Phase 1 Safety and Immunogenicity Trial of Recombinant Lactococcus lactis Expressing Human Papillomavirus Type 16 E6 Oncoprotein Vaccine

Abstract

The present study purposed to investigate the safety, tolerability, and immunogenicity of the therapeutic NZ8123-HPV16-optiE6 vaccine, following oral vaccination. The safety and tolerability were evaluated. Specific serum immunoglobulin G (IgG) and vaginal IgA antibodies were calculated by ELISA, and E6-specific IFN-γ-secreting T cells were counted by enzyme-linked immune absorbent spot (ELISpot) assay in cervical lymphocytes and PBMC samples. The vaccine was well tolerated, and no serious adverse effects were observed in vaccine recipients. Statistical analysis showed that all vaccine groups had significant increases in antibody levels at day 60 after baseline. The time to peak activation in E6-specific IFN-γ-secreting CD8+ CTL responses was seen at month 1 after last vaccination. According to the results, the humoral immune and cell-mediated responses for the vaccine groups that received 5 × 109 and 1 × 1010 CFU/mL of vaccine were similar and were higher than those of the 1 × 109 CFU/mL group, indicating the dose-dependency of the NZ8123-HPV16-optiE6 vaccine following oral administration. Low antibody levels compared with the placebo groups were recorded at month 6 after the last vaccination. Interestingly, long-term E6-specific CTL responses were observed during follow-up. It was concluded that oral immunization with the NZ8123-HPV-16-optiE6 vaccine is safe, induces persistent immunity, and is reasonably well tolerated.

Twenty years of research on HPV vaccines based on genetically modified lactic acid bacteria: an overview on the gut-vagina axis

“…They showed that oral consumption of recombinant L. casei in patients suffering from CIN3 can increase E7-specific cell-mediated immune responses in cervical lymphocytes [51]. Also, previous data, supporting the data published by Kawana et al, revealed that L. lactis vaccine, as for L. casei, can induce a systemic cell-mediated immunity which is weaker than mucosal cell-mediated immunity in the cervix and at mucosal inductive sites [49,50]. In agreement with reports by Iranian scientists regarding prophylactic and therapeutic role of recombinant L. lactis to fight against HPV-16, Korean researchers emphasized that oral immunization with L. casei vaccine harboring a modified HPV-16 E7 antigen (BLS-M07) can induce protective humoral immune responses via generating HPV-16 E7-specific IgG plasma antibody [52].…”

“…To address these shortcomings, in recent years, the next generations of HPV vaccines including LAB-based HPV vaccines have been developed and reached the clinical trial studies. Their results indicated that this type of vaccines can elicit both potent humoral and mucosal immune responses against E6 and E7 transforming proteins [49][50][51][52][53]. Data from preclinical studies [20,35] supported the results of phase I clinical trials of Iranian researchers and reported that L. lactis vaccines could produce HPV-16 specific serum-IgG and vaginal-IgA antibodies, along with CTL response in PBMCs and vaginal discharge of sexually active healthy females.…”

“…Data from preclinical studies [20,35] supported the results of phase I clinical trials of Iranian researchers and reported that L. lactis vaccines could produce HPV-16 specific serum-IgG and vaginal-IgA antibodies, along with CTL response in PBMCs and vaginal discharge of sexually active healthy females. Also, long-term E6-and E7-specific CTL responses were obtained during the 6-month follow-up period in the same participants [49,50]. Furthermore, the efficacy and safety of L. casei vaccine harboring a modified HPV-16 E7 antigen in patients with CIN 3 was evaluated by Kawana et al through phase I/IIa clinical trial.…”

Mucosal Vaccination with Lactococcus lactis-Secreting Surface Immunological Protein Induces Humoral and Cellular Immune Protection against Group B Streptococcus in a Murine Model

“…Viral, bacterial, and parasitic antigens have been expressed in L. lactis, and recombinant strains have been shown to be capable of delivering antigens at the intestinal mucosal sites, inducing a specific immune response in mice [23,24]. It has also been demonstrated that L. lactis can survive passage through the gastrointestinal tract in animals and human volunteers without colonizing it, which makes it a good candidate for vaccines in humans [25][26][27]. Immunization with L. lactis has advantages due to the vaccine adjuvant properties of its peptidoglycan wall and can also be used as a protein expression system that ensures the expression of the antigen [28].…”

<p>Therapeutic Vaccines for HPV-Associated Malignancies</p>

“…101 This oral vaccine (NZ8123-HPV-16-optiE6) was moved to a Phase I study with 46 healthy volunteers for dose-escalation, tolerability, and safety. 102 No significant AEs were reported, and a dose-dependence was observed for humoral and persistent cell-mediated responses. Lactobacillus casei has been used for early in vivo work using L. casei expressing HPV16 E7, and another strain of L. casei expressing HPV16 E6.…”