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

DTwP-HB-Hib: antibody persistence after a primary series, immune response and safety after a... 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). Keywords: Booster dose, DTwP-HB-Hib vaccine, Immunogenicity, Safety, Children * Correspondence: hartono@ikafkui.net Department of Child Health, Faculty of Medicine, Universitas Indonesia/Dr. Cipto Mangunkusumo Hospital, Jl. Diponegoro No 71, Jakarta 10430, Indonesia Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Gunardi et al. BMC Pediatrics (2018) 18:177 Page 2 of 8 Background immunoglobulin, blood-derived products or long-term Infections related with vaccine-preventable diseases includ- corticosteroid therapy (> 2 weeks); receiving other vac- ing hepatitis B, diphtheria, pertussis, and Haemophilus cines within 1 month prior to trial enrollment; any abnor- influenzae type B (Hib) were accounted for high morbidity malities or chronic diseases determined by investigators and mortality among children younger than 5 years of age that might interfere the trial objectives; and children with in many underdeveloped countries [1–4]. In accordance history of either diphtheria, tetanus, pertussis, Hib, and with the Expanded Program on Immunization (EPI) rec- hepatitis B infection. ommendation, the Indonesian National Immunization All subjects were recruited following written form of in- schedule comprises primary vaccination with 3 doses of formed consent authorized by parents or legal representa- DTwP-HB-Hib at 2, 3, and 4 months, followed by a tive after the explanation of the trial, potential risks, and booster dose at age 18–24 months. DTwP-HB-Hib is a his/her obligations. The study protocol had been approved new vaccine produced by Bio Farma, Indonesia, combining by the Quality Assurance Division of Bio Farma, the Insti- diphtheria toxoid and tetanus toxoid, inactive pertussis tutional Ethics Committee, and Indonesian Regulatory bacteria, hepatitis B surface antigen, and Hib [5]. Com- Authorities. This trial was conducted in accordance with bination vaccine reduces number of injections, number ICH Good Clinical Practice guidelines and local regulatory of visits to healthcare or hospital, cost, discomfort; these requirement. ultimately increase parental compliance and improve immunization coverage rates [6, 7]. Study procedure In India, DTwP-HB-Hib pentavalent vaccine trial showed There were two visit in the study. At the first visit, blood low reactogenicity, minimal adverse events (AEs), and high sample from the subjects aged 18–24 months (12– level of seroprotective rates [8, 9]. A randomized trial in 18 months after the last dose of three primary doses) Latin American children has also shown that primary and were obtained for pre-booster antibody titer. Then each booster vaccination with a DTwP-HB-Hib combination subject was given one dose (0.5 mL) of DTwP-HB-Hib vaccine showed good seroprotection rate and good persist- vaccine as a booster, intra-muscularly into the middle-third ence of antibodies against all vaccine antigens. The vaccine anterolateral region of the thigh or the deltoid muscle with was also well-tolerated as primary and booster doses [10]. a 23G, 25 mm needle. Anterolateral thigh muscle was the However, immunogenicity and safety of DTwP-HB-Hib preferred site but the deltoid muscle could also serve as combined vaccine has not been well understood in site of injection if pediatrician considered the muscle mass Indonesia, especially as a booster dose vaccination. was adequate. This study was a follow-up of the previous phase III After the booster vaccination, all parents were given a study [11]. The objectives of this study were to measure diary to record information for any local and systemic antibody persistence after three primary doses at age adverse events (AEs) until 28 days after the vaccination. 2,4,6 months old, to asses immune response, and to en- Collection of any local or systems AEs within 3 days sure safety of a booster dose of DTwP-HB-Hib vaccine. after immunization were conducted by a nurse or desig- nated person by home visit or phone call. Methods At the second visit (28 days after the booster vaccin- Study design and population ation), blood samples were acquired from the subjects to This open-labeled, prospective, interventional and multi- measure post-booster antibody. Subjects’ diary were then center trial was conducted from March to October 2014 reviewed for any notes in local and systemic AEs. in Bandung (Group A) and Jakarta (Group B), Indonesia. The main criteria of subjects were children aged 18– 24 months who had received hepatitis B birth dose and Study vaccine three primary doses of DTwP-HB-Hib vaccine from the DTwP-HB-Hib vaccine (Pentabio®, batch number 5010613, previous Phase III trial recruited from three primary with expired date: June 2015) used in this study were man- health centers in Bandung (Group A) and three primary ufactured by Bio Farma, Bandung, Indonesia. Each 0.5 mL health centers in Jakarta (Group B) [11]. dose of vaccine contained ≥30 IU of purified diphtheria Exclusion criteria in this trial were mild, moderate or toxoid, ≥60 IU of purified tetanus toxoid, ≥4IUofinac- severe illness, especially infectious diseases or fever (axillary tivated Bordetella pertussis,10 μg hepatitis B surface temperature ≥ 37.5°C on day 0); history of allergy to any antigen (HBsAg, recombinant), 10 μg Hib in the form components of the vaccines; history of uncontrolled coagu- of polyribosil-ribitol-phosphate (PRP) conjugated to tet- lopathy or blood disorders contraindicated intramuscular anus toxoid, 1.5 μg aluminium phosphate, 4.5 mg sodium injection; history of acquired immunodeficiency (including chloride, and 0.025 mg thimerosal. Vaccines were stored HIV infection); received a treatment likely to alter im- in the refrigerator at temperature + 2° to + 8°C (as standart mune response in the previous 4 weeks (e.g. intravenous protocol) at the clinical trial centers to assure quality. Gunardi et al. BMC Pediatrics (2018) 18:177 Page 3 of 8 Blood sampling and antibody measurement of any local or systemic adverse events (indicated as 1 For each subject, 4 mL of blood was drawn in vacutainer [mild], 2 [moderate], or 3 [severe]) were recorded at tubes and then coded. After clotted at room temperature home. Local reactions were defined as the presence of in 30 min to 2 h, each speciment was centrifuged at local pain, redness, induration, or swelling at the injection 3000 rpm for 15 min and the sera stored in cryotubes site; the systemic events were defined as the occurrence of within 24 h after sampling. Sera of the coded samples fever (axillary temperature ≥38.0°C), irritability, or both. were stored at − 20 C. Local and systemic AEs were recorded in two interval of Serology antibody testing was started after the samples time: (1) within 30 min to 72 h and (2) 72 h – 28 days had been blinded. The blinding code and list were pre- after vaccination. pared by the statistician and