Development of vaccines for effective control of pathogens in poultry and wild birds is in high demand. Among the many vaccine strategies, Salmonella-based vaccines that carry an antigenic property of selected pathogens is a promising strategy. Combining three technologies: overlapping extension PCR, Red recombinase system and the use of Scel enzyme site as a negative selection marker, we have recently created a novel low cost Salmonella-based vaccine system which targets short, linear and highly conserved epitopes displayed by the selected pathogens. Wild type Salmonella enteritidis 13A was attenuated (Δ aroA/ΔhtrA) and the genome was manipulated to display either M2e protein epitopes of Avian Influenza (Al) or outer membrane protein epitopes (cj0420, cj0113, or cj0982) of Campylobacter spp. as a fusion to the outer membrane protein LamB. In addition, a short 10aa sequence of CD154 (WAEKGYYTMS) was inserted to test its potential immune-enhancing function. In one set of experimental vaccination studies against Avian Influenza in chickens we demonstrated that chickens vaccinated with Δ aroA M2e-CD154, ΔhtrA M2e-CD154 or Δ aroA-ΔhtrA M2e(4)-CD154 exhibited significantly increased specific M2e-IgG titers when compared to chickens receiving saline only. Virus neutralization assays using chicken embryos gave neutralizing indices in the range of 5.8-6.3 (7.8 for positive control), indicating effective neutralization of Al by serum IgG of vaccinated chickens. In a subsequent direct challenge study, SPF Leghorn chicks immunized with Δ aroA-ΔhtrA M2e(4)-CD154 offered significant protection against direct challenge with low pathogenic Al (LPAl) H7N2, but not highly pathogenic H5N1 Al. In a another set of vaccination experiments directed at Campylobacter jejuni (C. jejuni), chickens were vaccinated by oral gavage at day 1, with the attenuated Salmonella-vectored vaccine candidates (cj0420, cj0113, or cj0420) then challenged with C.jejuni on day 21. All three-candidate vaccines produced good humoral immune responses with high levels of serum IgG and ileum slgA with the best response from the cj0113 candidate. C. jejuni challenge of all three candidate vaccinated group's decreased C. jejuni recovery from the ileum with the cj0113 candidate reducing C. jejuni to non-detectable levels. These results provide strong evidence that the Salmonella-vectored vaccines may provide a very effective tool to combat viral and bacterial pathogens; as well as other infectious agents.