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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<jats:named-content content-type=\"genus-species\">Shigella<\/jats:named-content>-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<jats:named-content content-type=\"genus-species\">Shigella flexneri<\/jats:named-content>2a lipopolysaccharide-specific serum IgG titers were determined in adult volunteers who received<jats:named-content content-type=\"genus-species\">Shigella<\/jats:named-content>vaccine candidate EcSf2a-2 and in unvaccinated controls, all of whom were challenged with virulent<jats:named-content content-type=\"genus-species\">Shigella flexneri<\/jats:named-content>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<jats:named-content content-type=\"genus-species\">Shigella<\/jats:named-content>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.<\/jats:p>","DOI":"10.1128\/cvi.00412-16","type":"journal-article","created":{"date-parts":[[2016,12,8]],"date-time":"2016-12-08T03:01:13Z","timestamp":1481166073000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":84,"title":["Functional and Antigen-Specific Serum Antibody Levels as Correlates of Protection against Shigellosis in a Controlled Human Challenge Study"],"prefix":"10.1128","volume":"24","author":[{"given":"Avital A.","family":"Shimanovich","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA"},{"name":"Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA"},{"name":"Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda D.","family":"Buskirk","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA"},{"name":"Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA"},{"name":"Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon J.","family":"Heine","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA"},{"name":"Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA"},{"name":"Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C.","family":"Blackwelder","sequence":"additional","affiliation":[{"name":"Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rezwanul","family":"Wahid","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA"},{"name":"Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA"},{"name":"Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen L.","family":"Kotloff","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA"},{"name":"Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA"},{"name":"Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcela F.","family":"Pasetti","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA"},{"name":"Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA"},{"name":"Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA"},{"name":"Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)60844-2"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0142927"},{"key":"e_1_3_3_4_2","first-page":"651","article-title":"Global burden of Shigella infections: implications for vaccine development and implementation of control strategies","volume":"77","author":"Kotloff KL","year":"1999","unstructured":"Kotloff KL WinickoffJP IvanoffB ClemensJD SwerdlowDL SansonettiPJ AdakGK LevineMM. 1999. 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