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Safety, reactogenicity, and immunogenicity of MTBVAC in infants: a phase 2a randomised, double-blind, dose-defining
Michele Tameris1, Virginie Rozot1, Claire Imbratta1
1South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Disease & Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
Insights
A novel tuberculosis (TB) vaccine, MTBVAC, demonstrated safety and immunogenicity in South African infants. The 2.5 × 10^5 CFU dose was well-tolerated and more effective than the current BCG vaccine.
Area of Science:
- Vaccinology
- Infectious Diseases
- Immunology
Background:
- Tuberculosis (TB) remains a global health challenge, necessitating safer and more effective vaccines than the current Bacille Calmette Guérin (BCG) vaccine.
- Live-attenuated Mycobacterium tuberculosis (Mtb) vaccine candidate, MTBVAC, offers a potential alternative.
Purpose of the Study:
- To evaluate the safety, reactogenicity, and immunogenicity of three dose levels of MTBVAC compared to BCG in South African infants.
- To identify an optimal MTBVAC dose for future clinical trials.
Main Methods:
- A randomized trial involving healthy, BCG-naïve infants.
- Infants received either BCG or one of three MTBVAC doses (2.5 × 10^4, 2.5 × 10^5, or 2.5 × 10^6 CFU).
- Safety was assessed through adverse events (AE) and serious adverse events (SAE); immunogenicity was measured by interferon-γ release assay (IGRA) and intracellular cytokine staining.
Main Results:
- MTBVAC was generally safe and well-tolerated across all tested doses.
- The 2.5 × 10^5 CFU MTBVAC dose showed reduced reactogenicity compared to BCG.
- MTBVAC induced a robust T-cell immune response, with higher immunogenicity than BCG at the 2.5 × 10^5 and 2.5 × 10^6 CFU doses.
Conclusions:
- MTBVAC is a promising TB vaccine candidate, demonstrating favorable safety and immunogenicity profiles in infants.
- The 2.5 × 10^5 CFU dose of MTBVAC was selected for further development due to its balance of safety and immunogenicity.
- These findings support advancing MTBVAC to a phase 3 trial for TB prevention.
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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