HPV-vaccines – a breakthrough in medicine Björn Strander Onkologiskt centrum Västra regionen and Kungsbacka Närsjukhus Sweden

Cervical cancer ”Unusual complication to persistent infection with high risk HPV”

2 vaccines Gardasil – MSD –Quadrivalent HPV 6,11,16,18 –Approved by European agency in september 2006 Cervarix – GSK –Bivalent HPV 16, 18 –Approved by European agency in september 2007

High antibody levels – VLPs injected i.m. give good access to lymphatics and draining lymph nodes where antibody responses are initiated and memory cells develop VLPs are very immunogenic, activating antigen presenting cells and B- and T-cells VLP vaccines

Duration of Efficacy Evaluation The duration of efficacy of HPV-vaccines have not been determined High efficacy of vaccines was observed through 4,5 - 5 years of follow-up Minimum protective anti-HPV level has not been defined –No breakthroughs due to waning immunity –Antibodies remain quite stable through 4,5 - 5 years Vaccines induces immune memory responses

HPV 16/18-Related Cervical, Vulvar, Vaginal Cancer Efficacy (Via Surrogates ) HPV 16/18- Related GardasilPlacebo % Efficacy95% CI CIN 2/3 or AIS , 100 VIN 2/3 or VAIN 2/ , 100 Per-Protocol Efficacy Population Follow up 3 years

Evidence of cross reactivity Gardasil: 38% efficacy against CIN2+ containing 10 non-16/18 high risk HPV- types Cervarix: 27% protection against 12 months persistent infection with 12 non- 16/18 hrHPV-types

Efficacy for all CIN2+ in population neg HPV 6/11/16/18 and with negativ cytologi at baseline Expected Efficacy without cross reactivity= 99% x 0.52 = 51% Endpoint Gardasil Cases Placebo Cases % Efficacy 95% CI 2.4 years follow up CIN2-3 or AIS , 62

Conclusion Efficacy Gardasil Follow up > 2 years HPV naïveMixed ITT population HPV 16/18- related CIN2+ -99%-41% All CIN %-17%

Conclusion Efficacy Cervarix Follow up 15 months HPV naïveMixed ITT population HPV 16/18- related CIN – 100% No data All CIN 2+ No data

Sweden Life time risk for cervical cancer 0.7% Can be reduced to 0.25% with screening + vaccination NNT for preventing 1 case of cervical cancer ~ 200 NNT for saving 1 life ~ 600 Other estimates Brisson et al CMAJ aug 2007

Numbers needed to vaccinate to save one life Varicellae Meningococcus Influenza Vaccinating people > 65 years of age

20% 18% 579 Head and neck ≥95% 70% 429Cervix 90% 80% 130Anus 40% 25% 80Penis 40% 30% 128Vulva 60% 55% 46Vagina % associated Cancer HPV and cancer 1. Parkin, Bray Vaccine Aug 21;24 2. Socialstyrelsen Cancerstatistik Accessed www.sos.se Number in Sweden 2005 HPV HPV 16/ Number of female cancers that could be prevented with HPV 16/18 vaccination Non-cervical in proportion of cervical cancers63 %

HPV vaccines Advantages – world wide Breakthrough in prevention of cervical cancer Can offer the protection for third world women with minimum side effects Can have dramatic effect on incidence and mortality on a world scale

HPV vaccines Advantages – Nordic countries Mass vaccination of girls in school can reach those who will not attend screening Will reduce mortality in cerival cancer Less treatment of cancer and dysplasia will give benefits in fertility and pregnancy losses Reduced anxiety associated with cancer and dysplasia Reduction of other cancers are to expect Reduction of warts (Gardasil) Not more serious adverse events than placebo Boys/men can benefit from herd immunity

HPV vaccines Concerns Cost Prevent improvement of existing screening? Need of booster vaccination? Efficacy against cancer? –will type replacement occur? Implementation in the third world –women hostile cultures