witnessed by the investigators. Vaccine AEs were retrieved by interviewing the parents Serology assays, except for anti-HBs, were conducted and assessing the diary card during the follow-up visit. in Immunology Laboratory of Product Evaluation Depart- ment of Bio Farma by technicians who were blinded to Statistical analysis samples’ visit. Test for anti-HBs was conducted in Prodia The vaccine immunogenicity and safety were analyzed Laboratory which had been assessed by Quality Assurance using intention-to-treat (ITT) and per-protocol (PP) of Bio Farma and had been certificated by ISO 9001 analyses. Immunogenicity analysis was done regarding and National Accreditation Committee. Tetanus and response to each vaccine antigen pre- and post-booster. diphtheria antibody were measured by validated ELISA. Seroprotection, increase in antibody level, and serocon- Pertussis antibody was measured by microagglutination version were calculated for each vaccine antigen. AEs were method. Antibody to hepatitis B surface antigen (anti-HBs) analyzed using Chi-square test with at least p value < 0.05 was measured by Chemiluminescent Microparticle Im- considered to be statistically significant. munoassay (CMIA) AUSAB reagent kit by Abbott. Antibody to PRP was measured by using Improved Phipps ELISA; a competitive ELISA was used for meas- Results uring the levels of serum antibody to Haemophilus influen- There were 399 subjects enrolled at the first visit. These zae type B. All antibody assays were validated previously. subjects were subsequently divided into two groups: of 238 children in Group A (Bandung); and 161 children in Measures Group B (Jakarta) (Fig. 1). One subject in Group B was This study measured antibody persistence after three doses lost to follow-up because the child moved to another of primary vaccinations and immune response after a province, and there were two subjects were withdrawn single booster dose at 18–24 months of age. Antibody from the study. After these drop-outs, the total of the persistence is defined as having antibody level above subjects were 396 subjects (238 subjects in Group A and the protective threshold for each given vaccination after 158 subjects in Group B). All subjects were of Indonesian primary doses. Immune response after booster was expressed race, with their demographic and baseline characteristics in three parameters: (1) seroprotection (antibody level above of presented in Table 1. the basic protective threshold), (2) seroconversion (conver- sion of seronegative to seropositive), and (3) four-times in- Diphtheria antibody crease of antibody level [12, 13]. Primary outcome was The protective level of diphtheria antibody was 74.5% the short-term or basic protective antibody, defined as: diph- prior the booster immunization, and 99.7% after booster. theria antibody ≥ 0.01 IU/mL, tetanus antibody ≥ 0.01 IU/ As many as 87.1% subjects had increment in their anti- mL, pertussis antibody ≥ 1/40, hepatitis B antibody ≥10 body titer ≥4 times, and all of seronegative subjects experi- mIU/mL, and Hib antibody titer (PRP) ≥0.15 μg/mL. Sec- nced seroconversion after the administration of booster ondary outcome was long-term or full protective antibody, dose. The Geometric Mean Titer (GMT) of the diphtheria defined as diphtheria antibody ≥ 0.1 IU/mL, tetanus antibody increased 9.4 times (0.054 to 0.508) after booster antibody ≥ 0.1 IU/mL, pertussis antibody ≥ 1/80, and Hib (Table 2). antibody titer (PRP) ≥1 μg/mL [14–18]. Safety assessment Tetanus antibody Immediate local and systemic AEs 30 min after vaccin- Subjects who had the protective level of tetanus anti- ation were observed and recorded at the health centers. body were 100%, before and after the booster. However, A digital thermometer, a plastic measuring scale, and a there was an increment of GMT 20.6 times, from 0.187 diary card were provided for the parents to measure and to 3.853 after the booster. The proportion of subjects record axillary temperature and the size of redness and with 4-times increased in antibody titer was 91.7% swelling, respectively. Appearance, duration, and intensity (Table 2). Gunardi et al. BMC Pediatrics (2018) 18:177 Page 4 of 8 Fig. 1 Subjects recruitment Pertussis antibody Overall, the GMT of Hib antibody increased 20.7 The subjects with pertussis micro-agglutination level ≥ times, from 3.399 to 70.226 after booster (Table 2). 1/40 were 40.4% before booster and this number was in- creased to 95.5% after the booster. There were 90.9% of Local adverse events 30 min after booster vaccination the subjects whose antibody titer was increased four Local AEs were reported in 17.3% subjects in the deltoid times from the baseline, and increased of the GMT by group and 14.9% subjects in the thigh group within 22.8 times, from 28.086 to 639.145, after the booster 30 min after vaccination. The pain was reported in 10.8% (Table 2). subjects in the deltoid group and in 8.3% subjects in the thigh group. All of the symptoms were slightly less Hepatitis B antibody common in the thigh than in the deltoid group, but not Prior the booster, the proportion of subjects with protect- statistically significant (P = 0.515). ive hepatitis B antibody were 90.2, and 99.5% after booster. As many as 97.2% subjects had four times increment in Systemic adverse events 30 min after booster vaccination their antibody titer and 94.9% subjects had seroconversion The most common AE was irritability, which was found to seropositive. The GMT of hepatitis B antibody in- in 11.7% subjects of the deltoid group and 6.5% of the creased 65.6 times from 85.27 to 5591.13 after booster thigh group. (Table 2). Local adverse events > 30 min to 72 h after booster Haemophilus influenza B vaccination The proportion of subjects with protective level of Hib Local AEs were reported in 51.3% subjects of the deltoid antibody was 97.7% before booster and 100% after booster. group and 41.7% of the thigh group within 30 min to As many as 82.3% subject had 4-times increment in anti- 72 h following booster vaccination. All of the symptoms body titer, and all subjects who previously were seronega- were less common in the thigh group than in the deltoid tive had converted to seropositive after the booster. group. Pain was reported in 43.4% subjects in the deltoid group and 38.1% subjects in the thigh group. Local AEs Table 1 Demographic characteristics of subjects such as redness, swelling, and induration were found sig- Description Group A (N = 238) Group B (N = 161) Total nificantly less common in the thigh group (7.7, 11.3, 7.1%), Gender compared to the deltoid group (28.9, 30.7, 25%) (P <0.001) Male (n) 112 69 181 (45.4%) (Fig. 2). Female (n) 126 92 218 (45.4%) Systemic adverse events > 30 min to 72 h after booster Age (months) vaccination Mean ± SD 19 ± 0.8 20 ± 0.9 20 ± 1.0 There were 42.1% subjects in the deltoid group and Min-max 18–22 19–24 18–24 51.2% subjects in the thigh group who had systemic Gunardi et al. BMC Pediatrics (2018) 18:177 Page 5 of 8 Table 2 Summary of