Using tobacco mosaic virus epitope display to enhance papillomavirus L2 antigen presentation

2004 
1267 Human papillomavirus (HPV), a family of pathogenic viruses, has been defined as the causal agent in cervical cancers, as well as a host of other human diseases. Cervical cancer incidence is rising at an alarming rate in third world countries, and there is great need for effective therapeutic and preventive vaccines for HPV. We are testing the ability of Tobacco Mosaic Virus (TMV) to function as a vaccine antigen carrier by displaying peptide epitopes on the surface of the TMV coat protein. TMV coat forms a semi-crystalline array of >2100 subunits around a non-integrating RNA, and molecular fusion of target epitopes to a surface-exposed region of TMV coat protein does not disrupt the TMV virus life cycle. Molecular fusion of epitopes to TMV coat, then, generates a high-density viral particle display of antigens that are ideally suited to stimulate high levels of specific immunogenicity. TMV is not pathogenic in mammalian hosts, and can be produced quickly and cost-effectively in plants. In these experiments, we created TMV fusions containing human or rabbit papillomavirus L2 minor capsid protein epitopes that have been shown previously to stimulate neutralizing immunity and protection from virus challenge (Embers et al, 2002, J. Immunol. 169, p350). TMV-peptide fusions were produced in tobacco plants by transient viral infection, extracted from whole tissue grinds, qualified for purity and identity, and then used to vaccinate mice at 10 μg per animal with no adjuvant. Specific immune responses to papillomavirus peptides were observed in all vaccines tested. Second generation vaccines are currently being developed that pair, on the surface of TMV, a papillomavirus antigen with a T-helper epitope, or a cellular fusion epitope, or both, in order to augment antigen uptake, processing and/or epitope-specific immunogenicity. Multivalent vaccines are being produced by molecular fusion, by chemical conjugation, or by both methods, and are being qualified and tested by similar methods as the mono-valent vaccines previously described. Vaccines that show improved immunogenicity in mice will be used to generate sera for virus neutralization studies, and for immunization of rabbits for viral challenge studies. TMV vaccines bearing a number of different CTL epitopes are being tested for their ability to stimulate specific T cell responses, as well as to prevent tumor outgrowth. Ultimately, we hope to develop a set of vaccines that can be used to either prevent or treat human papillomavirus disorders in a cost effective manner.
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