BECC-adjuvanted hemagglutinin influenza vaccine promotes enhanced immunogenicity and protective efficacy.

Seasonal influenza viruses continue to pose a significant threat, causing substantial morbidity and mortality in the US and worldwide despite the availability of vaccines and antivirals. These challenges may be addressed by improving vaccine immunogenicity through the inclusion of adjuvants that enhance immune responses against key antigens, including influenza hemagglutinin (HA). BECC (Bacterial Enzymatic Combinatorial Chemistry) adjuvants are novel Toll-like Receptor 4 (TLR4) ligands created by modifying enzymes from lipid A synthesis pathways in Gram-negative bacteria. This study specifically evaluated the immunogenicity and protective efficacy of biologically derived and fully synthetic Bacterial Enzymatic Combinatorial Chemistry (BECC) lipid A-based adjuvants in combination with recombinant hemagglutinin (rHA) antigens in a murine model of influenza virus infection. Immunization with BECC-adjuvanted rHA elicited strong activation of both humoral and cellular immune responses. Notably, BECC formulations induced robust HA-specific antibody responses, with a marked increase in the Th1-associated IgG2a subclass as compared to the benchmark adjuvants monophosphoryl lipid A (MPL) and PHAD. Among the BECC candidates, the synthetic compound BECC470s demonstrated superior efficacy, with rapid viral clearance observed by seven days post-challenge. Additionally, BECC-adjuvanted vaccination enhanced immune recognition of linear B- and T-cell epitopes and sustained durable immune memory responses for up to eighteen months following immunization. Collectively, these findings highlight BECC470s as a promising next-generation synthetic adjuvant with substantial potential for improving the breadth and durability of immune protection afforded by recombinant influenza vaccines.