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

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EBioMedicine Pub Date : 2025-03-17 DOI:10.1016/j.ebiom.2025.105628

Michele Tameris, Virginie Rozot, Claire Imbratta, Hennie Geldenhuys, Simon C Mendelsohn, Angelique Kany Kany Luabeya, Justin Shenje, Nicolette Tredoux, Michelle Fisher, Humphrey Mulenga, Nicole Bilek, Carly Young, Ashley Veldsman, Natasja Botes, Jelle Thole, Bernard Fritzell, Rajat Mukherjee, Ingrid Murillo Jelsbak, Esteban Rodriguez, Eugenia Puentes, Juana Doce, Dessislava Marinova, Jesús Gonzalo-Asensio, Nacho Aguilo, Carlos Martin, Thomas J Scriba, Mark Hatherill

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引用次数: 0

Abstract

Background: 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.

Funding: This trial was funded by the European and Developing Countries Clinical Trials Partnership (EDCTP).

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.