Temporal association between serious bleeding and immunization: vitamin K deficiency as main causative factor.

BACKGROUND: Bleeding as an adverse event following immunization (AEFI) that is rarely reported in children, although it can be a parental concern. Bleeding episodes ranging in severity from mild to severe and defined as any external and/or internal bleeding can be caused by acquired or hereditary disorders. This study analyzes whether bleeding episodes in children that were recorded as AEFIs are causally associated with immunization and elaborates their etiology. METHODS: A cross-sectional study of 388 AEFI cases in children from West Java Provincial Committee in Indonesia confirmed by case findings from 2000 until 2017. RESULTS: Of the total number of cases studied, 55 (14%) involved children aged 5 days to 12 years who presented with bleeding and were referred to a provincial hospital. Analysis revealed that 32 cases were most likely caused by acquired prothrombin complex deficiency (APCD) and 30 of these APCD cases were strongly suspected to be manifestations of vitamin K deficiency bleeding (VKDB). All VKDB subjects were aged 5 days to 3 months without a history of administration of prophylactic vitamin K. When a World Health Organization classification was used, most bleeding cases in this study became coincidental events with a temporal association with immunization. A causality assessment suggested that these cases were causally unrelated. CONCLUSION: Most cases of bleeding reported as an AEFI were found to be VKDB, which is considered a coincidental event following immunization with a temporal association, and an unrelated category based on the results of a causality assessment. Vitamin K should be administered to all newborns as a prophylactic and AEFI surveillance should be improved based on the low numbers of AEFI reported in Indonesia.

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).

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 immunogenicity, safety, and consistency of an Indonesia combined DTP-HB-Hib vaccine in expanded program on immunization schedule.

BACKGROUND: WHO recommended incorporation of Haemophilus influenzae type b (Hib) vaccination into immunization program. Indonesia would adopt Hib as a National Immunization Program in 2013. We aimed at analyzing immunogenicity, safety, and consistency of a new combined DTP-HB-Hib (diphtheria-tetanus-pertussis-Hepatitis B-Haemophilus influenza B) vaccine. METHODS: A prospective, randomized, double blind, multicenter, phase III study of Bio Farma DTP-HB-Hib vaccine conducted in Jakarta and Bandung, August 2012 - January 2013. Subjects were divided into three groups with different batch number. Healthy infants 6-11 weeks of age at enrollment were immunized with 3 doses of DTP-HB-Hib vaccine with interval of 4 weeks, after birth dose of hepatitis B vaccine. Blood samples obtained prior to vaccination and 28 days after the third dose. Safety measures recorded until 28 days after each dose. RESULTS: Of 600 subjects, 575 (96 %) completed study protocol. After 3 doses, 100.0 and 96.0 % had anti-PRP concentration ≥0.15 and ≥1.0 µg/ml. Anti-diphtheria and anti-tetanus concentration ≥0.01 IU/ml detected in 99.7 and 100.0 %; while concentration ≥0.1 IU/ml achieved in 84.0 and 97.4 %. Protective anti-HBs found in 99.3 %. The pertussis vaccine response rate was 84.9 %. None Serious Adverse events (SAEs) considered related to study vaccine or procedure. CONCLUSIONS: The 3-dose of DTP-HB-Hib was immunogenic, well tolerated and suitable for replacement of licensed-equivalent vaccines based on immunologic and safety profiles. TRIAL REGISTRATION: NCT01986335 - October 30(th) 2013.

Environment as a risk factor in delayed development in premature, low-birthweight and mild asphyxia children.

BACKGROUND: Premature infants with low birthweight (LBW) and asphyxia are at high risk of delay of language and visual-motor development. Environmental risk factors contributing to the delay include parents' education, family income, number of children in the family, exclusive breast-feeding, and the mother's parenting time. Lack of research in Indonesia on premature, LBW and mild asphyxia children minimizes information to parents on the importance of an optimal environment. The aim of this study was to observe the role of the environment as a risk factor for delay in language and visual-motor development. METHODS: A cross-sectional study was carried out from June to December 2011 of 12-24-month-old children born premature, with LBW and mild asphyxia at the Hasan Sadikin, Bandung City, and Muhammadiyah Hospitals. Language and visual-motor development were measured by Capute scales. Risk factors were analyzed using chi-squared test and multivariate logistic regression analysis. RESULTS: Of the 70 subjects, 49% had language and visual-motor delay. Environmental factors related to the delay were low parental education, low family income, non-exclusive breast-feeding (P < 0.001) and full-time maternal parenting (P < 0.05). On multivariate analysis non-exclusive breast-feeding was associated with a 175-fold risk (prevalence rate [PR], 174.756; 95% confidence interval [CI]: 10.407-2934.516, P < 0.001), and low family income, a 0.042-fold risk (PR 0.042; 95%CI: 0.005-0.321, P < 0.05). CONCLUSION: Low family income and non-exclusive breast-feeding are risk factors for delay in language and visual-motor development in 12-24-month-old children born premature, with LBW and mild asphyxia.

