Diphtheria immunogenicity following the administration of pentavalent DTwP-HB-Hib vaccine at 4- and 8-week intervals: A randomized controlled trial

Abstract

Objective: To evaluate the effectiveness of DTwP-HB-Hib vaccination dosing intervals at eight weeks versus four weeks on the immunogenicity of the diphtheria component.

Methods: This is a randomized, open-label, parallel, controlled trial on healthy two-month-old infants who had not received DTwP-HB- Hib vaccinations. The infants received three doses of the vaccine either at an eight-week or four-week interval. The anti-diphtheria toxoid IgG antibody levels before and after three doses of the vaccination were measured using ELISA.

Results: Eighty infants were enrolled in this study, with 64 fulfilling the study requirements and randomized into two groups. All study participants exhibited uncertain protection against diphtheria antibodies (0.01-0.99 IU/mL) at the beginning of the study with an average of (0.023±0.009) IU/mL and (0.026±0.009) IU/mL in eight weeks and four weeks groups. Following three doses of the vaccination, the antibody level rose to an average of (1.320±0.234) IU/mL in the eight-week group and (1.307±0.186) IU/mL in the four-week group, with no statistically significant difference in the antibody levels observed (P=0.814).

Conclusions: DTwP-HB-Hib vaccinations can be administered at an eight-week or four-week interval, as they do not significantly affect the level of anti-diphtheria IgG antibodies.

Keywords

Anti-diphtheria toxoid IgG antibody / DTwP-HB-Hib vaccine / Dosing interval / Immunogenicity

References

[1] Ade-adekunle OA, Adekunle FO, Idris ZO, Babalola DG. Enhancing diphtheria vaccination efficacy in Nigeria: Integrating community pharmacists for improved accessibility, distribution, and awareness. Clin Epidemiol Glob Health 2024; 27: 101609.

[2] Ikejezie J, Adebusoye B, Ekezie W, Langley T, Lewis S, Phalkey R. Modifiable risk factors for diphtheria: A systematic review and meta-analysis. Glob Epidemiol 2023; 5: 100100.

[3] World Health Organization. Regional Office for South-East Asia. Indonesia factsheet 2020: Expanded programme on Immunization (EPI). 2020. [Online]. Available from: https://iris.who.int/handle/10665/336758 [Accessed on 8 April 2025].

[4] Kementerian Kesehatan RI. Profil kesehatan Indonesia 2023. [Online]. Available from: https://kemkes.go.id/app_asset/file_content_download/172231123666a86244b83fd8.51637104.pdf. [Accessed on 27 April 2025].

[5] Shuja MH, Shakil F, Imran H, Feroz M. Diphtheria: A novel cause of concern for Pakistan. J Glob Health 2023; 13: 3038.

[6] Nettelfield S, Yu D, Cañete PF. Systemic immunometabolism and responses to vaccines: Insights from T and B cell perspectives. Int Immunol 2023; 35(12): 571-582.

[7] Clemente-Suárez VJ, Redondo-Flórez L, Bustamante-Sánchez A, Martín-Rodríguez A, Yáñez-Sepúlveda R, Tornero-Aguilera JF. Biometric strategies to improve vaccine immunogenicity and effectiveness. Biomimetics (Basel, Switzerland) 2025; 10(7): 439.

[8] Indonesian Pediatric Society. Jadwal imunisasi anak usia 0-18 tahun, rekomendasi ikatan dokter anak Indonesia tahun 2024. [Online]. Available from: https://www.idai.or.id/professional-resources/rekomendasi/jadwal-imunisasi-anak-usia-0-18-tahun. [Accessed on 30 April 2025].

[9] Centers for Disease Control and Prevention. Administering diphtheria, tetanus, and pertussis vaccines. 2022. [Online]. Available from: https://www.cdc.gov/vaccines/vpd/dtap-tdap-td/hcp/administering-vaccine.html. [Accessed on 15 March 2025].

[10] World Health Organization. Immunization, vaccines and biologicals: Pertussis. 2025. [Online]. Available from: https://www.who.int/teams/immunization-vaccines-and-biologicals/diseases/pertussis. [Accessed on 15 March 2025].

[11] Fadlyana E, Tanuwidjaja S, Rusmil K, Dhamayanti M, Soemara LH, Dharmayanti R. Imunogenitas dan keamanan vaksin DPT setelah imunisasi dasar. Sari Pediatr 2016; 4(3): 129.

[12] Liang JL, Tiwari T, Moro P, Messonnier NE, Reingold A, Sawyer M, et al. Prevention of pertussis, tetanus, and diphtheria with vaccines in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2018; 67(2): 1-44.

[13] Pasteur S. DAPTACEL (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed) [Package Insert]. Sanofi Pasteur, Ltd 2017. [Online]. Available from: https://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm101572.htm. [Accessed on 16 August 2025].

[14] 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: 219.

[15] Conway S, James J, Balfour A, Smithells R. Immunisation of the preterm baby. J Infect 1993; 27(2): 143-150.

[16] Wilkins J, Chan LS, Wehrle PF. Age and dose interval as factors in agglutinin formation to pertussis vaccine. Vaccine 1987; 5(1): 49-54.

[17] Booy R, Aitken SJ, Taylor S, Tudor-Williams G, Macfarlane JA, Moxon ER, et al. Immunogenicity of combined diphtheria, tetanus, and pertussis vaccine given at 2, 3, and 4 months versus 3, 5, and 9 months of age. Lancet (London, England) 1992; 339(8792): 507-510.

[18] Creech CB, Leguia M, Goll JB, Howard LM, Vila-Sanjurjo A, Yoder S, et al. Immunologic profiling of the infant immune response to whole-cell and acellular pertussis vaccines. NPJ Vaccines 2025; 10(1): 189.

[19] Jong DM, Suranto A, Gunardi H, Tumbelaka AR. Kejadian ikutan pasca imunisasi vaksin kombinasi DPwT (sel utuh) dan hepatitis B. Sari Pediatr 2016; 3(2): 72.

[20] Aristegui J, Garrote E, González A, Arrate JP, Perez A, Vandepapelière P. Immune response to a combined hepatitis B, diphtheria, tetanus and whole-cell pertussis vaccine administered to infants at 2, 4 and 6 months of age. Vaccine 1997; 15(1): 7-9.

[21] Usonis V, Bakasenas V, Taylor D, Vandepapeliere P. Immunogenicity and reactogenicity of a combined DTPw-hepatitis B vaccine in Lithuanian infants. Eur J Pediatr 1996; 155(3): 189-193.

[22] Gustafsson L, Hallander HO, Olin P, Reizenstein E, Storsaeter J. A controlled trial of a two-component acellular, a five-component acellular, and a whole-cell pertussis vaccine. N Engl J Med 1996; 334(6): 349-355.

[23] Greco D, Salmaso S, Mastrantonio P, Giuliano M, Tozzi AE, Anemona A, et al. A controlled trial of two acellular vaccines and one whole-cell vaccine against pertussis. Progetto Pertosse Working Group. N Engl J Med 1996; 334(6): 341-348.

[24] Barkin RM, Samuelson JS, Gotlin LP, Barkin SZ. Primary immunization with diphtheria-tetanus toxoids vaccine and diphtheria-tetanus toxoids-pertussis vaccine adsorbed: Comparison of schedules. Pediatr Infect Dis 1985; 4(2): 168-171.

[25] Cody CL, Baraff LJ, Cherry JD, Marcy SM, Manclark CR. Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children. Pediatrics 1981; 68(5): 650-660.