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Table 1. Some probiotics are designed as mucosal vaccines
Expression Route of Targeting
Strains Antigen Response method Ref.
vector vaccination pathogens
Lactococcus pMG36e Oral Clostridioides Non-toxic C-terminal The immunized mice all produced high [137]
lactis ATCC difficile receptor binding levels of IgG and IgA antibodies
11454 domains of the toxins
TcdA and TcdB
Lactococcus pTnis Endonasal Streptococcus PspA Associated with a shift to a Th1-mediated [127]
lactis F17847 pneumoniae immune response characterized by
reduced PspA antibody potency
Lactococcus pNZ8110 Oral Helicobacter Lpp20 antigen Significantly elevated serum Lpp20- [130]
lactis NZ3900 pylori specific IgG antibody levels
Lactobacillus pSIP409 Oral Trichinella, Tsgal Triggered significant intestinal mucosal [129]
plantarum NC8 Trichinella sIgA responses and specific systemic
spiralis Th1/Th2 immune responses
Lactococcus pNZ8148- Oral Helicobacter Urease, HpaA, HSP60, Showed increased levels of antibodies [131]
lactis NZ9000 SAM plSAM- pylori NAP against Helicobacter pylori, including IgG
WAE and sIgA, and significantly reduced
Helicobacter pylori colonization
EcN pNZ8148 Oral, endonasal Birch and pollen Bet v 1 Phl p 1, Phl p 5 Intra-application of EcN-Chim [138]
allergens significantly reduced lung inflammation,
decreased specific IgE levels, and
increased specific IgA and IgG2a levels
EcN pEHLYA2-SD Oral, rectal HIV gp41 protein Secretion of C52-HlyA218 peptide [139]
inhibits HIV infection of human
peripheral blood mononuclear cells in
vitro
EcN ΔdapB pKT-5M2e- Endonasal Influenza A 5M2e antigen EcN-5M2e induces effective humoral, [140]
HlyABD virus mucosal, and T cell responses

PsPA: Pneumococcal surface protein A; Tsgal: Trichinella spiralis galactose agglutinin; EcN: Escherichia coli Nissle 1917; HIV: human
immunodeficiency virus.

Viral infections like high-risk HPV-16 are closely associated with tumorigenesis, implying that recombinant
Lactobacillus vaccines targeting these viruses may exert antitumor effects. This hypothesis was validated in
an experimental animal study conducted by Mohseni et al. . They utilized the vector pNZ8123-HPV16-
[141]
optiE7 to express the HPV-16 E7 antigen in the Lactococcus lactis NZ9000 strain, which was orally
administered to female mice. This approach induced high levels of E7-specific antibodies, along with a
+
+
robust presence of E7-specific CD4 T helper cells and CD8 T cell precursors, thereby demonstrating
potent protection against an E7-expressing tumor cell line (TC-1) . In a related study, Li et al. engineered
[141]
Lactococcus lactis to co-express HPV-16 E7 protein and IL-12, thereby enhancing mucosal immune
activation through intranasal administration. IL-12 functions as an immune adjuvant, stimulating a Th1-
type immune response and enhancing IFN-γ production, which in turn boosts cytotoxic T-lymphocyte
[142]
(CTL) activity and enhances tumor cell killing .
In addition to probiotic Lactococcus lactis, EcN has demonstrated significant potential for mucosal vaccine
development. As early as the last century, the non-fimbrial adhesin AIDA-I associated with diffuse adhesion
of enteropathogenic Escherichia coli (EPEC) was successfully cloned and expressed, contributing to the
AIDA autotransporter system . Subsequent studies explored integrating this system into EcN’s cell
[143]
membrane using synthetic biology, incorporating virulence factor antigens to display heterologous
polypeptides on the bacterial surface. This approach aims to activate the host mucosal immune system upon
mucosal administration, potentially producing immunoprotective effects . On this basis, the plasmid
[144]
pAIDA1-SP, containing the SARS-CoV-2 spike protein (SP) gene, was designed and transfected into EcN.
This innovation resulted in the development of a mucosal vaccine against COVID-19, which induced time-
dependent increases in specific IgG and IgA antibodies in mice following both oral and intranasal