Safety and Immunogenicity of a New Formulation of a Pentavalent DTwP-HepB Vaccine in Healthy Indian Infants–A Randomized Study

Abstract

Pentavalent vaccines (DTP-HepB-Hib) have been introduced in many countries in their routine public immunization programmes to protect against diphtheria (D), tetanus (T), pertussis (P), hepatitis B (Hep B) and Hemophilus influenzae type b (Hib) diseases. This study compared the safety and immunogenicity of a new formulation of a whole-cell Bordetella pertussis (wP) based pentavalent vaccine (DTwP-HepB-Hib). The new formulation was developed using well-characterized hepatitis B and pertussis whole cell vaccine components.

This was a phase III, observer-blind, randomized, non-inferiority, multi-center study conducted in India among 460 infants who were followed up for safety and immunogenicity for 28 days after administration of three doses of either investigational or licensed comparator formulations at 6–8, 10–12 and 14–16 weeks of age.

Introduction

Diphtheria, tetanus, pertussis (DTP) combination vaccines were first introduced in 1948 [1]. Since several decades, they have been the cornerstone of immunization programs to vaccinate infants and children. Subsequently other vaccines have been added to the combination to rapidly achieve better coverage against other childhood pathogens like hepatitis B (HepB) and Haemophilus influenzae type b (Hib). There are several advantages of combination vaccines including fewer injections, increased compliance and timeliness to vaccination, higher immunization coverage, less storage space, simplified acquisition and cold chain logistics and reduced administration costs.

Methods

This was a phase 3, randomized, observer-blind study conducted in 8 centers across India among 460 infants who were followed up for safety and immunogenicity for 28 days after administration of three doses of either investigational or licensed comparator DTwP-HepB-Hib formulations at 6–8, 10–12 and 14–16 weeks of age. The study was performed from December 2018 to July 2019. The study was approved by the Indian National Regulatory Authority (The Drugs Controller General of India [DCGI]) and appropriate independent ethics committees and institutional review boards prior to the start of the study. The study was registered in the Clinical Trials Registry—India (CTRI/2018/12/016692). The conduct of this study was consistent with the standards established by the Declaration of Helsinki and compliant with the ICH guidelines for good clinical practice as well as with all local and / or national regulations and directives. Written signed informed consent was obtained from the subject’s parent/ legally acceptable representative (LAR) before any study procedures were performed. The entire informed consent process was audio-visually recorded as per Indian regulations.

Results

A total of 460 subjects were enrolled between December 22, 2018, and April 08, 2019, and randomized into 2 groups, group 1 (Investigational DTwP-HepB-Hib vaccine formulation, primary series, n = 232) and group 2 (Comparator (licensed) DTwP-HepB-Hib vaccine formulation, primary series, n = 228). A total of 447 subjects completed the vaccination schedule (3-dose primary series) (225 and 222 subjects in groups 1 and 2 respectively), whereas 439 patients completed the study till D84 (221 and 218 subjects in groups 1 and 2 respectively). Protocol deviations including incomplete vaccination schedule, out of window visits, and randomization errors were reported among 45 subjects (19 and 26 subjects in groups 1 and 2 respectively); (Fig 1). The FAS included all 460 subjects while PPAS included 415 subjects. The baseline demographics of the study population is showed in Table 1.

Discussion

This phase 3 study conducted in India evaluated the safety and immunogenicity in 460 infants followed up for 28 days after administration of three doses of either investigational or existing vaccine formulations of the SHIPL DTwP-HepB-Hib pentavalent vaccine at 6–8 weeks, 10–12 weeks and 14–16 weeks of age when administered concomitantly with other age-recommended vaccines.

Conclusions
The study demonstrated that the investigational DTwP-HepB-Hib vaccine formulation was non-inferior to the licensed comparator DTwP-HepB-Hib vaccine formulation both in terms of HepB seroprotection rate and in terms of pertussis immune responses. The immune responses to all the antigens (D, T, P, HepB and Hib) in both the DTwP-HepB-Hib vaccine formulations were also similar.

Acknowledgments

The authors would like to thank the parents of all study subjects for consenting to participate in this research study; all the investigators and their site staff of the Departments of Paediatrics, Mysore Medical College, Mysore, KLES Dr Prabhakar Kore Hospital, Belagavi, Government Victoria Hospital, Visakhapatnam, Prakhar Hospital Pvt. Ltd., Kanpur, SBKS Medical College, Vadodara, Christian Medical College & Hospital, Ludhiana, Department of Pharmacology, SRM Medical College Hospital, Chennai, and Department of Community Medicine, Kalinga Institute of Medical Sciences, Bhubaneswar; the staff of Zifo Technologies, India (for data management) and Global Clinical Immunology, Sanofi, Swiftwater, USA (for laboratory analysis).

Citation: Aloysia D’Cor N, Siddaiah P, Mohapatra S, Dhaded SM, I. V. P, Kar S, et al. (2023) Safety and immunogenicity of a new formulation of a pentavalent DTwP-HepB-Hib vaccine in healthy Indian infants–A randomized study. PLoS ONE 18(8): e0284898. https://doi.org/10.1371/journal.pone.0284898

Editor: Ray Borrow, Public Health England, UNITED KINGDOM

Received: September 6, 2022; Accepted: April 11, 2023; Published: August 15, 2023

Copyright: © 2023 Aloysia D’Cor 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.

Data Availability: Qualified researchers may request access to patient-level data and related study documents, including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient-level data will be anonymized, and study documents will be redacted to protect the privacy of study participants. Further details on Sanofi’s data-sharing criteria, eligible studies, and process for requesting access can be found at: https://www.vivli.org/.

Funding: This study was funded by Sanofi. Sanofi was responsible for the study design, clinical data management, analysis, decision to publish, and preparation of the manuscript.

Competing interests: PM reports grants and non-financial support from Sanofi Pharma, during the conduct of the study; JC reports grants from Sanofi Pharma, during the conduct of the study; NADC, EV, BNP, AM, VJM, SP and FN are Sanofi employees and own stocks of the company. DMP and SRJ were employees of Sanofi at the time of study. PS, SM, SMD, SK, PIV have nothing to disclose

Abbreviations: Ab, antibody; AE, adverse event; AESI, AEs of special interest; aGMCs, adjusted geometric mean concentrations; CI, confidence interval; D, diphtheria; DCGI, Drugs Controller General of India; DTP-ECL, DTP immunoassay by multiplexed Electro Chemiluminescent method; FAS, full analyses set; FHA, filamentous hemagglutinin; FIM, fimbriae; GMCs, geometric mean concentrations; GMCR, geometric mean concentration ratio; HepB, hepatitis B; HHE, hypotonic hyporesponsive episode; Hib, Hemophilus influenza type B; IPV, inactivated poliovirus vaccine; LAR, legally acceptable representative; LLOQ, lower limit of quantification; MLE, Marcy l’Etoile; MSD-ECL, MesoScale Discovery ElectroChemiLuminescence immunoassay; OPV, oral poliovirus vaccine; ORV, oral rotavirus vaccine; PPAS, per-protocol analysis set; PRN, pertactin; PT, pertussis toxin; RIA, radioimmunoassay; rHBsAg, recombinant Hepatitis B surface Antigen; SAE, serious AE; SafAS, safety analyses set; T, tetanus; WHO, World Health Organization; WHO PQ, WHO Pre-Qualification; wP, whole-cell pertussis

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0284898#abstract0