Safety and Immunogenicity of Recombinant Bacille Calmette-Guérin Strain VPM1002 and Its Derivatives in a Goat Model

Abstract

A more effective vaccine against tuberculosis than Bacille Calmette-Guérin (BCG) is urgently needed. BCG derived recombinant VPM1002 has been found to be more efficacious and safer than the parental strain in mice models. Newer candidates, such as VPM1002 Δpdx1 (PDX) and VPM1002 ΔnuoG (NUOG), were generated to further improve the safety profile or efficacy of the vaccine. Herein, we assessed the safety and immunogenicity of VPM1002 and its derivatives, PDX and NUOG, in juvenile goats. Vaccination did not affect the goats’ health in regards to clinical/hematological features. However, all three tested vaccine candidates and BCG induced granulomas at the site of injection, with some of the nodules developing ulcerations approximately one month post-vaccination. Viable vaccine strains were cultured from the injection site wounds in a few NUOG- and PDX- vaccinated animals. At necropsy (127 days post-vaccination), BCG, VPM1002, and NUOG, but not PDX, still persisted at the injection granulomas. All strains, apart from NUOG, induced granuloma formation only in the lymph nodes draining the injection site. In one animal, the administered BCG strain was recovered from the mediastinal lymph nodes. Interferon gamma (IFN-γ) release assay showed that VPM1002 and NUOG induced a strong antigen-specific response comparable to that elicited by BCG, while the response to PDX was delayed. Flow cytometry analysis of IFN-γ production by CD4+, CD8+, and γδ T cells showed that CD4+ T cells of VPM1002- and NUOG-vaccinated goats produced more IFN-γ compared to BCG-vaccinated and mock-treated animals. In summary, the subcutaneous application of VPM1002 and NUOG induced anti-tuberculous immunity, while exhibiting a comparable safety profile to BCG in goats.

Comparative pathology of experimental pulmonary tuberculosis in animal models

“…Fewer lymphocytes than in other models (76)(77)(78). Diagram of a general pulmonary tuberculous granuloma.…”

“…Goat TB closely resembles bovine and human TB in terms of immune response and pathological characteristics. They exhibit comparable patterns of disease progression, with a predominant anatomical localisation within the respiratory tract and the formation of caseous granulomas ( 77 , 107 ). In addition, goats demonstrate notable similarities in the anatomical structure of their respiratory tract, as well as a comparable size and body weight to that of humans ( 107 ).…”

“…In addition, goats demonstrate notable similarities in the anatomical structure of their respiratory tract, as well as a comparable size and body weight to that of humans ( 107 ). These shared features present a unique opportunity to bridge the gap between murine preclinical studies and subsequent human investigations ( 77 , 105 ), thereby providing valuable insights into the intricate mechanisms of host-mycobacteria interaction ( 77 ).…”

Animal models for COVID-19 and tuberculosis

“…However, one report suggested that BCG has only a limited protective efficacy after challenge with M. caprae ( 259 ). More recent advanced goat models using video endoscopy for infection via intrabronchial spray inoculation ( 283 ) have demonstrated the relevance and suitability of goats for vaccine studies using BCG and new clinical candidates ( 284 , 285 ). Considering that BCG is the only licensed vaccine against TB it still remains the gold standard when testing new vaccine concepts.…”