Prevention of cancer by prophylactic human papillomavirus vaccines

Oncogenic human papillomaviruses (HPVs) are exclusively mucosal pathogens that are noncytopathic and the basal epithelial cells harboring and maintaining an infection do not produce either capsid antigen or virus. The efficacy of the licensed L1 virus-like particle (VLP) vaccines has encouraged development of several second generation vaccines aimed at expanding the coverage to all oncogenic HPV types and reducing barriers to global implementation. Currently there is no defined immune correlate of protection that can be used to determine if an individual patient is protected and for the evaluation of these second generation vaccines. Surprisingly, passive transfer of neutralizing serum antibody is protective in animal models. Recent studies suggest how neutralizing antibody mediates immunity against mucosal HPV and the possible impact of memory B cells.     

ISCOMATRIX adjuvant for prophylactic and therapeutic vaccines

The ISCOMATRIX adjuvant has antigen-delivery and -presentation properties, as well as immunomodulatory capabilities that combine to provide enhanced and accelerated immune responses. The responses are broad, including a range of subclasses of antibodies as well as both CD4+ and CD8+ T cells. A range of ISCOMATRIX vaccines (ISCOMATRIX adjuvant combined with antigen) have been evaluated in clinical trials. The results of these completed and ongoing studies indicate that the ISCOMATRIX adjuvant is safe and generally well tolerated and increases the vaccine immune responses.     

Recombinant vaccines for the prevention of human papillomavirus infection and cervical cancer

Carcinogenic human papillomaviruses (HPVs) that cause cervical cancer preferentially infect basal, metaplastic squamous cells of the transformation zone. If infection persists, and a vegetative infection ensues, a premalignant lesion may develop with the potential to progress into an invasive squamous cell carcinoma. Papillomavirus prophylactic vaccines target the systemic immune system for induction of neutralizing antibodies that protect the basal cells against infection. Because the carcinogenic HPVs are susceptible to neutralization by antibodies for 9–48 h after reaching the basal cells, both low and high titered HPV type-specific antibodies induced by HPV L1 and L2-based vaccines are highly efficacious. The greatest burden of HPV-associated cancers occurs in poor areas of the world where women do not have access to routine gynecological care. The burden of HIV/AIDS in these same regions of the world has added to the burden of HPV-associated disease. There is an urgent need for a cost-effective, broad-spectrum HPV prophylactic vaccine in developing countries, which necessitates substantial cost subsidization of the virus-like particle (VLP) based vaccines licensed in industrialized countries or an alternative approach with second-generation vaccines that are specifically designed for delivery to women in resource-poor communities.     

治疗性疫苗的研究进展

治疗性疫苗能激发和诱导机体对某些抗原,如肿瘤抗原、病毒抗原的特异性免疫应答,为肿瘤、慢性感染性疾病、自身免疫性疾病的治疗提供了新方法。据美国国家卫生研究院（NIH）临床试验数据库统计,目前已有347种治疗性疫苗进入了临床试验阶段,其中肿瘤治疗性疫苗、乙肝治疗性疫苗以及自身免疫性疾病治疗性疫苗是近年来研发的热点,然而热点也是难点,迄今为止,在全球范围内,尚无没有成熟的产品问世。     

治疗性人乳头瘤病毒疫苗研究进展

人乳头瘤病毒是以表皮细胞为感染对象的小型DNA病毒,HPV感染与子宫颈癌的发生、发展有着十分密切的关系.宫颈癌位居女性恶性肿瘤的第二位,且呈逐年上升的趋势.已上市的疫苗主要用于预防HPV的感染,对已感染HPV人群的治疗效果欠佳,治疗性疫苗可以通过诱导特异性的细胞免疫应答,阻止甚至清除HPV感染引起的病变及肿瘤.动物实验和临床试验结果显示,治疗性HPV疫苗在治疗HPV感染相关疾病有重要作用.因此,治疗性HPV疫苗的研制及应用已成为近年来研究热点.     

