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Gamma interferon (IFN-\u03b3) produced by CD4<jats:sup>+<\/jats:sup>T cells and, recently, multifunctional CD4<jats:sup>+<\/jats:sup>T cells secreting IFN-\u03b3, tumor necrosis factor (TNF), and interleukin-2 (IL-2) have been used in vaccine studies as a measurable immune parameter, reflecting activity of a vaccine and potentially predicting protection. However, accumulating experimental evidence suggests that host resistance against<jats:named-content content-type=\"genus-species\">Mycobacterium tuberculosis<\/jats:named-content>infection is independent of IFN-\u03b3 and TNF secretion from CD4<jats:sup>+<\/jats:sup>T cells. Furthermore, the booster vaccine MVA85A, despite generating a high level of multifunctional CD4<jats:sup>+<\/jats:sup>T cell response in the host, failed to confer enhanced protection in vaccinated subjects. These findings suggest the need for identifying reliable correlates of protection to determine the efficacy of TB vaccine candidates. This article focuses on alternative pathways that mediate<jats:named-content content-type=\"genus-species\">M. tuberculosis<\/jats:named-content>control and their potential for serving as markers of protection. The review also discusses the significance of investigating the natural human immune response to<jats:named-content content-type=\"genus-species\">M. tuberculosis<\/jats:named-content>to identify the correlates of protection in vaccination.<\/jats:p>","DOI":"10.1128\/cvi.00721-14","type":"journal-article","created":{"date-parts":[[2015,1,15]],"date-time":"2015-01-15T06:36:36Z","timestamp":1421303796000},"page":"258-266","source":"Crossref","is-referenced-by-count":127,"title":["Quest for Correlates of Protection against Tuberculosis"],"prefix":"10.1128","volume":"22","author":[{"given":"Kamlesh","family":"Bhatt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheetal","family":"Verma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerrold J.","family":"Ellner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Padmini","family":"Salgame","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","published-online":{"date-parts":[[2015,1,14]]},"reference":[{"key":"key20180919073757_B1","volume-title":"Global tuberculosis report 2014","author":"World Health Organization","year":"2014"},{"key":"key20180919073757_B2","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1542\/peds.96.1.29","article-title":"The efficacy of bacillus Calmette-Guerin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literature","volume":"96","year":"1995","journal-title":"Pediatrics"},{"key":"key20180919073757_B3","doi-asserted-by":"publisher","first-page":"e1002607","DOI":"10.1371\/journal.ppat.1002607","article-title":"Vaccines against tuberculosis: where are we and where do we need to go?","volume":"8","year":"2012","journal-title":"PLoS Pathog"},{"key":"key20180919073757_B4","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1016\/j.it.2012.03.004","article-title":"Tuberculosis vaccine development: strength lies in tenacity","volume":"33","year":"2012","journal-title":"Trends Immunol"},{"key":"key20180919073757_B5","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1016\/S0140-6736(13)60177-4","article-title":"Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial","volume":"381","author":"Team MATS","year":"2013","journal-title":"Lancet"},{"key":"key20180919073757_B6","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.1038\/nm1128","article-title":"Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans","volume":"10","year":"2004","journal-title":"Nat Med"},{"key":"key20180919073757_B7","doi-asserted-by":"publisher","first-page":"2249","DOI":"10.1084\/jem.178.6.2249","article-title":"An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection","volume":"178","year":"1993","journal-title":"J Exp Med"},{"key":"key20180919073757_B8","doi-asserted-by":"publisher","first-page":"2243","DOI":"10.1084\/jem.178.6.2243","article-title":"Disseminated tuberculosis in interferon gamma gene-disrupted mice","volume":"178","year":"1993","journal-title":"J Exp Med"},{"key":"key20180919073757_B9","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1136\/thx.2005.051649","article-title":"Disseminated Mycobacterium tuberculosis infection due to interferon \u03b3 deficiency. 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