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Background: An inactivated Vero cell culture derived Japanese encephalitis virus vaccine (IXIARO) requires a booster dose 1 year after primary schedule for long-term antibody persistence in adults. The aim of this study is to evaluate immunogenicity and safety of a booster dose in children 2 months to <18 years of age., Methods: This is a randomized, controlled open-label study in the Philippines. Three hundred children vaccinated with IXIARO in a previous trial were randomized 1:1 to receive either no booster or a booster 12 months after initiation of the primary series. Neutralizing antibody titers were assessed before and after the booster and up to 3 years after primary series. Safety endpoints included the rate of subjects with solicited adverse events (AEs), unsolicited AEs and serious AEs within 1 month after the booster., Results: Geometric mean titer declined by 1 year after the primary series, but titers remained above the established protective threshold in 85%-100% of children depending on age group. The booster led to a pronounced increase in geometric mean titer and 100% seroprotection rate in all age groups. The booster was well tolerated, with AE rates lower compared with the primary series. Most AEs were mild., Conclusions: A booster dose of IXIARO administered 12 months after the primary immunization was well tolerated and highly immunogenic.

Background: Japanese encephalitis (JE) is a major public health concern in Asia and poses a small but potentially fatal threat to travelers from nonendemic countries, including children. No JE vaccine for pediatric use has been available in Europe and the United States., Methods: Age-stratified cohorts of children between 2 months and 17 years received 2 doses of Vero cell-derived inactivated JE virus vaccine (IXIARO; Valneva Austria GmbH, Vienna, Austria) administered 28 days apart [<3 years, 0.25 mL (half adult dose); ≥3 years, 0.5 mL (full adult dose)]. Immunogenicity endpoints were seroconversion rate, 4-fold increase in JE neutralizing antibody titer and geometric mean titer assessed 56 days and 7 months after the first vaccination in 496 subjects of the intent-to-treat population. The immune response to JE virus at both time points was also analyzed according to prevaccination JE virus and dengue virus serostatus., Results: At day 56, seroconversion was attained in ≥99.2% of subjects with age-appropriate dosing, 4-fold increases in titer were reported for 77.4%-100% in various age groups, and geometric mean titers ranged from 176 to 687, with younger children having the strongest immune response. At month 7, seroconversion was maintained in 85.5%-100% of subjects. Pre-existing JE virus immunity did not impact on immune response at day 56; however, it led to a better persistence of protective antibody titers at month 7., Conclusions: IXIARO is highly immunogenic at both doses tested in the pediatric population, leading to protective antibody titers at day 56 in >99% of subjects who received the age-appropriate dose.

Background: Japanese encephalitis remains a serious health concern in Asian countries and has sporadically affected pediatric travelers. In the present study, we monitored the safety profile of the Japanese encephalitis virus vaccine IXIARO (Valneva Austria GmbH, Vienna, Austria) in a pediatric population., Methods: We randomized 1869 children between 2 months and 17 years of age in an age-stratified manner to vaccination with IXIARO or one of the control vaccines, Prevnar (formerly Wyeth Pharmaceuticals Inc., now Pfizer Inc., Kent, United Kingdom) and HAVRIX 720 (GlaxoSmithKline Biologicals, Rixensart, Belgium). Adverse events (AEs) (unsolicited and solicited local and systemic AEs), serious AEs and medically attended AEs were assessed up to day 56 and month 7 after the first dose., Results: Incidences of AEs, serious AEs or medically attended AEs did not differ significantly between the groups in any age stratum. AEs were most frequent in children <1 year of age and decreased with age. AEs of special interest, predefined as AEs associated with potential hypersensitivity/allergy or neurologic disorders up to day 56, were reported in 4.6% (IXIARO) versus 6.3% (Prevnar) in the ≥2 months to <1 year age group and 3.4% (IXIARO) versus 3.3% (HAVRIX) in the ≥1 to <18 years age group. Fever, the most frequent systemic reaction in 23.7% of infants to 3.8% of adolescents, decreased with age and did not differ between groups., Conclusions: The safety profile of IXIARO was comparable to the control vaccines in terms of overall AE rates, serious AEs and medically attended AEs.