Immunogenicity and Safety of SARS-CoV-2 Protein Subunit Recombinant Vaccine (IndoVac®) as a Heterologous Booster Dose against COVID-19 in Indonesian Adolescents.

Adolescents are vulnerable to Coronavirus disease 2019 (COVID-19) infections; thus, their antibodies should be maintained above the protective value. This study aimed to evaluate the immune response and safety to the SARS-CoV-2 protein subunit recombinant vaccine (IndoVac®) as a heterologous booster dose against COVID-19 in Indonesian adolescents. This open-label prospective intervention study enrolled 150 clinically healthy adolescents aged 12-17 years who had received complete primary doses of the CoronaVac® vaccine from Garuda Primary Care Centres in Bandung City. The result of immunogenicity was presented with a 95% confidence interval (CI) and analyzed with t-tests from 14 days and 3, 6, and 12 months. The neutralizing antibody geometric mean titers (GMTs) (IU/mL) at baseline and 14 days after booster dose were 303.26 and 2661.2, respectively. The geometric mean fold rises (GMFR) at 3, 6, and 12 months after booster dose were 6.67 (5.217-8.536), 3.87 (3.068-4.886), and 2.87 (2.232-3.685), respectively. Both the neutralizing antibody and IgG antibody were markedly higher in the adolescents than in the adults at every timepoint. The incidence rate of adverse effects (AEs) until 28 days after booster dose was 82.7%, with a higher number of local events reported. Most reported solicited AEs were local pain followed by myalgia with mild intensity. Unsolicited AEs varied with each of the incidence rates < 10%, mostly with mild intensity. Adverse events of special interest (AESI) were not observed. At the 12-month follow-up after the booster dose, four serious adverse events (SAEs) not related to investigational products and research procedures were noted. This study showed that IndoVac® has a favorable immunogenicity and safety profile as a booster in adolescents and that the antibody titer decreases over time.

Immunogenicity and Safety of SARS-CoV-2 Protein Subunit Recombinant Vaccine (IndoVac®) as a Booster Dose against COVID-19 in Indonesian Adults.

According to the WHO target product profile for COVID-19 vaccines, the vaccine in development should be indicated for active immunisation in all populations. Therefore, PT Bio Farma developed a candidate vaccine in a subunit protein recombinant platform to help overcome the issue. This trial was an observer-blind, randomised, prospective intervention study. This study targeted individuals who had received complete primary doses of the authorised/approved COVID-19 vaccine. The groups were divided into the primary inactivated vaccine (CoronaVac®) group, the primary viral vector vaccine (ChAdOx1) group, and the primary mRNA vaccine (BNT162b2) group that received the recombinant protein (IndoVac®). The groups were compared with the control and primary mRNA vaccine (BNT162b2). The participants enrolled in the study were from two primary care centres in Bandung City and three primary care centres in Denpasar City. A total of 696 participants were enrolled from 1 September to 31 October 2022. The demographic characteristics of the all-vaccine group showed a uniform distribution. The results showed that, compared with the control, the investigational product had inferior effectiveness 14 days after the booster dose was administered. However, 28 days after the booster dose, the investigational product exhibited non-inferior effectiveness compared with the primary groups that received CoronaVac® (GMR 0.76 (0.57-0.99)) and ChAdOx1 (GMR 0.72 (0.56-59.93)), but the BNT162b2 group (GMR 0.61 (0.39-0.94)) was inferior to the control. At 12 months follow-up after the booster dose, three serious adverse events (SAEs) were reported in three participants, with causality not correlated with the investigated products. Neither AEs of special interest nor severe COVID-19 cases were reported throughout the follow-up period; thus, the IndoVac® vaccine as a booster was immunogenic and safe. Until the 6-month follow-up after the booster dose, the IndoVac® vaccine was well tolerated and all reported AEs resolved. This vaccine is registered and can be included in the immunisation programme.

