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Abstract: Evaluation of immunogenicity and safety of a 2-dose liquid formulation of human rotavirus vaccine, RIX4414 following WHO''s Expanded Program on Immunization (EPI) schedule (0, 1, and 2 months; Month 0 indicates day of enrolment) in Vietnam and the Philippines. Infants aged 6–10 (mean=8.7±1.07 weeks Vietnam) and 5–10 weeks (mean=6.6±1.03 weeks Philippines) received two doses of RIX4414 vaccine (V) and one dose of placebo (PL) or three placebo doses concomitantly with commercially available diphtheria-tetanus-whole-cell pertussis, hepatitis B and oral poliovirus vaccines. The vaccination schedules were: V–V–PL, V–PL–V and PL–PL–PL (Vietnam); PL–V–V, V–PL–V and PL–PL–PL (Philippines). Anti-rotavirus seroconversion rate was assessed pre-vaccination and post-vaccination (ELISA cut-off=20U/ml). 375 infants were enrolled in each country. Seroconversion rates at one month post-Dose 2 of RIX4414 were Vietnam 63.3% (95% CI: 54.3–71.6) in V–V–PL group and 81.5% (95% CI: 73.4–88) in V–PL–V group; Philippines 70% (95% CI: 61–78) in PL–V–V group and 59.2% (95% CI: 49.8–68) in V–PL–V group. Frequencies of solicited (8-day post-each dose) and unsolicited symptoms (31-day post-each dose) were similar. Two-doses of rotavirus vaccine administered within the WHO EPI offer flexibility in existing schedule, though both schedules provides good immune responses. [Copyright &y& Elsevier]

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.

As progress toward global poliovirus eradication continues, more and more countries are moving away from use of oral poliovirus vaccines (OPV) to inactivated poliovirus vaccines (IPV) in national vaccination schedules. Reduction of antigen dose in IPV could increase manufacturing capacity and facilitate the change from OPV to IPV. Combination vaccines reduce the number of injections required to complete vaccination, thus playing an important role in maintaining high vaccine coverage with good public acceptability. Three formulations of a combined, candidate hexavalent diphtheria-tetanus-whole cell pertussis-hepatitis B-inactivated poliovirus-Hemophilus influenzae type b conjugate vaccine (DTPw-HBV-IPV/Hib, GlaxoSmithKline Biologicals) differing only in IPV antigen content (full-dose, half-dose and one-third dose as compared with available stand-alone IPV vaccines), were evaluated when administered to healthy toddlers. Controls received separately administered licensed DTPw-HBV/Hib and IPV vaccines. Immunogenicity was assessed before and one month after vaccination. Safety and reactogenicity data were assessed for 30 d after vaccination. A total of 312 Filipino children were vaccinated in their second year of life. Each DTPw-HBV-IPV/Hib formulation was non-inferior to control in terms of pre-defined criteria for IPV immunogenicity. Post-vaccination GMTs against each poliovirus type were increased between 4.2- and 37.9-fold over pre-vaccination titers. Non-inferiority to other vaccine antigens was also demonstrated. The safety profile of the 3 DTPw-HBV-IPV/Hib formulations resembled licensed DTPw-HBV/Hib Kft and IPV in terms of the frequency and intensity of adverse reactions after vaccination. Further investigation of DTPw-HBV-IPV/Hib containing reduced quantity of IPV antigen for primary vaccination in infants is warranted. This study is registered at www.clinicaltrials.gov NCT number: NCT01106092.

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.

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.

Japanese encephalitis (JE) virus is a major cause of disease, disability, and death in Asia. An effective, live, attenuated JE vaccine (LJEV) is available; however, its use in routine immunization schedules is hampered by lack of data on concomitant administration with measles vaccine (MV). This study evaluated the immunogenicity and reactogenicity of LJEV and MV when administered at the same or separate study visits in infants younger than 1 year of age. Three groups of healthy infants were randomized to receive LJEV at age of 8 months and MV at 9 months (Group 1; n=100); MV and LJEV together at 9 months (Group 2; n=236); or MV and LJEV at 9 and 10 months, respectively (Group 3; n=235). Blood was obtained 4 weeks after each vaccine administration to determine antibody levels for measles and JE. Reactogenicity was assessed by parental diaries and clinic visits. Four weeks after immunization, measles seroprotection rates (defined as > or =340 mIU/ml) were high and comparable in all three groups and specifically, rates in the combined MV-LJEV (Group 2) were not statistically inferior to those in Group 3 receiving MV separately (96% versus 100%, respectively). Likewise, the LJEV seroprotection rates were high and similar between the three groups. The reactogenicity profiles of the three vaccine schedules were also analogous. LJEV and MV administered together are well tolerated and immunogenic in infants younger than 1 year. These results should facilitate incorporation of LJEV into routine immunization schedules with MV.

