Safety and Preliminary Immunogenicity of Recombinant Hepatitis B (Bio Farma) Vaccine in Adults and Children: A Phase 1 Clinical Trial

Eddy Fadlyana, Rodman Tarigan, Kusnandi Rusmil, Rini Mulia Sari, Cissy B Kartasmita, Behesti Zahra Mardiah, Muhammad Gilang Dwi Putra


Background: In order to fulfil the requirements of the national immunization program and sustain the production capacity of the monovalent Hepatitis B vaccine, this study aimed to assess the safety and immunogenicity of the recombinant Hepatitis B Vaccine (Bio Farma) using the new Hepatitis B bulk.

Methods: This study was an experimental, randomized, double-blinded, and controlled Phase I clinical trial, with 100 healthy subjects divided into 50 adults and 50 adolescents. Subjects were randomly assigned to receive either the Bio Farma registered Recombinant Hepatitis B Vaccine (group A) or a new source of Hepatitis B bulk (group B). Subjects received one or three doses of vaccine, depending on the baseline anti-Hbs titer. Subjects were given diary cards to record solicited and unsolicited adverse events for 28 days following vaccination. Vaccine immunogenicity was assessed by measuring the level of HBsAg antibody titer elevation.

Results: No serious adverse events were reported during clinical trials. The frequencies of adverse events were not significantly different between the two vaccine-randomized groups. The most immediately observed local reaction was local pain, reported by 35.7–42.8% of adults and 24.0–26.3% of adolescents, without any systemic reactions. Seroconversion in adults in group B reached 100% and 78.5% in group A, meanwhile in adolescent subjects in both groups it reached 100%. A substantial increase in geometric mean titer (GMT) was observed in the majority of subjects after immunization.

Conclusion: Recombinant Hepatitis B Vaccine with a new source of HBsAg B bulk is safe, well tolerated, and highly immunogenic.


adults; adolescents; immunogenicity; safety; recombinant hepatitis B vaccine

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  1. Trépo C, Chan HLY, Lok A. Hepatitis B virus infection. Lancet. 2014;384:9959
  2. Das S, Ramakrishnan K, Behera SK, Ganesapandian M, Xavier AS, Selvarajan S. Hepatitis B vaccine and immunoglobulin: key concepts. J Clin Transl Hepatol. 2019;7(2):165–71.
  3. World Health Organization. Global health sector strategy on viral hepatitis 2016–2021: towards ending viral hepatitis. Geneva: WHO; 2016.
  4. World Health Organization. Hepatitis B vaccines: WHO position paper, July 2017–Recommendations. Vaccine. 2019;37(2):223–5.
  5. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560–99.
  6. Koc ÖM, Damoiseaux J, van Loo IHM, Masquillier HIL, Oude Lashof AML. Case report of delayed seroprotection rather than non-response after primary three-dose hepatitis B vaccination. Vaccine. 2020;38(2):112–4.
  7. Nency YM, Rahmadi FA, Anantyo DT, Farhanah N, Hapsari R, Farida H, Sadhana U, Djagat H, Kristina TN, Juniarto AZ, Puspita M. Protectivity and safety following recombinant hepatitis B vaccine with different source of bulk compared to hepatitis B (Bio Farma) vaccine in Indonesia. Clinical and Experimental Vaccine Research. 2022;11(1):43.
  8. Fadlyana E, Rusmil K, Bachtiar NS. Kekebalan dan keamanan setelah mendapat imunisasi hepatitis B rekombinan pada anak remaja. Sari Pediatri. 2016;15(2):87–92.
  9. World Health Organization. guidelines on clinical evaluation of vaccines: regulatory expectations, Annex 1, TRS No 924. Geneva: WHO; 2004.
  10. Van Der Meeren O, Crasta P, Cheuvart B, De Ridder M. Characterization of an age-response relationship to GSK’s recombinant hepatitis B vaccine in healthy adults: An integrated analysis. Hum Vaccin Immunother. 2015;11(7):1725–8.
  11. Pattyn J, Hendrickx G, Vorsters A, Van Damme P. Hepatitis B vaccines. J Infect Dis. 2021;224(12 Suppl2):S343–51.
  12. Chaiklang K, Wipasa J, Chaiwarith R, Praparattanapan J, Supparatpinyo K. Comparison of immunogenicity and safety of four doses and four double doses vs. Standard doses of hepatitis b vaccination in hiv-infected adults: a randomized, controlled trial. PLoS One. 2013;8(11):e80409.
  13. Kalaivani M, Rastogi S, Kalaiselvan V, Singh GN. Adverse reactions after hepatitis B vaccination: a retrospective analysis using spontaneous reports. J Young Pharm. 2017;9(1):55–9.
  14. Sundoro J, Rusmil K, Sitaresmi MN, Arhana, Djelantik IGG, Hadinegoro SR, et al. Profil Keamanan setelah pemberian dosis primer vaksin Pentabio® pada bayi di Indonesia. Majalah Kedokteran Bandung. 2017;49(2):86–93.
  15. Rusmil K, Gunardi H, Fadlyana E, Soedjatmiko, Dhamayanti M, Sekartini R, et al. The immunogenicity, safety, and consistency of an Indonesia combined DTP-HB-Hib vaccine in expanded program on immunization schedule. BMC Pediatr. 2015;15(1):219.
  16. Rusmil K, Fadlyana E, Bachtiar NS. Booster vaksinasi Hepatitis B terhadap anak yang non responder. Sari Pediatri. 2010;12(2):88–91.
  17. Wilkins T, Sams R, Carpenter M. Hepatitis B: screening, prevention, diagnosis, and treatment. Am Fam Physician. 2019;99(5):314–23.
  18. Huang Y, Yang Y, Wu T, Li Z, Xu H, Huang A, et al. Complementary presence of HBV humoral and T-cell response provides protective immunity after neonatal immunization. J Clin Transl Hepatol. 2022;10(4):660–8.
  19. Van den Ende C, Marano C, van Ahee A, Bunge EM, de Moerlooze L. The immunogenicity and safety of GSK’s recombinant hepatitis B vaccine in adults: a systematic review of 30 years of experience. Expert Rev Vaccines. 2017;16(8):811–32.
  20. Zimmermann P, Curtis N. Factors that influence the immune response to vaccination. Clin Microbiol Rev. 2019;32(2):e00084.
  21. Yang S, Tian G, Cui Y, Ding C, Deng M, Yu C, et al. Factors influencing immunologic response to hepatitis B vaccine in adults. Sci Rep. 2016;6:27251.
  22. Koc ÖM, van Oorschot E, Brandts L, Oude Lashof A. Timing of primary three‐dose hepatitis B vaccination and post vaccination serologic testing among a large cohort of healthy adults. J Med Virol. 2022;94(9):4433–9.


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