DNA Vaccine Encoding HPV16 Oncogenes E6 and E7 Induces Potent Cell-mediated and Humoral Immunity Which Protects in Tumor Challenge and Drives E7-expressing Skin Graft Rejection.
We have previously shown that a novel DNA vaccine technology of codon optimization and the addition of ubiquitin sequences enhanced immunogenicity of a herpes simplex virus 2 polynucleotide vaccine in mice, and induced cell-mediated immunity when administered in humans at relatively low doses of naked DNA. We here show that a new polynucleotide vaccine using the same technology and encoding a fusion protein of the E6 and E7 oncogenes of high-risk human papillomavirus type 16 (HPV16) is immunogenic in mice. This vaccine induces long-lasting humoral and cell-mediated immunity and protects mice from establishment of HPV16-E7-expressing tumors. In addition, it suppresses growth of readily established tumors and shows enhanced efficacy when combined with immune checkpoint blockade targeted at PD-L1. This vaccine also facilitates rejection of HPV16-E7-expressing skin grafts that demonstrate epidermal hyperplasia with characteristics of cervical and vulvar intraepithelial neoplasia. Clinical studies evaluating the efficacy of this vaccine in patients with HPV16 premalignancies are planned.
*Admedus Vaccines Pty Ltd †Diamantina Institute, University of Queensland, Brisbane, Qld, Australia.
Janin
J
Chandra
Julie L
JL
Dutton
Bo
B
Li
Wai-Ping
WP
Woo
Yan
Y
Xu
Lynn K
LK
Tolley
Michelle
M
Yong
James W
JW
Wells
Graham
G
R Leggatt
Neil
N
Finlayson
Ian H
IH
Frazer
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D060890:B7-H1 Antigen / Q000276:immunology; D048708:Cell Growth Processes; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D052162:Human papillomavirus 16 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D051379:Mice; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000235:genetics; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism; D030361:Papillomavirus Infections / Q000150:complications / Q000276:immunology*; D053918:Papillomavirus Vaccines / Q000276:immunology*; D012097:Repressor Proteins / Q000235:genetics; D012867:Skin / Q000378:metabolism; D016038:Skin Transplantation; D002583:Uterine Cervical Neoplasms / Q000209:etiology / Q000517:prevention & control*; D014611:Vaccination; D019444:Vaccines, DNA
D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D012097:Repressor Proteins; D019444:Vaccines, DNA; C059731:oncogene protein E7, Human papillomavirus type 16