Development of prophylactic and therapeutic vaccines against hepatitis C virus

The hepatitis C virus was discovered 15 years ago as the agent responsible for most cases of transfusion-associated hepatitis non-A, non-B. At present, 180 million people worldwide are estimated to be infected with the virus, producing severe and progressive liver disease in millions and representing the most common reason for liver transplantation in adults. Although the spread of the virus can be halted by the application of primary prevention strategies, such as routine testing of blood donations, inactivation of blood products and systematic use of disposable needles and syringes, the development of a prophylactic vaccine could facilitate the control of this infection and protect those at high risk of being infected with hepatitis C virus. As the present therapy of chronic hepatitis C virus infections, consisting of a combined administration of pegylated interferon-alpha and ribavirin, is only successful in 50% of patients infected with genotype 1, and is costly and associated with serious side effects, there is an urgent need for better tolerated and more effective treatment modalities, and a therapeutic vaccine may be the solution. This review first provides an overview of the present knowledge regarding the interaction between the virus and immune system of the infected host, with special attention given to the possible mechanisms responsible for chronic evolution of the infection. The numerous candidate vaccines that have been developed in the past 10 years are discussed, including the studies in which their immunogenicity has been examined in rodents and chimpanzees. Finally, the only studies of therapeutic vaccines performed in humans to date are considered.     

Clinical trials of prophylactic and therapeutic herpes simplex virus vaccines

Herpes simplex virus type 2 (HSV-2) is a suitable target for a vaccine, despite available antiviral therapies, because the virus causes lifelong infection and significant medical and psychosocial morbidity. A vaccine has the potential to reduce HSV acquisition, disease severity and the number of cases of neonatal herpes. It could also reduce transmission of HIV, which is epidemiologically linked to HSV. Prophylactic vaccines for HSV-2 must give broad and durable immunity across all mucosal surfaces to be effective. This is a significant challenge, as the major determinants of effective immunity have not yet been identified. Even if full protection cannot be achieved, vaccines would still be useful if they could increase the threshold of infection, or prevent clinical disease. However, it is possible that a vaccine could reduce symptomatic disease, but not eliminate asymptomatic shedding, which could inadvertently increase transmission from individuals who believe they are not infectious. Investigated prophylactic vaccines for HSV-2, including subunit vaccines encoding HSV glycoproteins packaged with adjuvants, have shown some benefits. The Chiron gD2gB2-MF59 vaccine gave transient protection of less than 6 months. The GlaxoSmithKline gD2-alum MPL vaccine conferred a 73-74% reduction in acquisition of symptomatic HSV-2 disease and a 38-42% reduction in the acquisition of HSV-2 infection in HSV-seronegative women, but gave no protection in men or HSV-1 seropositive women. Therapeutic vaccines aim to prevent HSV recurrences or minimise disease severity and duration, thereby reducing transmission. Research indicates that to be effective, therapeutic vaccines need to stimulate strong cell-mediated immune responses. Vaccines have induced HSV-specific antibody responses alone but have failed to protect recipients from recurrences. Further research is needed to define determinants of immunity to HSV-2, including identifying HSV-2 antigens, in order to design more effective vaccines.     

Prophylactic human papillomavirus vaccines: potential for sea change

Persistent human papillomavirus (HPV) infection is the central cause in the development of anogenital warts, precancers and cancers of uterine cervix, and a major factor in the genesis of other malignancies of the lower anogenital and upper aerodigestive tracts. The burden of disease carries very high medical, financial and psychosocial costs. The role of prophylactic HPV vaccines in reducing the burden of disease is discussed in light of the results of multiple randomized, controlled trials conducted worldwide in thousands of young females. The review discusses some of the issues that are still unknown, with respect to long-term vaccine performance, challenges to be overcome to achieve universal, mass prophylactic HPV vaccination, as well as the potential impact of the vaccines on primary screening for, and management of, HPV-related anogenital infection and disease.     

