A Long Way: History of the Prophylactic Papillomavirus Vaccine

Müller, Martin; Gissmann, Lutz

doi:10.1155/2007/939634

Cited by 15 publications

(6 citation statements)

References 65 publications

(54 reference statements)

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“…A further important aspect favoring retroparticle-based immunization strategies is that VLPs provide strong cross-species T cell epitopes that are sufficient to induce Th function in mice and humans without additional adjuvants. Finally, VLP-based immunizations have been proven safe and versatile in clinical studies with papilloma virus-based VLPs (57)(58)(59) and importantly also recently with retroviral HIV-based particles as novel AIDS vaccines (60,61). In conclusion, A␤ retroparticles hold great promise to be further developed as a novel and safe active immunization strategy against AD.…”

Section: Discussionmentioning

confidence: 99%

Vaccination with Aβ-Displaying Virus-Like Particles Reduces Soluble and Insoluble Cerebral Aβ and Lowers Plaque Burden in APP Transgenic Mice

Bach

Tschäpe

Kopietz

et al. 2009

The Journal of Immunology

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In transgenic animal models, humoral immunity directed against the β-amyloid peptide (Aβ), which is deposited in the brains of AD patients, can reduce Aβ plaques and restore memory. However, initial clinical trials using active immunization with Aβ1–42 (plus adjuvant) had to be stopped as a subset of patients developed meningoencephalitis, likely due to cytotoxic T cell reactions against Aβ. Previously, we demonstrated that retrovirus-like particles displaying on their surface repetitive arrays of self and foreign Ags can serve as potent immunogens. In this study, we generated retrovirus-like particles that display the 15 N-terminal residues of human Aβ (lacking known T cell epitopes) fused to the transmembrane domain of platelet-derived growth factor receptor (Aβ retroparticles). Western blot analysis, ELISA, and immunogold electron microscopy revealed efficient incorporation of the fusion proteins into the particle membrane. Without the use of adjuvants, single immunization of WT mice with Aβ retroparticles evoked high and long-lived Aβ-specific IgG titers of noninflammatory Th2 isotypes (IgG1 and IgG2b) and led to restimulatable B cell memory. Likewise, immunization of transgenic APP23 model mice induced comparable Ab levels. The CNS of immunized wild-type mice revealed neither infiltrating lymphocytes nor activated microglia, and no peripheral autoreactive T cells were detectable. Importantly, vaccination not only reduced Aβ plaque load to ∼60% of controls and lowered both insoluble Aβ40 as well as Aβ42 in APP23 brain, but also significantly reduced cerebral soluble Aβ species. In summary, Aβ retroparticle vaccination may thus hold promise as a novel efficient future candidate vaccine for active immunotherapy of Alzheimer’s disease.

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Section: Discussionmentioning

confidence: 99%

Vaccination with Aβ-Displaying Virus-Like Particles Reduces Soluble and Insoluble Cerebral Aβ and Lowers Plaque Burden in APP Transgenic Mice

Bach

Tschäpe

Kopietz

et al. 2009

The Journal of Immunology

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“…The first two VLP-based vaccines using L1 protein as the selected antigen have recently been introduced onto the market (Harper et al 2004;Villa et al 2006;Müller and Gissmann 2007). One of these vaccines, obtained from a yeast expression system, is a tetravalent that covers HPV types 16, 18, 6 and 11, while the second is a bivalent vaccine covering HPV types 16 and 18 and is obtained from insect cells.…”

Section: Introductionmentioning

confidence: 99%

Transplastomic expression of a modified human papillomavirus L1 protein leading to the assembly of capsomeres in tobacco: a step towards cost-effective second-generation vaccines