pre-booster and post-booster antibody level of tested antibodies Antibody N = 396 Subjects (%) 95% CI GMT(Range) Diphtheria Pre-booster titer (IU/mL) 0.054 (0.047–0.061) Anti-D ≥ 0.01 295 74.5 Anti-D ≥ 0.1 81 20.5 16.8–24.7 Post-booster titer (IU/mL) 0.508 (0.446–0.580) Anti-D ≥ 0.01 394 99.7 Anti-D ≥ 0.1 344 87.1 83.4–90.0 Increased antibody titer 345 87.1 Seroconversion 98/98 100 Tetanus Pre-booster titer (IU/mL) 0.187 (0.169–0.206) Anti-tetanus ≥0.01 396 100 Anti-tetanus ≥0.1 286 72.2 67.4–76.2 Post-booster titer (IU/mL) 3.853 (3.531–4.205) Anti-tetanus ≥0.01 396 100 Anti-tetanus ≥0.1 394 95.5 98.2–99.9 Increased antibody titer 363 91.7 Pertussis Pre-booster titer 28.086 (24.791–31.812) ≥ 1/40 160 40.4 35.7–45.3 ≥ 1/80 99 25.0 21.0–29.5 Post-booster titer 639.145 (550.807–741.651) ≥ 1/40 378 95.5 92.9–97.1 ≥ 1/80 367 92.7 89.7–94.9 Increased antibody titer 360 90.9 Hepatitis B Pre-booster titer (mIU/mL) 85.27 (74.199–98.016) Anti-HBs ≥10 357 90.2 86.8–92.7 Post-booster titer (mIU/mL) 5591.13 (4761.02–6564.47) Anti-HBs ≥10 394 99.5 97.8–98.7 Increased antibody titer 385 97.2 Seroconversion 37/39 94.9 PRP-T (Hib) Pre-booster titer (μg/mL) 3.399 (3.006–3.844) Anti-Hib ≥0.15 387 97.7 Anti-Hib ≥1.0 343 86.6 82.9–89.6 Post-booster titer (μg/mL) 70.226 (61.249–80.501) Anti-Hib ≥0.15 396 100 Anti-Hib ≥1.0 394 99.5 98.2–99.9 Increased antibody titer 326 82.3 Seroconversion 9/9 100 Based on per-protocol analysis a b c d Short-term protection, Long-term protection, Increased antibody titer ≥4 times from the pre-booster level, Transition from seronegative to seropositive Gunardi et al. BMC Pediatrics (2018) 18:177 Page 6 of 8 Fig. 2 Local and systemic adverse events *local and systemic adverse events 30 minutes – 72 hours, #Systemic adverse events 72 hours – 28 days, No significant differences in AEs for pain, irritability, and others between deltoid and thigh group adverse events in > 30 min to 72 h after vaccination. Discussion The most common systemic AE was irritability (39.9% This study has demonstrated good immunogenicity and in deltoid group and 45.2% in thigh group), with the tolerability of the new combined DTwP-HB-Hib (Pentabio®) second most common systemic AE was fever (23.7% in vaccine as a booster dose in children age 18–24 months old. deltoid group and 25% in thigh group). Both occurred Although the persistence of antibody following the primary slightly less common in the deltoid groups. doses were quite good for each vaccine antigen, there were some degrees of waning immunity during 18–24 months of Local adverse events > 72 h to 28 days after booster age, especially diphtheria and pertussis. This justified the ne- vaccination cessity for a booster dose in children age 18–24 months. No local reaction occurred within 72 h to 28 days after In a previous study, 1 month after the third dose of the booster vaccination, except 3 subjects with induration DTwP-HB-Hib (Pentabio®) as primary vaccination, most in deltoid group. of the children (84–100%) had protective antibody level [11]. In this study, the antibodies prior booster vaccina- Systemic adverse events > 72 h to 28 days after booster tions were low in subjects with protective antibody of vaccination diphtheria and pertussis (74.5 and 40.4%, respectively). There were 23.2% subjects in the deltoid group and 16.1% After the booster, the seroprotection had increased to subjects in the thigh group who were reported to have 99.7 and 95.5% for diphtheria and pertussis, respectively. systemic adverse events within 72 h to 28 days after Another DTPw-HB-Hib vaccine trial in El Salvador finds vaccination. The most common symptom reported was the seroconversion of B. pertussis after a booster dose fever (14.5% in the deltoid group vs. 7.1% in the thigh was 94.4%. In addition, a trial in Latin America finds at group), which statistically more significant to be found least 99.1% had the seroprotective level of antibodies in the deltoid group (P = 0.02, Fig. 2). All of the other against diphtheria, tetanus and hepatitis B [10, 19]. symptoms (irritability and others) were found to be Currently, there is no international standard definition slightly less common in the thigh group than in the del- determined for the seroprotection for B. pertussis. A study toid group, but not statistically significant. in France used the ratio 1: 80 as cut-off, but in it was stated that the cut-off might had been too high as a cut- Local and systemic reaction intensity off [20]. We used the 1/40 as cut-off, only 40.4% of our Most of the adverse events that were reported were mild subjects had the seroprotection before the booster doses. and resolved spontaneously within the 72 h follow-up However, this proportion had increased greatly to 95.5% period. There was one report of acute diarrhea as a serious after one dose of booster. The 1/40 cut-off was also used AE from Group B, which was classified as unrelated. The in the pertussis outbreak in a university in Japan [21]. In subject was recovered after several days of hospitalization. this study, the protective titer was found in 92.7% subjects There was no other vaccine-related serious AE reported. for the long-term protection of using the 1/80 cut-off. Gunardi et al. BMC Pediatrics (2018) 18:177 Page 7 of 8 The persistent protective antibody after three primary The reason for this limitation was due to unpredictable doses in children aged 18–24 months was 90.2% for hepa- heavy flood in the study area, which caused so many titis B, and 97.7% for Hib. After primary immunization, subjects moved to other areas. Regardless the limitation, anti-HBs concentrations wane quite rapidly within the this was the first study of immunogenicity and safety of first year and more slowly thereafter. Even with the wan- DTwP-HB-Hib booster in Indonesian children. ing immunity, the immune memory to hepatitis B con- tinues to persist over a longer period. Protective antibody Conclusions had risen to 99.5 and 100%; and following the booster The new combination of DTwP-HB-Hib vaccines (Pen- dose, seroconversion occurred in 94.9 and 100% subjects tabio) as a booster at age 18–24 months is necessary to to hepatitis B and Hib, respectively, indicating effective achieve and maintain optimal protective antibody. The priming and induction of the immune memory [22]. vaccine is safe and immunogenic to be used for booster The long-term protection of tetanus from our earlier vaccination. study was 72.2% 1 month after primary DTP-HB-Hib Abbreviations vaccination [11], then decreased to 72.2% at 18–24 months DTwP: Diphtheria tetanus whole-cell pertussis; GMT: Geometric mean titer; of age. After the booster, the long-term protection had in- HB: Hepatitis B; HBsAg: Hepatitis B surface antigen; Hib: Haemophilus influenza type b; PRP: Polyribosil-ribitol-phosphate creased to 95.5% with the GMT level of 3.85 IU/mL, which will provide 3–5 years of protection [23]. Acknowledgments DTwP-HB-Hib vaccine was found to be highly im- PT Bio Farma was the funding stakeholder of this study. The authors would like to thank all of the children and parents who participated in this study, munogenic in our booster vaccination study. One month head of Bandung District Health Office, Jakarta Province Health Office, head following the booster vaccination of this vaccine, our and staff of Garuda, Ibrahim Adjie, Puter Primary Health Center in Bandung; study finds at least 95.5% of the study subjects reached head and staff of Jatinegara, Mampang, and Tebet Primary Health Center in Jakarta for their supports. We would also like to express our appreciation for protective levels of antibodies (seroprotected) against the the tremendous support of Indonesian National AEFI Committee as auditor of antigens employed in the vaccine. Another report of SAEs in this study. We also thank Mr. Hadyana Sukandar for his statistical work DTwP-HB-Hib (Quinvaxem®) immunogenicity showed in this study, and Dr. Natharina Yolanda for her invaluable editorial assistance. 