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Intro: Vaccination has not only become vital but a lot of revolutionary changes are being observable in the field of vaccine delivery. Vaccine antigens administered by the oral route are often degraded during gastrointestinal transit. Methods: Bile salt stabilized vesicles i.e. bilosomes are found to be effective in preventing antigen degradation and enhance mucosal penetration. The aim of the present work was to prepare a combination vaccine system against hepatitis- B (HBsAg) and influenza(r-H1N1Ags). Bilosomes containing HBsAg and r- H1N1Ags were prepared by a lipid cast film method. Findings: Antigen loaded bilosomes were characterized in-vitro for their shape, size, percent antigen entrapment and stability. Fluorescence microscopy was carried out to confirm the uptake of bilosomes. The in-vivo study comprised of estimation of IgG response in serum and sIgA in various body secretions using specific ELISA. Discussion: Bilosomes formed were multilamellar and were stable in gastric and intestinal fluids. Fluorescence microscopy suggested that bilosomes were taken up by gut-associated lymphoid tissues. In-vivo data demonstrates that bilosomes produced both systemic as well as mucosal antibody responses upon oral administration at higher dose levels as compared to intramuscular immunization but fail to produce any synergistic effect. Conclusion: Thus, HBsAg potentiates the production anti-r-H1N1 antibody. Also measurable sIgA in mucosal secretions were observed. Thus, bilosomes are a promising carrier for oral combination vaccines. This approach could be adapted for human use because mucosal surfaces are initial sites of infection and it therefore seems logical to attempt to develop vaccination strategies that evoke appropriate localized responses to counteract early events of pathogenesis.