Immunogenicity and safety of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) co-administered with DTPa vaccine in Japanese children: A randomized, controlled study

Abstract

This phase III, randomized, open-label, multicenter study (NCT01027845) conducted in Japan assessed the immunogenicity, safety, and reactogenicity of 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, given intramuscularly) co-administered with diphtheria-tetanus-acellular pertussis vaccine (DTPa, given subcutaneously). Infants (N=360 ) were randomized (2:1) to receive either PHiD-CV and DTPa (PHiD-CV group) or DTPa alone (control group) as 3-dose primary vaccination (3–4–5 months of age) and booster vaccination (17–19 months of age). Immune responses were measured before and one month after primary/booster vaccination and adverse events (AEs) were recorded. Post-primary immune responses were non-inferior to those in pivotal/efficacy European or Latin American pneumococcal protein D-conjugate vaccine studies. For each PHiD-CV serotype, at least 92.6% of infants post-primary vaccination and at least 97.7% of children post-booster had pneumococcal antibody concentrations ≥0.2 μg/ml, and at least 95.4% post-primary and at least 98.1% post-booster had opsonophagocytic activity (OPA) titers ≥8 . Geometric mean antibody concentrations and OPA titers (except OPA titer for 6B) were higher post-booster than post-priming for each serotype. All PHiD-CV-vaccinated children had anti-protein D antibody concentrations ≥100 EL.U/ml one month post-primary/booster vaccination and all were seroprotected/seropositive against each DTPa antigen. Redness and irritability were the most common solicited AEs in both groups. Incidences of unsolicited AEs were comparable between groups. Serious AEs were reported for 47 children (28 in PHiD-CV group); none were assessed as vaccine-related. In conclusion, PHiD-CV induced robust immune responses and was well tolerated when co-administered with DTPa in a 3-dose priming plus booster regimen to Japanese children.

Keywords:

• children
• co-administration
• immunogenicity
• Japan
• pneumococcal conjugate vaccine
• safety

Abbreviations:

• AE, adverse event
• AOM, acute otitis media
• ATP, according-to-protocol
• CAP, community-acquired pneumonia
• CI, confidence interval
• COMPAS, Clinical Otitis Media and PneumoniA Study
• DTPa, diphtheria-tetanus-acellular pertussis
• ELISA, enzyme-linked immunosorbent assay
• GMC, geometric mean concentration
• GMT, geometric mean titer
• HBV, hepatitis B virus
• Hib, Haemophilus influenzae type b
• IPD, invasive pneumococcal disease
• NTHi, nontypeable Haemophilus influenzae
• OPA, opsonophagocytic activity
• PCV, pneumococcal conjugate vaccine
• PHiD-CV, 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine
• POET, Pneumococcal Otitis Efficacy Trial
• SAE, serious adverse event
• SAS, Statistical Analysis System
• SDD, SAS Drug and Development
• 7vCRM, 7-valent pneumococcal CRM-conjugate vaccine
• WHO, World Health Organization

Disclosure of Potential Conflicts of Interest

SI, NK, HK, YT, MM, AI, and TO received grants from the GlaxoSmithKline group of companies as principal investigators during the conduct of the study. SI, NK, HK, YT, MM, and TO received support for travel to meetings for the study from the GlaxoSmithKline group of companies. NK and SI were also granted personal fees, consulting fees, or honoraria for consulting and/or participation in advisory board meetings from the GlaxoSmithKline group of companies. Outside the submitted work, HK received payment for lectures, including service on speaker's bureaus from Pfizer and MSD, and payment for manuscript preparation from Pfizer. MM obtained grants related to a clinical study from Pfizer and SI received grants and payment from the GlaxoSmithKline group of companies, Pfizer and MSD for lectures including services on speaker's bureaus and/or payment for manuscript preparation. AS, DB, FS, JRG, NF, and TS are employees of GlaxoSmithKline group of companies. DB, JRG, and TS own restricted shares/stock options of the GlaxoSmithKline group of companies.

Acknowledgments

The authors would like to thank the children and their families for participating in this trial and, for contributing in many ways to this study, the investigators, study nurses, and other staff members at the study sites, in particular: Miho Ohshima, investigator at Sapporo Tokushukai Hospital; Osamu Komiyama, investigator at Tokyo Medical Center; Hiroshi Ichiseki, investigator at Shonan Atsugi Hospital; Go Yamamoto and Tokutaro Mukae, investigators at Shonan Kamakura General Hospital; Takashi Higashide, investigator at HugHug Kids Clinic; Katsuhiko Yoshii, investigator at Cibune Clinic; Shigeru Mori, investigator at Momotaro Clinic; Masanori Ikeda, investigator at Fukuyama Medical Center; Tomoyuki Miyamoto, investigator at Yokosuka General Hospital Uwamachi; Nobuko Yokoyama, investigator at Chuden Hospital; Mikihiro Aoki, investigator at Nagasaki Medical Center; and Tetsuo Taguchi, investigator at Niigata Prefectural Hospital.

The authors also thank, from GlaxoSmithKline Vaccines, Makoto Ono and Atsushi Maruyama, and Sophie Ledant for local and global study management; Ann Dhoest (freelance for GlaxoSmithKline Vaccines) and Kristel Vercauteren (XPE Pharma and Science for GlaxoSmithKline Vaccines) for protocol and study report writing; Thomas Déplanque (XPE Pharma & Science for GlaxoSmithKline Vaccines) for manuscript coordination and Joanne Knowles (independent medical writer, on behalf of GlaxoSmithKline Vaccines) for initial drafting of the manuscript and incorporation of comments received from the authors.

Funding

GlaxoSmithKline Biologicals SA was the funding source and was involved in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals SA also took responsibility for all costs associated with the development and publishing of the present manuscript.

Supplemental Materials

Supplemental data for this article can be accessed on the http://www.tandfonline.com/khvi publisher's website.

Authors’ Contributions

The study was designed by JRG, TS, AS, NF, and DB. Centers and/or investigators were recruited by SI, TS, and AS. AI, HK, YT, NK, MM, TO, and SI contributed to the collection and assembly of data. The analysis was performed or supervised by FS, NF, JRG, and DB, and interpretation of results by SI, DB, JRG, TS, FS, NF, and AS. FS and NF provided statistical expertise. Each author made a significant contribution to the study and to the development of this manuscript, approved this final submitted version, and agrees with submission.

Trademark Statement

Synflorix is a trademark of the GlaxoSmithKline group of companies. DPT Kaketsuken Syringe is a trademark of Kaketsuken. Prevenar/Prevnar are trademarks of Pfizer Inc.