Immunogenicity of a new purified fusion protein vaccine to respiratory syncytial virus: a multi-center trial in children with cystic fibrosis☆
Introduction
Acute lower respiratory tract disease is the leading contributor to morbidity and mortality in young children throughout the world [1]. Respiratory syncytial virus (RSV) is the most important viral cause of serious lower respiratory tract disease in infants and children worldwide [2], [3], [4]. It is also a significant cause of lower respiratory tract disease in the elderly and those with pre-existing chronic cardiac or lung disease such as cystic fibrosis (CF) [5], [6], [7], [8], [9]. Currently, a vaccine to prevent or attenuate RSV-related illness is not available. Numerous candidate vaccines have been tested over the past 30 years but none have been licensed to date [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]. First and second generations of the purified fusion protein (PFP-1; PFP-2) vaccine, a subunit RSV vaccine, have been tested in RSV seropositive children and they have been shown to be safe and reasonably immunogenic [11], [12], [13], [14], [15], [16]. It is unlikely that in the near future subunit vaccines will be tested in RSV seronegative children in the US. This is because of the enhanced respiratory disease with natural RSV infection that occurred in young children who received the crude formalin-inactivated RSV vaccine in the 1960s [10]. Vaccine enhanced respiratory disease has not been associated with the PFP vaccines [11], [12], [13], [14], [15], [16]. A subunit vaccine like PFP could be a candidate vaccine for use in children with pre-existing chronic diseases in a way similar to the recommendations for the licensed inactivated influenza vaccine.
CF is a major lethal inherited disease. CF children are at risk for severe RSV disease during the acute phase of the RSV illness and may suffer long-term damage to the airways and accelerated deterioration in lung function [9], [27], [28]. PFP-2 vaccine has been tested in CF children with encouraging results [13]. The vaccine appeared to protect against RSV lower respiratory tract illness (LRTI) and resulted in decreased number of LRTIs, antibiotic courses, and ill days. A vaccine effective in preventing or reducing the severity of illness due to RSV would be of benefit to CF patients and to other high-risk groups with pre-existing lung or heart disease.
A third generation of the PFP vaccine (PFP-3) has been developed, which is antigenically equivalent to the PFP-2 vaccine. Unlike the PFP-2 vaccine, the fusion (F) protein of the PFP-3 vaccine can be purified in sufficiently high quantities for large-scale vaccine production. In a pilot study in healthy young adults, the PFP-3 vaccine was demonstrated to be safe and immunogenic (Wyeth-Lederle Clinical Investigators Brochure). Recently we completed a phase II, multi-center trial in CF children to determine the safety, immunogenicity, and effectiveness of the PFP-3 vaccine. This report presents the robustness of the RSV-specific, serum antibody responses induced by the PFP-3 vaccine in RSV seropositive CF children.
Section snippets
Study design
This was a prospective, multi-center, randomized, double blind, age-stratified, adjuvant-controlled trial of the safety, immunogenicity, and effectiveness of the PFP-3 vaccine against LRTI in CF children. All 18 CF centers had approval by their institutional review boards for the conduct of this trial. The trial was initiated in September 1999 and ended on June 1, 2000. Based on our pilot PFP-2 vaccine study in CF children we estimated that 150 children per group were needed to address the
Enrollment and demographics
Eighteen cystic fibrosis (CF) centers in the US participated in this trial. From September 2 to December 3, 1999 422 children 1–12 years of age were screened; 297 of them passed eligibility criteria. Of the children who passed eligibility criteria, 145 were randomized to the PFP-3 vaccine group and 152 were randomized to the adjuvant-control group. After randomization all children were vaccinated according to assignment except for two children in the PFP-3 vaccine group and one child in the
Discussion
The latest version of the purified fusion protein vaccine, PFP-3, was immunogenic in RSV seropositive children with CF. The PFP-3 vaccine-induced at least a four-fold increase in Nt Abs to RSV/A and RSV/B, and a 16-fold increase in ELISA-F Bd Ab. The Nt Ab GMTs achieved at 28 days post-vaccination in the PFP-3 vaccine group (Table 5) were in the range associated with protection against RSV replication in the lungs of cotton rats and in prevention of RSV-associated hospitalization in pre-term
Acknowledgements
We dedicate this study to Richard Ginsberg, a friend who is no longer with us. He worked tirelessly in making this trial come to fruition. We are thankful to the children and their parents for their active participation in this trial, to Denise Treece and Tammy Abuan who were instrumental in the coordination of the trial, and to site coordinators who without their participation the trial could not have been conducted. Site Coordinators: C. Hallmark, RN, R. Schwalm, RN, and R. McConnell, RN,
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Cited by (0)
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Presented in part at Fourteenth Annual North American Cystic Fibrosis Conference, November 11, 2000, Baltimore, Maryland, Support: Collaborative Research Agreement between the Cystic Fibrosis Foundation and Wyeth-Lederle Vaccines; Cystic Fibrosis Foundation grant number: Piedra-99AO.
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Members of the Purified Fusion Protein Vaccine Study Group: S. McColley, MD, Children’s Memorial Hospital, Chicago, IL; M. Bowman, PhD, MD, Children’s Hospital at Los Angeles, Los Angeles, CA; D. Borowitz, MD, Children’s Hospital at Buffalo, Buffalo, NY; R. Castile, MD, and K. McCoy, MD, Children’s Hospital, Columbus, OH; C. Prestige, MD, and M.E. Brown, MD, Children’s Medical Center at Dallas, Dallas, TX; J. Stevens, MD, Riley Hospital for Children, Indianapolis, IN; W. Regelmann, MD, and C. Milla, MD, University of Minnesota, Minneapolis, MN; P. Sammut, MD, and J. Colombo, MD, University of Nebraska Medical Center, Omaha, NE; J. Eisenberg, MD, Oregon Health Sciences University, Portland, OR; T.D. Murphy, MD, J. Finder, MD, G. Kurland, MD, G. Winnie, MD, and D. Orenstein, MD, Children’s Hospital of Pittsburgh, Pittsburgh, PA; K. Voter, MD, Children’s Hospital at Strong, Rochester, NY; M. Light, MD, and M.S. Pian, MD, University of California, San Diego, CA; C. Harris, MD, and D. Stokes, MD, Vanderbilt University Medical Center, Nashville, TN; R. Fink, MD, Children’s Research Institute, Washington, DC; C. Ren, MD, and J. Gorvoy, MD, SUNY at Stony Brook, Stony Brook, NY; L. Varlotta, MD, St. Christopher’s Hospital for Children, Philadelphia, PA; M. Dyson, MD, Cook Children’s Medical Center, Fort Worth, TX. The PFP-3 vaccine was produced in Pearl River, New York by the Viral Vaccine Development Department of Wyeth-Lederle Vaccines.