Correlation between anthropometric measurements of height and arm span in Indonesian children aged 7-12 years: a cross-sectional study.

BACKGROUND: Height is an anthropometric measurement that serves as the most constant indicator of growth. In certain circumstances, arm span can be used as an alternative to height measurements. This study aims to analyze the correlation between anthropometric measurements of height and arm span in children aged 7-12 years. METHODS: A cross-sectional study was carried out from September to December 2019 in six elementary schools in Bandung. Children aged 7-12 years were recruited with a multistage cluster random sampling method. Children with scoliosis, contractures, and stunting were excluded from the study. Height and arm span were measured by two pediatricians. RESULTS: A total of 1,114 children, comprising 596 boys and 518 girls, fulfilled the inclusion criteria. The ratio of height to arm span was 0.98-1.01. The regression equation used to predict height through measurement of arm span in male subjects was Height = 21.8623 + 0.7634 x Arm span (cm) + 0.0791 x age (month); R2 = 94%; standard error of estimate (SEE): 2.66 and that in female subjects was Height = 21.2395 + 0.7779 x Arm span (cm) + 0.0701 x age (month); R2 = 95.4%; SEE: 2.39. The predicted height and the average actual height were not significantly different. There is a strong correlation between height and arm span in children aged 7-12 years. CONCLUSIONS: Arm span can be used to predict the actual height of children aged 7-12 years and as an alternative measurement for growth.

Correlation Between Vitamin D Status and HBsAg Antibody Levels in Indonesian Adolescents Immunised Against Hepatitis B.

Introduction: Hepatitis B virus (HBV) infection is a global health problem. Anti-hepatitis B surface antigen (HBsAg) levels increase along with vitamin D levels in adults. However, few studies have examined this relationship in adolescents. Few studies have examined the relationship between vitamin D and HBsAg antibody levels, especially in Indonesia. Methods: This cross-sectional study examined vitamin D and anti-HBsAg levels before and after hepatitis B immunisation. All subjects blood was taken to check for vitamin D level. This study was part of the Safety and Preliminary of Immunogenicity Following Recombinant Hepatitis B (Bio Farma) Vaccine in Adults and Children Phase I trial. Results: This study found that 25-hydroxyvitamin D [25(OH)D] status was primarily deficient based on endocrine criteria. The children's hepatitis B antibody response was mostly <10 mIU/mL before and ≥10 mIU/mL after vaccination. There was a relationship between sex and 25(OH)D status, with median 25(OH)D levels higher in females (18.2 ng/mL) than in males (9.8 ng/mL). However, the relationship between vitamin 25(OH)D status and anti-HBsAg levels pre- and post-vaccination was not significant. Discussion: However, some research found that vitamin D supplementation after immunisation did not impact vaccine response, several studies have reported that vitamin D can decrease HBV replication through various mechanisms, including reducing viral transcription and interfering with viral protein synthesis. Conclusion: There was no relationship between 25(OH)D status and anti-HBsAg levels. Further research is needed to elucidate the underlying mechanisms and establish optimal treatment strategies.

Single-Blind Randomized Controlled Trial: Comparative Efficacy of Dark Chocolate, Coconut Water, and Ibuprofen in Managing Primary Dysmenorrhea.

Dysmenorrhea, the pain experienced by women during menstruation, affects a significant proportion of women worldwide and often leads to decreased productivity. Various pharmacological and non-pharmacological treatments are available for pain relief, but information on their effectiveness, particularly regarding green coconut water, dark chocolate, and Ibuprofen, remains limited. This study aimed to compare the effectiveness of green coconut water, dark chocolate bars, and Ibuprofen in reducing the intensity of primary dysmenorrhea. In this research, a randomized controlled trial with a quantitative design was conducted, involving 45 participants randomly assigned to receive 330 mL of green coconut water, 35 g of 70% dark chocolate, or 400 mg Ibuprofen. The interventions were administered on the first day of menstruation when dysmenorrhea symptoms typically occur in subjects. This study used a single-dose approach to evaluate the immediate impact of each treatment. The subjects were instructed to consume the given interventional product within 15 min. The pain intensity was measured using a Numeric Rating Scale before the intervention and 2 h after the subjects finished consuming the interventional product. The multivariate Kruskal-Wallis test revealed a significant difference in effectiveness among the three interventions (p < 0.05). The study found that Ibuprofen was the most effective intervention compared to the other interventions. These findings contribute to understanding the treatment options for primary dysmenorrhea and emphasize the efficacy of Ibuprofen (trial registration: ClinicalTrials.gov: NCT05971186).

