Abstract: Helicobacter pylori is a leading cause of gastric mucosal inflammation, peptic ulcers, and gastric adenocarcinoma. Emerging antimicrobial-resistant H. pylori has hampered the successful eradication of frequent chronic infections. Additionally, due to the absence of effective vaccines against H. pylori, a safe vaccine is highly demanded. Disclosed herein are innovative Protective Immunity Enhanced Salmonella Vaccine (PIESV) vector strains to deliver and express multiple H. pylori antigen genes Immunization of mice with a vaccine delivering the HpaA, NapA (also termed Hp-NAP), UreA and UreB antigens, provided sterile protection against H. pylori SS1 infection in 7 out of 10 tested mice. Compared to the control groups that had received PBS or a PIESV with an empty vector, immunized mice exhibited specific and significant cellular recall responses and antigen-specific IgG2c, IgG1, total IgG and gastric IgA antibody titers.