Safety, reactogenicity, and immunogenicity of MTBVAC in infants: a phase 2a randomised, double-blind, dose-defining trial in a TB endemic setting

Tameris, Michele ; Rozot, Virginie ; Imbratta, Claire ; Geldenhuys, Hennie ; Mendelsohn, Simon C. ; Kany Luabeya, Angelique Kany ; Shenje, Justin ; Tredoux, Nicolette ; Fisher, Michelle ; Mulenga, Humphrey ; Bilek, Nicole ; Young, Carly ; Veldsman, Ashley ; Botes, Natasja ; Thole, Jelle ; Fritzell, Bernard ; Mukherjee, Rajat ; Jelsbak, Ingrid Murillo ; Rodriguez, Esteban ; Puentes, Eugenia ; Doce, Juana ; Marinova, Dessislava ; Gonzalo-Asensio, Jesús (Universidad de Zaragoza) ; Aguilo, Nacho (Universidad de Zaragoza) ; Martin, Carlos (Universidad de Zaragoza) ; Scriba, Thomas J. ; Hatherill, Mark ; Abrahams, Charmaine ; Africa, Hadn ; Arendsen, Denis ; Barnard, Liezl ; Cloete, Yolundi ; Davids, Ilse ; Erasmus, Mzwandile ; Filander, Elizabeth ; Gregg, Yolande ; Herling, Roxane ; Jansen, Ruwiyda ; Jack, Lungisa ; Kelepu, Xoliswe ; Kyepa, Henriette ; Leopeng, Thelma ; Mabwe, Simbarahse ; Mactavie, Lauren ; Makhete, Lebohang ; Mangali, Sandisiwe ; Mouton, Angelique ; Nkambule, Hlengiwe ; Noble, Julia ; Nombida, Onke ; Nqakala, Nambitha ; Opperman, Fajwa ; Raphela, Rodney ; Rossouw, Susan ; Schoeman, Elisma ; Schreuder, Constance ; Steyn, Marcia ; Swanepoel, Liticia ; Toefy, Asma ; Tromp, Anele ; Tyambethu, Petrus ; Valley, Habibullah ; Van Rooyes, Johanna

Resumen: Safer and more effective tuberculosis (TB) vaccines than Bacille Calmette Guérin (BCG) are needed. We evaluated the safety, reactogenicity, and immunogenicity of three dose levels of the live-attenuated Mycobacterium tuberculosis (Mtb) vaccine, MTBVAC, compared to BCG, in South African infants.
Methods. Healthy, HIV-unexposed, BCG-naïve infants were randomised to receive a single intradermal dose of BCG (2.5 × 105 CFU, n = 24) or MTBVAC (2.5 × 104, 2.5 × 105, or 2.5 × 106 CFU, each n = 25). Safety endpoints were solicited systemic, solicited injection site, and unsolicited adverse events (AE), and serious AE (SAE). Immunogenicity was measured using interferon-γ release assay (IGRA) and whole blood intracellular cytokine staining assay. Follow-up was 12 months post-vaccination.
Findings. Ninety-nine infants were enrolled between 18 February 2019 and 08 March 2021. Seventy-eight infants experienced reactogenicity AE (all mild except one grade 2 erythema). Induration, swelling, and erythema were more frequent as MTBVAC dose increased. All reactogenicity events were less frequent in infants receiving MTBVAC 2.5 × 105 CFU compared with BCG. Twelve infants (three BCG and nine MTBVAC recipients) experienced 14 vaccine-unrelated SAE, including one death due to bronchopneumonia (MTBVAC recipient). Eight infants were treated for unconfirmed pulmonary TB (four BCG and four MTBVAC 2.5 × 104 CFU recipients); one BCG recipient was treated for unconfirmed TB meningitis. MTBVAC was immunogenic at all 3 doses, inducing predominantly Th1-cytokine-expressing CD4 T cells, which peaked at Day 56. The 2.5 × 105 and 2.5 × 106 CFU MTBVAC doses induced similar response magnitudes and were more immunogenic than BCG. Day 56 IGRA conversion was observed in 61 (87.4%) infants receiving any MTBVAC dose, but only 28 (42.4%) remained positive by Day 365.
Interpretation. MTBVAC appeared safe, well-tolerated, and immunogenic at doses between 2.5 × 104 and 2.5 × 106 CFU in South African infants. The 2.5 × 105 CFU MTBVAC dose, being less reactogenic and more immunogenic than BCG, was selected for a multi-centre, phase 3 trial.

Idioma: Inglés

DOI: 10.1016/j.ebiom.2025.105628

Año: 2025

Publicado en: EBioMedicine 114 (2025), 105628 [12 pp.]
ISSN: 2352-3964

Financiación: info:eu-repo/grantAgreement/EUR/EDCTP/RIA2016V-1637

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Microbiología (Dpto. Microb.Ped.Radio.Sal.Pú.)
Área (Departamento): Área Inmunología (Dpto. Microb.Ped.Radio.Sal.Pú.)