Oral Immunogenicity of Human Papillomavirus-Like Particles Expressed in Potato

Abstract

Human papillomavirus-like particles (HPV VLPs) have shown considerable promise as a parenteral vaccine for the prevention of cervical cancer and its precursor lesions. Parenteral vaccines are expensive to produce and deliver, however, and therefore are not optimal for use in resource-poor settings, where most cervical HPV disease occurs. Transgenic plants expressing recombinant vaccine immunogens offer an attractive and potentially inexpensive alternative to vaccination by injection. For example, edible plants can be grown locally and can be distributed easily without special training or equipment. To assess the feasibility of an HPV VLP-based edible vaccine, in this study we synthesized a plant codon-optimized version of the HPV type 11 (HPV11) L1 major capsid protein coding sequence and introduced it into tobacco and potato. We show that full-length L1 protein is expressed and localized in plant cell nuclei and that expression of L1 in plants is enhanced by removal of the carboxy-terminal nuclear localization signal sequence. We also show that plant-expressed L1 self-assembles into VLPs with immunological properties comparable to those of native HPV virions. Importantly, ingestion of transgenic L1 potato was associated with activation of an anti-VLP immune response in mice that was qualitatively similar to that induced by VLP parenteral administration, and this response was enhanced significantly by subsequent oral boosting with purified insect cell-derived VLPs. Thus, papillomavirus L1 protein can be expressed in transgenic plants to form immunologically functional VLPs, and ingestion of such material can activate potentially protective humoral immune responses.Infection with specific human papillomavirus (HPV) genotypes is a necessary factor in the development of cervical cancer and its precursor lesions (7, 43). Multiple sexually transmitted "high-risk" genotypes (e.g., types 16,18,31,33,35, 45, 51, 52, 58, and 59) have been associated with malignant disease, while other sexually transmitted types (notably 6 and 11) primarily cause only benign disease (e.g., anogenital warts) (20). Recombinant virus-like particles (VLPs) are promising immunogens for controlling HPV-associated diseases because they induce high-titer neutralizing antibody responses that have been associated with protection from infectious challenge (27, 36). Results from phase I studies in human subjects indicate that VLPs are safe, well-tolerated, and immunogenic when administered parenterally (12,16). Encouraging data from a recent phase II study suggest that VLPs may be highly efficacious for HPV prophylaxis (18).Vaccination for disease prevention is a major success of modern medicine; however, the full potential of this strategy to reduce human suffering has not yet been realized. For example, several so-called "vaccine-preventable" diseases continue to affect the lives of millions of individuals who live mostly in economically disadvantaged regions. With few exceptions, recommended immunizations rely on parenteral administration, and in...

Can genital-tract human papillomavirus infection and cervical cancer be prevented with a vaccine?

“…In one study, a plant-codonoptimised version of the HPV L1 major capsid protein coding sequence was introduced into tobacco and potato (Ref. 118). The plant-expressed L1 self-assembled into VLPs with immunological properties comparable with those of native HPV virions.…”

EUROGIN 2008 roadmap on cervical cancer prevention

“…41,44 HPV VLPs have been successfully produced in transgenic plants, but the production yield of HPV L1 VLPs has been disappointingly low in most natural plant-based systems. [45][46][47] A novel and transgenic plant-based system that enhanced the production of L1 VLPs using a human codon-optimising gene linked to a chloroplast-targeted signal has been reported, 48 and plant-based vaccine strategies to produce high-titre HPV-specific neutralising antibodies remain a promising area of research. Vaccines that can be administered orally could improve vaccine coverage in remote areas, reduce delivery costs and enhance compliance, particularly in children.…”

Plant Production of Vaccine Against HPV: A New Perspectives

“…Initially published yields of L1 expression was low, in a range of 1% of the total soluble protein, which is far lower than industrial demand of more than 5% (Rybicky, 2010). For example, Warzecha et al (2003) Nevertheless, during passed years, necessary steps to improve L1 gene expression were recognized and applied. Firstly it was removal of the carboxy-terminal nuclear localization signal sequence (NLS) of L1 that has been shown to enhance expression in transgenic plants.…”