000094448 001__ 94448
000094448 005__ 20200727115047.0
000094448 0247_ $$2doi$$a10.1016/S2213-2600(19)30251-6
000094448 0248_ $$2sideral$$a114020
000094448 037__ $$aART-2019-114020
000094448 041__ $$aeng
000094448 100__ $$aTameris, Michele
000094448 245__ $$aLive-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial
000094448 260__ $$c2019
000094448 5060_ $$aAccess copy available to the general public$$fUnrestricted
000094448 5203_ $$aBackground: Infants are a key target population for new tuberculosis vaccines. We assessed the safety and immunogenicity of the live-attenuated Mycobacterium tuberculosis vaccine candidate MTBVAC in adults and infants in a region where transmission of tuberculosis is very high. Methods: We did a randomised, double-blind, BCG-controlled, dose-escalation trial at the South African Tuberculosis Vaccine Initiative site near Cape Town, South Africa. Healthy adult community volunteers who were aged 18–50 years, had received BCG vaccination as infants, were HIV negative, had negative interferon-¿ release assay (IGRA) results, and had no personal history of tuberculosis or current household contact with someone with tuberculosis were enrolled in a safety cohort. Infants born to HIV-negative women with no personal history of tuberculosis or current household contact with a person with tuberculosis and who were 96 h old or younger, generally healthy, and had not yet received routine BCG vaccination were enrolled in a separate infant cohort. Eligible adults were randomly assigned (1:1) to receive either BCG Vaccine SSI (5 × 105 colony forming units [CFU] of Danish strain 1331 in 0·1 mL diluent) or MTBVAC (5 × 105 CFU in 0·1 mL) intradermally in the deltoid region of the arm. After favourable review of 28-day reactogenicity and safety data in the adult cohort, infants were randomly assigned (1:3) to receive either BCG Vaccine SSI (2·5 × 105 CFU in 0·05 mL diluent) or MTBVAC in three sequential cohorts of increasing MTBVAC dose (2·5 × 103 CFU, 2·5 × 104 CFU, and 2·5 × 105 CFU in 0·05 mL) intradermally in the deltoid region of the arm. QuantiFERON-TB Gold In-Tube IGRA was done on days 180 and 360. For both randomisations, a pre-prepared block randomisation schedule was used. Participants (and their parents or guardians in the case of infant participants), investigators, and other clinical and laboratory staff were masked to intervention allocation. The primary outcomes, which were all measured in the infant cohort, were solicited and unsolicited local adverse events and serious adverse events until day 360; non-serious systemic adverse events until day 28 and vaccine-specific CD4 and CD8 T-cell responses on days 7, 28, 70, 180, and 360. Secondary outcomes measured in adults were local injection-site and systemic reactions and haematology and biochemistry at study day 7 and 28. Safety analyses and immunogenicity analyses were done in all participants who received a dose of vaccine. This trial is registered with ClinicalTrials.gov, number NCT02729571. Findings: Between Sept 29, 2015, and Nov 16, 2015, 62 adults were screened and 18 were enrolled and randomly assigned, nine each to the BCG and MTBVAC groups. Between Feb 12, 2016, and Sept 21, 2016, 36 infants were randomly assigned—eight to the BCG group, nine to the 2·5 × 103 CFU MTBVAC group, nine to the 2·5 × 104 CFU group, and ten to the 2·5 × 105 CFU group. Mild injection-site reactions occurred only in infants in the BCG and the 2·5 × 105 CFU MTBVAC group, with no evidence of local or regional injection-site complications. Systemic adverse events were evenly distributed across BCG and MTBVAC dose groups, and were mostly mild in severity. Eight serious adverse events were reported in seven vaccine recipients (one adult MTBVAC recipient, one infant BCG recipient, one infant in the 2·5 × 103 CFU MTBVAC group, two in the 2·5 × 104 CFU MTBVAC group, and two in the 2·5 × 105 CFU MTBVAC group), including one infant in the 2·5 × 103 CFU MTBVAC group treated for unconfirmed tuberculosis and one in the 2·5 × 105 CFU MTBVAC group treated for unlikely tuberculosis. One infant died as a result of possible viral pneumonia. Vaccination with all MTBVAC doses induced durable antigen-specific T-helper-1 cytokine-expressing CD4 cell responses in infants that peaked 70 days after vaccination and were detectable 360 days after vaccination. For the highest MTBVAC dose (ie, 2·5 × 105 CFU), these responses exceeded responses induced by an equivalent dose of the BCG vaccine up to 360 days after vaccination. Dose-related IGRA conversion was noted in three (38%) of eight infants in the 2·5 × 103 CFU MTBVAC group, six (75%) of eight in the 2·5 × 104 CFU MTBVAC group, and seven (78%) of nine in the 2·5 × 105 CFU MTBVAC group at day 180, compared with none of seven infants in the BCG group. By day 360, IGRA reversion had occurred in all three infants (100%) in the 2·5 × 103 CFU MTBVAC group, four (67%) of the six in the 2·5 × 104 CFU MTBVAC group, and three (43%) of the seven in the 2·5 × 105 CFU MTBVAC group. Interpretation: MTBVAC had acceptable reactogenicity, and induced a durable CD4 cell response in infants. The evidence of immunogenicity supports progression of MTBVAC into larger safety and efficacy trials, but also confounds interpretation of tests for M tuberculosis infection, highlighting the need for stringent endpoint definition. Funding: Norwegian Agency for Development Cooperation, TuBerculosis Vaccine Initiative, UK Department for International Development, and Biofabri.
