Immunogenicity, Safety, and Reactogenicity of the 10-valent ... : The Pediatric Infectious Disease Journal (original) (raw)
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Immunogenicity, Safety, and Reactogenicity of the 10-valent Pneumococcal Nontypeable Haemophilus influenzae Protein D Conjugate Vaccine and DTPa-IPV-Hib When Coadministered as a 3-dose Primary Vaccination Schedule in the Netherlands
A Randomized Controlled Trial
van den Bergh, Menno R. MD*†; Spijkerman, Judith MD*†; François, Nancy MSc‡; Swinnen, Kristien PhD‡; Borys, Dorota MD‡; Schuerman, Lode MD‡; Veenhoven, Reinier H. MD, PhD†; Sanders, Elisabeth A. M. MD, PhD*
From the *Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, The Netherlands; †Research Center Linnaeus Institute, Spaarne Hospital, Hoofddorp, The Netherlands; and ‡Global Vaccine Development, GlaxoSmithKline Biologicals, Wavre, Belgium.
Accepted for publication March 11, 2011.
Supported by GlaxoSmithKline Biologicals, Rixensart, Belgium.
GlaxoSmithKline Biologicals was involved in all stages of the conduct of this study and the final analysis. The manuscript was written by M.R.B. and reviewed by the other authors. GlaxoSmithKline collaborated with the investigators in the reviewing process of the manuscript before being finalized for submission.
M.R.B. and J.S. have no conflicts of interest to declare. N.F., D.B., and L.S. declare that they are employed by GlaxoSmithKline Biologicals. K.S. works as a consultant for GlaxoSmithKline Biologicals. D.B. and L.S. have stock ownership. E.A.M.S. received unrestricted research support from Pfizer/Wyeth and Baxter, consulting fees from Pfizer/Wyeth and GlaxoSmithKline, lecturing fees from Pfizer/Wyeth and GlaxoSmithKline, and grant support for vaccine studies from Pfizer/Wyeth and GlaxoSmithKline; R.H.V. received research support from GlaxoSmithKline and Pfizer/Wyeth for vaccine studies and consulting fees from GlaxoSmithKline.
This trial is registered at www.ClinicalTrials.gov number NCT00652951.
Synflorix and Infanrix hexa are trademarks of the GlaxoSmithKline group of companies. Prevenar/Prevnar is a trademark of Pfizer, Inc. Pediacel is a trademark of Sanofi Pasteur MSD.
Address for correspondence: Menno R. van den Bergh, MD, Spaarne Hospital Hoofddorp, PO Box 770, 2130 AT Hoofddorp, The Netherlands. E-mail: [email protected].
Abstract
Background:
Recent reviews have highlighted the unpredictability of immunologic interference when multivalent conjugated vaccines are coadministered with other pediatric vaccines.
Objective:
To evaluate immunogenicity, safety, and reactogenicity of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV; Synflorix, GlaxoSmithKline Biologicals) and DTPa-IPV-Hib (Pediacel, Sanofi Pasteur MSD) when coadministered as a 3-dose primary vaccination course.
Material and Methods:
In a single-blind, single-center, randomized controlled trial in the Netherlands, healthy infants (n = 780) were randomly assigned (1:1:1) to receive either (1) PHiD-CV + DTPa-HBV-IPV/Hib (Infanrix Hexa, GlaxoSmithKline Biologicals), (2) PHiD-CV + DTPa-IPV-Hib, or (3) 7-valent pneumococcal conjugate vaccine (Prevenar/Prevnar, Pfizer Inc.) + DTPa-IPV-Hib at 2, 3, and 4 months of age. Blood samples were collected 1 month after dose 3. Diary cards were used to record safety and reactogenicity.
