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Safety and Immunogenicity of a Recombinant Multivalent Group A Streptococcal Vaccine in Healthy Adults
Phase 1 Trial
Karen L. Kotloff, MD;
Mary Corretti, MD;
Kathleen Palmer, RN;
James D. Campbell, MD;
Mark A. Reddish, MSc;
Mary C. Hu, PhD;
Steven S. Wasserman, PhD;
James B. Dale, MD
JAMA. 2004;292:709-715.
Context Group A streptococcal infections and their sequelae represent a global health problem. Recent advances have allowed previous obstacles associated with group A streptococcal vaccine development to be overcome.
Objective To preliminarily evaluate the safety and immunogenicity of ascending doses of a recombinant fusion peptide group A streptococcal vaccine containing N-terminal M protein fragments from serotypes 1, 3, 5, 6, 19, and 24 in healthy volunteers.
Design, Setting, and Participants An open-label, uncontrolled, dose-ascending phase 1 vaccine trial of 28 healthy adult volunteers aged 18 to 50 years recruited from the metropolitan area of Baltimore, Md, between October 5, 1999, and February 26, 2003, using newspaper advertisements and posted fliers, and evaluated in the outpatient facility of the Center for Vaccine Development.
Interventions Each volunteer received 3 spaced intramuscular injections of 50 µg (n = 8), 100 µg (n = 10), or 200 µg (n = 10) of hexavalent group A streptococcal vaccine formulated with aluminum hydroxide into the deltoid muscle of alternating arms.
Main Outcome Measures Assessments of clinical safety, including elicitation of antibodies that cross-react with host tissues, and immunogenicity as measured by enzyme-linked immunosorbent assay (ELISA) and assays of opsonophagocytic- and bactericidal-antibody responses.
Results One year of intensive follow-up revealed the vaccine to be well tolerated. There was no evidence of tissue cross-reactive antibodies or immunological complications. At the highest (200 µg) dose, vaccination elicited significant increases in geometric mean antibody levels to all 6 component M antigens by ELISA (all P<.01) and to 5 of 6 M types in the opsonophagocytosis assay (all P<.05). In addition, postvaccination increases in serum bactericidal activity of at least 30% were observed in 31 (55%) of 56 assays.
Conclusion These results provide the first evidence in humans that a hybrid fusion protein is a feasible strategy for evoking type-specific opsonic antibodies against multiple serotypes of group A streptococcus without eliciting antibodies that cross-react with host tissues, which represents a critical step in the development of a vaccine.
Author Affiliations: Departments of Pediatrics (Drs Kotloff and Campbell) and Medicine (Drs Kotloff, Corretti, and Wasserman, and Ms Palmer), Center for Vaccine Development (Drs Kotloff, Campbell, and Wasserman, and Ms Palmer), University of Maryland School of Medicine, Baltimore; ID Biomedical Corporation, Bothell, Wash (Dr Hu and Mr Reddish); and University of Tennessee and Department of Veterans Affairs Medical Center, Memphis (Dr Dale). Dr Corretti is now with Johns Hopkins University School of Medicine, Baltimore, Md. Ms Palmer is now with University of Maryland School of Medicine Dean's Office, Baltimore. Dr Wasserman is now with University of Virginia School of Medicine, Charlottesville.
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