Analysis of Hospitalized and Severe Dengue Cases Over the 6 years of Follow-up of the Tetravalent Dengue Vaccine (CYD-TDV) Efficacy Trials in Asia and Latin America.

BACKGROUND: CYD-TDV, a live, attenuated, tetravalent dengue vaccine, has been approved for the prevention of symptomatic dengue in previously dengue exposed individuals. This post hoc analysis assessed hospitalized and severe virologically confirmed dengue (VCD) over the complete 6-year follow-up of 3 CYD-TDV efficacy studies (CYD14, CYD15, and CYD23/CYD57). METHODS: The main outcomes were hazard ratios (HRs) for hospitalized or severe VCD by baseline dengue serostatus, focusing on those who were seropositive, and by age at immunization (<9 years/≥9 years). Baseline dengue serostatus was measured or inferred using several methods. Hospitalized VCD cases were characterized in terms of clinical signs and symptoms and wild-type viremia level. Antibody persistence was assessed up to 5 years after the last injection. RESULTS: In those aged ≥9 years and baseline seropositive, CYD-TDV protected against hospitalized and severe VCD over 6 years compared to placebo (HR [95% confidence interval] multiple imputation from month 0 method, .19 [.12-.30] and .15 [.06-.39]; other methods were consistent). Vaccine protection was observed over the different study periods, being highest during the first 2 years. Evidence for a decreased risk of hospitalized and severe VCD was also observed in seropositive participants aged 6-8 years. Clinical signs and symptoms, and quantified dengue viremia from participants with hospitalized VCD were comparable between groups. CONCLUSIONS: CYD-TDV demonstrated robust protection against hospitalized and severe VCD over the entire 6-year follow-up in participants who were seropositive and ≥9 years old. Protection was also observed in seropositive 6-8 year-olds. Clinical Trials Registration: NCT00842530, NCT01983553, NCT01373281, NCT01374516.

Pneumococcal nasopharyngeal carriage in Indonesia infants and toddlers post-PCV13 vaccination in a 2+1 schedule: A prospective cohort study.

BACKGROUND: The PCV13 immunization demonstration program began in October 2017 in Indonesia. The aim of this study is to assess the dynamic changes of pneumococcal serotype before and after PCV13 administration, with two primary and one booster doses. METHODS: The prospective cohort study was conducted as a follow up study measuring the impact of PCV13 demonstration program by the Indonesian Ministry of Health in Lombok Island, West Nusa Tenggara, Indonesia, from March 2018 to June 2019. The subjects were two-month-old healthy infants who were brought to the primary care facility for routine vaccination and followed until 18 months of age. We use convenience sampling method. There were 115 infants in the control group and 118 infants in the vaccine group, and the PCV immunization was given on a 2+1 schedule. Nasopharyngeal (NP) swabs were collected four times during the vaccination periods by trained medical staff. Specimens were analyzed by culture methods to detect S. pneumonia colonization and multiplex polymerase chain reaction (mPCR) to determine serotype. The most frequently detected serotypes will be named as dominant serotypes. Descriptive analysis of demographic characteristics, the prevalence of overall and serotype colonization, and the distribution of serotypes were performed. The prevalence of both cohort groups were compared using chi-square test. Statistical significance was set at p < 0.05. RESULTS: Two hundred and thirty three infants age two months old were recruited, with 48.9% of the subjects were male and 51.1% of the subjects were female. Sociodemographic data in both cohort groups were relatively equal. Nasopharyngeal pneumococcal colonization before PCV13 administration occurred in 19.1% of the control and 22.9% of the vaccine group. The prevalence increased with increasing age in both groups. The prevalence of VT serotypes in control groups aged 2 months, 4 months, 12 months, and 18 months was 40.9%, 44.2%, 53.8%, and 54.3%, respectively, and in the vaccine group, 25.9%, 40.4%, 38.0%, and 22.6%, respectively. The most common VT serotypes in both groups were 6A/6B, 19F, 23F, and 14. The prevalence of VT serotypes decreased significantly compared to non-vaccine type serotypes after three doses of the PCV13 vaccine (p < 0.001). Another notable change was the decline in prevalence of serotype 6A/6B after PCV13 administration using the 2+1 schedule. CONCLUSIONS: This study shows lower prevalence of VT and 6A/6B serotypes in the nasopharynx among children who were PCV13 vaccinated compared with those who were unvaccinated. The result from this study will be the beginning of future vaccine evaluation in larger population and longer period of study.

First Pediatric Outpatient Parenteral Antibiotic Therapy Clinic in Indonesia.

