Optimization of human papillomavirus (HPV) type 16 E7-expressing lactobacillus-based vaccine for induction of mucosal E7-specific IFNγ-producing cells

Atsushi Komatsu; Shizunobu Igimi; Kei Kawana

doi:10.1016/j.vaccine.2018.05.009

Optimization of human papillomavirus (HPV) type 16 E7-expressing lactobacillus-based vaccine for induction of mucosal E7-specific IFNγ-producing cells

Vaccine. 2018 Jun 7;36(24):3423-3426. doi: 10.1016/j.vaccine.2018.05.009. Epub 2018 May 5.

Authors

Atsushi Komatsu¹, Shizunobu Igimi², Kei Kawana³

Affiliations

¹ Department of Obstetrics and Gynecology, Nihon University School of Medicine, 30-1 Oyaguchi-kamimachi, Itabashi-ku, Tokyo 173-8610, Japan; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
² Department of Applied Biology and Chemistry, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan. Electronic address: s3igimi@nodai.ac.jp.
³ Department of Obstetrics and Gynecology, Nihon University School of Medicine, 30-1 Oyaguchi-kamimachi, Itabashi-ku, Tokyo 173-8610, Japan; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Electronic address: kkawana-tky@umin.org.

PMID: 29735324
DOI: 10.1016/j.vaccine.2018.05.009

Abstract

Therapeutic HPV vaccine is an agent to induce E7-specific Th1 immune responses to treat cervical neoplasia (CIN2-3). Our previous clinical trial has demonstrated that oral administration of HPV16 E7-expressing Lactobacillus casei (L. casei), GLBL101c, resulted in the regression of HPV16-related CIN3. Here we examined optimization of the E7-expressing L. casei for induction of the mucosal immune responses to E7. Various doses of HPV16 E7 molecule were displayed on the L. casei. Immunization with E7-bound L. casei showed the induction of E7-specific mucosal IFNγ-producing cells was dependent on displayed E7-doses but saturated beyond 0.3 μg/10⁸ cells. A new agent, L. casei with endogenous expression of E7 (IGMKK16E7), showed the optimal amount of displayed-E7. Immunization with IGMKK16E7 demonstrated 4-fold higher induction of E7-specific mucosal IFNγ-producing cells when compared with the former one. Our new system provided the optimal E7-expressing L. casei for displayed-E7 amount and induction of mucosal Th1 immune response.

Keywords: Cervical cancer; Cervical intraepithelial neoplasia (CIN); Human papillomavirus (HPV); Lactobacillus-based vaccine; Mucosal immunity; Therapeutic HPV vaccine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Antigens, Viral / genetics
Antigens, Viral / immunology*
Dose-Response Relationship, Immunologic
Female
Gene Expression
Genetic Engineering
Genetic Vectors / chemistry
Genetic Vectors / metabolism
Human papillomavirus 16 / genetics
Human papillomavirus 16 / immunology*
Humans
Immunity, Mucosal
Immunization / methods
Interferon-gamma / biosynthesis*
Interferon-gamma / metabolism
Lacticaseibacillus casei / genetics
Lacticaseibacillus casei / immunology*
Mice
Mice, Inbred C57BL
Papillomavirus E7 Proteins / genetics
Papillomavirus E7 Proteins / immunology*
Papillomavirus E7 Proteins / metabolism
Papillomavirus Infections / immunology
Papillomavirus Infections / prevention & control*
Papillomavirus Infections / virology
Papillomavirus Vaccines / genetics
Papillomavirus Vaccines / immunology*
Th1 Cells / immunology*
Th1 Cells / virology
Transgenes / immunology
Uterine Cervical Dysplasia / immunology
Uterine Cervical Dysplasia / prevention & control
Uterine Cervical Dysplasia / virology
Uterine Cervical Neoplasms / immunology
Uterine Cervical Neoplasms / prevention & control
Uterine Cervical Neoplasms / virology

Substances

Antigens, Viral
Papillomavirus E7 Proteins
Papillomavirus Vaccines
oncogene protein E7, Human papillomavirus type 16
Interferon-gamma