Strategies for Enhancement of Live-Attenuated Salmonella-Based Carrier Vaccine Immunogenicity

Abstract

: The use of live-attenuated bacterial vaccines as carriers for the mucosal delivery of foreign antigens to stimulate the mucosal immune system was first proposed over three decades ago. This novel strategy aimed to induce immunity against at least two distinct pathogens using a single bivalent carrier vaccine. It was first tested using a live-attenuated Salmonella enterica serovar Typhi strain in clinical trials in 1984, with excellent humoral immune responses against the carrier strain but only modest responses elicited against the foreign antigen. Since then, clinical trials with additional Salmonella-based carrier vaccines have been conducted. As with the original trial, only modest foreign antigen-specific immunity was achieved in most cases, despite the incorporation of incremental improvements in antigen expression technologies and carrier design over the years. In this review, we will attempt to deconstruct carrier vaccine immunogenicity in humans by examining the basis of bacterial immunity in the human gastrointestinal tract and how the gut detects and responds to pathogens versus benign commensal organisms. Carrier vaccine design will then be explored to determine the feasibility of retaining as many characteristics of a pathogen as possible to elicit robust carrier and foreign antigen-specific immunity, while avoiding over-stimulation of unacceptably reactogenic inflammatory responses.

Live-Attenuated Salmonella-Based Oral Vaccine Candidates Expressing PCV2d Cap and Rep by Novel Expression Plasmids as a Vaccination Strategy for Mucosal and Systemic Immune Responses against PCV2d

“…In this study, the oral vaccination of the vaccine candidates elicited a broad spectrum of immunity, covering both systemic and mucosal sites through the safe and efficient vaccine delivery of the Salmonella vaccine strain to different organs such as liver, spleen, and lungs [ 29 , 35 , 36 ] and expression of the target antigens, Cap and Rep, in antigen-presenting cells ( Figure 2 ). Salmonella Typhimurium is one of several bacterial species that can transfer eukaryotic expression plasmids into host cells, which can serve as a carrier for vaccine antigens or its genetic material [ 37 , 38 ]. Several studies have also demonstrated that oral vaccination with a live-attenuated Salmonella Typhimurium carrying immunogenic and protective homologous antigens of the target pathogens can induce humoral, cellular, and mucosal immune responses as well as protect animal models from challenges with either human or animal pathogens [ 18 , 39 , 40 , 41 ].…”

Development of a Trivalent Construct Omp18/AhpC/FlgH Multi Epitope Peptide Vaccine Against Campylobacter jejuni

“…Therefore, it is of utmost practical significance to develop a genetically engineered vaccine that is novel, efficient, and safe against C. jejuni . Over the recent years, the MAP vaccine has become a hotspot issue during the research and development of the third generation genetic engineering vaccine against pathogenic microorganisms thanks to its numerous advantages, including but not limited to the ability to simultaneously present multiple antigen epitopes; strong antigen presentation; establishment of constitutional epitopes after non-covalent binding between each antigen-peptide branch; enhanced immune effect; and the fact that individual amino acid mutations will not affect antigen presentation and subsequent immune response ( Neal-McKinney et al, 2014 ; Hisham and Ashhab, 2018 ; Galen et al, 2021 ). However, there have been no reports on the MAP vaccine against C. jejuni so far.…”

Mucosal Vaccination: A Promising Alternative Against Flaviviruses

“…The facultative anaerobic Gram-negative S. enterica is an important pathogen of animals and humans, causing a variety of infectious diseases. It has also demonstrated its potential as a live attenuated bacterial vector to carry heterologous antigens for vaccine purposes ( Galen et al., 2016 ; Galen et al., 2021 ). After the oral administration and following the natural route of infection, S. enterica colonizes internal lymphoid tissues and remains there to continuously synthesize (as inner factories) and deliver recombinant antigens.…”