Comparison of Immunogenicity and Safety of Diphtheria-Tetanus-Pertussis-Hepatitis B-Haemophilus influenza B (Bio Farma) with Pentabio® Vaccine Primed with Recombinant Hepatitis B at Birth (Using Different Source of Hepatitis B) in Indonesian Infants.

Satisfying the needs of the national immunization program requires maintaining diphtheria-tetanus-pertussis (DTP)-hepatitis B (HB)-Haemophilus influenza B (Hib) production. Therefore, new hepatitis B sources are needed. This study aimed to evaluate the immunogenicity of the DTP-HB-Hib vaccine (Bio Farma) that used a different source of hepatitis B. A prospective randomized, double-blind, bridging study was conducted. Subjects were divided into two groups with different batch numbers. Healthy infants 6-11 weeks of age at enrollment were immunized with three doses of the DTP-HB-Hib vaccine after a birth dose of hepatitis B vaccine. Blood samples were obtained prior to vaccination and 28 days after the third dose. Adverse events were recorded until 28 days after each dose. Of the 220 subjects, 205 (93.2%) completed the study protocol. The proportion of infants with anti-diphtheria and anti-tetanus titers ≥ 0.01 IU/mL was 100%, with anti-HBsAg titers ≥ 10 mIU/mL was 100%, and with Polyribosylribitol Phosphate-Tetanus Conjugate (PRP-TT) titers > 0.15 µg/mL was 96.1%. The pertussis response rate was 84.9%. No serious adverse events related to the study vaccine occurred. The three-dose DTP-HB-Hib vaccine (Bio Farma) is immunogenic, well tolerated, and suitable to replace licensed-equivalent vaccines.

Immunogenicity and safety of Quadrivalent Influenza HA vaccine compared with Trivalent Influenza HA vaccine and evaluation of Quadrivalent Influenza HA vaccine batch-to-batch consistency in Indonesian children and adults.

One of the newest strategies developed by the Global Influenza Strategy has been to broaden the composition of the current influenza vaccine formulations from trivalent products to quadrivalent products. This study aimed to assess the immunogenicity and safety of Quadrivalent Influenza HA vaccine (QIV) compared with Trivalent Influenza HA vaccine (TIV) and to evaluate three consecutive batches of QIV equivalence in Indonesian children and adults. This was an experimental, randomized, double blind, four arm parallel group bridging study involving unprimed healthy children and adults aged 9-40 years. A total of 540 subjects were enrolled in this study and randomized into four arm groups. Each subject received one dose of TIV or QIV with three different batch codes. Serology tests were performed at baseline and 28 days after vaccination. Hemagglutination inhibition (HI) antibody titers were analyzed for Geometric Mean Titer (GMT), seroprotection, and seroconversion rates. Solicited, unsolicited, and serious adverse events were observed up to 28 days after vaccination. A total of 537 subjects completed the study per protocol and were analyzed for immunogenicity criteria. All randomized subjects were analyzed for safety criteria. The percentage of the subjects with anti-HI titer ≥1:40 28 days after QIV vaccination was 99.5% for A/H1N1; 99.5% for A/H3N2; 93.1% for B/Texas, and 99.0% for B/Phuket. The seroprotection, GMT, and seroconversion rates of QIV were not significantly different from those of TIV for the common vaccine strains (p > 0.01) and were significantly different from those of TIV for the added B/Phuket strains (p < 0.01). Most solicited injection-site and systemic reactions with either vaccine were mild to moderate and resolved within a few days. Antibody response to QIV were equivalence among vaccine batches and comparable between age groups for each of the 4 strains. QIV was immunogenic and well-tolerated and had immunogenicity and safety profiles compared with TIV for all common strains. The immunogenicity of the three batches of QIV was equivalent for the four strains. Trial registration. Clinical Trial registration: NCT03336593.

A randomized, placebo-controlled trial of zinc supplementation during pregnancy for the prevention of stunting: analysis of maternal serum zinc, cord blood osteocalcin and neonatal birth length.

