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
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
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.