The Journal of infectious diseases · 2024
Phase 1 Open-Label Dose Escalation Trial for the Development of a Human Bacillus Calmette-Guérin Challenge Model for Assessment of Tuberculosis Immunity In Vivo.
СтатьяКлиническое исследование I фазыПоддержка службы здравоохранения СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Blazevic Azra, Edwards Rachel L, Xia Mei, Eickhoff Christopher S, Hamzabegovic Fahreta, Meza Krystal A, Ning Huan, Tennant Janice, Mosby Karla J, Ritchie James C, Girmay Tigisty, Lai Lilin, McCullough Michele, Beck Allison, Kelley Colleen, Edupuganti Srilatha, Kabbani Sarah, Buchanan Wendy, Makhene Mamodikoe K, Voronca Delia, Cherikh Sami, Goll Johannes B, Rouphael Nadine G, Mulligan Mark J, Hoft Daniel F
Аннотация
BACKGROUND: A controlled human infection model for assessing tuberculosis (TB) immunity can accelerate new vaccine development.
METHODS: In this phase 1 dose escalation trial, 92 healthy adults received a single intradermal injection of 2 × 106 to 16 × 106 colony-forming units of Bacillus Calmette-Guérin (BCG). The primary endpoints were safety and BCG shedding as measured by quantitative polymerase chain reaction, colony-forming unit plating, and MGIT BACTEC culture.
RESULTS: Doses up to 8 × 106 were safe, and there was evidence for increased BCG shedding with dose escalation. The MGIT time-to-positivity assay was the most consistent and precise measure of shedding. Power analyses indicated that 10% differences in MGIT time to positivity (area under the curve) could be detected in small cohorts (n = 30). Potential biomarkers of mycobacterial immunity were identified that correlated with shedding. Transcriptomic analysis uncovered dose- and time-dependent effects of BCG challenge and identified a putative transcriptional TB protective signature. Furthermore, we identified immunologic and transcriptomal differences that could represent an immune component underlying the observed higher rate of TB disease incidence in males.
CONCLUSIONS: The safety, reactogenicity, and immunogenicity profiles indicate that this BCG human challenge model is feasible for assessing in vivo TB immunity and could facilitate the vaccine development process.
CLINICAL TRIALS REGISTRATION: NCT01868464 (ClinicalTrials.gov).
METHODS: In this phase 1 dose escalation trial, 92 healthy adults received a single intradermal injection of 2 × 106 to 16 × 106 colony-forming units of Bacillus Calmette-Guérin (BCG). The primary endpoints were safety and BCG shedding as measured by quantitative polymerase chain reaction, colony-forming unit plating, and MGIT BACTEC culture.
RESULTS: Doses up to 8 × 106 were safe, and there was evidence for increased BCG shedding with dose escalation. The MGIT time-to-positivity assay was the most consistent and precise measure of shedding. Power analyses indicated that 10% differences in MGIT time to positivity (area under the curve) could be detected in small cohorts (n = 30). Potential biomarkers of mycobacterial immunity were identified that correlated with shedding. Transcriptomic analysis uncovered dose- and time-dependent effects of BCG challenge and identified a putative transcriptional TB protective signature. Furthermore, we identified immunologic and transcriptomal differences that could represent an immune component underlying the observed higher rate of TB disease incidence in males.
CONCLUSIONS: The safety, reactogenicity, and immunogenicity profiles indicate that this BCG human challenge model is feasible for assessing in vivo TB immunity and could facilitate the vaccine development process.
CLINICAL TRIALS REGISTRATION: NCT01868464 (ClinicalTrials.gov).