New combination vaccines and reliable sources of vaccine components are essential to ensure the success of mass immunisation programmes in the 21st century. We evaluated a new combined diphtheria-tetanus-whole-cell-pertussis-hepatitis B vaccine, extemporaneously mixed with a Haemophilus influenzae type b conjugate vaccine (DTPw-HBV/Hib) containing 2.5 microg PRP in 913 Philippino infants, administered according to the EPI schedule at 6, 10 and 14 weeks of age after a birth dose of hepatitis B vaccine (HBV; trial DTPw-HBV/Hib-001). One month after the third dose of DTPw-HBV/Hib (N = 182), 99.4% and 94.2% of subjects had anti-PRP antibody levels > or =0.15 microg/mL and > or =1.0 microg/mL, respectively. In addition, 95.9%, 100.0% and 87.6% of subjects had seroprotective antibody concentrations against diphtheria, tetanus and hepatitis B, respectively. The seroprotection rate to hepatitis B increased significantly to 94.3% in subjects who received a dose of HBV at birth. The pertussis vaccine response rate was > or =95%. Seroprotection/vaccine response rates to all antigens after DTPw-HBV/Hib were at least as good as those observed after vaccination with GSK Biologicals' licensed Tritanrix HepB/Hiberix (containing 10 microg PRP) which was used as comparator. Although redness >20 mm in diameter and fever > or = 37.5 degrees C (axillary route) occurred more often after the new DTPw-HBV/Hib vaccine (p < 0.05), other Grade 3 adverse events occurred similarly between the groups. The new DTPw-HBV/Hib vaccine was as immunogenic and well tolerated as the licensed control vaccine when administered according to the immunologically challenging EPI schedule. A birth dose of HBV is important to maximize protection against hepatitis B in endemic regions where the EPI schedule is in place.

This trial was conducted to assess the immunogenicity and safety of the varicella vaccine, Okavax, when administered concomitantly with the measles, mumps and rubella vaccine, MMR-II, to children aged 12-24 months. A total of 299 children were randomized into three groups, those receiving Okavax only, MMR-II only, or both vaccines concomitantly. Antibody titers were determined by ELISA in blood samples taken immediately before, and 6 weeks after, vaccination. Parents recorded local and systemic reactions. Okavax elicited similar varicella seroconversion rates (> or = 93.9%) and high GMTs when given alone or with MMR-II (99.6 and 95.7 mIU/ml, respectively). The seroconversion rates (measles and rubella 100%, mumps > or = 75.0%) and high GMTs elicited by MMR-II were not affected by concomitant administration of Okavax. The incidence of adverse events was similar whether MMR-II and Okavax were administered concomitantly or separately, and the majority of local reactions were mild and transient, with fever the most frequent systemic event in all groups. In conclusion, these results show that the immune response and the reactogenicity profile of Okavax and MMR-II were similar when given together or alone. Concomitant administration of these vaccines can therefore be recommended for children in their second year of life.

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.

An open, randomized multi-center trial, involving 700 infants, was conducted in order to compare a new measles mumps rubella (MMR) vaccine, SB MMR (containing a Jeryl Lynn derived mumps strain RIT 4385) with a widely used vaccine, Merck MMR, when given to children between 12-24 months. Infants were divided between 2 groups; group 1 received SB MMR while group 2 received Merck MMR. Solicited local and general symptoms were recorded using diary cards and antibody levels were measured using ELISA assays. There was a significantly lower incidence of redness (p < 0.001) and swelling (p = 0.03) observed in group 1 compared with group 2. The incidence of all other solicited local and general symptoms were comparable between groups. In initially seronegative subjects equivalent seroconversion rates and post-vaccination GMTs were observed between groups. In conclusion, these results demonstrate that SB MMR is safe and well tolerated when given to children at this age range, and has an equivalent immunogenic profile compared to the widely used Merck MMR vaccine.

Parental history on antibiotic use and the urine antibacterial assay (UABA) result were compared in a study on Filipino children with acute lower respiratory tract infection (ALRI). Among 108 patients in whom urine for the UABA could be collected prior to starting antibiotic treatment in the hospital, 59 (55%) guardians reported preceding antibiotic use, 54% of whom were positive in the UABA. In another 37 (34%), the UABA result was positive, indicating nonreported use of antibiotics. Among 190 patients in whom urine could be collected only after intravenous administration of antibiotic, the UABA demonstrated large inhibition zones after the first dose in most patients but a negative result was seen in 14 cases. The inhibition zone radius was significantly smaller for chloramphenicol than for beta-lactam antibiotics (8.3 mm versus 16.1 mm after one dose; 95% confidence intervals = 7.0-9.7 and 14.9-17.2, respectively). Parental history on antibiotic use gives an underestimate of preceding antibiotic use in children with ALRI in the Philippines. The result partly explains the low yield of blood culture in many studies on ALRI, and stresses the need to develop new diagnostic methods not based on culture for those organisms highly sensitive to antibiotics such as Streptococcus pneumoniae and Haemophilus influenzae.