Aim To investigate the influence of zinc supplementation on pregnant women for the prevention of stunting through an analysis of maternal serum zinc, cord blood osteocalcin and neonatal birth length. Methods This study was conducted with pre-test/post-test control groups and double-blind randomization. Patients were pregnant mothers in second or third trimester and with their newborns who met the inclusion criteria. A total of 71 pregnant mothers and their newborns completed this study. They were divided into two groups of 35 and 36 patients, the supplementation (20 mg/day) and placebo groups, respectively for 12 weeks. The parameters assessed were maternal serum zinc levels, cord blood osteocalcin and birth length measurements. Results The mean maternal serum zinc level was 54.6±8.7 µg/dL from 71 patients. The mean maternal serum zinc levels after zinc supplementation were significantly higher than those of the placebo group: 55.1±9.9 to 59.1±8.6) µg/dL (p=0.017) and 54.2±7.5 to 50±8.6 µg/dL (p=0.001), respectively. The comparison of mean cord blood osteocalcin levels and median neonatal birth lengths in the supplementation group was higher than in the placebo group: 131.8±35.3 vs 90.6±35.4 ng/ml (p=0.001) and 49.3 (46.5-51.3) vs 48.3 (46-50.8) cm (p=0.004), respectively. Maternal serum zinc levels after zinc supplementation had a positive significant correlation with cord blood osteocalcin and neonatal birth length: r=0.434 (p=0.001) and r=0.597 (p=0.001), respectively. Conclusion There was a significant correlation of maternal serum zinc with cord blood osteocalcin and neonatal birth length after zinc supplementation.

Height Prediction Using the Knee Height Measurement Among Indonesian Children.

BACKGROUND: Height is essential for assessing growth and nutrition in children. Assessing height with appropriate measurement is important, although in certain physically disabled and hospitalized children direct height measurement is almost not possible. In these situations, segmental measurements can be used as proxy height. Knee height (KH) has been determined as the most reliable surrogate. OBJECTIVE: This study aimed to establish a height-predicted equation using KH for use in both community and clinical practices. METHODS: This was a cross-sectional study design that collected data from 1114 healthy children (596 boys and 518 girls) aged 7 to 12 years to develop the equations for predicting height from KH. A multiple linear regression analysis was used to develop the equations. RESULTS: Two equations were established to predict height using KH: (1) for boys H = 29.895 + (0.081 × age [months] + (2.267 × KH)) and (2) for girls H = 26.297 + (0.110 × age [months] + (2.278 × KH)). The very high correlation between KH and actual height indicates a very strong agreement. CONCLUSIONS: Knee height can be used for prediction equations for height with a very good predictive power. The age variable using the month unit generates a more accurate equation.

A phase III, observer-blind, randomized, placebo-controlled study of the efficacy, safety, and immunogenicity of SARS-CoV-2 inactivated vaccine in healthy adults aged 18-59 years: An interim analysis in Indonesia.

BACKGROUND: The WHO declared COVID-19 a pandemic on March 11th, 2020. This serious outbreak and the precipitously increasing numbers of deaths worldwide necessitated the urgent need to develop an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. The development of COVID-19 vaccines has moved quickly. In this study, we assessed the efficacy, safety, and immunogenicity of an inactivated (SARS-CoV-2) vaccine. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to evaluate the efficacy, immunogenicity, and safety of an inactivated SARS-CoV-2 vaccine and its lot-to-lot consistency. A total of 1620 healthy adults aged 18-59 years were randomly assigned to receive 2 injections of the trial vaccine or placebo on a day 0 and 14 schedule. This article was based on an interim report completed within 3 months following the last dose of study vaccine. The interim analysis includes safety and immunogenicity data for 540 participants in the immunogenicity subset and an efficacy analysis of the 1620 subjects. For the safety evaluation, solicited and unsolicited adverse events were collected after the first and second vaccination within 14 and 28 days, respectively. Blood samples were collected for an antibody assay before and 14 days following the second dose. RESULTS: Most of the adverse reactions were in the solicited category and were mild in severity. Pain at the injection site was the most frequently reported symptom. Antibody IgG titer determined by enzyme-linked immunosorbent assay was 97.48% for the seroconversion rate. Using a neutralization assay, the seroconversion rate was 87.15%. The efficacy in preventing symptomatic confirmed cases of COVID-19 occurring at least 14 days after the second dose of vaccine using an incidence rate was 65.30%. CONCLUSIONS: From the 3-month interim analysis, the vaccine exhibited a 65.30% efficacy at preventing COVID-19 illness with favorable safety and immunogenicity profiles.

