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The F1 capsule antigen stimulates a protective immune response to most strains of<jats:italic>Yersinia pestis<\/jats:italic>. However, strains of<jats:italic>Y. pestis<\/jats:italic>that are F1<jats:sup>\u2212<\/jats:sup>but still virulent have been isolated, and an in vitro assay, the results which can predict protection against both F1<jats:sup>+<\/jats:sup>and F1<jats:sup>\u2212<\/jats:sup>strains, is needed. The virulence antigen (V) is an essential virulence factor of<jats:italic>Y. pestis<\/jats:italic>and stimulates protective antibodies. We investigated potential correlates of plague immunity that are based on anti-V antibody-mediated neutralization of<jats:italic>Yersinia<\/jats:italic>-induced macrophage cytotoxicity. The neutralizing activity of sera from mice vaccinated with an F1-V fusion candidate vaccine was determined. The decrease in the level of the apoptosis-specific enzyme caspase-3 significantly predicted survival in one- and two-dose vaccination experiments. Sera from F1-V-vaccinated nonhuman primates were evaluated with macrophage assays based on caspase-3 and on other markers manifested at the different stages in cell death. Using murine- and human-derived macrophages in microscopic and fluorescence-activated-cell-sorting-based live\/dead staining assays of terminal necrosis, we demonstrated a strong association between in vitro neutralization of macrophage cytotoxicity induced by serum-treated<jats:italic>Yersinia<\/jats:italic>and in vivo protection against lethal infection. These results provide a strong base for the development of reliable in vitro correlate bioassays that are predictive of protective immunity to plague.<\/jats:p>","DOI":"10.1128\/cvi.00398-06","type":"journal-article","created":{"date-parts":[[2007,3,22]],"date-time":"2007-03-22T00:38:46Z","timestamp":1174523926000},"page":"605-616","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":57,"title":["Development of In Vitro Correlate Assays of Immunity to Infection with<i>Yersinia pestis<\/i>"],"prefix":"10.1128","volume":"14","author":[{"given":"J.","family":"Bashaw","sequence":"first","affiliation":[{"name":"Bacteriology Division, U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Frederick, Maryland 21702"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Norris","sequence":"additional","affiliation":[{"name":"Bacteriology Division, U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Frederick, Maryland 21702"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Weeks","sequence":"additional","affiliation":[{"name":"Bacteriology Division, U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Frederick, Maryland 21702"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Trevino","sequence":"additional","affiliation":[{"name":"Bacteriology Division, U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Frederick, Maryland 21702"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. 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