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. 2022 Oct 7;14(19):4909. doi: 10.3390/cancers14194909

Table 2.

Lactic acid bacteria (LAB)-based vaccine studies.

Vaccines
Animal Studies
Studied Agent Route of Administration Type of Study Observed Effects Ref
Recombinant Lactobacillus casei expressing HPV16 E7 (LacE7) Mucosal (oral) Animal study - Elicit E7-specific IFN gamma-producing cells (T cells with E7-type 1 immune responses)
- Greater induction of T cells compared to subcutaneous or intramuscular antigen delivery.
- Trigger mucosal cytotoxic cellular immune responses
[185]
L. lactis MG1363 was transformed with two types of HPV16 L1-encoding plasmids for intracellular expression or secretion. Oral Animal study - Serum IgG responses after immunizations with L. lactis secreting HPV16 L1.
- Vaginal IgA immune responses after oral immunization with L. lactis expressing HPV16 L1, but secreting HPV
- HPV16 L1-specific mucosal immune responses affected by immunization frequency.
[197]
N-terminal L2 polypeptides comprising residues 11 to 200 derived from HPV16 produced in bacteria (HPV16 L2 11–200) Vaccination Animal study - Effective protection of rabbits against cutaneous and mucosal challenge with CRPV and ROPV
- Generation of broadly cross-neutralizing serum antibody - potential of L2 as a second-generation preventive HPV vaccine antigen.
[200]
A partial HPV-16 L2 protein (N-terminal 1–224 amino acid) on the surface of L. casei. Mucosal (oral) Animal study - Production of L2-specific serum IgG and vaginal IgG and IgA in Balb/c mice
- Trigger systemic and mucosal cross-neutralizing effects in mice
[201]
L. lactis NZ9000 expressing human papillomavirus type 16 E7 antigen Mucosal (oral) Animal study - Elicit the highest levels of E7-specific antibody and numbers of E7-specific CD4+ T helper and CD8+ T cell precursors.
- Potent protective effects against challenge with the E7-expressing tumour cell line (TC-1)
- pNZ8123-HPV16-optiE7 containing L. lactis showed strong therapeutic antitumour effects against established tumours in vivo.
- Trigger humoral and cellular immune responses in mice
[202]
Recombinant strains of L. lactis NZ9000 expressing native and codon-optimized E6 protein (fused to the SPusp45 secretion signal) Mucosal (oral) Animal study - Improved inhibitory effect on tumour growth, improved treatment effects on progression of tumour size, and improved survival rates in comparison with L. lactis having native E6 oncogene
- Induce humoral and cellular immunity
[203]
HPV16 E7 antigen expressed on the surface of L. casei Mucosal (oral) vaccine Animal study - Enhanced E7-specific serum IgG and mucosal IgA production.
- Reduced tumour size and increased survival rate in E7-based mouse tumour model compared to versus mice receiving control (L. casei-PgsA) immunization.
[204]
HPV16 E7-expressing L. casei (L. casei-E7) combined with γ-PGA secreted by Bacillus subtilis Mucosal (oral) vaccine Animal study (TC-1 mouse model) - Enhanced innate immune response including activation of dendritic cells
- Significantly suppressed growth of TC-1 tumour cells and an increased survival rate compared to mice vaccinated with L. casei-E7 alone.
- Markedly enhanced activation of natural killer (NK) cells, no impact on E7-specific cytolytic activity of CD8+ T lymphocytes.
[211]
Combination of adenovirus expressing calreticulin-E7 (Ad-CRT-E7) and L. lactis encoding HPV-16 E7 (Ll-E7) anchored to its surface Intranasal preimmunization of Ll-E7, followed by a single Ad-CRT/E7 application Animal study (mouse model) - ∼80% of tumour suppression compared to controls.
- 70% survival rate 300 days post-treatment (100% of controls died by 50 days).
- Significant CD8+ cytotoxic T-lymphocytes infiltration in tumours of mice treated with Ll-E7+Ad-CRT/E7.
[212]
Clinical Studies and Trials
Attenuated L. casei expressing modified full-length HPV16 E7 protein Oral (during dose optimization studies (1, 2, 4, or 6 capsules/day) at weeks 1, 2, 4, and 8 (n = 10) or optimized vaccine formulation (n = 7) Patients with HPV16-associated CIN3 - Most patients (70%) receiving the optimized dose experienced a pathological down-grade to CIN2 at week 9 of treatment
- E7-specific mucosal immunity was elicited in the uterine cervical lesions.
[192]
NZ8123-HPV16-optiE7 vaccine involving recombinant L. lactis expressing the codon-optimized human papillomavirus (HPV)-16 E7 oncogene Oral vaccine or placebo A dose-escalation, randomized, double-blind, placebo-controlled phase I clinical trial was performed in healthy Iranian volunteer women - Vaccination was well tolerated, and no serious adverse effects were reported
- Dose-dependent response to NZ8123-HPV16-optiE7 vaccine following oral administration
- Safety and immunogenicity profile achieved in this study encourages further phase II trials with the 5 × 109 CFU/mL dose vaccine
[205].
BLS-M07 (HPV 16 E7 antigen expressed on the surface of L. casei) Oral administration
Phase 1: 5 times a week, on weeks 1, 2, 4, and 8 with dosages of 500 mg, 1000 mg, and 1500 mg
Phase 2a: 1000 mg dose.
A phase 1/2a, dose-escalation, safety, and preliminary efficacy study performed in patients with CIN 3 - No dose limiting toxicity.
- No grade 3 or 4 treatment-related adverse events or deaths
- Improved RCI grading (16 weeks after treatment)
- Increased serum HPV16 E7 specific antibody production.
[206]