1. Papilloma viruses: from tip to tail Tim Palmer

3. Taxonomic level CriteriaNumber Genera Less than 60% nucleotide (nt) identity in entire L1 ORF 18 genera (alpha to sigma) 2 additional new genera, yet unnamed (containing TtPV2 and RaPV1 respectively) SpeciesBetween 60% and 70% nt identity in L1 From 1 species (in most genera) up to 15 species (in genus alpha) GenotypesBetween 71 and 89 % nt identity in L1 Currently 120 papillomavirus genotypes completely genomically characterized and available in Genbank (98 human: HPV; 32 non-human) SubtypesBetween 90 and 98 % identity in L1 Very rare VariantsMore than 98 % identity in L1

4. Lineage C more persistent than A or B A and B more commonly associated with CIN3 Lineage B - higher association with CIN3 (2.7 OR) HPV 31

5. Non-human papilloma viruses Bovine (6 types) Equine Canine Feline Rabbit (2 types) Mouse Hamster Deer Reindeer European elk Sheep Porpoise Monkey (Rhesus and chimpanzees) Parrots Chaffinch Tortoise Manatees

6. Squamous epithelia – keratinising and non-keratinising o Cutaneous o Genital o Aero-digestive tract Papillomas Fibropapillomas ‘Sarcoids’ Malignant transformation

7. Illustration from Tableau Encylopedique and Methodique 1789 Cottontail rabbit with cutaneous papillomatosis – Shope papilloma virus (Museum Nat Hist, Kansas)

9. Evolved at the same time as reptiles DNA virus Protein coat (capsid) Early and late genes E6 and E7 necessary for transformation (immortalisation) L1 and L2 form capsule L1 most conserved part of genome L1 capsid protein used for vaccines Papilloma viruses

10. HPV genome

11. Human disease Cutaneous warts o Ano-genital warts o Verruca vulgaris, plana, plantaris etc o Epidermodysplasia verruciformis Mucosal warts o Cervical o Oral o Anal o Laryngeal

12. HPV immunisation in Scotland September 2008 Cervarix ® immunisation starts at age 12-13 yr Catch-up cohorts up to age 18 (dob 1990) September 2010 First immunised women start screening September 2013 Three full years of data available from four year cohorts of catch-up programme September 2015 First ‘HPV-naïve’ women start screening

14. Data available for analysis Year of birth Total in year of birth Number with smearsTotal with smears Full1 or 2 doses None 19904025933079342031924560 199139362129822247701722246 199237908128531373130015056 19933094428893607724021 Total1484733203149142940866353

15. Immunised women more likely to be screened - p <0.0001 for all cohorts

16. Any immunisation associated with less HG dykaryosis – p <0.0001

17. Immunisation associated with less low grade dyskaryosis – p <0.0001 Significant difference between cohorts in percent low grade dyskaryosis

18. Full immunisation only associated with less borderline changes – p <0.0001

19. Full immunisation only associated with less HG CIN in all cohorts – p<0.0001 Partial immunisation associated with less HG CIN in 1990 only – p<0.0001

20. Full immunisation associated with less LG CIN in all cohorts – p<0.0001 Partial immunisation associated with less LG CIN in 1991-3 only – p<0.0001

21. Oro-pharyngeal cancer Explosion in last 15 years Tonsil, base of tongue, basaloid HPV 16 almost exclusively ? Pre-invasive phase >= 50% HPV driven non-smoker, non drinker, male > female, young > old, I >V Better prognosis, stage for stage

22. Anal squamous carcinoma Used to be uncommon HPV driven in many cases HIV +ve: almost all are HPV+ Anal canal may be reservoir for HPV in male and female Pre-invasive disease Screening