title: Safety and Immunogenicity of a Parenterally Administered, Structure-Based Rationally Modified Recombinant Staphylococcal Enterotoxin B Protein Vaccine, STEBVax.
abstract: Staphylococcus aureus produces several enterotoxins and superantigens, exposure to which can elicit profound toxic shock. A recombinant staphylococcal enterotoxin B (rSEB) containing 3 distinct mutations in the major histocompatibility complex class II binding site was combined with an alum adjuvant (Alhydrogel) and used as a potential parenteral vaccine named STEBVax. Consenting healthy adult volunteers (age range, 23 to 38 years) participated in a first-in-human open-label dose escalation study of parenteral doses of STEBVax ranging from 0.01 μg up to 20 μg. Safety was assessed by determination of the frequency of adverse events and reactogenicity. Immune responses to the vaccination were determined by measurement of anti-staphylococcal enterotoxin B (anti-SEB) IgG by enzyme-linked immunosorbent assay and a toxin neutralization assay (TNA). Twenty-eight participants were enrolled in 7 dosing cohorts. All doses were well tolerated. The participants exhibited heterogeneous baseline antibody titers. More seroconversions and a faster onset of serum anti-SEB IgG toxin-neutralizing antibodies were observed by TNA with increasing doses of STEBVax. There was a trend for a plateau in antibody responses with doses of STEBVax of between 2.5 and 20 μg. Among the participants vaccinated with 2.5 μg to 20 μg of STEBVax, ∼93% seroconverted for SEB toxin-neutralizing antibody. A strong correlation between individual SEB-specific serum IgG antibody titers and the neutralization of gamma interferon production was found in vitro STEBvax appeared to be safe and immunogenic, inducing functional toxin-neutralizing antibodies. These data support its continued clinical development. (This study has been registered at ClinicalTrials.gov under registration no. NCT00974935.).
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA wchen@medicine.umaryland.edu.
authors.forename: Wilbur H
authors.identifier: http://orcid.org/0000-0001-7741-5536
authors.initials: WH
authors.lastname: Chen
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Marcela F
authors.initials: MF
authors.lastname: Pasetti
authors.affiliation: Integrated BioTherapeutics, Inc., Rockville, Maryland, USA.
authors.forename: Rajan P
authors.initials: RP
authors.lastname: Adhikari
authors.affiliation: The Emmes Corporation, Rockville, Maryland, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Baughman
authors.affiliation: Integrated BioTherapeutics, Inc., Rockville, Maryland, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Douglas
authors.affiliation: The Emmes Corporation, Rockville, Maryland, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: El-Khorazaty
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Greenberg
authors.affiliation: Integrated BioTherapeutics, Inc., Rockville, Maryland, USA.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Holtsberg
authors.affiliation: Integrated BioTherapeutics, Inc., Rockville, Maryland, USA.
authors.forename: Grant C
authors.initials: GC
authors.lastname: Liao
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Mardi K
authors.initials: MK
authors.lastname: Reymann
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Integrated BioTherapeutics, Inc., Rockville, Maryland, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Warfield
authors.affiliation: Integrated BioTherapeutics, Inc., Rockville, Maryland, USA.
authors.forename: M Javad
authors.initials: MJ
authors.lastname: Aman
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000737:chemistry; D000328:Adult; D000907:Antibodies, Bacterial / Q000097:blood* / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004768:Enterotoxins / Q000235:genetics* / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D000071497:Immunogenicity, Vaccine; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D011994:Recombinant Proteins / Q000276:immunology; D013209:Staphylococcal Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology*; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D057134:Antibodies, Neutralizing; D004768:Enterotoxins; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D013209:Staphylococcal Vaccines; C031818:enterotoxin B, staphylococcal; D007371:Interferon-gamma