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Feedback Please let us know what you think of our products and services. Give Feedback. Get Information. MOL Viewer. Open Access Review. Lactic acid bacteria LAB are Gram-positive, acid-tolerant bacteria that have long been used in food fermentation and are generally recognized as safe GRAS.

LAB are a part of a normal microbiome and act as probiotics, improving the gastrointestinal microbiome and health when consumed.

An increasing body of research has shown the importance of the microbiome on both mucosal immune heath and immune response to pathogens and oral vaccines. Currently, there are few approved mucosal vaccines, and most are attenuated viruses or bacteria, which necessitates cold chain, carries the risk of reversion to virulence, and can have limited efficacy in individuals with poor mucosal health. On account of these limitations, new types of mucosal vaccine vectors are necessary. There has been increasing interest and success in developing recombinant LAB as next generation mucosal vaccine vectors due to their natural acid and bile resistance, stability at room temperature, endogenous activation of innate and adaptive immune responses, and the development of molecular techniques that allow for manipulation of their genomes.

To enhance the immunogenicity of these LAB vaccines, numerous adjuvant strategies have been successfully employed. Here, we review these adjuvant strategies and their mechanisms of action which include: Toll-like receptor ligands, secretion of bacterial toxins, secretion of cytokines, direct delivery to antigen presenting cells, and enterocyte targeting. The ability to increase the immune response to LAB vaccines gives them the potential to be powerful mucosal vaccine vectors against mucosal pathogens.

To combat with host defensive system, microorganism employs mechanisms to maintain intracellular metal homeostasis. Therefore, these mechanisms could be suitable targets for therapeutic antibody development. For example, an Fab was screened to inhibit acquisition pathway for Mn II , which is essential for detoxification of reactive oxygen species ROS [ 87 , 88 ].

In vitro assay showed that the Fab increased the sensitivity of S. An earlier report identified ABC transporter as the most commonly associated protein with IgG from the sera of 26 patients suffered with septicemia [ 89 ]. ScFvs against the conserved peptides from the ABC transporter were then panned from a phage display library and were shown to reduce the bacterial burden in a mouse model.

So far, neither passive nor active immunization has shown potent efficacy on humans. The failure from basic research to clinical practice could partly be attributed to the limited understanding of the sophisticated events associated with every stage of infection. Prior strategies targeting on single virulent factor showed efficacy only in certain experimental settings.

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In this regard, novel vaccine formulations targeting on multiple pathogenic components are proposed to offer protection from distinct aspects through a synergistic working mode. Recently, efficacy of a combination vaccine, 4C—Staph four-component S. In addition, mechanistic study showed that the protection was mainly antibody dependent.

Mucosal delivery of anti-inflammatory IL-1Ra by sporulating recombinant bacteria

SA3Ag Pfizer , a tri-component vaccine, consists of CP5 and CP8 individually linked with a nontoxic form of diphtheria toxin, and a recombinant mutant form of clumping factor A rClfAm [ 91 ]. A phase I clinical trial was completed to evaluate safety, tolerability, and effect of SA3Ag [ 92 ]. This vaccine showed a relatively safe profile among older and young adults. In order to further enhance protection against S. More excitingly, SA4Ag induced a rapid, robust, and sustained functional antibody response. While S. Meanwhile, intracellular persistence allows bacteria to escape from antibiotic and immune attack.

Indeed, most of the current antibiotics are less efficient in intracellular S.


Based on these findings, therapies specifically targeting on intracellular pathogen may promote clinical outcome. Similar to antibody-drug conjugate ADC , which has been successfully applied for cancer therapy, antibody-antibiotic conjugate AAC was first proposed and evaluated by Lehar and his colleagues in [ ]. The AAC is composed of three building blocks: an antibody to target on bacteria, a highly bactericidal antibiotic payload, and a linker to attach antibiotic payload to the antibody. The AAC was designed with no antibacterial activity as antibiotic serves as a prodrug when covalently linked.