99.4% seroprotection at 1-month after booster dose [24]. Funding Other previous studies of similar pentavalent vaccine in This study was funded by PT Bio Farma, number 06815/DIR/XII/2013 Latin America and Costa Rica showed that it could in- (Bandung site) and 06818/DIR/XII/2013 (Jakarta site). duce both persisting immunity and boostable memory, Availability of data and materials therefore provided an efficient and reliable way of imple- The datasets analyzed during the current study available from the menting this vaccine to the routine program [25, 26]. corresponding author on reasonable request. In this study, no serious adverse events were consid- Authors’ contributions ered related to vaccine or procedure. This study has KR was a national principal investigator and principal investigator in Bandung demonstrated that the occurrence of local AEs such as city. HG was the principal investigator in Jakarta city. KR, HG, EF, RMS, and NSB conceived the study and its design. HG, KR, EF, and S wrote and review the redness, swelling and induration within 30 min – 72 h, manuscript. MD and RT reviewed the design, recruited the subjects and and fever as systemic AE in 72 h – 28 days were signifi- conducted the study in Bandung city. S, RS, BEM and HIS reviewed the design, cantly less common in the thigh group than in the del- recruited the subjects and conducted the study in Jakarta city. SRH was the medical advisor of Jakarta site and reviewed the study and manuscript. CBK was toid group. This findings are similar to a previous study the medical advisor of Bandung site and reviewed the study and manuscript. conducted in Vaccine Safety Datalink population that in- All authors read and approved the final manuscript. cluded 1.4 million of children in the USA, which finds Ethics approval and consent to participate injection in thigh was associated with significantly lower This trial has been approved by Health Research Ethics Committee Faculty of risk of local reaction to DTaP vaccination among chil- Medicine Universitas Padjajaran Bandung (418/UN6.C2.1.2/KEPK/PPN/2013) dren 1–2 years of age. This finding supports the current and The Ethics Committee of the Faculty of Medicine, University of Indonesia (735/H2.F1/ETIK/2013). recommendation for thigh as intramuscular site injec- A written form of informed consent was obtained from every child’s parent tion in this age group [27]. or legal guardian before the recruitment. The three doses of primary immunization and a booster dose of DTwP-HB-Hib were all immunogenic Competing interests Hartono Gunardi, Kusnandi Rusmil, Eddy Fadlyana, Soedjatmiko, Meita and well-tolerated by the study subjects. DTwP-HB-Hib Dhamayanti, Rini Sekartini, Rodman Tarigan, Hindra Irawan Satari, Bernie vaccine is a suitable for immunization program in devel- Endyarni Medise, Cissy B Kartasasmita, Sri Rezeki S Hadinegoro, received oping countries. [9, 11, 19, 25, 26]. grant support through their institutions. Rini Mulia Sari and Novilia Sjafri Bachtiar were employees of PT Bio Farma at the time of the conduct of this study and manuscript preparation. Limitation of study There were only 399 (69.4%) out of 575 subjects were Publisher’sNote recruited. A total of 396 subjects who completed the Springer Nature remains neutral with regard to jurisdictional claims in DTwP-HB-Hib primary immunization were analyzed. published maps and institutional affiliations. Gunardi et al. 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Determination of circulating antibodies directed to pertussis toxin and of agglutinogens in children vaccinated with either the whole cell or component pertussis vaccine in France, Japan and Senegal. Vaccine. 1991;9:843–50. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Pediatrics Springer Journals

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

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Medicine & Public Health; Pediatrics; Internal Medicine
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Abstract

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). Keywords: Booster dose, DTwP-HB-Hib vaccine, Immunogenicity, Safety, Children * Correspondence: hartono@ikafkui.net Department of Child Health, Faculty of Medicine, Universitas Indonesia/Dr. Cipto Mangunkusumo Hospital, Jl. Diponegoro No 71, Jakarta 10430, Indonesia Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Gunardi et al. BMC Pediatrics (2018) 18:177 Page 2 of 8 Background immunoglobulin, blood-derived products or long-term Infections related with vaccine-preventable diseases includ- corticosteroid therapy (> 2 weeks); receiving other vac- ing hepatitis B, diphtheria, pertussis, and Haemophilus cines within 1 month prior to trial enrollment; any abnor- influenzae type B (Hib) were accounted for high morbidity malities or chronic diseases determined by investigators and mortality among children younger than 5 years of age that might interfere the trial objectives; and children with in many underdeveloped countries [1–4]. In accordance history of either diphtheria, tetanus, pertussis, Hib, and with the Expanded Program on Immunization (EPI) rec- hepatitis B infection. ommendation, the Indonesian National Immunization All subjects were recruited following written form of in- schedule comprises primary vaccination with 3 doses of formed consent authorized by parents or legal representa- DTwP-HB-Hib at 2, 3, and 4 months, followed by a tive after the explanation of the trial, potential risks, and booster dose at age 18–24 months. DTwP-HB-Hib is a his/her obligations. The study protocol had been approved new vaccine produced by Bio Farma, Indonesia, combining by the Quality Assurance Division of Bio Farma, the Insti- diphtheria toxoid and tetanus toxoid, inactive pertussis tutional Ethics Committee, and Indonesian Regulatory bacteria, hepatitis B surface antigen, and Hib [5]. Com- Authorities. This trial was conducted in accordance with bination vaccine reduces number of injections, number ICH Good Clinical Practice guidelines and local regulatory of visits to healthcare or