Development and evaluation of candidate recombinant Salmonella-vectored Salmonella vaccines

Abstract

Attenuated Salmonella Enteriditis (ΔSE) recombinant vaccine vectors incorporating a Salmonella flagellar filament protein (fliC) subunit, a putative cell-mediated epitope, for expression of the lamB gene (encoding a maltose outer membrane porin), with or without co-expression of a putative immune-enhancing CD154 oligopeptide, were developed and compared with wild-type Salmonella Enteriditis (experiments 1 and 2) or the attenuated ΔSE empty vector (experiment 3) as initial vaccine candidates against Salmonella infection. A total of 3 experiments were performed to assess the infection and clearance rate of each of these constructs. Each construct or Salmonella Enteriditis was orally administered to broiler chicks at day of hatch by oral gavage (~10(8) cfu/chick). In experiments 1 to 3, liver-spleen and cecal tonsils were removed aseptically for recovery of wild-type Salmonella Enteriditis or ΔSE mutants. These experiments suggested that cell surface expression of fliC alone markedly increased the clearance rate of the vector at or before 21d postvaccination in all 3 experiments. In a fourth experiment, broilers were vaccinated with one of the vaccine constructs or the ΔSE empty vector and then challenged with wild-type Salmonella Typhimurium. At 19 d posthatch, 16 d postinfection, neither candidate protected against challenge significantly better than the ΔSE empty vector, although there was significantly less Salmonella recovered from vaccinated chickens as compared with nonvaccinated controls. These experiments indicate that these experimental vaccines did not protect against heterologous challenge or enhance clearance after Salmonella Typhimurium challenge; as such, their value as vaccines is limited. The increased clearance of the candidate vaccines, particularly the vector expressing fliC alone, may have value in that the fliC epitope may decrease the clearance time of other recombinant vectored Salmonella vaccines.

Altered host immune responses to membrane vesicles from Salmonella and Gram-negative pathogens

“…Gram-negative MVs contain several compounds recognized by host microbial pattern-recognition receptors [26,[30][31][32]. Our group and others have suggested that MVs are the biologically relevant form of pathogen-associated molecular pattern (PAMP) complexes recognized by host defenses in vivo [9,[33][34][35]. Additional work has demonstrated the utility of S. Typhimurium MVs as a strong inducer of immunity against S. Typhimurium, but also as a carrier for antigens against other pathogens [36][37][38] when genetically expressed in the parental bacteria.…”

“…In this effort, attenuated microbial vaccine vectors are intensively studied as an alternate strategy to induce prophylactic immunity to infection [5]. Of these, Salmonella enterica Typhimurium, a Gram-negative facultative intracellular bacterial pathogen that causes gastroenteritis in humans and livestock, and systemic disease in mice, is a leading bacterial vector being tested in strategies for inducing protective immunity to a variety of pathogens [6][7][8][9].…”

Immunomodulatory effects of recombinant BCG expressing MSP-1C ofPlasmodium falciparumon LPS- or LPS+IFN-γ-stimulated J774A.1 cells

“…10,13,19,20 However, overproduction of inflammatory cytokines and NO leads to malarial anemia. [20][21][22] Development of recombinant DNA using live vectors from viruses 23,24 and bacteria [25][26][27][28] to deliver foreign antigens to the immune system has become a popular technique nowadays for developing new generation vaccines. Mycobacterium bovis bacille Calmette-Guérin (BCG), the only vaccine currently available for the prevention of tuberculosis, is among the most extensively used vector for developing recombinant vaccines for other diseases, including malaria.…”

Engineering commensal bacteria for prophylaxis against infection

“…Attenuated pathogens or LAB have been engineered to function as vaccine delivery vehicles against pathogens including Yersinia pseudotuberculosis [27], Salmonella Typhimurium [28,29], and Pneumococcal nasopharyngeal [30,31]. One particular study by Mohamadzadeh et al showed that a recombinant LAB vaccine could be as effective as a traditional injected vaccine in an animal model [32•].…”