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HPV infection and humoral immunity

Douglas R. Lowy National Cancer Institute National Institutes of Health Bethesda, Maryland

The views expressed are my own. They do not represent those of NCI/NIH

Disclosure

The NIH has patents on papillomavirus VLP vaccine technology, and I am a coinventor of this technology. The NIH has licensed this technology to Merck and GlaxoSmithKline, the pharmaceutical companies that are developing the candidate commercial HPV VLP vaccines.

Worldwide Incidence and Distribution of Cancers Attributable to HPV

Cervix Oropharnyx Anus Oral cavity Larynx Vulva Penis

HPV cases Total cases

0

100,000

200,000

300,000

400,000

500,000

Annual number of cases

Cervical cancer represents ~10% of all female cancers worldwide

Estimates from IARC

Papillomaviruses Infect Skin and Mucosal Sites

plantar warts cutaneous, mostly asymptomatic

genital mucosa, cancerassociated common & flat warts external genital warts

de villiers et al, Classification of papillomaviruses. Virology 324:17-24, 2004

Papillomaviruses Encode Two Structural Proteins

· L1: the major (most abundant) structural protein. Each viral particle has 360 copies. · L2: the minor structural protein. Each particle has fewer copies.

L1 L1 Open Reading Frames URR E7 E6 E1 E2 E4 Non-Structural Genes Structural Genes E5 L2 L1 L1 L1 L1

Papillomavirus Virion

Papillomavirus Genome

Howley & Lowy, Papillomaviruses and their replication. In Fields Virology, 4th ed, pp. 2197-229, 2001

L1 Neutralization Epitopes: Immunodominant & Type-specific

· Virion immunodominant epitopes: L1 neutralization epitopes, which are predominantly type-specific and conformation dependent

Open Reading Frames URR E7 E6 E1 E2 E4 Non-Structural Genes Structural Genes L1 L1 E5 L2 L1 L1 L1

Papillomavirus Vrion

L1

Papillomavirus Genome

Roden et al, J. Vriol 70:3298-3301, 1996; Roden et al, Virology 270:254-7, 2000

Prophylactic Vaccines are Based on Papillomavirus-Like Particles (VLPs)

· Empty shells composed of the L1 major virion protein (or L1 + L2) · Generated in yeast or Baculovirus/insect cells · Non-infectious and non-oncogenic · Induce high titers of conformationdependent and largely type-specific virion neutralizing antibodies · Vaccination with VLPs of animal PVs protects animals from experimental infection with high dose virus

Kirnbauer et al, Proc Natl Acad Sci USA 89:12180-4, 1992; Schiller & Lowy, Sem Cancer Biol 7:373-82, 1996

Systemic VLP Vaccination is Protective in 3 Animal Papillomavirus Models: Skin (rabbits) and Oral Mucosa (cows & dogs) · Protection: ­ prophylactic, not therapeutic ­ efficient without adjuvant ­ passively transferred with immune IgG (neutralizing antibodies) ­ type-specific (not cross protective)

Oral Papillomas in Cows (BPV-4): Prevention by Systemic Immunization with VLPs

8 7 6 5

Papillomas 4 per cow

3 2 1 0

Unvaccinated cows

L1 VLP vaccinated cows

L1/L2 VLP vaccinated cows

Kirnbauer et al, Virus-like particles of Bovine Papillomavirus type 4 in prophylactic and therapeutic immunization. Virology 219:37-44, 1996

Neutralizing L1 Antibodies Bound to Papillomavirus Particle

Booy et al, J Mol Biol 281:95-106, 1998

How serum antibodies may protect against cervical infection

Endocervix

· IgG is the main immunoglobulin

Transformation Zone

in the female genital tract · Transudation of serum Abs

Cervical Mucus

into the cervical mucus · Direct exudation of serum Abs

Ectocervix

at sites of trauma that expose basal epithelial cells to infection

Schiller & Davies, Nat Rev Microbiol 2:343-7, 2004

Papillomavirus Life Cycle

virions

Viral Proteins

micro-trauma Capsid & Early

Epidermis Early only Basal Layer

Dermis

None

Slide courtesy M. Kast

How antibodies may protect against HPV acquisition

HPV virus Abraded epithelium

Abraded epithelium Abraded epithelium Lesion (in sexual partner)

Epithelium of vaccinee

Antibody

L1 VLPs are unlikely to be directly therapeutic: L1 expression pattern in dysplasias

L1 expression CIN 1 CIN 2 CIN 3

Doorbar, The papillomavirus life cycle. J Clin Virol 32:7-15, 2005

How antibodies might reduce auto-inoculation in a vaccinee with prevalent HPV infection

HPV virus Abraded epithelium

Productive lesion in infected vaccinee

Abraded epithelium Abraded epithelium

Epithelium of vaccinee

Antibody

Summary and Conclusions

· Virion immunodominant epitopes are on L1. They are conformation-dependent neutralization epitopes that are predominantly HPV type-specific. Pre-clinical studies of L1 VLP vaccination indicate that VLPs protect mainly by inducing neutralizing antibodies. Micro-trauma is believed to occur with most HPV infection. Systemic antibodies could be available at these sites. Established HPV infection is maintained by the presence of the viral genome in basal cells. In productive lesions, L1 is expressed is suprabasal cells. L1 is not usually expressed in severe dysplasias. An L1 VLP vaccine might reduce the spread of prevalent infection via auto-inoculation, but is unlikely to treat established lesions.

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Information

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