hospital, cost, discomfort; these requirement. ultimately increase parental compliance and improve immunization coverage rates [6, 7]. Study procedure In India, DTwP-HB-Hib pentavalent vaccine trial showed There were two visit in the study. At the first visit, blood low reactogenicity, minimal adverse events (AEs), and high sample from the subjects aged 18–24 months (12– level of seroprotective rates [8, 9]. A randomized trial in 18 months after the last dose of three primary doses) Latin American children has also shown that primary and were obtained for pre-booster antibody titer. Then each booster vaccination with a DTwP-HB-Hib combination subject was given one dose (0.5 mL) of DTwP-HB-Hib vaccine showed good seroprotection rate and good persist- vaccine as a booster, intra-muscularly into the middle-third ence of antibodies against all vaccine antigens. The vaccine anterolateral region of the thigh or the deltoid muscle with was also well-tolerated as primary and booster doses [10]. a 23G, 25 mm needle. Anterolateral thigh muscle was the However, immunogenicity and safety of DTwP-HB-Hib preferred site but the deltoid muscle could also serve as combined vaccine has not been well understood in site of injection if pediatrician considered the muscle mass Indonesia, especially as a booster dose vaccination. was adequate. This study was a follow-up of the previous phase III After the booster vaccination, all parents were given a study [11]. The objectives of this study were to measure diary to record information for any local and systemic antibody persistence after three primary doses at age adverse events (AEs) until 28 days after the vaccination. 2,4,6 months old, to asses immune response, and to en- Collection of any local or systems AEs within 3 days sure safety of a booster dose of DTwP-HB-Hib vaccine. after immunization were conducted by a nurse or desig- nated person by home visit or phone call. Methods At the second visit (28 days after the booster vaccin- Study design and population ation), blood samples were acquired from the subjects to This open-labeled, prospective, interventional and multi- measure post-booster antibody. Subjects’ diary were then center trial was conducted from March to October 2014 reviewed for any notes in local and systemic AEs. in Bandung (Group A) and Jakarta (Group B), Indonesia. The main criteria of subjects were children aged 18– 24 months who had received hepatitis B birth dose and Study vaccine three primary doses of DTwP-HB-Hib vaccine from the DTwP-HB-Hib vaccine (Pentabio®, batch number 5010613, previous Phase III trial recruited from three primary with expired date: June 2015) used in this study were man- health centers in Bandung (Group A) and three primary ufactured by Bio Farma, Bandung, Indonesia. Each 0.5 mL health centers in Jakarta (Group B) [11]. dose of vaccine contained ≥30 IU of purified diphtheria Exclusion criteria in this trial were mild, moderate or toxoid, ≥60 IU of purified tetanus toxoid, ≥4IUofinac- severe illness, especially infectious diseases or fever (axillary tivated Bordetella pertussis,10 μg hepatitis B surface temperature ≥ 37.5°C on day 0); history of allergy to any antigen (HBsAg, recombinant), 10 μg Hib in the form components of the vaccines; history of uncontrolled coagu- of polyribosil-ribitol-phosphate (PRP) conjugated to tet- lopathy or blood disorders contraindicated intramuscular anus toxoid, 1.5 μg aluminium phosphate, 4.5 mg sodium injection; history of acquired immunodeficiency (including chloride, and 0.025 mg thimerosal. Vaccines were stored HIV infection); received a treatment likely to alter im- in the refrigerator at temperature + 2° to + 8°C (as standart mune response in the previous 4 weeks (e.g. intravenous protocol) at the clinical trial centers to assure quality. Gunardi et al. BMC Pediatrics (2018) 18:177 Page 3 of 8 Blood sampling and antibody measurement of any local or systemic adverse events (indicated as 1 For each subject, 4 mL of blood was drawn in vacutainer [mild], 2 [moderate], or 3 [severe]) were recorded at tubes and then coded. After clotted at room temperature home. Local reactions were defined as the presence of in 30 min to 2 h, each speciment was centrifuged at local pain, redness, induration, or swelling at the injection 3000 rpm for 15 min and the sera stored in cryotubes site; the systemic events were defined as the occurrence of within 24 h after sampling. Sera of the coded samples fever (axillary temperature ≥38.0°C), irritability, or both. were stored at − 20 C. Local and systemic AEs were recorded in two interval of Serology antibody testing was started after the samples time: (1) within 30 min to 72 h and (2) 72 h – 28 days had been blinded. The blinding code and list were pre- after vaccination. pared by the statistician and witnessed by the investigators. Vaccine AEs were retrieved by interviewing the parents Serology assays, except for anti-HBs, were conducted and assessing the diary card during the follow-up visit. in Immunology Laboratory of Product Evaluation Depart- ment of Bio Farma by technicians who were blinded to Statistical analysis samples’ visit. Test for anti-HBs was conducted in Prodia The vaccine immunogenicity and safety were analyzed Laboratory which had been assessed by Quality Assurance using intention-to-treat (ITT) and per-protocol (PP) of Bio Farma and had been certificated by ISO 9001 analyses. Immunogenicity analysis was done regarding and National Accreditation Committee. Tetanus and response to each vaccine antigen pre- and post-booster. diphtheria antibody were measured by validated ELISA. Seroprotection, increase in antibody level, and serocon- Pertussis antibody was measured by microagglutination version were calculated for each vaccine antigen. AEs were method. Antibody to hepatitis B surface antigen (anti-HBs) analyzed using Chi-square test with at least p value < 0.05 was measured by Chemiluminescent Microparticle Im- considered to be statistically significant. munoassay (CMIA) AUSAB reagent kit by Abbott. Antibody to PRP was measured by using Improved Phipps ELISA; a competitive ELISA was used for meas- Results uring the levels of serum antibody to Haemophilus influen- There were 399 subjects enrolled at the first visit. These zae type B. All antibody assays were validated previously. subjects were subsequently divided into two groups: of 238 children in Group A (Bandung); and 161 children in Measures Group B (Jakarta) (Fig. 1). One subject in Group B was This study measured antibody persistence after three doses lost to follow-up because the child moved to another of primary vaccinations and immune response after a province, and there were two subjects were withdrawn single booster dose at 18–24 months of age. Antibody from the study. After these drop-outs, the total of the persistence is defined as having antibody level above subjects were 396 subjects (238 subjects in Group A and the protective threshold for each given vaccination after 158 subjects in Group B). All