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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., Competing Interests: Novilia Sjafri Bachtiar and Rini Mulia Sari are employees of PT Bio Farma at the time of the conduct of this study and manuscript preparation. PT Bio Farma Indonesia was involved in the study design, data collection, data analysis and preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Fadlyana et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Inactivated COVID-19 vaccines effectively prevent death, but their effectiveness for preventing infection or severe illness is known to decrease within 3-6 months following the second priming dose. Here we aimed to evaluate the immunogenicity and safety of three potential booster vaccines administered as a full-dose homologous booster or full-dose or half-dose heterologous boosters among individuals primed with CoronaVac., Methods: We did an observer and participant masked, randomised controlled trial study of healthy Indonesian adults from five recruitment sites in Bandung and Jakarta, Indonesia, aged 18 years and older who had previously received two doses of CoronaVac within 3 to less than 6 months or 6 to 9 months before the booster dose. Participants were randomly assigned (1:1:1:1:1) by means of stratified randomisation with random block size to a homologous booster with full-dose CoronaVac or heterologous boosters with ChAdOx1-S or BNT162b2 in full dose or half dose. The primary outcome was to evaluate the seropositive, seroconversion rate, and the geometric mean titres of IgG anti-spike-receptor binding domain and neutralising antibodies, 28 days after booster dose vaccination in the per-protocol population. Safety was assessed as a secondary outcome in all vaccinated booster participants by the incidence rate and intensity of adverse events within 24 h, 7 days, and 28 days after the booster dose. This study is registered with ina-registry.org, INA-GO0HLGB, and is complete., Findings: Between Nov 26 and Dec 16, 2021, 1015 people were screened, and 960 healthy adults were enrolled; 190-193 were included in each group. 28 days after receiving the booster, combining the 3 to less than 6 months and 6 to 9 months groups, the proportions of seroconversion rates in each vaccine group were ChAdOx1-S 75 (82%) of 92 to 87 (88%) of 99 for full dose and half dose, BNT162b2 92 (92%) of 100 to 90 (98%) of 92 for full dose and half dose, and CoronaVac in 38 (41%) of 92 to 65 (66%) of 98. All booster groups achieved 100% seropositivity 28 days after the booster dose. Participants in the 6 to 9 months priming group achieved higher titres compared with participants in the 3 to less than 6 months priming group. The geometric mean titres in participants in the 6 to 9 months priming group in each vaccine group were ChAdOx1-S 11258·69 (9562·43-13 255·85) and 7853·04 (6698·92-9206·00) for full dose and half dose, BNT162b2 19999·84 (17 720·58-22 572·25) and 17 017·62 (14 694·40-19 708·16) for full dose and half dose and CoronaVac 1440·55 (1172·81-1769·42) achieved higher titres compared with participants in the 3 to less than 6 months priming group which in each vaccine group were ChAdOx1-S 7730·39 (6401·87-9334·60) and 6684·34 (5678·94-7867·73) for full dose and half dose, BNT162b2 16594·08 (13 993·08-19 678·55) and 12 121·67 (9925·21-14 804·19) for full dose and half dose, and CoronaVac 1210·23 (976·49-1499·92). The median percentage inhibition for the surrogate virus neutralisation test against the delta B.1.617.2 and wild-type (WT) variant before the booster and 28 days after the booster dose was very high in all groups (p<0·001), all with greater than 90% inhibition against both delta and WT strains. No serious adverse events were associated with the vaccines. Within the heterologous booster groups, the adverse event rates in the half-dose groups were lower compared with the full-dose groups., Interpretation: Geometric mean titre values between participants in the 6 to 9 months priming group and the 3 to less than 6 months priming group before the booster dose and between half-dose and full-dose groups 28 days before the booster were not significantly different for half-dose ChAdOx1-S, full-dose BNT162b2, and CoronaVac and were significantly different for full-dose ChAdOx1-S and half-dose BNT162b2. Among individuals primed with CoronaVac, boosting with BNT162b2 (full dose or half dose) or ChAdOx1-S (full dose or half dose) produces substantially better immune responses than in those boosted with CoronaVac. Full-dose and half-dose boosting with either BNT162b2 or ChAdOx1-S produced similar responses. Heterologous booster with half-dose might be considered in adults primed with two doses of CoronaVac vaccine., Funding: Ministry of Health, Indonesia., Translation: For the Indonesian translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests PM is employed by the National Institute of Health Research and Development. CBK, SRH, and JS are members of the Indonesian Technical Advisory Group on Immunization. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Various studies in adults have shown a strong association between vitamin D and tuberculosis (TB), both in terms of vitamin D status and the benefits of vitamin D in managing TB. Studies on vitamin D and its relationship with childhood TB still lack in Indonesia as a country with the second-highest TB incidence globally. This study evaluated the effect of vitamin D supplementation on resolution of cough and fever in Indonesian children with pulmonary TB., Methods: We conducted a randomized controlled trial of vitamin D supplementation in children with pulmonary TB and vitamin D insufficiency. Patients were randomly allocated with 1:1 ratio to receive either 1000 IU vitamin D or placebo daily after starting standard TB treatment. The primary outcome in this study was the resolution of fever and cough symptoms reviewed weekly after starting the treatment until the symptoms are resolved. The secondary outcome in this study was 25-hydroxyvitamin D serum level and nutritional status which was reviewed at the end of the trial. Intention to treat analyses were applied. Differences in clinical outcomes between two groups were calculated using Mann-Whitney U test or χ 2 test, where appropriate., Findings: A total of 84 patients met the inclusion criteria, aged 6 to 18 years old, newly diagnosed with pulmonary TB and vitamin D insufficiency. Eighty patients (95,2%) completed the six months follow-up. Faster resolution of fever, cough, improved malnutrition status, and higher vitamin D level were found in the intervention group compared to the placebo group (all P  < 0.001)., Conclusions: Vitamin D is beneficial in improving fever and cough resolution, and improving nutritional status in children with pulmonary TB and vitamin D insufficiency. Determination of adequate supplementation levels of more than 1000 IU requires further research to achieve normal vitamin D levels during the duration of treatment for pulmonary TB in children., Trial Registration: ClinicalTrials.gov (NCT05073965)., Competing Interests: Competing interests: The authors completed the ICMJE Unified Competing Interest Form (available upon request from the corresponding author), and declare no conflicts of interest., (Copyright © 2022 by the Journal of Global Health. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Although risk factors for hospitalization from a respiratory syncytial virus (RSV) are well known, RSV lower respiratory tract infections (LRIs) in the community are much less studied or understood, especially in developing countries. In a prospective, cohort study we studied factors predisposing Indonesian infants and children under 5 years of age to developing RSV LRIs. Subjects were enrolled in two cohorts: a birth cohort and a cross-sectional cohort of children <48 months of age. Subjects were visited weekly at home to identify any LRI, using the World Health Organization's criteria. RSV etiology was determined through analysis of nasal washings by enzyme immunoassay and polymerase chain reaction. Risk factors for the development of the first documented RSV LRI were identified by multivariate analysis using logistic regression and Cox proportional hazard modeling. Of the 2014 children studied, 999 were enrolled within 30 days of birth. There were 149 first episodes of an RSV. Risk factors for an RSV LRI were poverty ( p < 0.01), use of kerosene as a cooking fuel ( p < 0.05), and household ownership of rabbits and chickens ( p < 0.01). Our findings suggested that in a middle-income country such as Indonesia, with a substantial burden of RSV morbidity and mortality, lower socioeconomic status, environmental air quality, and animal exposure are predisposing factors for developing an RSV LRI.