Abstract
Mycobacterium tuberculosis (Mtb) represents a major burden to global health, and refined vaccines are needed. Replication-deficient lymphocytic choriomeningitis virus (rLCMV)-based vaccine vectors against cytomegalovirus have proven safe for human use and elicited robust T cell responses in a large proportion of vaccine recipients. Here, we developed an rLCMV vaccine expressing the Mtb antigens TB10.4 and Ag85B. In mice, rLCMV elicited high frequencies of polyfunctional Mtb-specific CD8 and CD4 T cell responses. CD8 but not CD4 T cells were efficiently boosted upon vector re-vaccination. High-frequency responses were also observed in neonatally vaccinated mice, and co-administration of rLCMV with Expanded Program of Immunization (EPI) vaccines did not result in substantial reciprocal interference. Importantly, rLCMV immunization significantly reduced the lung Mtb burden upon aerosol challenge, resulting in improved lung ventilation. Protection was associated with increased CD8 T cell recruitment but reduced CD4 T cell infiltration upon Mtb challenge. When combining rLCMV with BCG vaccination in a heterologous prime-boost regimen, responses to the rLCMV-encoded Mtb antigens were further augmented, but protection was not significantly different from rLCMV or BCG vaccination alone. This work suggests that rLCMV may show utility for neonatal and/or adult vaccination efforts against pulmonary tuberculosis.
Highlights
Tuberculosis (TB) is a chronic infectious disease caused by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb)
The present work indicates that replication-deficient Lymphocytic choriomeningitis virus (LCMV) vectors represent a valuable addition to a growing quiver of vaccination technologies and vaccine candidates, which in combination may eventually afford the long-sought life-long protection against pulmonary tuberculosis
Excellent immunogenicity even in the neonatal period and only limited interference with Expanded Program of Immunization (EPI) vaccines suggest that Replication-deficient lymphocytic choriomeningitis virus (rLCMV) may lend itself to inclusion in early life vaccination programs
Summary
Tuberculosis (TB) is a chronic infectious disease caused by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb). RLCMV can be re-administered repeatedly without eliciting substantial antivector antibody immunity, resulting in incremental increases in T cell responses against vectorized cargo [24] These mechanistic observations were originally described in mice and have been confirmed in NHPs and humans [20,23,24]. The homologous boost increased the proportion of polyfunctional splenic CD8 T cells secreting IFN-γ and TNF-α in conjunction with surface expression of the lytic granule release marker CD107a (LAMP1, Figure 2B) to ~10% of CD8 T cells, markedly exceeding the ~2% of cells in mice having received only one dose of rLCMV In contrast to this pronounced homologous booster effect on CD8 T cells, the analysis of Ag85B-specific CD4 T cell responses by either MHC class II tetramers or intracellular cytokine assays indicated at best a modest booster effect on CD4 T cell responses (Figure 2C,D)
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