective antibody concentrations to all antigens that persist for at least 5 years, with continued protection against rabies in over 60% of subjects. These results are consistent with integration of pre-exposure rabies vaccination into the Expanded Program on Immunization (EPI) in countries where rabies is endemic.

An event generator for same-sign W-boson scattering at the LHC including electroweak corrections.

In this article we present an event generator based on the Monte Carlo program Powheg in combination with the matrix-element generator Recola. We apply it to compute NLO electroweak corrections to same-sign W-boson scattering, which have been shown to be large at the LHC. The event generator allows for the generation of unweighted events including the effect of the NLO electroweak corrections matched to a QED parton shower and interfaced to a QCD parton shower. In view of the expected experimental precision of future measurements, the use of such a tool will be indispensable.

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. Twelve children had serologic evidence of dengue infection. The nadir of dengue antibodies in children was at 12 months of age. In highly endemic areas, dengue vaccination could be needed at an early age.

Long-term anti-rabies antibody persistence following intramuscular or low-dose intradermal vaccination of young Vietnamese children.

Vietnamese children received purified Vero cell rabies vaccine 1 year after a primary series (Y0) and again 5 years later (Y5), either as intramuscular or 1/5th dose intradermal injections concomitant with diphtheria, tetanus, pertussis and oral poliomyelitis vaccines. Antibody levels were assayed annually for 5 years. All subjects in both groups had anti-rabies antibody titres considered protective after the Y0 booster. Rabies seroprotection rates and geometric mean titres gradually decreased similarly in both groups. Seroprotection after the Y5 booster was 100% in both groups. Satisfactory immunogenicity, long-term antibody persistence and an anamnestic response were conferred by both routes, greatly simplifying any future post-exposure prophylaxis.