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BCG, the vaccine against tuberculosis, can potentiate immune responses to other vaccines through induction of trained innate immunity and heterologous adaptive immunity. We performed an explorative, randomized, noncontrolled open trial to investigate whether BCG vaccination increases humoral and cellular response to TFV and whether BCG and TFV modulate nonspecific immune responses. Thirty volunteers were randomized to receive either TFV alone or BCG followed by TFV after 2\u00a0weeks. Ex vivo leukocyte responses and anti-Vi IgG antibody titers were measured 2\u00a0weeks and 3\u00a0months after TFV. BCG administration prior to TFV vaccination did not increase specific humoral or cellular immune responses to <jats:italic>Salmonella typhi<\/jats:italic>. TFV vaccination decreased pro-inflammatory responses to non-related stimuli. This effect was counteracted by prior BCG administration, which also led to decreased IL-10 and increased IL-22 responses to non-related stimuli. In an in vitro model of trained immunity TFV led to immunotolerance, which was partially reversed by BCG-induced trained immunity. BCG does not modulate adaptive immune responses to TFV but partially prevents inhibition of innate immune responses induced by TFV. Nonspecific effects of vaccines to unrelated microbial stimuli must be considered in the evaluation of their biological effects (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link> NCT02175420).<\/jats:p>","DOI":"10.1007\/s10096-020-03813-y","type":"journal-article","created":{"date-parts":[[2020,7,8]],"date-time":"2020-07-08T10:03:43Z","timestamp":1594202623000},"page":"1177-1184","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Differential effects of BCG vaccine on immune responses induced by vi polysaccharide typhoid fever vaccination: an explorative randomized trial"],"prefix":"10.1007","volume":"39","author":[{"given":"Bastiaan A.","family":"Blok","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rob J.W.","family":"Arts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reinout","family":"van Crevel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Aaby","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leo A.B.","family":"Joosten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine S.","family":"Benn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mihai G.","family":"Netea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,2,17]]},"reference":[{"key":"3813_CR1","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1086\/649541","volume":"50","author":"JAA Crump","year":"2010","unstructured":"Crump JAA, Mintz EDD (2010) Global trends in typhoid and paratyphoid fever. 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RJW, RvC, LJ, and MGN declare no conflict of interest. All authors have approved the final article.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Potential conflicts of interest"}}]}}