An RNA-Based Vaccine Platform for Use against Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis (M.tb), a bacterial pathogen that causes tuberculosis disease (TB), exerts an extensive burden on global health. The complex nature of M.tb, coupled with different TB disease stages, has made identifying immune correlates of protection challenging and subsequently slowing vaccine candidate progress. In this work, we leveraged two delivery platforms as prophylactic vaccines to assess immunity and subsequent efficacy against low-dose and ultra-low-dose aerosol challenges with M.tb H37Rv in C57BL/6 mice. Our second-generation TB vaccine candidate ID91 was produced as a fusion protein formulated with a synthetic TLR4 agonist (glucopyranosyl lipid adjuvant in a stable emulsion) or as a novel replicating-RNA (repRNA) formulated in a nanostructured lipid carrier. Protein subunit- and RNA-based vaccines preferentially elicit cellular immune responses to different ID91 epitopes. In a single prophylactic immunization screen, both platforms reduced pulmonary bacterial burden compared to the controls. Excitingly, in prime-boost strategies, the groups that received heterologous RNA-prime, protein-boost or combination immunizations demonstrated the greatest reduction in bacterial burden and a unique humoral and cellular immune response profile. These data are the first to report that repRNA platforms are a viable system for TB vaccines and should be pursued with high-priority M.tb antigens containing CD4+ and CD8+ T-cell epitopes.

Protective RNA nanovaccines against Mycobacterium avium subspecies hominissuis

“…Indeed, it has been previously shown that RNA vaccine (repRNA-ID91/ID91+GLA-SE) encoding four M. ah antigens produced significant cellular and humoral immune responses leading to reduced bacterial burden (33). The same group showed that repRNA-ID91/ID91+GLA-SE provided similar protection against M. tb infection in mice (29). However, the highest protection generated by this vaccine was when it is used in a prime (RNA)-boost (protein) regimen (29,33).…”

“…The same group showed that repRNA-ID91/ID91+GLA-SE provided similar protection against M. tb infection in mice (29). However, the highest protection generated by this vaccine was when it is used in a prime (RNA)-boost (protein) regimen (29,33). Beyond design, mRNA vaccines require sufficient immunostimulatory adjuvants to achieve optimal protective efficacy (49, 50).…”

“…Currently, there is no licensed vaccine for M. ah infection, a significant health problem for the aging and immunocompromised population (26,27). In pursuit of addressing this problem, several platform technologies were tested before including nucleic acid (NA) vaccines (28)(29)(30). Mycobacteria rely on a plethora of antigens to drive its virulence in the host making vaccine development a challenge (31,32), and M. ah is not an exception.…”

Clinical manifestations and immune response to tuberculosis

“…Excitingly, prime-boost strategy groups that received heterologous RNA-prime, protein-boost or combination immunisations had the greatest reduction in bacterial burden and a unique humoral and cellular immune response profile. Such data represents the first report that repRNA platforms are a viable system for TB vaccines and should be pursued using high-priority Mtb antigens containing CD4 + and CD8 + T-cell epitopes (Larsen et al 2023 ).…”

mRNA vaccines: a new opportunity for malaria, tuberculosis and HIV

“…Intranasal immunisation with naked mRNA coding for Hsp65 protein also demonstrated significant protection against M.tb in mouse model ( 145 ). More recently, a replicating mRNA-based vaccine coding for a fusion protein comprising 4 M.tb Antigens (Rv3619, Rv2389, Rv3478, Rv1886) formulated with a lipid nanocarrier induced cellular immune response and protection against M.tb and M. avium challenge in mice in a heterologous RNA-prime and protein-boost vaccination protocol ( 146 , 147 ). Of note, a phase I clinical trial evaluating two investigational RNA-based vaccines against TB in BCG-vaccinated volunteers have been launched by BioNTech ( Table 1 ).…”