1 / 70

HPV Vaccines

HPV Vaccines. Dr W H LI Queen Elizabeth Hospital 5 August 2007. Content. Introduction Basic Information for Human Papillomavirus HPV Vaccine Target Antigens Vaccine Types Phase II/III clinical trials Gardasil / Cervarix FAQ Conclusion. Introduction (1).

fred
Download Presentation

HPV Vaccines

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. HPV Vaccines Dr W H LI Queen Elizabeth Hospital 5 August 2007

  2. Content • Introduction • Basic Information for Human Papillomavirus • HPV Vaccine Target Antigens • Vaccine Types • Phase II/III clinical trials • Gardasil / Cervarix • FAQ • Conclusion

  3. Introduction (1) • Cervical cancer is one of the leading causes of cancer mortality worldwide • Estimated to have 470 000 new cases and 230 000 deaths every year worldwide with 80% of the cases occurred in developing countries

  4. Cervical Cancer in Hong Kong 439 (2004) 126 (2005)

  5. Introduction (2) • Even though screening reduces the risk of cervical cancer, it does not prevent pre-cancerous lesions, which need careful / expensive follow-ups and intervention • Although there are effective treatment for CIN lesions, recurrence still occur and management of recurrent disease maybe difficult • Establishing screening programs is not the only solution to the problem

  6. Introduction (3) • Especially in developing / under-developed countries, limited national screening program, late presentation of disease and limited treatment facilities are the main obstacles in fighting against cervical cancer • High morbidity / mortality for advanced disease • New modality for prevention and treatment of cervical cancer is required

  7. Introduction (4) Cancer Association with HPV Cervical ≥95% Vaginal 50% Vulval >50% Penile 50% Anal >70% Human papillomavirus is the perfect candidate to investigate for Prevention and Treatment of Anogenital Tract Cancers

  8. Introduction (5) • HPV infection is primarily transmitted by genital contact: • Penetrative sexual intercourse • Oral-genital, manual-genital, genital-genital • Sharing sex toys / auto-innoculation (from your own hand to your genital tract) • Non sexual route include transmission from mother to newborn baby (Caesarean section not indicated)

  9. Introduction (6) • Up to 70% of sexually active women will become infected with HPV during their sexual life, but the majority of these infections are transient with 70-90% spontaneously cleared within 12-30 months • High-risk HPV highly associated with pre-cancerous cervical lesions and cervical cancer (up to 99.7% with highly sensitive PCR tests) • Most important factor is persistent type-specific high-risk HPV infection

  10. Introduction (7) • Most prevalent HPV types associated with cervical cancer are: • HPV 16 (54.3%) HPV 18 (12.6%) • HPV 45 (4.2%) HPV 31 (4.2%) • HPV 33 (4.3%) HPV 58 (3%) • HPV 52 (2.5%) *Prevalence of HPV 58 in Chinese may be up to 23.8%

  11. Introduction (8) • HPV vaccines that protect against HPV infections theoretically prevent women from developing pre-cancerous lesions and cervical cancer (Prophylactic vaccine) • HPV vaccine that control the HPV infected cells theoretically treat women with active disease or act as adjuvant agent (Therapeutic vaccine)

  12. Introduction (9) • HPV type 16 and 18 present in • ~70% of Ca cervix cases • ~50 % HGSIL cases • ~14-25% LGSIL cases • Provides an estimate of the potential impact of a vaccine against HPV-16 and HPV-18

  13. Basic Information for Human Papillomavirus

  14. Human Papillomavirus

  15. Human Papillomavirus • Non enveloped virions consists of 72-capsomere capsid (outer coat) containing the double stranded circular DNA genome • Capsid made up of the major structural protein L1 (80%) and minor structural protein L2 (20%)

  16. HPV genome • 3 regions: • Long control region (LCR) without coding potential • Origin of replication and regulation of HPV gene expression • Regulatory (early) proteins E1-E8 • Structural (late) proteins L1 and L2 (capsid)