000094448 536__ $$9info:eu-repo/grantAgreement/EC/H2020/643381/EU/TBVAC2020; Advancing novel and promising TB vaccine candidates from discovery to preclinical and early clinical development/TBVAC2020$$9This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 643381-TBVAC2020$$9info:eu-repo/grantAgreement/ES/MINECO/BIO2014-5258P
000094448 540__ $$9info:eu-repo/semantics/openAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/
000094448 590__ $$a25.094$$b2019
000094448 591__ $$aCRITICAL CARE MEDICINE$$b1 / 36 = 0.028$$c2019$$dQ1$$eT1
000094448 591__ $$aRESPIRATORY SYSTEM$$b1 / 64 = 0.016$$c2019$$dQ1$$eT1
000094448 592__ $$a7.516$$b2019
000094448 593__ $$aPulmonary and Respiratory Medicine$$c2019$$dQ1
000094448 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/acceptedVersion
000094448 700__ $$aMearns, Helen
000094448 700__ $$aPenn-Nicholson, Adam
000094448 700__ $$aGregg, Yolande
000094448 700__ $$aBilek, Nicole
000094448 700__ $$aMabwe, Simbarashe
000094448 700__ $$aGeldenhuys, Hennie
000094448 700__ $$aShenje, Justin
000094448 700__ $$aLuabeya, Angelique Kany K.
000094448 700__ $$aMurillo, Ingrid
000094448 700__ $$aDoce, Juana
000094448 700__ $$0(orcid)0000-0001-7897-9173$$aAguilo, Nacho$$uUniversidad de Zaragoza
000094448 700__ $$0(orcid)0000-0001-8644-120X$$aMarinova, Dessislava$$uUniversidad de Zaragoza
000094448 700__ $$aPuentes, Eugenia
000094448 700__ $$aRodríguez, Esteban
000094448 700__ $$0(orcid)0000-0001-8841-6593$$aGonzalo-Asensiom, Jesús$$uUniversidad de Zaragoza
000094448 700__ $$aFritzell, Bernard
000094448 700__ $$aThole, Jelle
000094448 700__ $$0(orcid)0000-0003-2993-5478$$aMartin, Carlos$$uUniversidad de Zaragoza
000094448 700__ $$aScriba, Thomas J.
000094448 700__ $$aHatherill, Mark
000094448 700__ $$aAfrica, Hadn
000094448 700__ $$aArendsen, Denis
000094448 700__ $$aBotes, Natasja
000094448 700__ $$aCloete, Yolundi
000094448 700__ $$aDe Kock, Marwou
000094448 700__ $$aErasmus, Margaret
000094448 700__ $$aJack, Lungisa
000094448 700__ $$aKafaar, Fazlin
000094448 700__ $$aKalepu, Xoliswa
000094448 700__ $$aKhomba, Nondumiso Gloria
000094448 700__ $$aKruger, Sandra
000094448 700__ $$aLeopeng, Thelma
000094448 700__ $$aMakhethe, Lebohang
000094448 700__ $$aMouton, Angelique
000094448 700__ $$aMulenga, Humphrey
000094448 700__ $$aMusvosvi, Munyaradzi
000094448 700__ $$aNoble, Julia
000094448 700__ $$aOpperman, Fajwa
000094448 700__ $$aReid, Tim
000094448 700__ $$aRossouw, Susan
000094448 700__ $$aSchreuder, Constance
000094448 700__ $$aSmit, Erica
000094448 700__ $$aSteyn, Marcia
000094448 700__ $$aTyambethu, Petrus
000094448 700__ $$aVan Rooyen, Elma
000094448 700__ $$aVeldsman, Ashley
000094448 700__ $$aMTBVAC Clinical Trial Team
000094448 7102_ $$11008$$2630$$aUniversidad de Zaragoza$$bDpto. Microb.Med.Pr.,Sal.Públ.$$cÁrea Microbiología
000094448 7102_ $$11008$$2X$$aUniversidad de Zaragoza$$bDpto. Microb.Med.Pr.,Sal.Públ.$$cProy. investigación HQA
000094448 773__ $$g7, 9 (2019), 757-770$$pThe Lancet. Respir. med.$$tThe Lancet. Respiratory medicine$$x2213-2600
000094448 8564_ $$s507367$$uhttps://zaguan.unizar.es/record/94448/files/texto_completo.pdf$$yPostprint
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000094448 951__ $$a2020-07-27-11:09:41
000094448 980__ $$aARTICLE