subjects were of Indonesian primary doses. Immune response after booster was expressed race, with their demographic and baseline characteristics in three parameters: (1) seroprotection (antibody level above of presented in Table 1. the basic protective threshold), (2) seroconversion (conver- sion of seronegative to seropositive), and (3) four-times in- Diphtheria antibody crease of antibody level [12, 13]. Primary outcome was The protective level of diphtheria antibody was 74.5% the short-term or basic protective antibody, defined as: diph- prior the booster immunization, and 99.7% after booster. theria antibody ≥ 0.01 IU/mL, tetanus antibody ≥ 0.01 IU/ As many as 87.1% subjects had increment in their anti- mL, pertussis antibody ≥ 1/40, hepatitis B antibody ≥10 body titer ≥4 times, and all of seronegative subjects experi- mIU/mL, and Hib antibody titer (PRP) ≥0.15 μg/mL. Sec- nced seroconversion after the administration of booster ondary outcome was long-term or full protective antibody, dose. The Geometric Mean Titer (GMT) of the diphtheria defined as diphtheria antibody ≥ 0.1 IU/mL, tetanus antibody increased 9.4 times (0.054 to 0.508) after booster antibody ≥ 0.1 IU/mL, pertussis antibody ≥ 1/80, and Hib (Table 2). antibody titer (PRP) ≥1 μg/mL [14–18]. Safety assessment Tetanus antibody Immediate local and systemic AEs 30 min after vaccin- Subjects who had the protective level of tetanus anti- ation were observed and recorded at the health centers. body were 100%, before and after the booster. However, A digital thermometer, a plastic measuring scale, and a there was an increment of GMT 20.6 times, from 0.187 diary card were provided for the parents to measure and to 3.853 after the booster. The proportion of subjects record axillary temperature and the size of redness and with 4-times increased in antibody titer was 91.7% swelling, respectively. Appearance, duration, and intensity (Table 2). Gunardi et al. BMC Pediatrics (2018) 18:177 Page 4 of 8 Fig. 1 Subjects recruitment Pertussis antibody Overall, the GMT of Hib antibody increased 20.7 The subjects with pertussis micro-agglutination level ≥ times, from 3.399 to 70.226 after booster (Table 2). 1/40 were 40.4% before booster and this number was in- creased to 95.5% after the booster. There were 90.9% of Local adverse events 30 min after booster vaccination the subjects whose antibody titer was increased four Local AEs were reported in 17.3% subjects in the deltoid times from the baseline, and increased of the GMT by group and 14.9% subjects in the thigh group within 22.8 times, from 28.086 to 639.145, after the booster 30 min after vaccination. The pain was reported in 10.8% (Table 2). subjects in the deltoid group and in 8.3% subjects in the thigh group. All of the symptoms were slightly less Hepatitis B antibody common in the thigh than in the deltoid group, but not Prior the booster, the proportion of subjects with protect- statistically significant (P = 0.515). ive hepatitis B antibody were 90.2, and 99.5% after booster. As many as 97.2% subjects had four times increment in Systemic adverse events 30 min after booster vaccination their antibody titer and 94.9% subjects had seroconversion The most common AE was irritability, which was found to seropositive. The GMT of hepatitis B antibody in- in 11.7% subjects of the deltoid group and 6.5% of the creased 65.6 times from 85.27 to 5591.13 after booster thigh group. (Table 2). Local adverse events > 30 min to 72 h after booster Haemophilus influenza B vaccination The proportion of subjects with protective level of Hib Local AEs were reported in 51.3% subjects of the deltoid antibody was 97.7% before booster and 100% after booster. group and 41.7% of the thigh group within 30 min to As many as 82.3% subject had 4-times increment in anti- 72 h following booster vaccination. All of the symptoms body titer, and all subjects who previously were seronega- were less common in the thigh group than in the deltoid tive had converted to seropositive after the booster. group. Pain was reported in 43.4% subjects in the deltoid group and 38.1% subjects in the thigh group. Local AEs Table 1 Demographic characteristics of subjects such as redness, swelling, and induration were found sig- Description Group A (N = 238) Group B (N = 161) Total nificantly less common in the thigh group (7.7, 11.3, 7.1%), Gender compared to the deltoid group (28.9, 30.7, 25%) (P <0.001) Male (n) 112 69 181 (45.4%) (Fig. 2). Female (n) 126 92 218 (45.4%) Systemic adverse events > 30 min to 72 h after booster Age (months) vaccination Mean ± SD 19 ± 0.8 20 ± 0.9 20 ± 1.0 There were 42.1% subjects in the deltoid group and Min-max 18–22 19–24 18–24 51.2% subjects in the thigh group who had systemic Gunardi et al. BMC Pediatrics (2018) 18:177 Page 5 of 8 Table 2 Summary of pre-booster and post-booster antibody level of tested antibodies Antibody N = 396 Subjects (%) 95% CI GMT(Range) Diphtheria Pre-booster titer (IU/mL) 0.054 (0.047–0.061) Anti-D ≥ 0.01 295 74.5 Anti-D ≥ 0.1 81 20.5 16.8–24.7 Post-booster titer (IU/mL) 0.508 (0.446–0.580) Anti-D ≥ 0.01 394 99.7 Anti-D ≥ 0.1 344 87.1 83.4–90.0 Increased antibody titer 345 87.1 Seroconversion 98/98 100 Tetanus Pre-booster titer (IU/mL) 0.187 (0.169–0.206) Anti-tetanus ≥0.01 396 100 Anti-tetanus ≥0.1 286 72.2 67.4–76.2 Post-booster titer (IU/mL) 3.853 (3.531–4.205) Anti-tetanus ≥0.01 396 100 Anti-tetanus ≥0.1 394 95.5 98.2–99.9 Increased antibody titer 363 91.7 Pertussis Pre-booster titer 28.086 (24.791–31.812) ≥ 1/40 160 40.4 35.7–45.3 ≥ 1/80 99 25.0 21.0–29.5 Post-booster titer 639.145 (550.807–741.651) ≥ 1/40 378 95.5 92.9–97.1 ≥ 1/80 367 92.7 89.7–94.9 Increased antibody titer 360 90.9 Hepatitis B Pre-booster titer (mIU/mL) 85.27 (74.199–98.016) Anti-HBs ≥10 357 90.2 86.8–92.7 Post-booster titer (mIU/mL) 5591.13 (4761.02–6564.47) Anti-HBs ≥10 394 99.5 97.8–98.7 Increased antibody titer 385 97.2 Seroconversion 37/39 94.9 PRP-T (Hib) Pre-booster titer (μg/mL) 3.399 (3.006–3.844) Anti-Hib ≥0.15 387 97.7 Anti-Hib ≥1.0 343 86.6 82.9–89.6 Post-booster titer (μg/mL) 70.226 (61.249–80.501) Anti-Hib ≥0.15 396 100 Anti-Hib ≥1.0 394 99.5 98.2–99.9 Increased antibody titer 326 82.3 Seroconversion 9/9 100 Based on per-protocol analysis a b c d Short-term protection, Long-term protection, Increased antibody titer ≥4 times from the pre-booster level, Transition from seronegative to seropositive Gunardi et al. BMC Pediatrics (2018) 18:177 Page 6 of 8 Fig. 2 Local and systemic adverse events *local and systemic adverse events 30 minutes – 72 hours, #Systemic adverse events 72 hours – 28 days, No significant differences in AEs for pain, irritability, and others between deltoid and thigh group adverse events in > 30 min to 72 h after vaccination. Discussion The most common systemic AE was irritability (39.9% This study has demonstrated good immunogenicity and in deltoid group and 45.2% in thigh group), with the tolerability of the new combined DTwP-HB-Hib (Pentabio®) second most common systemic AE was fever (23.7% in vaccine