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Meita Dhamayanti, Kusnandi Rusmil, Eddy Fadlyana, Rodman Tarigan, Dwi Prasetyo, Nelly Amalia, Viramitha, K Rusmil, Hadyana Sukandar, Cissy B Kartasasmita, received grant support through their institutions. Rini Mulia Sari and Novilia Sjafri Bachtiar are employees of PT Bio Farma at the time of this study and manuscript preparation., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: There are scant recent studies from low middle-income countries that investigate the impact of otitis media (OM) on hearing loss (HL) in school children., Methods: This was a prospective epidemiological survey conducted by otorhinolaryngologists and audiologists in a sample of 7005 public school children (6-15 years) from 6 urban and rural sub-districts, in Indonesia. Children with otoscopic abnormalities or who failed a hearing-screening test conducted at school, underwent diagnostic audiometry and tympanometry., Results: OM was detected in 172 children (2.5%), acute otitis media - AOM (17%), otitis media with effusion - OME (15%), and chronic suppurative otitis media - CSOM (67%). The overall rate of HL in the school children was 181/10,000, which was almost three-fold higher in rural (273/10,000) than urban areas 92.6/10,000. OME accounted for much of the mild HL, while CSOM accounted for most of the moderate HL. There was a significantly higher rate of OM related HL in rural areas (116.2/10,000), than in urban areas (47.4/10,000), p = 0.002. OM related disabling HL was found at a rate of 44.2/10,000, mostly due to CSOM (37.1/10,000)., Conclusion: Otitis media contributed to 57% of all HL in school children, and posed a significant burden on Indonesian school children. Most of the disabling HL was due to CSOM. Efforts to find these children and offer ear and hearing care are important., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Although the epidemiology of otitis media is well-known in industrialized countries, the extent of otitis media in developing Asian countries, especially in south East Asia is not well studied., Methods: To define the burden of otitis media and its sequelae in children 6-15 years of age, we enrolled elementary and junior high school children in 6 areas in rural and urban Indonesia. Randomly selected schools and classrooms were selected. All children were administered a questionnaire and had ear examinations, pneumatic otoscopy and screening audiometry. Children with any abnormality on examination or with a relevant history underwent diagnostic audiometry and tympanometry, if indicated., Results: Of the 7005 children studied, 116 had chronic suppurative otitis media (CSOM), 30 had acute otitis media and 26 had otitis media with effusion. 2.7% of rural children had CSOM compared with 0.7% of urban children (P < 0.0001). The rates per 1000 of CSOM in rural Bali and Bandung were significantly higher (75 and 25, respectively) than in the rest of Indonesia (P < 0.05). In rural Bali, the rate per 1000 children of inactive CSOM was 63 in 6- to 9-year-old children, compared with 37 in children aged 13-15 years. Concomitantly, the rates of tympanosclerosis were 7 and 26/1000, respectively, in these age groups., Conclusions: In Indonesia, the prevalence of CSOM is relatively high with most disease occurring in rural areas. The high rates in rural Bali with early progression to tympanosclerosis suggest a significant burden of potentially vaccine preventable illness.

Background: Although the epidemiology of respiratory syncytial virus (RSV) lower respiratory tract infections (LRI) is well known in industrialized countries, the burden in developing Asian countries is not well studied., Methods: To define the burden of RSV disease in children <5 years of age in rural and urban Indonesia, infants and children were enrolled from peri-urban and rural subdistricts, in the following 2 cohorts: (a) a cross-sectional cohort of approximately 100 children from each of 2 subdistricts in the following 5 age groups: 3 to 5, 6 to 8, 9 to 11, 12 to 23, and 24 to 48 months; (b) a birth cohort of all newborns in both subdistricts during the 28 months of the study. All subjects were visited weekly at home. Children with World Health Organization-defined LRI or wheezing had a nasal wash for detection of RSV using an enzyme immunoassay and polymerase chain reaction., Results: Of the 2014 children studied, 1074 were in the cross-sectional and 940 in the newborn cohorts. Of the 802 episodes of LRI, 163 were caused by RSV. The RSV LRI incidence per 1000 child-years (C-Y) was higher in rural areas (57.25 vs. 38.54), P < 0.05. No RSV LRI occurred in the first 2 months of life and the peak incidence was in the 6- to 8-month-old infants (103/1000 C-Y). The rates were lowest in those <6 months, 16.5 per 1000 C-Y, compared with 83.1 per 1000 C-Y in those 6 to 11 months of age (P < 0.001), 66.99 in those 12 to 23 months of age, and 28.1 in 2- to 5-year-olds., Conclusions: In Indonesia, the incidence of RSV LRI in the first 6 months of life is relatively low with most disease occurring in older children.

