The First Clinical Use of a Recombinant Lactococcus lactis Expressing Human Papillomavirus Type 16 E7 Oncogene Oral Vaccine: A Phase I Safety and Immunogenicity Trial in Healthy Women Volunteers.

A dose-escalation, randomized, double-blind, placebo-controlled phase I clinical trial was performed in healthy Iranian volunteer women to assess the safety, tolerability, and immunogenicity of NZ8123-HPV16-optiE7 vaccine involving recombinant Lactococcus lactis expressing the codon-optimized human papillomavirus (HPV)-16 E7 oncogene. Fifty-five eligible subjects were divided into 6 cohorts based on the dosages (1 × 109, 5 × 109, and 1 × 1010 CFU/mL) of either vaccine or placebo, which were administrated orally a total of 4 times at weeks 1, 2, 4, and 8. Then, adverse events, specific serum IgG and vaginal IgA, and E7-specific IFNγ-secreting CD8+ CTL responses were evaluated. The vaccination was well tolerated by 40 subjects who completed the immunization schedule, and no serious adverse effects were reported. The IgG and IgA levels peaked at day 60, and the levels for the 5 × 109 CFU/mL and 1 × 1010 CFU/mL dose groups were higher than those for the 1 × 109 CFU/mL dose group. Time-to-peak stimulation in E7-specific IFNγ-secreting CD8+ CTL responses was seen in cervical lymphocytes 1 month after the last vaccination. Again, no significant increase was seen in the peripheral blood mononuclear cells (PBMC) of the same volunteers. CTL responses in cervical lymphocytes and PBMCs at day 90 were markedly higher in the 5 × 109 and 1 × 1010 CFU/mL groups than in the 1 × 109 CFU/mL group, demonstrating the dose dependency of NZ8123-HPV16-optiE7 vaccine following oral administration. The 6-month follow-up revealed that antibody levels decreased up to day 240; nevertheless, long-term E7-specific IFNγ-secreting CD8+ CTL responses were recorded during follow-up. Overall, the safety and immunogenicity profile achieved in this study encourages further phase II trials with the 5 × 109 CFU/mL dose vaccine.