However, when planktonic AAC-tagged bacteria are internalized by host cells, the antibiotics can be efficiently released in their active form by cleavage from host protease. To their anticipation, the AAC was shown to efficiently restrict intracellular S. In contrast, poor efficacy was observed by delayed treatment of vancomycin.

Moreover, the AAC was able to limit metastasis of S. Different from S.

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Several most-studied components include aggregation substance proteins, collagen adhesins, enterococcal leucine-rich repeat-containing proteins, pili, polysaccharides, and glycolipid [ ], which are potential targets for antibody and vaccine development. Enterococcal surface pili are filamentous proteins with Ig-like folds and LPXTG motifs, which have been implicated in biofilm formation, endocarditis, and catheter-associated urinary tract infections CAUTIs [ , ].

Endocarditis and biofilm-associated pilus A EbpA , one of the most-studied pili in Enterococci , is widely present among Enterococcal species and highly conserved in N-terminal domains [ ]. Sera against EbpANTD was recently shown to provide universal protection in a murine model by reducing bacterial titers of a broad spectrum of Enterococcal isolates, including E.

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Therefore, capsule may be a natural barrier to access therapeutic antibody by masking antigens underneath. A transcriptomic analysis from an E. Treatment of antibodies raised from recombinant proteins showed increased opsonic killing in vitro and reduced colony counts in a mouse bacteremia model. Protective role was also seen in treatment with antibodies against distinct ABC transporter proteins [ ], suggesting the potential of ABC transporter as a therapy target in enterococcal infection.

Effective control of P.

Antibodies and vaccines are considered to be a promising and alternative strategy to treat or prevent P. The identified P. PcrV is located at the tip of needle-like apparatus and closely involved in translocation of effector proteins from P. Fab 1A8, a human Fab antibody fragment, can specifically target against P. Although statistical significance was not observed for patients with KB treatment and placebo treatment, incidence of P. Moreover, human high titer anti-PcrV sera clearly have prophylactic effect for mice with lung P. By construction and phenotypic screening of human scFv phage display libraries from peripheral blood B cells of healthy individuals and patients recovered from recent P.

Also, this finding suggests that PsI can be used as a vaccine target. However, most patients suffered from P. Moreover, MEDI can synergize several classes of antibiotics for the treatment of clinical antibiotics resistant isolates [ ].

Vaccine Vehicles for Mucosal Immunization

OMPs form porins and other structural and functional components on the bacterial cell surface. CFC was safe and immunogenic in eliciting human mAbs after immunization that can passively protect mice from lethal P. In phase I human trials, OprF-OprI vaccine IC43 conjugating with aluminum hydroxide was safe and induced specific antibodies in healthy volunteers and burn patients by intramuscular administration [ , ].

Intranasal immunization of OprF-OprI vaccine followed by systemic boost elicited a long-lasting systemic and local lung mucosal antibody response in patients with chronic pulmonary diseases [ ]. Flagella are essential for motility, chemotaxis, invasiveness, and adhesion of P. Flagellin is the primary protein component of flagella and consists of subtype a and subtype b [ ]. A monovalent P. Then, a bivalent flagella vaccine, containing some of the flagella subtype antigens a0a1a2 and b , was evaluated over a 2-year period on cystic fibrosis CF patients not colonized with P. The vaccine lowered the risk of patients for initial infection as compared with that from the placebo group, though not statistically significant.

Therefore, multivalent vaccine against P. A multivalent protein fusion vaccine consisting of flagellin subtype a and b, Oprl and OprF epitope 8, was used to immunize mice that induced specific IgGs against each individual antigen [ ].

Recombinant Gram-positive bacteria as vehicles of vaccine antigens - ScienceDirect

Conjugation vaccine of flagellin subtype a FLA with polymannuronic acid PMA built from mannuronic acid, the major component of alginate and biofilm, induced protection against mucoid P. Pili, as one key virulent factor, are filaments of pilin polymers located at the pole of P. Immunization of mice with full length pilin of P.