  17. Gene Function/HPV Proteins • L1: Major capsid protein: can form virus-like particles. • L2: Minor capsid protein: possible DNA packaging protein • E1: DNA-dependent ATPase, ATP dependent helicase: allow unwinding of the viral genome and act as an elongation factor for DNA replication. • E2: Responsible for recognition and binding of origin of replication. Exists in two forms: full length (transcriptional transactivator) and truncated (transcriptional repressor). The ratio of these found in the heterotrimeric complex formed before complexing with E1 regulates transcription of viral genome. • E3: ??? • E4: Late Expression: C terminal binds intermediate filament, allowing release of virus-like particles. Also involved in transformation of host cell by deregulation of host cell mitogenic signalling pathway. • E5: Obstruction of growth suppression mechanisms: e.g EGF receptor; activation of mitogenic signalling pathways via transcription factors: c-Jun and c-Fos (important in ubiquitin pathway degradation of p53 complex by E6). Inactivation of p21 (p53 induced expression halts cell cycle until DNA is proof-read for mutations). • E6: E6 Transformation of host cell by binding p53 tumour suppressor protein. • E7: Transforming protein, binds to pRB • E8-E2 fusion protein: Long distance transcription and replication repressor protein

  18. HPV Proteins • Structural proteins L1 and L2: • Building the capsid (outer coat) • Replication proteins E1 and E2 • Viral replication inside the infected cells • Oncoproteins E6 and E7 • Inhibiting tumour suppressor genes (p53 and pRB)

  19. Life Cycle • After HPV infection, early (replication) proteins (E1, E2, E6 and E7) are expressed within the basal epithelial layers and viral replication occurs • As infected cells reach the surface, late proteins (structural) L1 and L2 proteins are produced and allow shedding of mature virions with exfoliated cells

  20. Tumourigenesis • Majority of tumour showed integration of HR HPV DNA into host genome • Integration disrupts the HPV virus in the E2 open reading frame. • Loss of E2 increase expression of E6 and E7 leading to uncontrolled proliferation and tumour formation

  21. HPV Vaccine Target Antigens • Capsid proteins L1 and L2 (Viral entry) • Replication proteins E1 and E2 • Oncoproteins E6 and E7

  22. HPV Vaccine Target Antigens (1) • Capsid proteins L1 and L2 (outer coat of the HPV particles) • Interact with the surface molecules of human epithelial cells during early stages of infection to gain entry for the viral DNA • Ideal targets for prophylactic but not therapeutic vaccines since L1/L2 are not present when HPVs are integrated into tumour cells • Most candidate vaccines target L1 since L1>L2 for 30x

  23. HPV Vaccine Target Antigens (2) • Replication proteins E1 and E2 • Necessary for HPV to replicate within cells before the virus is integrated into host DNA • Expressed in early stage of HPV infection • Targets for therapeutic vaccines to treat early stages of disease such as low-grade dysplasia

  24. HPV Vaccine Target Antigens (3) • Oncoproteins E6 and E7 • Bind tumour supressor genes (p53/pRB) which are involved in malignant transformation / continue tumour growth • Expressed in the later stage of disease • Targets for therapeutic vaccines to treat later stages of disease

  25. Prophylactic Vaccines Before HPV exposure Antibody-mediated immunity at genital mucosal surface Inactivate HPV before the virus infects the host cells Takes many years to make impact on the prevalence of cervical cancer Therapeutic Vaccines Already exposed to HPV Cell-mediate immunity at the genital mucosal surface Adjunct to standard therapies Prevent progression of low-grade lesions Induce regression of existing lesions Control metastasis Prevent recurrence HPV Vaccines

  26. Ideal HPV Vaccine • Safe and effective • Both prophylactic and therapeutic • Stimulating cell-mediated immunity to eliminate lesions when neutralizing antibodies fail to block all of the virus • Distributed to young women whether or not that are infected with HPV • Single inoculation with long-term protection • Cheap and easy to handle and administer

