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However, optimal timing to boost BCG-immunity using subunit vaccines remains unclear in clinical trials. Here, we followed the adhesin Apa-specific T-cell responses in BCG-primed mice and investigated its BCG-booster potential. The Apa-specific T-cell response peaked 32\u201352 weeks after parenteral or mucosal BCG-priming but waned significantly by 78 weeks. A subunit-Apa-boost during the contraction-phase of BCG-response had a greater effect on the magnitude and functional quality of specific cellular and humoral responses compared to a boost at the peak of BCG-response. The cellular response increased following mucosal BCG-prime\u2013Apa-subunit-boost strategy compared to Apa-subunit-prime\u2013BCG-boost approach. However, parenteral BCG-prime\u2013Apa-subunit-boost by a homologous route was the most effective strategy in-terms of enhancing specific T-cell responses during waning in the lung and spleen. Two Apa-boosters markedly improved waning BCG-immunity and significantly reduced <jats:italic>Mycobacterium tuberculosis<\/jats:italic> burdens post-challenge. Our results highlight the challenges of optimization of prime\u2013boost regimens in mice where BCG drives persistent immune-activation and suggest that boosting with a heterologous vaccine may be ideal once the specific persisting effector responses are contracted. Our results have important implications for design of prime\u2013boost regimens against tuberculosis in humans.<\/jats:p>","DOI":"10.1038\/srep25837","type":"journal-article","created":{"date-parts":[[2016,5,13]],"date-time":"2016-05-13T11:22:39Z","timestamp":1463138559000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Boosting BCG-primed responses with a subunit Apa vaccine during the waning phase improves immunity and imparts protection against Mycobacterium tuberculosis"],"prefix":"10.1038","volume":"6","author":[{"given":"Subhadra","family":"Nandakumar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunil","family":"Kannanganat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen M.","family":"Dobos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan","family":"Lucas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John S.","family":"Spencer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rama Rao","family":"Amara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bonnie B.","family":"Plikaytis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James E.","family":"Posey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suraj B.","family":"Sable","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,5,13]]},"reference":[{"key":"BFsrep25837_CR1","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1016\/S0140-6736(95)92348-9","volume":"346","author":"PE Fine","year":"1995","unstructured":"Fine, P. 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