MTBVAC vaccination protects rhesus macaques against aerosol challenge with M. tuberculosis and induces immune signatures analogous to those observed in clinical studies

Abstract

A single intradermal vaccination with MTBVAC given to adult rhesus macaques was well tolerated and conferred a significant improvement in outcome following aerosol exposure to M. tuberculosis compared to that provided by a single BCG vaccination. Vaccination with MTBVAC resulted in a significant reduction in M. tuberculosis infection-induced disease pathology measured using in vivo medical imaging, in gross pathology lesion counts and pathology scores recorded at necropsy, the frequency and severity of pulmonary granulomas and the frequency of recovery of viable M. tuberculosis from extrapulmonary tissues following challenge. The immune profiles induced following immunisation with MTBVAC reflect those identified in human clinical trials of MTBVAC. Evaluation of MTBVAC- and TB peptide-pool-specific T-cell cytokine production revealed a predominantly Th1 response from poly- (IFN-γ+TNF-α+IL2+) and multi-(IFN-γ+TNF-α+) functional CD4 T cells, while only low levels of Th22, Th17 and cytokine-producing CD8 T-cell populations were detected together with low-level, but significant, increases in CFP10-specific IFN-γ secreting cells. In this report, we describe concordance between immune profiles measured in clinical trials and a macaque pre-clinical study demonstrating significantly improved outcome after M. tuberculosis challenge as evidence to support the continued development of MTBVAC as an effective prophylactic vaccine for TB vaccination campaigns.

TB and SIV Coinfection; a Model for Evaluating Vaccine Strategies against TB Reactivation in Asian Origin Cynomolgus Macaques: A Pilot Study Using BCG Vaccination

“…Throughout the study, the ELISPOT assay was employed to measure the frequency of antigen-specific IFNγ-producing cells to provide an indicator of Th1 immune responses. An increase in PPD-specific IFNγ-secreting cells was observed in the animals in group 1 after BCG vaccination, although the response was lower and more short-lived than those observed after BCG vaccination in studies conducted with rhesus macaques [23,25,31]. However, the response profiles were similar to those we observed in cynomolgus macaques of Chinese origin, which were able to control a high-dose aerosol challenge of M. tb [32] and may point to other mechanisms of immune protection afforded by BCG in these cynomolgus macaque populations.…”

“…Each slide was evaluated for the presence of tuberculous lesions. The TB-associated lesions were recorded using the scoring system described previously [25,26]. Briefly, six different types of granulomas were identified.…”

“…Peripheral blood mononuclear cells (PBMCs) were isolated from heparin-treated blood using standard methods. An IFNγ ELISpot assay was used to quantify the number of mycobacteria-specific IFNγ-producing T cells in PBMCs using a human/simian IFNγ kit (MabTech, Nacka, Sweden), as described previously [12,23,25]. In brief, 2 × 10 5 PBMCs were cultured with 10 μg/mL PPD (SSI, Copenhagen, Denmark) or pools of overlapping 15-mer peptides spanning CFP10 or ESAT6 (Peptide Protein Research Ltd., Wickham, UK) in duplicate, or without antigen, in quadruplicate, and incubated for 18 h. Phorbol 12myristate (Sigma-Aldrich Dorset, UK) (100 ng/mL) and ionomycin (CN Biosciences, Nottingham, UK) (1 μg/mL) were used as a positive control.…”

Engineering a new vaccine platform for heterologous antigen delivery in live-attenuated Mycobacterium tuberculosis

“…MTBVAC presents some advantages relative to BCG: it is based on the human pathogen M. tuberculosis [38] ; it maintains all epitopes present in M. tuberculosis [13] , including those lost in BCG; it secretes higher amounts of immunodominant antigens compared to BCG; and it is produced in uniform clinical lots, avoiding the risk of the emergence of “daughter strains” as happened with BCG. Furthermore, recent animal studies have demonstrated that MTBVAC confers a significant improvement, compared to BCG, in protecting rhesus macaques against an aerosol challenge with M. tuberculosis [43] and that MTBVAC protects mice against the most widely distributed M. tuberculosis lineages in the human population [38] . These advantages are endorsed by the successful results in phase I and IIa clinical trials [7] , [44] .…”

Pulmonary MTBVAC vaccination induces immune signatures previously correlated with prevention of tuberculosis infection

“…13 In guinea pigs, revaccination with MTBVAC after BCG priming resulted in a further reduction of Mtb burden in the lung compared with BCG alone, 14 and non-human primate data on the efficacy of (re)vaccination with intradermal MTBVAC have been established recently. 15 Although initially designed as a vaccine for newborns, MTBVAC is also considered for revaccination of BCG-primed adolescents and adults. 12 Phase2 dose-finding, safety, and immunogenicity studies in neonates (NCT03536117) and Quanti-FERON-negative and -positive adults (NCT02933281) are in progress, and a subsequent phase 3 efficacy study in neonates is scheduled to start in 2021.…”