Background: Infection remains a major pediatric health problem in Indonesia and usually leads to longer hospitalization due to the need for extended intravenous antibiotic administration. In developed countries, pediatric outpatient parenteral antibiotic therapy (P-OPAT) is well-established and proven to be safe and effective at reducing the length of hospital stay; however, data on low- and middle-income countries such as Indonesia remain limited. This P-OPAT service is new and the first service in Indonesia. Methods: The medical records of patients attending Indonesia's first P-OPAT clinic between April 2015 and March 2017 were retrospectively investigated. Results: During the 24-month period, 32 patients received treatment at the P-OPAT clinic, saving a total of 258 bed days. The majority of patients (n = 16; 50%) were diagnosed with urinary tract infection, followed by cellulitis (n = 4; 12.5%) and osteomyelitis (n = 4; 12.5%). Ceftriaxone was the most commonly used antibiotic (n = 16; 50%). All patients used a peripheral intravenous catheter and were sent home with this device. Twelve patients (37.5%) needed to change IV access more than once. None of the patients used elastomeric infusor device. The median duration of OPAT was 5 days (range 1-27 days). All patients were successfully treated with no recurrence after 30 days. One patient (3.1%) experienced drug-related complication and another one (3.1%) was readmitted due to an underlying medical condition. All the patients complied with P-OPAT schedules. Conclusions: P-OPAT service offers a safe and effective option for the delivery of outpatient intravenous antibiotics in selected patients even in resource-poor settings.

DTwP-HB-Hib: antibody persistence after a primary series, immune response and safety after a booster dose in children 18-24 months old.

BACKGROUND: The new combination of DTwP-HB-Hib vaccines has been developed in Indonesia following World Health Organization (WHO) recommendation and integrated into national immunization program. The aims of the study were to measure 1) antibody persistence 12-18 months after a primary series, 2) immune response and safety after a booster dose of DTwP-HB-Hib. METHODS: This was a multi-center, open-labeled, prospective, interventional study. Subjects who had received complete primary dose of DTwP-HB-Hib vaccine from the previous phase III trial were recruited in this trial. Subjects were given one dose of DTwP-HB-Hib (Pentabio®) booster at age 18-24 months old. Diphtheria, tetanus, pertussis, hepatitis B, Hemophilus influenza type B antibodies were measured before and after booster to determine antibody persistence and immune response. Vaccine adverse events were assessed immediately and monitored until 28 days after the booster recorded with parent's diary cards. RESULTS: There were 396 subjects who completed the study. Increased proportion of seroprotected subjects from pre-booster to post-booster were noted in all vaccine antigens: 74.5 to 99.7% for diphtheria; 100 to 100% for tetanus; 40.4 to 95.5% for pertussis; 90.2 to 99.5% for hepatitis B; and 97.7 to 100% for Hib. Common systemic adverse events (AEs) were irritability (23.7-25%) and fever (39.9-45.2%). Local AEs such as redness, swelling, and induration were significantly less common in the thigh group (7.7, 11.3, and 7.1%) than in the deltoid group (28.9, 30.7, and 25%) (P < 0.001). Most AEs were mild and resolved spontaneously within three-day follow-up period. CONCLUSIONS: Booster of DTwP-HB-Hib vaccine at age 18-24 months is required to achieve and maintain optimal protective antibody. The vaccine is safe and immunogenic to be used for booster vaccination. TRIAL REGISTRATION: NCT02095314 (retrospectively registered, March 24, 2014).

Pneumococcal vaccination for splenectomized patients with thalassemia major in Indonesia.

INTRODUCTION: Streptococcus pneumoniae is a capsulated bacterium that can cause severe infection in patients with thalassemia major, particularly those who have undergone splenectomy. The absence of the spleen as well as zinc deficiency in splenectomized patients with thalassemia major increases the possibility of developing invasive pneumococcal infection. The aims of this study are to evaluate pneumococcal IgG levels following PCV and PPV immunizations and the effect of zinc supplementation on qualitative specific immune responses in splenectomized patients with thalassemia. METHODS: Splenectomized patients with thalassemia major were administered a PCV pneumococcal vaccine (Prevenar 13®) at the start of the trial, after which they were randomly assigned to 2 groups (zinc and placebo group). After 8weeks, the patients received a PPV pneumococcal vaccine (Pneumovax®). Zinc syrup was provided to the zinc group at a dose of 1.5mg/kg/day (maximum of 50mg/day). Pneumococcal IgG examinations were conducted at the start of the trial and after 12weeks. RESULTS: In the group without PPV, the median initial pneumococcal IgG value was 315 (ranging from 65 to 1419) mU/mL for the zinc group and 338.5 (ranging from 82 to 1648) mU/mL for the placebo group. The median final pneumococcal IgG value was 1812.5 (ranging from 834 to 2444) mU/mL for the zinc group and 2857.5 (ranging from 834 to 2624) for the placebo group. The increase in the pneumococcal IgG value between the two groups was comparable (p=0.642). In the group with previous PPV, the median initial pneumococcal IgG value was 1333 (ranging from 793 to 2031) mU/mL for the zinc group and 880 (ranging from 74 to 1686) mU/mL for the placebo group. The median final pneumococcal IgG value was 1487 (ranging from 635 to 1757) mU/mL for the zinc group and 1012 (ranging from 292 to 1732) mU/mL for the placebo group. The increase in the pneumococcal IgG value between the two groups was comparable (p=0.528). CONCLUSION: There is no difference in the increase in pneumococcal IgG level in splenectomized patients with thalassemia major prior to and after receiving PPV. There were no differences observed in the development of pneumococcal IgG following zinc supplementation.