  27. Vaccine Types • Virus-like particles (VLPs) • Recombinant live vector vaccine • Protein and peptide vaccines • “Naked” DNA vaccines • Edible vaccines

  28. Virus-Like Particles (VLPs) - 1 • Capsid proteins L1 and L2 will self-assemble into virus-like particles (VLPs) when expressed in cells – Empty viral capsids • VLPs resembles native HPV particles and include the conformational epitopes that induce virus-neutralizing antibodies • The immune system perceives VLPs as infectious (indeed they are not since they do not include viral DNA) and induce the immune response

  29. Virus-Like Particles (VLPs) - 2 • Immune response targets the capsid proteins (at the time of viral entry), therefore ideal for prophylactic vaccine Vaccination No Vaccination

  30. Selection of HPV Types in Vaccine Development • HPV type 16 and 18 present in • ~70% of Ca cervix cases • ~50 % HGSIL cases • ~14-25% LGSIL cases • Provides an estimate of the potential impact of a vaccine against HPV-16 and HPV-18 • Quadrivalent vaccine also include HPV 6/11 to prevent genital warts • HPV 6/11 account for 90% of genital warts • Clinically apparent in 1% of sexually active US adult population • Estimated lifetime risk of genital warts ~10%

  31. Selection of Trial Endpoints • Although prevention of cancer is the final endpoint for the success of a prophylactic vaccine • Studies to allow patients to develop cancers as endpoint are unethical • Surrogate endpoints are precancerous lesions (CIN, AIS, VAIN, VIN)

  32. Multicenter Randomised Double Blind Controlled (Phase II) Trials

  33. Multicenter Randomised Double Blind Controlled (Phase III) Trials FUTURE I/II Trials: Females United to Unilaterally Reduce Endo/Ectocervical Disease

  34. Study Design

  35. Phase II / III Clinical Trials

  36. Side Effects

  37. Two HPV Vaccines Available • Gardasil (HPV 6/11/16/18) approved in many countries including HK (Oct 2006) • Cervarix (HPV16/18) approved in Australia (July 2007), Indonesia, Kenya and pending approval in Europe and USA etc

  38. Gardasil (0/2/6m IMI) Storage 0-8 deg C HPV 6/11/16/18 Adjuvant contained aluminum Age 9-26 yrs Up to 5 years Efficacy 99% 1 case CIN 3: HPV 58 at baseline and 5 histology samples, HPV 16 in only 1 sample Cervarix (0/1/6m IMI) Storage 0-8 deg C HPV 16/18 Adjuvant AS04 Claimed to enhance immune response and longer duration Age10-45yrs (Australia) Up to 4.5 years Efficacy 90.4% 2 cases CIN 2+: Multiple infection with preceding cytology HPV 16/18 -ve (Efficacy 100%) Cross-protection ? 45 and 31 Which is better ? Pending results from a head-to-head trial to compare immunogenicity of Cervarix and Gardasil initiated in 2007

  39. Phylogenetic Tree of HPV Family 18 Genotypying of HPV is based on DNA sequences of the L1 genes 45 11 6 Human Genital Papillomavirus 33 16 35 31 Human Cutaneous Papillomavirus

  40. Cross-Protection for Bivalent Vaccine (Cervarix) No cross protection for other HPV types other than 16/18 has been approved

  41. FAQ (For Gardasil) • When and whom to vaccinate ? • Vaccination for females <9yr and >26 yrs ? • Vaccination in sexually active females • Prior HPV testing before vaccination • Past history of abnormal pap smear / histology ? • History of genital warts • Antibody testing before vaccination • Will a booster be required ? • Vaccination in pregnancy / during lactation • Duration of protection • Interrupted schedules / Incorrectly vaccinated individuals • Simultaneous administration of other vaccines • Immunocompromised patients • Precautions / Contraindications • Any therapeutic effect ? • Role of cervical screening ? • Other ways to prevent HPV infection • Vaccination in males ? • Social acceptance