Objective: To assess the burden of respiratory syncytial virus (RSV)-associated lower respiratory infections (LRI) in children in four developing countries., Methods: A WHO protocol for prospective population-based surveillance of acute respiratory infections in children aged less than 5 years was used at sites in Indonesia, Mozambique, Nigeria and South Africa. RSV antigen was identified by enzyme-linked immunosorbent assay performed on nasopharyngeal specimens from children meeting clinical case definitions., Findings: Among children aged < 5 years, the incidence of RSV-associated LRI per 1000 child-years was 34 in Indonesia and 94 in Nigeria. The incidence of RSV-associated severe LRI per 1000 child-years was 5 in Mozambique, 10 in Indonesia, and 9 in South Africa. At all study sites, the majority of RSV cases occurred in infants., Conclusion: These studies demonstrate that RSV contributes to a substantial but quite variable burden of LRI in children aged < 5 years in four developing countries. The possible explanations for this variation include social factors, such as family size and patterns of seeking health care; the proportion of children infected by human immunodeficiency syndrome (HIV); and differences in clinical definitions used for obtaining samples. The age distribution of cases indicates the need for an RSV vaccine that can protect children early in life.

Study Objective: To evaluate the relationship between vitamin A supplementation, plasma retinol level (PRL) and incidence, severity and duration of acute respiratory infect ions (ARI) in children 1-5 years old., Design and Setting: A one year prospective randomized intervention study from June 1989 to May 1990 in Cikutra, a suburb of Bandung, Indonesia., Subjects and Measurements: Out of almost 2000 children aged 12-54 months, 269 were selected by stratified randomization. Vitamin A (200,000 IU orally) was administered at 6-monthly intervals in a double blind, placebo controlled programme. Every 2 weeks, primary health care workers collected data on respiratory symptoms in the children, and every month a pediatrician examined the children. Venous blood samples were obtained at the start and at 3 and 6 months for plasma retinol levels (PRL)., Results: The mean PRL at the start of the study was 20 +/- 8 micrograms/dl; 8% of the children showed a deficient level of less than 10 micrograms/dl. The incidence or ARI was 6.7 +/- 3.5 episodes per child per year with a mean duration of 5.3 +/- 3.1 days per episode. In vitamin A supplemented children the duration of ARI was slightly shorter (5.2 +/- 3.1 versus 5.6 +/- 3.1 days, P < 0.01) but no effect on the incidence or severity of ARI was detected. Low, and especially deficient, PRL had improved after 3 months and even after 6 months, but this was unrelated to vitamin A supplementation. There was also no relationship between PRL and incidence, severity or duration of ARI., Conclusions: Only a slight relationship is found between vitamin A supplementation and ARI duration in under-fives.

By questionnaire we studied the occurrence of acute respiratory infections (ARI) in 1961 children between 0 and 5 years old from a total of 3225 families in Cikutra, Bandung. In 38.7% of them 200.000 IU vitamin A supplement had been given at least once during the preceding year. Mild or moderate ARI occurred in 54.7% of the children during the previous month and in 87.9% during the previous year; severe ARI occurred in 5.5% during the previous month and in 16.8% during the previous year. Surprisingly slightly more ARI occurred in children with vitamin A supplementation. However, vitamin A had been distributed more to low income than high income families, and in the latter group significantly less children suffered from ARI (p less than 0.05; 44% versus 54 a 56%).