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SUBUNIT VACCINES GROUP

SUBUNIT VACCINES GROUP. Inst of Infectious Disease and Molecular Medicine and Dept Molecular and Cell Biology University of Cape Town Inga Becker/Hitzeroth. PRF. Papillomaviruses. Why are they interesting? What does the virus look like? What disease do they cause?

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SUBUNIT VACCINES GROUP

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  1. SUBUNIT VACCINES GROUP Inst of Infectious Disease and Molecular Medicineand DeptMolecular and Cell Biology University of Cape Town Inga Becker/Hitzeroth PRF

  2. Papillomaviruses • Why are they interesting? • What does the virus look like? • What disease do they cause? • Warts • Cervical cancer • How do you catch genital HPV? • Strategies to prevent infections

  3. PV structure 600Å diameter with 72 pentameric capsomeres in a T=7 icosahedral lattice Capsomeres contain 5 monomers of L1 (360) L2 in capsid ranges form 11 - 30 or 72 ds DNA virus DNA size 8kb

  4. HPV DNA

  5. HPV genes • L1 major capsid protein • L2 minor capsid protein • E6 and E7oncogene • E7 binds to pRB, acitivates E2F transcription factor get expression of proteins for DNA replication then p53 should send cell into apoptosis, but • E6 targets p53 for proteolytic degradation • E2 and E1 transcription/translation control • E4 and E5

  6. Infectious cycle • Infect basal epithelial cells • Replicate to about 100 copies, maintained like that for long times • E1 and E2 are essential • HPV replicates in suprabasal cells and are released into environment • E6 and E7 are important in viral replication by interacting with pRB and p53 which control the normal cell cycle • During tumor progression viral DNA often integrates into host chromosome

  7. Papillomaviruses • Species specific • CRPV, BPV, • Human papillomavirus: HPV • Over 100 types • Tissue specific • Epithelial, mucosal

  8. Diseases caused by HPV • Warts and papillomas have been noted since prehistoric times • Infectious nature only discovered later • 1970-80 studied structure of virus, gene functions • Middle 1970’s zur Hausen postulated role of virus in cervical cancer • By 1980’s lots of knowledge about virus had accumulated

  9. HPV types and genes • Mainly HPV 16 DNA was found in cervical cancer biopsies • E6 and E7 were expressed in these cancers • These genes were able to immortalize epithelial cells • These genes were necessary to maintain cancer

  10. Cervical Cancer • Cervical cancer is the 2nd leading cancer amongst women worldwide • 500,000 new cases, 300,000 deaths • >99% related to human papillomavirus (HPV) infection • HPV infect epithelial cells including the genital tract • HPV type 16 related to half of these cases • HPV –18, -45, -31, -33, -52, -58 and -35 together with HPV-16 responsible for 90% of all cervical cancers worldwide

  11. Burden of HPV-related cancers • 500 000 new cases per year • 300 000 deaths of which • 83% occur in developing countries • Cervical cancer accounts for 15% of female cancers • Risk before age of 65 is 1.5% • Developed countries its 3.6% of new cancers with 0.8% risk • Only 55% mortality

  12. Age-standardised (World) incidence rates of cervical cancer 2002

  13. Mostly squamous cell carcinomasAge-standardised (World) incidence rates of cervical cancer by histological subtype in selected cancer registries circa 1993–1997

  14. HPV types • Important to do worldwide study to find out which type is most common in cancer for development of vaccine • Mainly done by PCR and Hybrid capture assay

  15. Percentages of cervical cancer cases attributed to the most frequent HPV types in all world regions combined

  16. Eight most common HPV types in more than 14,500 cervical cancer cases, by region

  17. Progression of natural infection to cancer

  18. HPV Infection • Infection occurs mostly between age 20-30 • Infection is mostly cleared spontaneously • 90% clear a HPV type in 2 years • Some established infections manifest as microscopic abnormality • Also cleared by host immune system • Viral persistence can lead to cancer

  19. Overview of factors most consistently reported to play a role at different stages in the natural history of HPV and cervical neoplasia

  20. Screening for Cervical Cancer • Why get screened? • Screening was developed to detect abnormal cervical cells in the early stages when it is easy to remove them • Who should be screened? • Women from 25-65 years • Once every 3 years

  21. Abnormal cervical smear • What now? • Most abnormal smear revert back to normal spontaneously • Get re-screened in 3 - 6 month • If progress to abnormal cells • Referred for colposcopy – look at cervix, do biopsy and determine if its CIN3 • Remove abnormal cells: cryotherapy, laser, loop or cone biopsy

  22. HPV screening • Why? • If have no HPV DNA go back to routine screening • If high risk HPV DNA is found and it persist, then follow up is very important • HPV screening not recommended for women under 30

  23. HPV Vaccines • HPV L1 • Form VLPs with or without L2 • Look same as viral particles and can be used as vaccine • Problem: • Very type specific • Only protect against the one L1

  24. Structure of HPV M. Stanley et al. / Vaccine 24S3 (2006) S3/106–S3/113

  25. Properties of the HPV L1 capsid protein L1 protein can self-assemble into Virus-like Particles (VLPs) that are antigenically identical to virions - and are already in Phase III human trials (made via yeast and baculovirus) ProjectedCost: US$40-100 per dose of 40-100ug… Natural capsid:L1+L2+DNA Capsid consisting only of L1

  26. Yeast Cell Culture Insect Cell Culture HPV Vaccines • L1 VLPs made in insect cells – GSK 16 and 18 • Cervarix • i.m. 3 shots 0, 1 and 6 month • VLPs made in yeast – Merck 16,18,11 and 6 • Gardasil • i.m. 3 shots 0, 2 and 6 month

  27. Mechanism of protection • Neutralising antibodies • Antibodies are type specific and not cross-neutralising • Duration of protection • Ab persist 48 month post-vaccination • Who and when to vaccinate • Pre-exposure, pre-puberty

  28. New problems • Who should be vaccinated when? • Childhood vaccination programs are well-structures, well-established and accepted • Vaccination must occur prior to onset of sexual activity • Girls at 9-13 years • Few school-based vaccination programs • Boys as well? • Reduce anogenital warts • Increase herd immunity • Target groups: adolescent/young adult women (perhaps men) • Will HPV included in national immunisation program? • Booster vaccination?

  29. Screening programs • Need to continue • Older women • Infection by other HPV types • Even if HPV vaccine is approved, need awareness for need to vaccinate in professional, public, and political communities

  30. Our Research • Production of VLPs in plants • Easy to make • Cheap • L2 contains cross-protective epitopes • L2 has been shown to stabilize capsid formation and allow formation at a physiological pH Belnap et al. (1996).

  31. UCT baculovirus-produced VLPs

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