et al. 2010

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Certain types of human papillomaviruses (HPV) are causatively associated with cervical carcinoma, the second most common cancer in women worldwide. Due to limitations in the availability of currently used virus-like particle (VLP)-based vaccines against HPV to women of developing countries, where most cases of cervical cancer occur, the development of a cost-effective second-generation vaccine is a necessity. Capsomeres have recently been demonstrated to be highly immunogenic and to have a number of advantages as a potential cost-effective alternative to VLP-based HPV vaccines. We have expressed a mutated HPV-16 L1 (L1_2xCysM) gene that retained the ability to assemble L1 protein to capsomeres in tobacco chloroplasts. The recombinant protein yielded up to 1.5% of total soluble protein. The assembly of capsomeres was examined and verified by cesium chloride density gradient centrifugation and sucrose sedimentation analysis. An antigen capture enzyme-linked immunosorbent assay confirmed the formation of capsomeres by using a conformation-specific monoclonal antibody which recognized the conformational epitopes. Transplastomic tobacco plants exhibited normal growth and morphology, but all such lines showed male sterility in the T₀, T₁ and T₂ generations. Taken together, these results indicate the possibility of producing a low-cost capsomere-based vaccine by plastids.

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“…Furthermore, in the cottontail rabbit papillomavirus and the canine oral papillomavirus models, it was shown previously that immunized animals are protected against challenge with infectious virions (8,26,51). As an achievement based on these initial studies and many clinical trials in the following years, two VLP-based vaccines were recently introduced to the market (21,31,54). Gardasil, produced by Merck & Co, contains in addition to the VLPs of the two oncogenic human papillomavirus types 16 and 18 (HPV16 and HPV18) particles of the low-risk types 6 and 11 and was approved in the United States and in Europe in 2006.…”

mentioning

confidence: 99%

A Direct Comparison of Human Papillomavirus Type 16 L1 Particles Reveals a Lower Immunogenicity of Capsomeres than Viruslike Particles with Respect to the Induced Antibody Response

Thönes

Herreiner

Schädlich

et al. 2008

J Virol

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Capsomeres are considered to be an alternative to viruslike particle (VLP)-based vaccines as they can be produced in prokaryotic expression systems. So far, no detailed side-by-side comparison of VLPs and capsomeres has been performed. In the present study, we immunized mice with insect cell-derived human papillomavirus type 16 VLPs and capsomeres. VLPs induced consistently higher antibody titers than capsomeres but the two forms induced similar CD8 T-cell responses after subcutaneous, intranasal, and oral immunization, and at least 20 to 40 times more L1 in the form of capsomeres than in the form of VLPs was needed to achieve comparable antibody responses. These results were confirmed by DNA immunization. The lower immunogenicity of capsomeres was independent of the isotype switch, as it was also observed for the early immunoglobulin M responses. Although there were differences in the display of surface epitopes between the L1 particles, these did not contribute significantly to the differences in the immune responses. capsomeres were less immunogenic than VLPs in Toll-like receptor 4 (TLR4)-deficient mice, suggesting that the lower immunogenicity is not due to a failure of capsomeres to trigger TLR4. We observed better correlation between antibody results from enzyme-linked immunosorbent assays and neutralization assays for sera from VLPimmunized mice than for sera from capsomere-immunized mice, suggesting qualitative differences between VLPs and capsomeres. We also showed that the lower immunogenicity of capsomeres could be compensated by the use of an adjuvant system containing MPL. Taken together, these results suggest that, presumably because of the lower degree of complexity of the antigen organization, capsomeres are significantly less immunogenic than VLPs with respect to the humoral immune response and that this characteristic should be considered in the design of putative capsomere-based prophylactic vaccines.

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A Long Way: History of the Prophylactic Papillomavirus Vaccine

Cited by 15 publications

References 65 publications

Vaccination with Aβ-Displaying Virus-Like Particles Reduces Soluble and Insoluble Cerebral Aβ and Lowers Plaque Burden in APP Transgenic Mice

Vaccination with Aβ-Displaying Virus-Like Particles Reduces Soluble and Insoluble Cerebral Aβ and Lowers Plaque Burden in APP Transgenic Mice

Transplastomic expression of a modified human papillomavirus L1 protein leading to the assembly of capsomeres in tobacco: a step towards cost-effective second-generation vaccines

A Direct Comparison of Human Papillomavirus Type 16 L1 Particles Reveals a Lower Immunogenicity of Capsomeres than Viruslike Particles with Respect to the Induced Antibody Response

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