A loopless subdomain of transferrin binding protein B can elicit a broadly cross-reactive humoral immune response targeting variants from both encapsulated and non-typeable Haemophilus influenzae

Haemophilus influenzae, a Gram-negative bacterium responsible for pneumonia, otitis media, and invasive infections, remains a significant health concern due to the presence of non-b serotypes and non-typeable strains. A highly effective vaccine exists for H. influenzae serotype b, yet a broadly cross-protective vaccine remains necessary to combat all H. influenzae strains.

Researchers focused on the surface lipoprotein component, transferrin binding protein B (TbpB), which is universally present but essential for bacterial colonization and pathogenesis. By examining the sequence and structural diversity of TbpB variants from various H. influenzae isolates, they discovered that these sequences cluster independently of encapsulation status, indicating that a TbpB-based vaccine could potentially protect against all H. influenzae strains.

Analysis of the TbpB structure revealed that the C-terminal lobe (C-lobe) contains several large, highly variable loops. While immunizing mice with a trivalent vaccine consisting of representative TbpB variants yielded modest cross-reactivity, immunizing with a loopless C-lobe (LCL) that lacked these loops resulted in broad cross-reactivity against a range of intact TbpB variants.

This suggests that a vaccine consisting of a single LCL may generate a sufficiently cross-reactive antibody response, potentially conferring broad protection against both encapsulated and non-typeable H. influenzae strains.