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

Abstract

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: Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Klebisella pneumoniae, Branhamella catarrhalis and Haemophilus influenzae. 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.

Keywords: MV130; bacteria; cross-reactivity; epitope; influenza A virus; respiratory viruses.

Figure 1

Comparison of peptidomes shared by respiratory viruses and bacteria in MV130. The sets of peptides that are shared between 8 respiratory viruses and each bacterium included in the MV130 formulation were compared and represented using Venn diagrams to visualize the overlaps. The number of peptides in overlapping and non-overlapping regions is indicated. The represented viruses are (from left to right and up to down): IAV: Influenza A virus; IBV: Influenza B virus; HRVA: human rhinovirus A; HRVB: human rhinovirus B; HRVC: human rhinovirus C, RSVA: Respiratory Syncytial virus A, RSVB: Respiratory Syncytial virus B; SARS: SARS-CoV-2. The six bacteria species included in MV130 are indicated and colored as follows: S. pneumoniae (SPN, red); S. aureus (SAU, green); S. epidermidis (SEP, yellow); K. pneumoniae (KPN, blue); B. catarrhalis (BCA, orange); H. influenzae (HIN, purple).

Figure 2

Antigen-size distribution of MV130 cross-reactive CD8 T cell epitopes in IAV. (A) Contribution to χ² -statics of each IAV antigen for the distribution of cross-reactive epitopes according to the size of antigens (B) Representation of the number of observed (grey bars) and expected (black bars) cross-reactive CD8 T cell epitopes in each IAV antigen. The number of residues of each antigen is shown in parenthesis adjacent to the antigen name.

Figure 3

Cross-reactive B cell epitopes between MV130 and HA. (A) Molecular surface of HA with ribbon structure underneath showing cross-reactive B cell epitopes. HA1 and HA2 chains have been colored in blue and pink, respectively, and the RBD in yellow. Cross-reactive epitopes mapping in HA1 and HA2 are colored in orange and deep purple, respectively. Globular and stem domains are labeled as well as the RBD. The regions circled and labeled as B and C points to cross-reactive B cell epitopes PDESSWPN and AIAGQIEG, which are zoomed in the corresponding right panels. (B) Stick rendering of cross-reactive B cell epitope PDESSWPN. (C) Detail of cross-reactive B cell epitope AIAGQIEG in stick rendering.