Background: Meningococcal disease remains an important cause of invasive bacterial infections in children less than 5 years of age. Immunogenicity and safety of the investigational ACWY vaccine conjugated with tetanus toxoid (ACWY-TT, GlaxoSmithKline Biologicals) were evaluated in 1501 healthy 2- to 10-year-old children in the Philippines, India, Lebanon, and Saudi Arabia., Methods: Children were randomized (3:1) to receive ACWY-TT or licensed tetravalent meningococcal polysaccharide vaccine (Mencevax, GlaxoSmithKline, Men-PS). Diary cards were used to collect solicited symptoms for 4 days after vaccination. Serious adverse events were reported for 6 months. Serum bactericidal activity (rSBA, rabbit complement) was measured before and 1 month after vaccination in the first 75% of subjects enrolled in each country., Results: The statistical criteria for noninferiority in terms of rSBA vaccine responses were reached. Exploratory analyses showed that postvaccination rSBA titers ≥ 1:8 and ≥ 1:128 were significantly higher after ACWY-TT than Men-PS for serogroups C, W-135, and Y, and rSBA vaccine responses and geometric mean antibody titers were significantly higher for all 4 serogroups after administration of ACWY-TT. Noninferiority in terms of incidences of grade 3 general symptoms was not demonstrated. ACWY-TT was well tolerated with grade 3 events reported in <1% of subjects per group. No serious adverse events were considered related to vaccination., Conclusion: ACWY-TT was immunogenic in children between 2 to 10 years of age with a clinically acceptable safety profile that resembled licensed Men-PS. These data support a positive benefit/risk ratio for the ACWY-TT vaccine.

The safety and reactogenicity profiles of the 10-valent pneumococcal conjugate vaccine, PHiD-CV, and 7vCRM were comparable within the Philippines and Poland when coadministered as a booster dose with DTPw-HBV/Hib and poliovirus vaccines to toddlers primed with the same vaccines. Robust immune responses for all 10 vaccine pneumococcal serotypes and protein D following PHiD-CV booster vaccination were indicative of effective priming.

Background: Immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) was evaluated when coadministered with DTPw-HBV/Hib and OPV at 6, 10, and 14 weeks of age in the Philippines, or with DTPw-HBV/Hib and IPV at 2, 4, and 6 months of age in Poland., Methods: In this double-blind, controlled study (107007/NCT00344318), 400 Filipino and 406 Polish infants 6 to 12 weeks of age were randomized (3:1) to receive either PHiD-CV or the 7-valent pneumococcal conjugate vaccine (7vCRM). Immune responses were assessed 1 month post-dose III., Results: Percentages of infants with anti-pneumococcal antibody concentrations >or=0.2 microg/mL (GSK's 22F-inhibition ELISA) were within the same range for both pneumococcal conjugate vaccine groups, with the exception of serotypes 6B and 23F for which lower percentages were observed in the PHiD-CV group in Poland. At least 98.2% of PHiD-CV vaccinees had antibody concentrations >or=0.2 microg/mL against pneumococcal serotypes 1, 5, and 7F. In both countries, anti-pneumococcal antibody geometric mean concentrations against serotypes 18C and 19F were higher in the PHiD-CV group than in the 7vCRM group. Antibody geometric mean concentrations for most of the other common serotypes were within the same range for both groups in the Philippines and were lower in the PHiD-CV group in Poland. Functional responses (opsonophagocytic activity [OPA]) were observed for all vaccine serotypes in both countries., Conclusions: PHiD-CV was immunogenic against each of the 10 pneumococcal vaccine serotypes when coadministered with DTPw-HBV/Hib and poliovirus vaccines.

Background: Neonatal infections are a major cause of death worldwide. Simple procedures for identifying infants with infection that need referral for treatment are therefore of major public health importance., Methods: We investigated 3303 infants <2 months of age presenting with illness to health facilities in Ethiopia, The Gambia, Papua New Guinea and The Philippines, using a standardized approach. Historical factors and clinical signs predicting sepsis, meningitis, hypoxemia, deaths and an ordinal scale indicating severe disease were investigated by logistic regression, and the performance of simple combination rules was explored., Results: In multivariable analysis, reduced feeding ability, no spontaneous movement, temperature >38 degrees C, being drowsy/unconscious, a history of a feeding problem, history of change in activity, being agitated, the presence of lower chest wall indrawing, respiratory rate >60 breaths/min, grunting, cyanosis, a history of convulsions, a bulging fontanel and slow digital capillary refill were independent predictors of severe disease. The presence of any 1 of these 14 signs had a sensitivity for severe disease (defined as sepsis, meningitis, hypoxemia, or radiologically proven pneumonia) of 87% and a specificity of 54%. More stringent combinations, such as demanding 2 signs from the list, resulted in a considerable loss of sensitivity. By contrast only slight loss of sensitivity and considerable gain of specificity resulted from reducing the list to 9 signs. Requiring the presence of fever and any other sign produced a diagnostic rule with extremely low sensitivity (25%)., Conclusions: Physical signs can be used to identify young infants at risk of severe disease, however with limited specificity, resulting in large numbers of unnecessary referrals. Further studies are required to validate and refine the prediction of severe disease, especially in the first week of life, but there appear to be limits on the accuracy of prediction that is achievable.

