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.
Highlights
The concept of bacterial-based carrier vaccines rests on the notion that an attenuated strain of bacteria, genetically engineered to be safe yet still immunogenic, can be further engineered by the introduction of additional genes encoding protective antigens from unrelated pathogens; the resulting multivalent candidate vaccine should be capable of eliciting biologically relevant protective immune responses against both the carrier vaccine itself as well as the additional target pathogens
A When provided in publication, the specific expression plasmid is listed; B Subjects primed orally with carrier vaccine and boosted with purified adjuvanted foreign antigen via the intramuscular (IM, adjuvanted with Al(OH)3) route; C Both 9639 and 9640 carry engineered araC-controlled mutations in multiple chromosomal loci, which become attenuating as the carrier vaccine replicates in vivo and diminishes intracellular concentrations of arabinose; 1 Plasmodium falciparum circumsporozoite surface protein; 2 protein fusion of peptide fragments from the hepatitis B virus core protein (HBcAg), pre-S1, and pre-S2 regions of the envelope protein (HBsAg); 3 non-toxigenic fragment C of tetanus toxin; 4 Helicobacter pylori urease subunits A and B
We have explored the current state of carrier vaccine performance in clinical trials and have further discussed the influence of four key factors in determining immune responses against both the carrier strain itself and, perhaps more importantly, the foreign antigen (Tables 1 and 2)
Summary
The concept of bacterial-based carrier vaccines rests on the notion that an attenuated strain of bacteria, genetically engineered to be safe yet still immunogenic, can be further engineered by the introduction of additional genes encoding protective antigens from unrelated pathogens; the resulting multivalent candidate vaccine should be capable of eliciting biologically relevant protective immune responses against both the carrier vaccine itself as well as the additional target pathogens. A When provided in publication, the specific expression plasmid is listed; B Subjects primed orally with carrier vaccine and boosted with purified adjuvanted foreign antigen via the intramuscular (IM, adjuvanted with Al(OH)3) route; C Both 9639 and 9640 carry engineered araC-controlled mutations in multiple chromosomal loci, which become attenuating as the carrier vaccine replicates in vivo and diminishes intracellular concentrations of arabinose; 1 Plasmodium falciparum circumsporozoite surface protein; 2 protein fusion of peptide fragments from the hepatitis B virus core protein (HBcAg), pre-S1, and pre-S2 regions of the envelope protein (HBsAg); 3 non-toxigenic fragment C of tetanus toxin; 4 Helicobacter pylori urease subunits A and B. To gain insights into mechanisms potentially influencing the immunogenicity of live oral Salmonella-based carrier vaccines and the antigens that they co-express, we will briefly step back to examine a broader question of how the human intestine regulates immunity against pathogens versus non-pathogenic bacteria in the gut
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