Polynucleotide viral vaccines: codon optimisation and ubiquitin conjugation enhances prophylactic and therapeutic efficacy.
Papillomavirus infection is a major antecedent of anogenital malignancy. We have previously established that the L1 and L2 capsid genes of papillomavirus have suboptimal codon usage for expression in mammalian cells. We now show that the lack of immunogenicity of polynucleotide vaccines based on the L1 gene can be overcome with codon modified L1, which induces strong immune responses, including conformational virus neutralising antibody and delayed type hypersensitivity. Conjugation of a ubiquitin gene to a hybrid gene incorporating L1 and the E7 non-structural papillomavirus protein improved E7 specific CTL responses, and induced protection against an E7 expressing tumour, but induced little neutralising antibody. However, a mixture of ubiquitin conjugated and non-ubiquitin conjugated polynucleotides induced virus neutralising antibody and E7 specific CD8 T cells. An optimal combined prophylactic/therapeutic viral vaccine might therefore comprise ubiquitin conjugated and non-ubiquitinated genes, to induce prophylactic neutralising antibody and therapeutic cell mediated immune responses.
Liu
W J
WJ
Centre for Immunology and Cancer Research, Princess Alexandra Hospital, University of Queensland, Woolloongabba 4102, Queensland, Australia.
Zhao
K N
KN
Gao
F G
FG
Leggatt
G R
GR
Fernando
G J
GJ
Frazer
I H
IH
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D003062:Codon / Q000235:genetics; D005260:Female; D005814:Genes, Viral; D006801:Humans; D006968:Hypersensitivity, Delayed; D007111:Immunity, Cellular; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D027383:Papillomaviridae / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D030361:Papillomavirus Infections / Q000276:immunology / Q000517:prevention & control / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014412:Tumor Virus Infections / Q000276:immunology / Q000517:prevention & control / Q000628:therapy; D025801:Ubiquitin / Q000276:immunology; D018074:Vaccines, Conjugate / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D019444:Vaccines, DNA / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D014765:Viral Vaccines / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use
D000914:Antibodies, Viral; D003062:Codon; D025801:Ubiquitin; D018074:Vaccines, Conjugate; D019444:Vaccines, DNA; D014765:Viral Vaccines