Safety and immunogenicity of a recombinant multivalent group A streptococcal vaccine in healthy adults

Phase 1 trial

Karen L. Kotloff, Mary Corretti, Kathleen Palmer, James D. Campbell, Mark A. Reddish, Mary C. Hu, Steven S. Wasserman, James Dale

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

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 out- patient 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.

Original languageEnglish (US)
Pages (from-to)709-715
Number of pages7
JournalJournal of the American Medical Association
Volume292
Issue number6
DOIs
StatePublished - Aug 11 2004

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Streptococcal Vaccines
Safety
Vaccines
Antibodies
Healthy Volunteers
Enzyme-Linked Immunosorbent Assay
Outcome Assessment (Health Care)
Deltoid Muscle
Aluminum Hydroxide
Myeloma Proteins
Streptococcal Infections
Baltimore
Newspapers
Intramuscular Injections
Streptococcus
Antibody Formation
Volunteers
Vaccination
Proteins
Outpatients

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Safety and immunogenicity of a recombinant multivalent group A streptococcal vaccine in healthy adults : Phase 1 trial. / Kotloff, Karen L.; Corretti, Mary; Palmer, Kathleen; Campbell, James D.; Reddish, Mark A.; Hu, Mary C.; Wasserman, Steven S.; Dale, James.

In: Journal of the American Medical Association, Vol. 292, No. 6, 11.08.2004, p. 709-715.

Research output: Contribution to journalArticle

Kotloff, Karen L. ; Corretti, Mary ; Palmer, Kathleen ; Campbell, James D. ; Reddish, Mark A. ; Hu, Mary C. ; Wasserman, Steven S. ; Dale, James. / Safety and immunogenicity of a recombinant multivalent group A streptococcal vaccine in healthy adults : Phase 1 trial. In: Journal of the American Medical Association. 2004 ; Vol. 292, No. 6. pp. 709-715.
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abstract = "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 out- patient 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.",
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AU - Kotloff, Karen L.

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AU - Campbell, James D.

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AU - Hu, Mary C.

AU - Wasserman, Steven S.

AU - Dale, James

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