Combining different bacteria in vaccine formulations enhances the chance for antiviral cross-reactive immunity: a detailed analysis for influenza A virus.

Bacteria are well known to provide heterologous immunity against viral infections through various mechanisms including the induction of innate trained immunity and adaptive cross-reactive immunity. Cross-reactive immunity from bacteria to viruses is responsible for long-term protection and yet its role has been downplayed due the difficulty of determining antigen-specific responses. Here, we carried out a systematic evaluation of the potential cross-reactive immunity from selected bacteria known to induce heterologous immunity against various viruses causing recurrent respiratory infections. The bacteria selected in this work were Bacillus Calmette Guerin and those included in the poly-bacterial preparation MV130: , , , , and . The virus included influenza A and B viruses, human rhinovirus A, B and C, respiratory syncytial virus A and B and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Through BLAST searches, we first identified the shared peptidome space (identity ≥ 80%, in at least 8 residues) between bacteria and viruses, and subsequently predicted T and B cell epitopes within shared peptides. Interestingly, the potential epitope spaces shared between bacteria in MV130 and viruses are non-overlapping. Hence, combining diverse bacteria can enhance cross-reactive immunity. We next analyzed in detail the cross-reactive T and B cell epitopes between MV130 and influenza A virus. We found that MV130 contains numerous cross-reactive T cell epitopes with high population protection coverage and potentially neutralizing B cell epitopes recognizing hemagglutinin and matrix protein 2. These results contribute to explain the immune enhancing properties of MV130 observed in the clinic against respiratory viral infections.