Results:
Antibody concentrations elicited by PHiD-CV coadministered with DTPa-IPV-Hib were noninferior to those following DTPa-HBV-IPV/Hib coadministration for 9 of 10 vaccines pneumococcal serotypes and protein D. For serotype 18C (conjugated to tetanus toxoid), the antibody concentration was higher with DTPa-HBV-IPV/Hib coadministration (1.73 vs. 1.07 μg/mL). The percentages of infants with antibody concentrations ≥0.2 μg/mL (68.9%–100% in the PHiD-CV + DTPa-HBV-IPV/Hib group vs. 64.9%–100% in the PHiD-CV + DTPa-IPV-Hib group) and with measurable opsonophagocytic activity (56.1%–100% in the PHiD-CV + DTPa-HBV-IPV/Hib group vs. 61.1%–100% in the PHiD-CV + DTPa-IPV-Hib group) were comparable for all serotypes in both PHiD-CV groups. Group differences in antibody responses to the DTPa-IPV-Hib antigens remained within the predefined limit for noninferiority. Safety and reactogenicity profiles were comparable across groups.
Conclusions:
PHiD-CV and DTPa-IPV-Hib were immunogenic and well tolerated when coadministered as a 3-dose primary vaccination course.
Erratum
In regard to the article appearing on page e170 of volume 30, issue 9, the study sponsor, GlaxoSmithKline Biologicals, has been recently investigating the quality of some serology assays used to determine the antibody titers reported in the publication.
The technical investigations of the following assays have now been completed and have led to the following findings:
A decrease in the specificity of this assay had been observed in some studies, and investigations have confirmed a poor assay performance for low levels of antibody titers (10–100 mIU/mL); in contrast, concentrations above 100 mIU/mL were confirmed valid.
The root cause was identified as the change of sourcing of a key assay reagent. The specificity of the in-house assay could not be restored, and therefore, testing was resumed using the commercial assay Centaur (ADVIA Centaur Immunoassay System, Siemens Healthcare Diagnostics), an Food and Drug Administration-approved and CE-marker chemiluminescence immunoassay with a cut-off defining seropositivity of 6.2 mIU/mL.
To generate corrected seroprotection rates, samples of this study that were originally tested in the range 10–100 mIU/mL have been retested using the commercial assay, within the limits of the serum volumes that remained available. Anti-hepatitis B surface (anti-HBs) seroprotection was redefined as in-house enzyme-linked immunosorbent assay concentration >100 mIU/mL or chemiluminescence immunoassay concentration >10 mIU/mL. Corrected seroprotection rates with 95% confidence intervals were calculated using multiple imputation method for subjects with in-house enzyme-linked immunosorbent assay titers between 10 and 100 mIU/mL.
The anti-HBs data resulting from this retesting differ from the published results, as shown in , and indicate that the study results with regard to the seroprotection rates for hepatitis B are impacted. The high seroprotection rates in children not receiving a hepatitis B vaccine was discussed as an unexpected finding in the original paper. This finding needs to be removed from the paper because seroprotection rates in these unvaccinated children are actually much lower and within the usual range.
A trend toward lower anti- poliovirus titers was observed when testing was performed by an external contractor when compared with GlaxoSmithKline Biologicals’ internal laboratory.
The lower sensitivity of the assay performed by the contractor was mainly because of a change in the dilution of the poliovirus used in the challenge phase of the neutralization assay.
A clinical assessment was made to evaluate whether the trend for measuring lower anti-poliovirus neutralizing titers at our external contractor has impacted the conclusions relating to predefined immunogenicity clinical study objectives. Based on this assessment, it was concluded that the poliovirus immunogenicity conclusions for all clinical studies tested at our external contractor were valid.
Furthermore, retesting of a panel of samples from different studies by an independent external reference laboratory confirmed the validity of the initial testing at our external contractor in terms of seroprotection rates.
As a result, GlaxoSmithKline Biologicals considers that the conservative estimates of anti-poliovirus titers tested at our external contractor have no impact on the results and conclusions of this study.
The Pediatric Infectious Disease Journal. 34(8):918, August 2015.
© 2011 Lippincott Williams & Wilkins, Inc.