  42. When and Whom to Vaccinate • Licensed for use in 9-26 yr females • Age 16-26: • Based on phase II/III studies conducted among females aged 16-26 yrs • Age 9-15: • Based on immunological studies • Not inferior to 16-26yrs • Recommendation at age 11-12: • Before sexual exposure • US: 3.7% females sexually active before age 13 • HK: 4.9% before age 15 • High probability of HPV acquisition within several yrs of sexual exposure • Immune system “ages” after puberty • Antibody level after vaccination 9-10y > 13-15y > 16-23y • Incorporate into adolescent vaccination program

  43. Vaccination for females<9yrs and > 26 yrs • Not licensed for use in these age range • Protocol 019 (FUTURE III) • In 3870 24-45yr women followed for 3 years • Primary endpoint: • Persistent HPV 16/18 infection and related disease • Efficacy against HPV 16/18-related CIN 2/3 and AIS • Off-label use: Counseling on limitations and based on clinical judgment • No studies are under way among children aged <9 years

  44. Vaccination in Sexually Active Females • May also benefit from the vaccine • May have less benefit since they may have already been infected • Unlikely that they acquired all 4 types • Even if the patient has been infected, vaccination would provide protection against infection with HPV vaccine types not already acquired

  45. Prior HPV Testing before Vaccination • No indication for prior HPV testing: • Specific HPV testing not performed routinely in clinical setting • Although Hybrid Capture 2 is available to test for high-risk HPV(16/18/31/33/35/39/45/51/52/56/58/59/68) • Does not identify specific HPV types • Unlikely that the women having all 4 HPV types (0.1%) Positive to >= 1 types 23.7% Positive to >= 2 types 6% Positive to >= 3 types 1.1% Positive to >= 4 types 0.1% • Even if the patient has been infected, vaccination would provide protection against infection with HPV vaccine types not already acquired • HPV infection mostly transient in young women and a positive HC 2 test may cause confusion and unnecessary anxiety

  46. Prior HPV Testing before Vaccination In the combined analysis of previous studies • Analysis of Intent-To-Treat subset: • Received at least 1 dose of vaccine (Protocol violation) • Any follow-up 1 month after the first dose • Even if pap smear abnormal on day 1 • Regardless of initial PCR or serology for HPV (Overall 27% of the study population at baseline had evidence of infection with a vaccine HPV type) i.e. Presumed HPV status unknown / no prior HPV testing before vaccination / Regardless of pap smears results (General Population) • Prevention of vaccine-related (6/11/16/18) lesions: • CIN2/3/AIS – 39% - 46.4% • VAIN 2/3 and VIN 2/3 – 69.1% • Genital warts – 68.5%

  47. Past history of Abnormal Pap Smears / Histology • No contraindication for vaccination: • Females with equivocal / abnormal pap smears could be infected with any HPV types (high/low-risk) • Might not be infected with any of the 4 vaccine-types (6/11/16/18) • Unlikely to have infected all 4 types (0.1%) • Vaccination would protect them against infection with HPV vaccine types not already acquired • With increasing severity of pap smear (such as HGSIL) • Likelihood of infection with HPV 16/18 increases • Benefit of vaccine wound decrease

  48. History of Genital Warts • No contraindication • Most often HPV 6 or HPV 11 • But might not have infection with both types or infection with HPV 16 or HPV 18 • Vaccination would protect them against infection with HPV vaccine types not already acquired

  49. Antibody Testing before Vaccination • No indication for prior antibody testing: • Not all naturally infected individuals have antibodies • Only 54%-69% with incident HPV 6/16/18 seroconvert • Serological assays are only available in research settings and only being done by the manufacturer • Key laboratory reagents are not standardized • No gold standard for setting a threshold for a positive result

  50. Decision to Vaccinate should NOT be based on Pap testing, HPV DNA or HPV serologic testing

More Related