as a booster dose in children age 18–24 months old. deltoid group and 25% in thigh group). Both occurred Although the persistence of antibody following the primary slightly less common in the deltoid groups. doses were quite good for each vaccine antigen, there were some degrees of waning immunity during 18–24 months of Local adverse events > 72 h to 28 days after booster age, especially diphtheria and pertussis. This justified the ne- vaccination cessity for a booster dose in children age 18–24 months. No local reaction occurred within 72 h to 28 days after In a previous study, 1 month after the third dose of the booster vaccination, except 3 subjects with induration DTwP-HB-Hib (Pentabio®) as primary vaccination, most in deltoid group. of the children (84–100%) had protective antibody level [11]. In this study, the antibodies prior booster vaccina- Systemic adverse events > 72 h to 28 days after booster tions were low in subjects with protective antibody of vaccination diphtheria and pertussis (74.5 and 40.4%, respectively). There were 23.2% subjects in the deltoid group and 16.1% After the booster, the seroprotection had increased to subjects in the thigh group who were reported to have 99.7 and 95.5% for diphtheria and pertussis, respectively. systemic adverse events within 72 h to 28 days after Another DTPw-HB-Hib vaccine trial in El Salvador finds vaccination. The most common symptom reported was the seroconversion of B. pertussis after a booster dose fever (14.5% in the deltoid group vs. 7.1% in the thigh was 94.4%. In addition, a trial in Latin America finds at group), which statistically more significant to be found least 99.1% had the seroprotective level of antibodies in the deltoid group (P = 0.02, Fig. 2). All of the other against diphtheria, tetanus and hepatitis B [10, 19]. symptoms (irritability and others) were found to be Currently, there is no international standard definition slightly less common in the thigh group than in the del- determined for the seroprotection for B. pertussis. A study toid group, but not statistically significant. in France used the ratio 1: 80 as cut-off, but in it was stated that the cut-off might had been too high as a cut- Local and systemic reaction intensity off [20]. We used the 1/40 as cut-off, only 40.4% of our Most of the adverse events that were reported were mild subjects had the seroprotection before the booster doses. and resolved spontaneously within the 72 h follow-up However, this proportion had increased greatly to 95.5% period. There was one report of acute diarrhea as a serious after one dose of booster. The 1/40 cut-off was also used AE from Group B, which was classified as unrelated. The in the pertussis outbreak in a university in Japan [21]. In subject was recovered after several days of hospitalization. this study, the protective titer was found in 92.7% subjects There was no other vaccine-related serious AE reported. for the long-term protection of using the 1/80 cut-off. Gunardi et al. BMC Pediatrics (2018) 18:177 Page 7 of 8 The persistent protective antibody after three primary The reason for this limitation was due to unpredictable doses in children aged 18–24 months was 90.2% for hepa- heavy flood in the study area, which caused so many titis B, and 97.7% for Hib. After primary immunization, subjects moved to other areas. Regardless the limitation, anti-HBs concentrations wane quite rapidly within the this was the first study of immunogenicity and safety of first year and more slowly thereafter. Even with the wan- DTwP-HB-Hib booster in Indonesian children. ing immunity, the immune memory to hepatitis B con- tinues to persist over a longer period. Protective antibody Conclusions had risen to 99.5 and 100%; and following the booster The new combination of DTwP-HB-Hib vaccines (Pen- dose, seroconversion occurred in 94.9 and 100% subjects tabio) as a booster at age 18–24 months is necessary to to hepatitis B and Hib, respectively, indicating effective achieve and maintain optimal protective antibody. The priming and induction of the immune memory [22]. vaccine is safe and immunogenic to be used for booster The long-term protection of tetanus from our earlier vaccination. study was 72.2% 1 month after primary DTP-HB-Hib Abbreviations vaccination [11], then decreased to 72.2% at 18–24 months DTwP: Diphtheria tetanus whole-cell pertussis; GMT: Geometric mean titer; of age. After the booster, the long-term protection had in- HB: Hepatitis B; HBsAg: Hepatitis B surface antigen; Hib: Haemophilus influenza type b; PRP: Polyribosil-ribitol-phosphate creased to 95.5% with the GMT level of 3.85 IU/mL, which will provide 3–5 years of protection [23]. Acknowledgments DTwP-HB-Hib vaccine was found to be highly im- PT Bio Farma was the funding stakeholder of this study. The authors would like to thank all of the children and parents who participated in this study, munogenic in our booster vaccination study. One month head of Bandung District Health Office, Jakarta Province Health Office, head following the booster vaccination of this vaccine, our and staff of Garuda, Ibrahim Adjie, Puter Primary Health Center in Bandung; study finds at least 95.5% of the study subjects reached head and staff of Jatinegara, Mampang, and Tebet Primary Health Center in Jakarta for their supports. We would also like to express our appreciation for protective levels of antibodies (seroprotected) against the the tremendous support of Indonesian National AEFI Committee as auditor of antigens employed in the vaccine. Another report of SAEs in this study. We also thank Mr. Hadyana Sukandar for his statistical work DTwP-HB-Hib (Quinvaxem®) immunogenicity showed in this study, and Dr. Natharina Yolanda for her invaluable editorial assistance. 99.4% seroprotection at 1-month after booster dose [24]. Funding Other previous studies of similar pentavalent vaccine in This study was funded by PT Bio Farma, number 06815/DIR/XII/2013 Latin America and Costa Rica showed that it could in- (Bandung site) and 06818/DIR/XII/2013 (Jakarta site). duce both persisting immunity and boostable memory, Availability of data and materials therefore provided an efficient and reliable way of imple- The datasets analyzed during the current study available from the menting this vaccine to the routine program [25, 26]. corresponding author on reasonable request. In this study, no serious adverse events were consid- Authors’ contributions ered related to vaccine or procedure. This study has KR was a national principal investigator and principal investigator in Bandung demonstrated that the occurrence of local AEs such as city. HG was the principal investigator in Jakarta city. KR, HG, EF, RMS, and NSB conceived the study and its design. HG, KR, EF, and S wrote and review the redness, swelling and induration within 30 min – 72 h, manuscript. MD and RT reviewed the design, recruited the subjects and and fever as systemic AE in 72 h – 28 days were signifi- conducted the study in Bandung city. S, RS, BEM and HIS reviewed