Background: The broad antimicrobial spectrum and affordable price of chloramphenicol make it an attractive first line treatment option for children with severe illnesses in developing countries. Little is known, however, about its pharmacokinetics in young infants in these settings., Methods: We studied infants younger than 3 months of age hospitalized in Manila, Philippines and The Gambia with possible severe bacterial infections likely to benefit from treatment with chloramphenicol. Infants in the first week of life received intramuscular doses of 25 mg/kg chloramphenicol once daily, twice daily in the second through fourth week of life and three times daily from 5 to 12 weeks of age. Blood samples were taken at 0.5, 1, 2 and 3 h after the first dose, 1 h before the second dose and before the repetition doses on subsequent days. In the Philippines a second group of infants was treated with oral chloramphenicol according to the same dosage schedule., Results: Thirty-eight infants received intramuscular chloramphenicol, and 20 received oral drug. Intramuscular administration resulted in therapeutic concentrations (10 to 25 microg/ml) in 73 to 86% of children in each of the three age groups in the first 6 h and in 50 to 80% on Days 2 and 3. Between 33 and 38% of children had potentially toxic values on Days 2 and 3. In contrast, after oral administration, only about one-half of the children reached therapeutic values in serum at any time up to Day 3 after start of treatment., Conclusions: Intramuscular chloramphenicol can be used as a second line drug for the treatment of severe infections in infants younger than 90 days of age, where third generation cephalosporins are not available. It quickly achieves therapeutic values in a high proportion of children. However, severe infections should not be treated with oral chloramphenicol in this age group, because therapeutic serum concentrations were inconsistently achieved.

Objective: Pneumonia, meningitis and other serious infections are leading causes of death in developing countries. As part of a multicenter study we aimed to determine the etiology of pneumonia, meningitis and other serious infections in a cohort of Filipino infants ages 90 days or younger., Method: During a 2-year period, 2053 infants age 90 days or younger presenting to 1 of 3 Manila community hospitals were screened; 873 had signs or symptoms suggestive of an infectious illness, and 608 were judged to have clinical features suggestive of severe infection and had laboratory workup including blood for culture and white blood cell count, nasopharyngeal aspirate for virology, cerebrospinal fluid culture when indicated and chest radiograph. Chest radiographs were read independently by 3 radiologists without knowledge of clinical findings., Results: Of the 873 enrolled infants, 81 died (91%). After exclusion of presumed contaminants, positive bacterial culture from blood and/or cerebrospinal fluid was obtained in 35 infants (5.8%; 95% confidence interval 4%, 8%), 9 of whom died. The organisms responsible for meningitis were Acinetobacter spp. (4), Streptococcus pneumoniae (2), Escherichia coli (2), Enterobacter spp. (1), Pseudomonas aeruginosa (1), Haemophilus influenzae (1) and Staphylococcus aureus (1); those responsible for the other clinical diagnoses were Salmonella spp. (6), Enterobacter spp. (3), Streptococcus pyogenes (3), other Gram-negative organisms (8), S. pneumoniae (1) and Staphylococcus aureus (2). In 685 infants examined for viral causes of their illness, 223 viruses were isolated from 219 infants (32%; 95% confidence interval 28%, 36%). Enteroviruses were the most common potential pathogens identified (22% of infants studied), followed by respiratory syncytial virus (17%), rhinovirus (10%) and adenovirus (4%). Concomitant virus identification occurred in 10 of those with positive bacterial culture (29%; 95% confidence interval, 15%, 46%), with enterovirus being found in 7 of these cases., Conclusion: Many young Filipino infants with life-threatening illness were evaluated in this study. Thirty-five had infections attributable to bacteria, with Salmonella spp. being the most common, followed by Gram-negative organisms. Pneumococcus was an unusual cause.

Background: Measles continues to be a significant health problem in developing countries., Objectives: To describe the clinical features of measles-associated pneumonia (MAP) and to identify other pathogens involved., Methods: Measles diagnosis was ascertained either by the typical symptom complex or by a sensitive enzyme immunoassay for antibody among children < 5 years of age admitted to the hospital with pneumonia. Other pathogens were identified by blood culture, virus isolation or antigen detection from nasopharyngeal aspirate and antibody determination from serum., Results: Of 182 MAP cases 162 (89%) had clinically typical measles. Twenty patients had a diagnostic antibody finding with an atypical clinical presentation. Thirteen percent were younger than 9 months of age. The case fatality rate was 17%, with a significantly increased odds ratio (OR) for those with cyanosis [OR 4.6, 95% confidence interval (CI) 1.7 to 13], respiratory rate > or = 60/min (OR 3, 95% CI 1.3 to 7) or fulfilling criteria for very severe pneumonia (OR 5.3, 95% CI 2.3 to 12). Mixed infection was found in 53% of patients. Blood culture was positive in 10 patients, Streptococcus pneumoniae (N = 5) being the most common finding. Adenovirus (19%) and parainfluenza (25%) viruses were the most frequent other viruses. A dense infiltrate was seen significantly more often among measles patients with bacterial coinfection (87.5%) than those with other viruses (36%, P = 0.007) or no evidence of other infection (33%, P = 0.004)., Conclusion: In MAP, coinfection with other microbes is common. Cyanosis and a respiratory rate of > or = 60/min predict a greater risk of dying.