Immunogenicity and safety profile of a primary dose of bivalent oral polio vaccine given simultaneously with DTwP-Hb-Hib and inactivated poliovirus vaccine at the 4th visit in Indonesian infants.

In this study, we aimed to evaluate the immunological protectivity of infants following four doses of bivalent oral polio vaccine (bOPV; Bio Farma), which were given simultaneously with DTwP-Hb-Hib (Pentabio®), along with one dose of inactivated poliovirus vaccine (IPV) at the fourth visit. A total of 143 newborn infants who fulfilled the inclusion criteria were enrolled and completed the study. Subjects received the first dose of bOPV at birth. On days 60, 90 and 120, bOPV was given simultaneously with Pentabio®. On day 120, one dose of IPV was also administered. Serum samples for serology analysis were collected before the first dose of bOPV (at day 0), before the second dose of bOPV (at day 60) and 30 days after the last dose of bOPV. In addition, the intensity, duration and relationship of each adverse event to the trial vaccines were assessed. Seroprotection rates after the fourth dose of bOPV were 100%, 91.6% and 99.3% for poliovirus P1, P2 and P3, respectively. Seroconversion rates after the fourth dose of bOPV were 100.0%, 93.3% and 100% for poliovirus P1, P2 and P3, respectively. There were no severe adverse events, and systemic reactions were generally mild during the 1-28 day post-vaccination period. Collectively, our findings indicate that bOPV given simultaneously with Pentabio® and one dose of IPV at the 4th visit was immunogenic and well tolerated.

Immunogenicity and safety of Quadrivalent Influenza HA vaccine in Indonesian children: An open-labeled, bridging, clinical study.

BACKGROUND: Influenza B (Yamagata/Victoria lineage) can cause severe forms of respiratory infection among the pediatric population as well as influenza A strains (H3N2/H1N1). Vaccination against all four strains is required to prevent infection and severe outcome. This study is the first study to assess the immunogenicity of Quadrivalent Influenza HA vaccine (QIV) and ascertain safety among children in Indonesia. METHODS: This is an open labeled, single arm, bridging clinical study involving unprimed healthy children 6-35 months of age (Group I) and 3-8 years of age (Group II). Subjects on both groups receiving two doses of QIV with a 28 days interval. Serology tests were performed on baseline and 28 days post-vaccination. Hemagglutination inhibition antibody titers were analyzed for Geometric Mean Titer (GMT), seroprotection, and seroconversion rates. Solicited reactions, unsolicited adverse events, and serious adverse events were observed up to 28 days post-vaccination. RESULTS: Out of 270 subjects enrolled, 269 subjects completed the study. Immunogenicity analysis were evaluated on 254 subjects. Seroprotection rates were ≥85% for all vaccine strains in both groups. Seroconversion of more than 4 folds for all strains occurred in both groups post-vaccination. In Group I, the increase of GMT for A/H1N1, A/H3N2, B/Texas, and B/Phuket was 12.5, 14.5, 8.2, and 6.4 folds, respectively. In Group II the increase of GMT for A/H1N1, A/H3N2, B/Texas, and B/Phuket was 14, 17, 10, and 8 folds, respectively. The majority of local adverse events (AEs) after the first and second immunizations were immediate injection-site pain (10.4% and 12.6%). The majority of systemic AEs after the first and second immunizations were delayed unsolicited AEs (14.8% and 14.9%). No vaccine-related serious adverse events or deaths were reported. CONCLUSION: The investigational QIV was immunogenic with an acceptable safety profile in children 6 months to 8 years of age. CLINICAL TRIAL REGISTRATION: NCT03336593.

Pneumococcal carriage, density, and co-colonization dynamics: A longitudinal study in Indonesian infants.

OBJECTIVES: Nasopharyngeal carriage of Streptococcus pneumoniae underpins disease development and transmission. This study was performed to examine pneumococcal carriage dynamics, including density and multiple serotype carriage, in Indonesian infants during the first year of life. METHODS: Two hundred healthy infants were enrolled at 2 months of age. Eight nasopharyngeal swabs were collected from enrolment until 12 months of age. Pneumococci were detected using quantitative PCR and serotyped by microarray. Regression models assessed factors influencing pneumococcal carriage and density. RESULTS: Eighty-five percent of infants carried pneumococci at least once during the study. The median age at first acquisition was 129 days (interquartile range 41-216 days). The median duration of carriage was longer for the first pneumococcal acquisition compared with subsequent acquisitions (151 days vs. 95 days, p<0.0001). Of the 166 infants who carried pneumococci during the study, the majority (63.9%) carried a single pneumococcal serotype at a time. Pneumococcal carriage density was higher when upper respiratory tract infection symptoms were present, lower during antibiotic usage, decreased with age, and tended to decrease over time during a carriage episode. CONCLUSIONS: The majority of Indonesian infants carry pneumococcus at least once during the first year of life. Pneumococcal carriage is a dynamic process, with pneumococcal density varying during a carriage episode.

