A review of the efficacy of clinical tuberculosis vaccine candidates in mouse models

Abstract

Tuberculosis (TB) remains one of the deadliest infectious diseases worldwide, causing over a million deaths annually. The only licensed TB vaccine for human use, Bacille Calmette-Guérin (BCG), a mycobacteria-based live-attenuated vaccine, confers immunity to children but fails to efficiently protect adults from pulmonary TB. Several TB vaccine candidates have been developed over the last two decades, but some have failed to provide substantially better protection than BCG in clinical trials. Most of these vaccine candidates were initially evaluated for their protective capacity in mouse models of TB. With the availability of several mouse strains, vaccination routes and Mycobacterium tuberculosis (Mtb) challenge strains, to-date there is no consensus in the field about the predictive value of different murine models of TB, and it remains a matter of debate whether host genetics or vaccine-driven parameters primarily determine vaccine efficacy. Here we reviewed the performance of all TB vaccine candidates that have entered clinical trials over the last 25 years. We extracted protective efficacy data from all published studies that utilized mouse models to assess vaccination efficacy. The efficacy of each vaccine candidate to reduce lung bacterial burden depending on the mouse genotype, the vaccine administration route, and the Mtb challenge strain at different time-points was evaluated. Our data reveals insights into the effect of experimental parameters on vaccine performance and emphasizes the potential benefits of standardizing TB mouse models across vaccination-challenge studies to identify pre-clinical vaccine candidates with the highest potential to succeed.

Keywords: BCG; clinical; host genetics; mouse models; tuberculosis; vaccine.

Figure 1

TB vaccine candidates in the clinical trial pipeline. Schematic showing the developmental stages of various TB vaccine candidates, depending on target population, clinical trial phase, and vaccine type. Vaccine type is indicated by color. Modified from the Tuberculosis Vaccine Initiative TB Vaccine Pipeline, last updated October 2024 (22).

Figure 2

Comparison of BCG efficacy across various mouse models and vaccination routes. (A) Δlog₁₀ change in lung Mtb CFU in various mouse strains compared to unvaccinated controls. Symbol color indicates time point of efficacy measurement post Mtb challenge (black: early time points < 60 days post-challenge; red: late time points > 60 days post-challenge). Symbol shape indicates different combinations of mouse strain, route of vaccination, and Mtb challenge strain. (B, C) Enlargement of results from C57BL/6 (B) and BALB/c mice (C) shown in (A). (D) Δlog₁₀ lung bacterial loads in Collaborative Cross (CC) and Diversity Outbred (DO) mice following BCG vaccination. Dotted lines indicate Δlog₁₀ reference values of 0 and -1.

Figure 3

Efficacy of current and former clinical TB vaccine candidates relative to BCG vaccination in various mouse models. (A-N) Δlog₁₀ change in lung Mtb CFU following vaccination with VPM1002 (A), MTBVAC (B), AERAS-422 (C), MIP-Immuvac (D), DAR-901 (E), Vaccae (F) RUTI (G), ID93GLA-SE (H), H1:IC31 (I), H4:IC31 (J), H56:IC31 (K), M72 (L), H107 (M), GamTBVac (N), ChadOxMVA85A (O), Ad5 Ag85A (P), MVA85A (Q), TBFlu-04L (R) and AERAS-402 (S) in various vaccination route - Mtb strain - Mtb dose - timepoint combinations compared to BCG vaccinated controls. Symbol color indicates mouse strain used (red; C57BL/6), (blue; BALB/C), (green; C3H), (turquoise; B6C3F1), (olive; CBA), (purple; CB6F1), (black; H-2Kb^-/-Db^-/-). Dotted lines indicate Δlog₁₀ reference values of 0 and -0.5.

Figure 4

Efficacy of TB vaccine candidates relative to BCG vaccination grouped by vaccine type. (A-D) Δlog₁₀ change in lung Mtb CFU following vaccination with different live attenuated (A), subunit (B), vectored (C), or whole cell (D) vaccine candidates in various vaccination route - Mtb strain - Mtb dose - timepoint combinations compared to BCG vaccinated controls. Symbol color indicates mouse strain used (red; C57BL/6), (blue; BALB/C), (green; C3H), (turquoise; B6C3F1), (olive; CBA), (black; H-2Kb^-/-Db^-/-). Dotted lines indicate Δlog₁₀ reference values of 0 and -1.