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Peter L. Stern. Immune control of human papillomavirus (HPV) associated anogenital disease and potential for vaccination. Journal o f Clinical Virol ogy, 2005. Human papillomavirus. Transmitted through sexual contact Infects the skin and mucous membranes which can lead to wart formation

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Peter L. Stern

Immune control of human papillomavirus (HPV) associated anogenital disease and potential for vaccination

Journal of ClinicalVirology, 2005.

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

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

HPV infection

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

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

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

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

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

Viral vector vaccines

  • HPV vaccinevectorsbasedonrecombinantvaccinia

    • HPV proteins are endogenously synthesized from viral DNA by host cells

    • No restriction on patient HLA genotypes

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

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

Thanks for your attention

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