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Genital infection with any of several human papillomaviruses (HPVs) is necessary but not sufficient to cause uterine cervical cancer, the second most common female malignancy worldwide. In the late 1980s we established antibody-mediated virus neutralization as a vaccine concept for prevention of genital HPV infections by using authentic virions of a genital HPV type (type 11 or “HPV11”) to demonstrate that viral infectivity could be blocked with capsid-specific antibodies.
This observation led us to produce non-infectious "virus-like particles" (VLPs) of prevalent genital HPV types associated with either benign genital warts (HPV11) (1) or cervical cancer (HPV16 and HPV18) (3).
By comparing HPV11 recombinant VLPs with authentic native genital HPV11 virions, we were able to show that VLPs accurately mimic viral structure and immunological properties. We then formally demonstrated that this approach to vaccine development was valid by showing that antibodies raised against HPV11 L1 VLPs efficiently neutralized authentic HPV11 virus particles
(2).Our subsequent evaluations of antibody responses against VLPs derived from three genetically distinct genital HPV types (i.e., types 11, 16 and 18) led us to conclude that antibody-mediated neutralization was genotype-specific, and that multivalent HPV VLP vaccine formulations would be required for the induction of broadly protective immunity against genital HPV disease (3)(4).
We next developed a collaboration with a small biotechnology company (MedImmune, Inc., Gaithersburg, MD), and performed the first-in-humans administration of VLPs in a controlled phase 1 clinical study of VLP safety and tolerability. The results of our study indicated that VLPs are safe and well-tolerated (11).
Next, phase 2 and phase 3 clinical studies were performed by GlaxoSmithKline, and by Merck, Sharp & Dohme. Results from those studies demonstrated that VLP vaccines are highly effective for preventing cervical cancer precursor lesions. In June 2006, Gardasil (a tetravalent VLP vaccine formulation made by Merck) was approved by the FDA, and recommended by the CDC’s Advisory Committee on Immunization Practices (ACIP) for universal immunization of 11 and 12 year old females. A bivalent formulation developed by Glaxosmithkline is now under FDA review.
More recently our work has involved the development of alternative needle-free methods for VLP administration that we hope will prove to be more suitable for use in developing world regions where most cervical cancer occurs (8, 9, 13). We are also developing chimeric VLP-based vaccines for therapy of established genital HPV disease, or for preventing or treating diseases caused by other viruses including HIV and Dengue.
Rose Lab Group
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1. Rose, RC; Bonnez, W; Reichman, RC; Garcea, RL (1993): Expression of the human papillomavirus type 11 (HPV-11) L1 protein in insect cells: in vivo and in vitro assembly of virus-like particles. J. Virol. 67:1936-1944.
(First production of genital HPV L1 virus-like particles (VLPs)).
2. Rose, RC; Reichman, RC; Bonnez, W (1994): HPV-11 recombinant virus-like particles (VLPs) induce the formation of neutralizing antibodies and detect HPV-specific antibodies in human sera.J. Gen. Virol., 75:2075-9.
(First demonstration that genital HPV VLPs induce a protective immune response, i.e., virus-neutralizing antibodies)
3. Rose, RC; Bonnez, W; McCance, DJ; Da Rin, C; Reichman, RC (1994): Serologic differentiation of human papillomavirus (HPV) types 11, 16, and 18 L1 virus-like particles (VLPs).J. Gen. Virol., 75:2445-2449.
(First production of VLPs of oncogenic HPV genotypes 16 and 18, and first demonstration that VLPs of different genotypes induce genotype-specific neutralizing antibody responses, thus establishing the need for multivalent VLP vaccines to induce broadly protective immunity against cervical HPV disease)
4. Rose, RC (1994). Ph.D. Dissertation: Production and Characterization of Human Papillomavirus (HPV) Virus-like Particles (VLPs): Novel Diagnostic Reagents and Vaccine Candidates For Genital HPV Disease. The University of Rochester, Rochester, New York.
5. Rose, RC; W Bonnez; Reichman, RC. (1997). Human Papillomavirus Infections. In G. J. Galasso, R. J. Whitley, and T. C. Merigan (eds.), Antiviral Agents and Human Viral Diseases, 4th ed. Raven Press, NY.
6. Rose, RC; White, WI; Li, M; Suzich, JA; Lane, C; Garcea, RL. (1998). Human papillomavirus type 11 (HPV-11) recombinant L1 capsomeres induce virus-neutralizing antibodies. J.Virology 72(7):6151-6154.
(First demonstration that capsomers (a subunit of the viral capsid) induce virus-neutralizing antibodies)
7. Bonnez, W; DaRin, C; Borkhuis, C; de Mesy Jensen, K; Reichman, RC; Rose, RC (1998). Isolation and propagation of human papillomavirus type 16 in human xenografts implanted in the severe combined immunodeficiency mouse.J. Virology 72(6):5256-5261.
(First production of authentic HPV16 virions in an animal model)
8. Rose, RC; Lane, C; Wilson, S; Suzich, JA; Rybicki, E; Williamson, A-L. (1999). Oral vaccination of mice with human papillomavirus virus-like particles induces systemic virus-neutralizing antibodies. Vaccine 17(17):2129-2135.
(First demonstration that VLPs can be administered orally for induction of serum virus-neutralizing antibody responses)
9. Gerber S, Lane C, Brown DM, Lord E, DiLorenzo M, Clements JD, Rybicki E, Williamson AL, Rose RC. Human Papillomavirus Virus-Like Particles Are Efficient Oral Immunogens when Coadministered with Escherichia coli Heat-Labile Enterotoxin Mutant R192G or CpG DNA. J Virol 75:4752-60, 2001.
10. Giroglou T, Sapp M, Lane C, Fligge C, Christensen ND, Streeck RE, Rose RC. Immunological analyses of human papillomavirus capsids. Vaccine 19:1783-93, 2001.
11. Evans TG, Bonnez W, Rose RC, Koenig S, Demeter L, Suzich JA, O'Brien D, Campbell M, White WI, Balsley J, Reichman RC. A Phase 1 Study of a Recombinant Viruslike Particle Vaccine against Human Papillomavirus Type 11 in Healthy Adult Volunteers. J Infect Dis 183:1485-93, 2001.
(First phase 1 clinical evaluation of HPV VLPs in human subjects).
12. Rose, RC. (2002). Human Papillomavirus Immunology and Vaccine Development. Human Papillomaviruses; In Perspectives in Medical Virology, 8, pp 165-184; Ed. D. McCance; Elsevier, Amsterdam.
13. Warzecha H, Mason HS, Lane C, Tryggvesson A, Rybicki E, Williamson AL, Clements JD, Rose RC. Oral immunogenicity of human papillomavirus-like particles expressed in potato. J Virol. 77:8702-11, 2003.
(First demonstration that VLPs can be produced in edible plants, and that ingestion of this material can induce virus-neutralizing antibody responses).
14. Sasagawa T, Rose RC, Azar KK, Sakai A, Inoue M. Mucosal immunoglobulin-A and -G responses to oncogenic human papilloma virus capsids. Int J Cancer. 104:328-35, 2003.
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