Peter L. Stern

1. Peter L. Stern Immune control of human papillomavirus (HPV) associated anogenital disease and potential for vaccination Journal of ClinicalVirology, 2005.

2. Human papillomavirus • Transmitted through sexual contact • Infects the skin and mucous membranes which can lead to wart formation • ~130 HPV types • Associated with cervical cancer • 0.25 million deaths per year • 30-60% of sexually active men and women are infected with genital HPV • No specific therapy available

3. Human papillomavirus • Non-enveloped dsDNA virus • E1 and E2: minimal gene expression, suppress expression of E6 and E7 • E6: prevents cell differentiation and promotes p53 degradation • E7: prevents cell-growth arrest/differentiation • L1, L2: capsid proteins

4. HPV infection

5. Viral strategies to evade or subvert immune attack • Keeping very low profile • Non-secreting proteins • No viraemia • No lysis → limited antigen production • HPV 16 E7 inhibits interferon regulatory factor 3 • HPV 18 E6 inhibits the JAK-STAT activation response → reduced inflammatory response • E5 can modulate antigen processing pathways Influence the polarization of Th cell types

6. Immune escape as a feature of the evolution of invasive cancer • HPV integrates in the genome leading to E2 inactivation which suppresses E6 and E7 transcription • E6 and E7 interact with cellular tumour suppressor gene products p53 and pRb • Accumulation of genetic changes and development of cancer • High frequency of HLA class I down-regulation • CTLs triggered after HPV integration leading to selection of immune-resistant tumour cells

7. Prophylactic vaccines • Viral capsid proteins have the intrinsic capacity to self assemble into virus-like particles (VLP) →Highly immunogenic but lacking viral DNA • First trial with HPV 16 L1 VLPs induced strong immune responses and were well tolerated

8. Peptides or recombinant proteins • Peptide vaccines with HPV 16 E7 as therapy for patients with neoplasia • Possible because 40% of Caucasians carry HLA-A2 allele • Advantage: costeffectiveness • Use of longer peptides that can be presented to CD4 and CD8 T cells driving a more vigorous CD8 CTL response • Recombinant proteins have the advantage in delivery of all potential epitopes to the APC Safe but show only in a fraction of patients immunogenicity

9. Plasmid DNA vaccines • Plasmid DNA encoding antigen • E6 and E7 of HPV16, 18 • Encapsulation in a biodegradable polymer microparticle format potentiating the delivery to APCs • Trial showed no specificity for HPV-16- or HPV-18-positive lesions

10. Viral vector vaccines • HPV vaccinevectorsbasedonrecombinantvaccinia • HPV proteins are endogenously synthesized from viral DNA by host cells • No restriction on patient HLA genotypes

11. Prime-boost strategies • Priming immunization (e.g. DNA plasmid or viral vector or protein) followed by a heterologous boost with a different viral vector encoding the immunogen • Example: • Fusion protein: HPV 16 L2E6E7 (TA-CIN) • Well tolerated, induced antibody and proliferation response • Induced INFγ ELISPOT response to HPV16 oncogenes • Boost with TA-HPV • Enhanced immunogenicity compared with either agent alone

12. Currently available vaccines • Gardasil (Merck) • Based on recombinant L1 VLP • Vaccination for: • high risk HPV 16, 18 (cause 70% of cervical cancer) • low risk HPV 6, 11 (cause 90% of genital warts) • Approved June 2006 • Cervarix (GlaxoSmithKline) • Vaccination for: • high risk HPV 16, 18

13. Thanks for your attention