The role of apolipoprotein E polymorphism in improving dyslipidemia in obese adolescents following physical exercise and National Cholesterol Education Program Step II intervention.

BACKGROUND: Lifestyle changes are important factors for managing dyslipidemia before considering blood lipid-lowering drugs. However, genetic factors can influence the response outcome. OBJECTIVE: We aimed to determine a dyslipidemia management strategy in obese adolescents. PATIENTS AND METHODS: A total of 60 dyslipidemic obese adolescents received physical exercise and the NCEP step II diet for 28 days. Apolipoprotein E (apo E) genotypes and blood lipid levels were compared before and after interventions. RESULTS: The apo E3/E3 genotype was found to be common in all subjects. Mean levels of total cholesterol, triglyceride, and low-density lipoprotein-cholesterol (LDL-C) improved in subjects with the E3 allele after the intervention, but not the E2 allele. Total cholesterol and LDL-C, but not triglyceride levels, improved in subjects with the E4 allele. DISCUSSION: Apo E alleles might influence improvement in lipid profiles after diet and exercise interventions. These results could inform personalized dyslipidemia management in obese adolescents, to determine which subjects would benefit from blood lipid-lowering drugs.

Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial.

BACKGROUND: An estimated 100 million people have symptomatic dengue infection every year. This is the first report of a phase 3 vaccine efficacy trial of a candidate dengue vaccine. We aimed to assess the efficacy of the CYD dengue vaccine against symptomatic, virologically confirmed dengue in children. METHODS: We did an observer-masked, randomised controlled, multicentre, phase 3 trial in five countries in the Asia-Pacific region. Between June 3, and Dec 1, 2011, healthy children aged 2-14 years were randomly assigned (2:1), by computer-generated permuted blocks of six with an interactive voice or web response system, to receive three injections of a recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV), or placebo, at months 0, 6, and 12. Randomisation was stratified by age and site. Participants were followed up until month 25. Trial staff responsible for the preparation and administration of injections were unmasked to group allocation, but were not included in the follow-up of the participants; allocation was concealed from the study sponsor, investigators, and parents and guardians. Our primary objective was to assess protective efficacy against symptomatic, virologically confirmed dengue, irrespective of disease severity or serotype, that took place more than 28 days after the third injection. The primary endpoint was for the lower bound of the 95% CI of vaccine efficacy to be greater than 25%. Analysis was by intention to treat and per procotol. This trial is registered with ClinicalTrials.gov, number NCT01373281. FINDINGS: We randomly assigned 10,275 children to receive either vaccine (n=6851) or placebo (n=3424), of whom 6710 (98%) and 3350 (98%), respectively, were included in the primary analysis. 250 cases of virologically confirmed dengue took place more than 28 days after the third injection (117 [47%] in the vaccine group and 133 [53%] in the control group). The primary endpoint was achieved with 56·5% (95% CI 43·8-66·4) efficacy. We recorded 647 serious adverse events (402 [62%] in the vaccine group and 245 [38%] in the control group). 54 (1%) children in the vaccine group and 33 (1%) of those in the control group had serious adverse events that happened within 28 days of vaccination. Serious adverse events were consistent with medical disorders in this age group and were mainly infections and injuries. INTERPRETATION: Our findings show that dengue vaccine is efficacious when given as three injections at months 0, 6, and 12 to children aged 2-14 years in endemic areas in Asia, and has a good safety profile. Vaccination could reduce the incidence of symptomatic infection and hospital admission and has the potential to provide an important public health benefit. FUNDING: Sanofi Pasteur.

The revised WHO dengue case classification: does the system need to be modified?

There has been considerable debate regarding the value of both the 1997 and 2009 World Health Organization (WHO) dengue case classification criteria for its diagnosis and management. Differentiation between classic dengue fever (DF) and dengue haemorrhagic fever (DHF) or severe dengue is a key aspect of dengue case classification. The geographic expansion of dengue and its increased incidence in older age groups have contributed to the limited applicability of the 1997 case definitions. Clinical experience of dengue suggests that the illness presents as a spectrum of disease instead of distinct phases. However, despite the rigid grouping of dengue into DF, DHF and dengue shock syndrome (DSS), overlap between the different manifestations has often been observed, which has affected clinical management and triage of patients. The findings of the DENCO study evaluating the 1997 case definitions formed the basis of the revised 2009 WHO case definitions, which classified the illness into dengue with and without warning signs and severe dengue. Although the revised scheme is more sensitive to the diagnosis of severe dengue, and beneficial to triage and case management, there remain issues with its applicability. It is considered by many to be too broad, requiring more specific definition of warning signs. Quantitative research into the predictive value of these warning signs on patient outcomes and the cost-effectiveness of the new classification system is required to ascertain whether the new classification system requires further modification, or whether elements of both classification systems can be combined.