BackgroundCurrent eradication therapies for Helicobacter pylori (H. pylori) are increasingly compromised by the emergence of antibiotic resistance and adverse side effects. Exploration of non-antibiotic, targeted therapeutic alternatives is essential for effective H. pylori management.AimTo evaluate the therapeutic efficacy of a rationally designed specific antiserum targeting a BabA189−244-FrpB4380−395 fusion peptide against H. pylori infection.MethodsUsing immunoinformatics, the Leb antigen binding domain of BabA (residues 189–244) and the immunogenic regions of FrpB4 (residues 380–395) were selected and synthesized as a fusion peptide. This engineered peptide was used to immunize rabbits to generate specific polyclonal antiserum. The direct antimicrobial effect was evaluated via an in vitro disk diffusion assay, and its impact on H. pylori adhesion to AGS (human gastric adenocarcinoma cell line) was assessed following bacterial pre-incubation with the antiserum. In vivo, C57BL/6J mice were inoculated intragastrically with H. pylori (1 × 109 CFU). After confirming bacterial colonization in the gastric mucosa, the infected mice (n=6 per group) received a daily oral administration of the antiserum (0.2 mL) for 2 weeks. Therapeutic efficacy was quantified via gastric bacterial load counting, urease activity measurement, and histological evaluation.ResultsImmunization with the BabA189−244-FrpB4380−395 fusion peptide successfully elicited high-titer specific antibodies. In vitro, the antiserum significantly restricted H. pylori growth and reduced bacterial adherence to AGS cells (P < 0.05). In vivo, 2 weeks of oral antiserum administration markedly reduced the gastric bacterial burden, suppressed mucosal urease activity (P < 0.05), and attenuated histological colonization compared with untreated controls.ConclusionsThe specific antiserum targeting the BabA-FrpB4 fusion peptide exhibits significant antimicrobial and anti-adhesive activities against H. pylori, effectively restricting gastric colonization in vivo. This immunotherapeutic approach represents a viable non-antibiotic strategy for H. pylori intervention.