title: Functional and Antigen-Specific Serum Antibody Levels as Correlates of Protection against Shigellosis in a Controlled Human Challenge Study.
abstract: Shigella is an important cause of diarrheal disease in young children living in developing countries. No approved vaccines are available, and the development of vaccine candidates has been hindered by the lack of firm immunological correlates of protection, among other reasons. To address this gap in knowledge, we established quantitative assays to measure Shigella-specific serum bactericidal antibody (SBA) and opsonophagocytic killing antibody (OPKA) activities and investigated their potential association with protection against disease in humans. SBA, OPKA, and Ipa-, VirG (IscA)-, and Shigella flexneri 2a lipopolysaccharide-specific serum IgG titers were determined in adult volunteers who received Shigella vaccine candidate EcSf2a-2 and in unvaccinated controls, all of whom were challenged with virulent Shigella flexneri 2a. Prechallenge antibody titers were compared with disease severity after challenge. SBA and OPKA, as well as IpaB- and VirG-specific IgG, significantly correlated with reduced illness. SBA and OPKA assays were also used to evaluate the immunogenicity of leading live attenuated vaccine candidates Shigella CVD 1204 and CVD 1208S in humans. A single oral immunization with CVD 1204 or CVD 1208S resulted in SBA seroconversion rates of 71% and 47% and OPKA seroconversion rates of 57% and 35%, respectively. Higher functional antibody responses were induced by CVD 1204, which is consistent with its lower attenuation. This is the first demonstration of SBA, OPKA, and IpaB- and VirG-specific IgG levels as potential serological correlates of protection against shigellosis in humans. These results warrant further studies to establish their capacity to predict protective immunity and vaccine efficacy.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.|Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.|Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Avital A
authors.initials: AA
authors.lastname: Shimanovich
authors.affiliation: Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA.|Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.|Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Amanda D
authors.initials: AD
authors.lastname: Buskirk
authors.affiliation: Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA.|Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.|Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Shannon J
authors.initials: SJ
authors.lastname: Heine
authors.affiliation: Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Blackwelder
authors.affiliation: Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA.|Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.|Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Rezwanul
authors.initials: R
authors.lastname: Wahid
authors.affiliation: Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA.|Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.|Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Kotloff
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA mpasetti@medicine.umaryland.edu.|Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA.|Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.|Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Marcela F
authors.initials: MF
authors.lastname: Pasetti
mesh_terms: D000328:Adult; D000907:Antibodies, Bacterial / Q000097:blood*; D000942:Antigens, Bacterial / Q000276:immunology*; D001770:Blood Bactericidal Activity; D004405:Dysentery, Bacillary / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D009895:Opsonin Proteins / Q000097:blood; D010587:Phagocytosis; D012720:Severity of Illness Index; D022281:Shigella Vaccines / Q000008:administration & dosage / Q000276:immunology*; D012763:Shigella flexneri / Q000276:immunology*; D014838:Volunteers
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D009895:Opsonin Proteins; D022281:Shigella Vaccines
keywords: Shigella; correlates of protection; functional antibodies