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Therapeutic Vaccine Strategies against Human Papillomavirus.

ABSTRACT: High-risk types of human papillomavirus (HPV) cause over 500,000 cervical, anogenital and oropharyngeal cancer cases per year. The transforming potential of HPVs is mediated by viral oncoproteins. These are essential for the induction and maintenance of the malignant phenotype. Thus, HPV-mediated malignancies pose the unique opportunity in cancer vaccination to target immunologically foreign epitopes. Therapeutic HPV vaccination is therefore an ideal scenario for proof-of-concept studies of cancer immunotherapy. This is reflected by the fact that a multitude of approaches has been utilized in therapeutic HPV vaccination design: protein and peptide vaccination, DNA vaccination, nanoparticle- and cell-based vaccines, and live viral and bacterial vectors. This review provides a comprehensive overview of completed and ongoing clinical trials in therapeutic HPV vaccination (summarized in tables), and also highlights selected promising preclinical studies. Special emphasis is given to adjuvant science and the potential impact of novel developments in vaccinology research, such as combination therapies to overcome tumor immune suppression, the use of novel materials and mouse models, as well as systems vaccinology and immunogenetics approaches.

SUBMITTER: Khallouf H

PROVIDER: S-EPMC4494257 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Therapeutic Vaccine Strategies against Human Papillomavirus.

Khallouf Hadeel H Grabowska Agnieszka K AK Riemer Angelika B AB

Vaccines 20140613 2

High-risk types of human papillomavirus (HPV) cause over 500,000 cervical, anogenital and oropharyngeal cancer cases per year. The transforming potential of HPVs is mediated by viral oncoproteins. These are essential for the induction and maintenance of the malignant phenotype. Thus, HPV-mediated malignancies pose the unique opportunity in cancer vaccination to target immunologically foreign epitopes. Therapeutic HPV vaccination is therefore an ideal scenario for proof-of-concept studies of canc ...[more]

PMID: 26344626

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Project description:Human papillomavirus (HPV) tumor disease is a critical public health problem worldwide, especially in the developing countries. The recognized pathogenic function of E5, E6, and E7 oncoproteins offers the opportunity to devise therapeutic vaccines based on engineered recombinant proteins. The potential of plants to manufacture engineered compounds for pharmaceutical purposes, from small to complex protein molecules, allows the expression of HPV antigens and, possibly, the regulation of immune functions to develop very specific therapies as a reinforcement to available nonspecific therapies and preventive vaccination also in developed countries. Among plant-based expression formats, hairy root cultures are a robust platform combining the benefits of eukaryotic plant-based bioreactors, with those typical of cell cultures. In this work, to devise an experimental therapeutic vaccine against HPV, hairy root cultures were used to express a harmless form of the HPV type 16 E7 protein (E7*) fused to SAPKQ, a noncytotoxic form of the saporin protein from Saponaria officinalis, that we had shown to improve E7-specific cell-mediated responses as a fusion E7*-SAPKQ DNA vaccine. Hairy root clones expressing the E7*-SAPKQ candidate vaccine were obtained upon infection of leaf explants of Solanum lycopersicum using a recombinant plant expression vector. Yield was approximately 35.5 μg/g of fresh weight. Mouse immunization with vaccine-containing crude extracts was performed together with immunological and biological tests to investigate immune responses and anticancer activity, respectively. Animals were primed with either E7*-SAPKQ DNA-based vaccine or E7*-SAPKQ root extract-based vaccine and boosted with the same (homologous schedule) or with the other vaccine preparation (heterologous schedule) in the context of TC-1 experimental mouse model of HPV-associated tumor. All the formulations exhibited an immunological response associated to anticancer activity. In particular, DNA as prime and hairy root extract as boost demonstrated the highest efficacy. This work, based on the development of low-cost technologies, highlights the suitability of hairy root cultures as possible biofactories of therapeutic HPV vaccines and underlines the importance of the synergic combination of treatment modalities for future developments in this field.