the design, cantly less common in the thigh group than in the del- recruited the subjects and conducted the study in Jakarta city. SRH was the medical advisor of Jakarta site and reviewed the study and manuscript. CBK was toid group. This findings are similar to a previous study the medical advisor of Bandung site and reviewed the study and manuscript. conducted in Vaccine Safety Datalink population that in- All authors read and approved the final manuscript. cluded 1.4 million of children in the USA, which finds Ethics approval and consent to participate injection in thigh was associated with significantly lower This trial has been approved by Health Research Ethics Committee Faculty of risk of local reaction to DTaP vaccination among chil- Medicine Universitas Padjajaran Bandung (418/UN6.C2.1.2/KEPK/PPN/2013) dren 1–2 years of age. This finding supports the current and The Ethics Committee of the Faculty of Medicine, University of Indonesia (735/H2.F1/ETIK/2013). recommendation for thigh as intramuscular site injec- A written form of informed consent was obtained from every child’s parent tion in this age group [27]. or legal guardian before the recruitment. The three doses of primary immunization and a booster dose of DTwP-HB-Hib were all immunogenic Competing interests Hartono Gunardi, Kusnandi Rusmil, Eddy Fadlyana, Soedjatmiko, Meita and well-tolerated by the study subjects. DTwP-HB-Hib Dhamayanti, Rini Sekartini, Rodman Tarigan, Hindra Irawan Satari, Bernie vaccine is a suitable for immunization program in devel- Endyarni Medise, Cissy B Kartasasmita, Sri Rezeki S Hadinegoro, received oping countries. [9, 11, 19, 25, 26]. grant support through their institutions. Rini Mulia Sari and Novilia Sjafri Bachtiar were employees of PT Bio Farma at the time of the conduct of this study and manuscript preparation. Limitation of study There were only 399 (69.4%) out of 575 subjects were Publisher’sNote recruited. A total of 396 subjects who completed the Springer Nature remains neutral with regard to jurisdictional claims in DTwP-HB-Hib primary immunization were analyzed. published maps and institutional affiliations. Gunardi et al. BMC Pediatrics (2018) 18:177 Page 8 of 8 Author details 21. Kamano H, Mori T, Maeta H, Taminato T, Ishida T, Kishimoto N, et al. Department of Child Health, Faculty of Medicine, Universitas Indonesia/Dr. Analysis of Bordetella pertussis agglutinin titers during an outbreak of Cipto Mangunkusumo Hospital, Jl. Diponegoro No 71, Jakarta 10430, pertussis at a university in Japan. Jpn J Infect Dis. 2010;63:108–12. Indonesia. Department of Child Health, Faculty of Medicine, Padjadjaran 22. Marshall H, McIntyre P, Roberton D, Dinan L, Hardt K. Primary and booster University/Dr. Hasan Sadikin Hospital, Jl. Pasteur No 38, Bandung 40161, immunization with a diphtheria, tetanus, acellular pertussis, hepatitis B Indonesia. PT Bio Farma, Jl. Pasteur No 28, Bandung, Jawa Barat, Indonesia. (DTPa-HBV) and Haemophilus influenzae type b (Hib) vaccine administered separately or together is safe and immunogenic. Int J Infect Dis. 2010;14:e41–9. Received: 11 July 2017 Accepted: 3 May 2018 23. World Health Organization (WHO). Tetanus vaccines: WHO position paper. February 2017. Wkly Epidemiol Rec. 2017;92:53–76. 24. Schmid DA, Macura-Biegun A, Rauscher M. Development and introduction of a ready-to-use pediatric pentavalent vaccine to meet and sustain the needs of developing countries–Quinvaxem(R): the first 5 years. Vaccine. References 2012;30:6241–8. 1. CDC. Haemophilus influenzae type B. In: Hamborsky J, Kroger A, Wolfe S, 25. Tregnaghi M, Lopez P, Rocha C, Rivera L, David MP, Ruttimann R, et al. A editors. Epidemiology and prevention of vaccine-preventable diseases. 13th new DTPw-HB/Hib combination vaccine for primary and booster vaccination ed. Washington D.C.: Public Health Foundation; 2015. p. 119–34. of infants in Latin America. Rev Panam Salud Publica. 2006;19:179–88. 2. Pertussis CDC. In: Hamborsky J, Kroger A, Wolfe S, editors. Epidemiology and 26. Faingezicht I, Avila-Aguerro ML, Cervantes Y, Fourneau M, Clemens SA. prevention of vaccine-preventable diseases. 13th ed. Washington D.C.: Primary and booster vaccination with DTPw/HB/Hib pentavalent vaccine in Public Health Foundation; 2015. p. 261–78. Costa Rican children who had received a birth dose of hepatitis B vaccine. 3. CDC. Hepatitis B. In: Hamborsky J, Kroger A, Wolfe S, editors. Epidemiology Rev Panam Salud Publica. 2002;12:247–57. and prevention of vaccine-preventable diseases. 13th ed. Washington D.C.: 27. Jackson LA, Peterson D, Nelson JC, Marcy SM, Naleway AL, Nordin JD, et al. Public Health Foundation; 2015. p. 149–74. Vaccination site and risk of local adverse events in children 1 through 6 years 4. CDC. Diphtheria. In: Hamborsky J, Kroger A, Wolfe S, editors. Epidemiology of age. Pediatrics. 2013;131:283–9. and prevention of vaccine-preventable diseases. 13th ed. Washington D.C.: Public Health Foundation; 2015. p. 107–18. 5. Rusmil K, Fadlyana E, Bachtiar NS. Safety and immunogenicity of the DTP/ HB/Hib combination vaccine: phase I study. Paed Indones. 2013;53:309–14. 6. Decker MD. Principles of pediatric combination vaccines and practical issues related to use in clinical practice. Pediatr Infect Dis J. 2001;20(11 Suppl):S10–8. 7. Marshall GS, Happe LE, Lunacsek OE, Szymanski MD, Woods CR, Zahn M, et al. Use of combination vaccines is associated with improved coverage rates. Pediatr Infect Dis J. 2007;26:496–500. 8. Gandhi DJ, Dhaded SM, Ravi MD, Dubey AP, Kundu R, Lalwani SK, et al. Safety, immune lot-to-lot consistency and non-inferiority of a fully liquid pentavalent DTwp-HepB-Hib vaccine in healthy Indian toddlers and infants. Hum Vaccin Imunother. 2016;12:946–54. 9. Sharma H, Yadav S, Lalwani S, Gupta V, Kapre S, Jadhav S, et al. A phase III randomized, controlled study to assess the immunogenicity and tolerability of DTPw-HBV-Hib, a liquid pentavalent vaccine in Indian infants. Vaccine. 2011;29:2359–64. 10. 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Module 2 diphtheria. Geneva: WHO; 2009. p. 4–19. 15. Borrow R, Balmer P, Roper MH. The immunological basis for immunization series. Module 3, tetanus. Geneva: WHO; 2006. p. 2–24. 16. WHO. The immunological basis for immunization series. Module 22 hepatitis B. Geneva: WHO; 2011. p. 2–15. 17. WHO. The immunological basis for immunization series. Module 4: pertussis update; 2009. p. 26–36. 18. WHO. Recommendations for the production and control of Haemophilus influenza type b conjugate vaccine. Technical Report Series 897 Annex 1. Geneva 2000;57–59. 19. Suarez E, Asturias EJ, Hilbert AK, Herzog C, Aeberhard U, Spyr C. A fully liquid DTPw-HepB-Hib combination vaccine for booster vaccination of toddlers in El Salvador. Rev Panam Salud Publica 2010;27:117–124. 20. Relyveld E, Oato NH, Guerin N, Coursaget P, Huet M, Gupta RK. 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BMC PediatricsSpringer Journals

Published: May 28, 2018

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