Risk factors associated with nasopharyngeal carriage and density of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus in young children living in Indonesia.

BACKGROUND: Potentially pathogenic bacteria Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus are commonly carried in the nasopharynx of young children. Host and environmental factors have been linked with pathogen carriage, and in many studies rural children have higher carriage rates than their urban counterparts. There are few published data on what factors contribute to increased pathogen density. The objectives of this study were to identify risk factors for nasopharyngeal carriage and density of S. pneumoniae, H. influenzae, M. catarrhalis, and S. aureus in young children in Indonesia. METHODS: Risk factor analysis was done using data on bacterial carriage and participant characteristics from a cross-sectional study that enrolled 302 children aged 12-24 months living in urban or semi-rural areas of Indonesia. Associations between host factors and odds of pathogen carriage were explored using logistic regression. Characteristics identified to be independent predictors of carriage by univariable analysis, as well as those that differed between urban and semi-rural participants, were included in multivariable models. Risk factors for increased pathogen density were identified using linear regression analysis. RESULTS: No differences in carriage prevalence between urban and semi-rural children were observed. Multiple children under the age of 5 years in the household (< 5y) and upper respiratory tract infection (URTI) symptoms were associated with S. pneumoniae carriage, with adjusted odds ratios (aOR) of 2.17 (95% CI 1.13, 4.12) and 2.28 (95% CI 1.15, 4.50), respectively. There was some evidence that URTI symptoms (aOR 1.94 [95% CI 1.00, 3.75]) were associated with carriage of M. catarrhalis. Children with URTI symptoms (p = 0.002), and low parental income (p = 0.011) had higher S. pneumoniae density, whereas older age was associated with lower S. pneumoniae density (p = 0.009). URTI symptoms were also associated with higher M. catarrahlis density (p = 0.035). Low maternal education (p = 0.039) and multiple children < 5y (p = 0.021) were positively associated with H. influenzae density, and semi-rural residence was associated with higher S. aureus density (p < 0.001). CONCLUSIONS: This study provides a detailed assessment of risk factors associated with carriage of clinically-relevant bacteria in Indonesian children, and new data on host factors associated with pathogen density.

Carriage of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus in Indonesian children: A cross-sectional study.

Streptococcus pneumoniae is an important cause of infection and commonly colonizes the nasopharynx of young children, along with other potentially pathogenic bacteria. The objectives of this study were to estimate the carriage prevalence of S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus in young children in Indonesia, and to examine interactions between these bacterial species. 302 healthy children aged 12-24 months were enrolled in community health centers in the Bandung, Central Lombok, and Padang regions. Nasopharyngeal swabs were collected and stored according to World Health Organization recommendations, and bacterial species detected by qPCR. Pneumococcal serotyping was conducted by microarray and latex agglutination/Quellung. Overall carriage prevalence was 49.5% for S. pneumoniae, 27.5% for H. influenzae, 42.7% for M. catarrhalis, and 7.3% for S. aureus. Prevalence of M. catarrhalis and S. pneumoniae, as well as pneumococcal serotype distribution, varied by region. Positive associations were observed for S. pneumoniae and M. catarrhalis (OR 3.07 [95%CI 1.91-4.94]), and H. influenzae and M. catarrhalis (OR 2.34 [95%CI 1.40-3.91]), and a negative association was found between M. catarrhalis and S. aureus (OR 0.06 [95%CI 0.01-0.43]). Densities of S. pneumoniae, H. influenzae, and M. catarrhalis were positively correlated when two of these species were present. Prior to pneumococcal vaccine introduction, pneumococcal carriage prevalence and serotype distribution varies among children living in different regions of Indonesia. Positive associations in both carriage and density identified among S. pneumoniae, H. influenzae, and M. catarrhalis suggest a synergistic relationship among these species with potential clinical implications.