Project description:Human papillomavirus (HPV) is the most common sexually transmitted infection, with 15 HPV types related to cervical, anal, oropharyngeal, penile, vulvar, and vaginal cancers. However, cervical cancer remains one of the most common cancers in women, especially in developing countries. Three HPV vaccines have been licensed: bivalent (Cervarix, GSK, Rixensart, Belgium), quadrivalent (Merck, Sharp & Dome (Merck & Co, Whitehouse Station, NJ, USA)), and nonavalent (Merck, Sharp & Dome (Merck & Co, Whitehouse Station, NJ, USA)). The current HPV vaccine recommendations apply to 9 years old and above through the age of 26 years and adults aged 27-45 years who might be at risk of new HPV infection and benefit from vaccination. The primary target population for HPV vaccination recommended by the WHO is girls aged 9-14 years, prior to their becoming sexually active, to undergo a two-dose schedule and girls ≥ 15 years of age, to undergo a three-dose schedule. Safety data for HPV vaccines have indicated that they are safe. The most common adverse side-effect was local symptoms. HPV vaccines are highly immunogenic. The efficacy and effectiveness of vaccines has been remarkably high among young women who were HPV seronegative before vaccination. Vaccine efficacy was lower among women regardless of HPV DNA when vaccinated and among adult women. Comparisons of the efficacy of bivalent, quadrivalent, and nonavalent vaccines against HPV 16/18 showed that they are similar. However, the nonavalent vaccine can provide additional protection against HPV 31/33/45/52/58. In a real-world setting, the notable decrease of HPV 6/11/16/18 among vaccinated women compared with unvaccinated women shows the vaccine to be highly effective. Moreover, the direct effect of the nonavalent vaccine with the cross-protection of bivalent and quadrivalent vaccines results in the reduction of HPV 6/11/16/18/31/33/45/52/58. HPV vaccination has been shown to provide herd protection as well. Two-dose HPV vaccine schedules showed no difference in seroconversion from three-dose schedules. However, the use of a single-dose HPV vaccination schedule remains controversial. For males, the quadrivalent HPV vaccine possibly reduces the incidence of external genital lesions and persistent infection with HPV 6/11/16/18. Evidence regarding the efficacy and risk of HPV vaccination and HIV infection remains limited. HPV vaccination has been shown to be highly effective against oral HPV type 16/18 infection, with a significant percentage of participants developing IgG antibodies in the oral fluid post vaccination. However, the vaccines' effectiveness in reducing the incidence of and mortality rates from HPV-related head and neck cancers should be observed in the long term. In anal infections and anal intraepithelial neoplasia, the vaccines demonstrate high efficacy. While HPV vaccines are very effective, screening for related cancers, as per guidelines, is still recommended.

Project description:Over the last 5 years, prophylactic vaccination against human papillomavirus (HPV) in pre-adolescent females has been introduced in most developed countries, supported by modeled evaluations that have almost universally found vaccination of pre-adolescent females to be cost-effective. Studies to date suggest that vaccination of pre-adolescent males may also be cost-effective at a cost per vaccinated individual of ~US$400-500 if vaccination coverage in females cannot be increased above ~50%; but if it is possible, increasing coverage in females appears to be a better return on investment. Comparative evaluation of the quadrivalent (HPV16,18,6,11) and bivalent (HPV16,18) vaccines centers around the potential trade-off between protection against anogenital warts and vaccine-specific levels of cross-protection against infections not targeted by the vaccines. Future evaluations will also need to consider the cost-effectiveness of a next generation nonavalent vaccine designed to protect against ~90% of cervical cancers. The timing of the effect of vaccination on cervical screening programs will be country-specific and will depend on vaccination catch-up age range and coverage and the age at which screening starts. Initial evaluations suggest that if screening remains unchanged, it will be less cost-effective in vaccinated compared to unvaccinated women but, in the context of current vaccines, will remain an important prevention method. Comprehensive evaluation of new approaches to screening will need to consider the population-level effects of vaccination over time. New screening strategies of particular interest include delaying the start age of screening, increasing the screening interval and switching to primary HPV screening. Future evaluations of screening will also need to focus on the effects of disparities in screening and vaccination uptake, the potential effects of vaccination on screening participation, and the effects of imperfect compliance with screening recommendations. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.

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Therapeutic Vaccine Strategies against Human Papillomavirus.

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Therapeutic Vaccine Strategies against Human Papillomavirus.

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