Transcript (HPV) associated anogenital disease and potential for vaccination

Immune control of human papillomavirus
(HPV) associated anogenital disease and
potential for vaccination
Peter L. Stern
Journal of Clinical Virology, 2005.
Human papillomavirus
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Transmitted through sexual
contact
Infects the skin and mucous
membranes which can lead to
wart formation
~130 HPV types
Associated with cervical cancer
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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
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Keeping very low profile
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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
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E5 can modulate antigen processing pathways
Influence the polarization of Th cell types
Immune escape as a feature of the
evolution of invasive cancer
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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
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Viral capsid proteins have the intrinsic capacity
to self assemble into virus-like particles (VLP)
→ Highly immunogenic but lacking viral DNA
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First trial with HPV 16 L1 VLPs induced strong
immune responses and were well tolerated
Peptides or recombinant proteins
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Peptide vaccines with HPV 16 E7 as therapy for
patients with neoplasia
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Possible because 40% of Caucasians carry HLA-A2
allele
Advantage: cost effectiveness
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
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Plasmid DNA encoding
antigen
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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
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HPV vaccine vectors based on recombinant vaccinia
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HPV proteins are endogenously synthesized from viral DNA
by host cells
No restriction on patient HLA genotypes
Prime-boost strategies
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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:
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Fusion protein: HPV 16 L2E6E7
(TA-CIN)
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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
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Gardasil (Merck)
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Based on recombinant L1 VLP
Vaccination for:
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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)
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Vaccination for:
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high risk HPV 16, 18