BCG based vaccine compositions and methods of use thereof
The present disclosure relates to a BCG based therapeutic agent using a BCG strain that overexpresses the STING agonist, c-di-AMP. This BCG strain, called BCG-disA-OE, enhances the elevated trained immunity of macrophages and promotes early anti-viral Type I interferon responses in a subject, providing protection against viral infections such as primary respiratory infections and SARS-CoV-2 infection.
1 . A method of preventing, ameliorating or treating a viral infection in a subject comprising administering to the subject a recombinant bacille Calmette-Guerin (BCG) bacterial strain of Mycobacterium bovis comprising an exogenous nucleic acid construct comprising:
a mycobacterial promoter and a disA gene,
wherein the disA gene is a Mycobacterium tuberculosis gene, and
wherein the viral infection is a primary respiratory infection thereby treating the infection.
2 . The method of claim 1 , wherein the infection is a SARS-CoV-2 infection.
3 . The method of claim 1 , wherein the subject has a condition selected from the group consisting of obesity, diabetes, cystic fibrosis (CF), non-cystic-fibrosis bronchiectasis, and HIV/AIDS.
4 . The method of claim 1 , wherein the bacterial strain over expresses a stimulator of interferon genes (STING) agonist.
5 . The method of claim 4 , wherein the STING agonist is c-di-AMP.
6 . The method of claim 1 , wherein the disA gene is fused to the mycobacterial promoter.
7 . The method of claim 1 , wherein the nucleic acid construct does not have kanamycin resistance markers.
8 . The method of claim 1 , wherein the bacterial strain is optionally resistant to kanamycin.
9 . The method of claim 1 , wherein the bacterial strain comprises a selectable marker.
10 . The method of claim 1 , wherein the mycobacterial promoter is Hsp60 promoter.
11 . The method of claim 1 , wherein the exogenous nucleic acid construct further comprises a ppiA signal sequence and optionally a spike protein of SARS-COV-2.
12 . The method of claim 1 , wherein the exogenous nucleic acid construct further comprises a ppiA signal sequence and optionally the receptor binding domain of the spike protein of SARS-COV-2.
13 . The method of claim 11 , wherein the nucleic acid construct further comprises a signal peptide.
14 . The method of claim 13 , wherein the signal peptide comprises a ppiA signal sequence.