Interferonogenicity of rabies vaccines as related to their therapeutic and prophylactic activities

Non-interferonogenic rabies vaccine prepared from a virus grown in sheep brain and devoid of neuroallergenic factor and an interferonogenic vaccine from the same virus strain cultured in Japanese quail embryo cells have been compared. In mouse experiments both preparations appeared to have identical therapeutic and prophylactic efficacy. It seems that interferonogenicity of rabies vaccines cannot be used as a criterion of their prophylactic or therapeutic effects. The effectiveness of exogenous and endogenous interferon (IFN) in mice infected by the highly pathogenic fixed rabies virus has been experimentally demonstrated. Combined application of the vaccine and IFN or its inducer exerted the most marked therapeutic effect. Administration of IFN inducer into mouse brain was much more effective than its extraneural inoculation.     

重组人干扰素治疗宫颈HPV感染的临床观察

目的探讨重组人干扰素α-2b凝胶治疗不伴高级别宫颈病变HPV持续感染的临床疗效及对不同HPV亚型的清除效果。方法选取271例不伴高级别宫颈病变的HPV持续感染者,治疗组（234例）：局部使用重组人干扰素α2b凝胶治疗;对照组（37例）：不使用任何药物干预。所有患者均于入组后的第3个月和第6个月复查HPV和TCT,比较疗效。结果 3个月和6个月后,治疗组HPV清除率和有效率均明显高于对照组（P〈0.05）。干扰素治疗HPV潜伏感染效果显著（P〈0.05）。干扰素对易致高级别宫颈病变或癌变且自然清除率较低的HPV亚型（hr HPV16、18、31、33、45、52和58）,6个月内的清除率均较对照组有统计学差异（P〈0.05）。结论干扰素对HR-HPV感染的治疗效果显著,于那些致病能力强且自然清除率低的HPV感染建议尽早干预并密切随访。     

人乳头瘤病毒感染与头颈癌关系的研究进展

人乳头瘤病毒(HPV)与部分头颈癌的发病相关,HPV阳性头颈癌在流行病学、病因学、病理学、分子特征等方面与HPV阴性头颈癌存在明显差异.并且头颈癌中HPV基因组存在形式及转录活性对头颈癌的预后都会产生影响.生物信息手段分析头颈癌中HPV的存在形式成为热点,而采集患者脱落细胞进行HPV检测是另一种简单易行的检测方法.     

Cutaneous delivery of prophylactic and therapeutic vaccines: historical perspective and future outlook

The skin has long been recognized as an attractive target for vaccine administration. A number of clinical studies have tested the epidermal and dermal routes of delivery using a variety of vaccines over the years. In many cases, cutaneous administration has been associated with immunological benefits, such as the induction of greater immune responses compared with those elicited by conventional routes of delivery. Furthermore, there is a growing body of evidence to suggest that such benefits may be particularly important for certain higher-risk populations, such as the elderly, the immunocompromised and cancer patients. Despite the potential advantages of vaccination via the skin, results have sometimes been conflicting and the full benefits of this approach have not been fully realized, partly due to the lack of delivery devices that accurately and reproducibly administer vaccines to the skin. The 5-year outlook, however, appears quite promising as new cutaneous delivery systems advance through clinical trials and become available for more widespread clinical and commercial use.     

Prophylactic human papillomavirus vaccines: past, present and future

Human papillomavirus (HPV) is a highly transmissible infection responsible for a range of diseases in women including cervical carcinomas, vulval carcinomas, anogenital carcinomas and genital warts. In men it is associated with penile carcinomas, anogenital carcinomas and oropharyngeal carcinomas. The history of the development of HPV vaccines includes a significant Australian input and represents a tremendous advancement in our understanding of HPV virology as well as further elucidating the overall contribution of viruses to carcinogenesis. Prophylactic HPV vaccines were licensed for use in Australia in 2007 in order to protect against development of future cases of cervical carcinoma and early results are promising. The benefit of the vaccine will not be restricted to cervical lesions and cross protection amongst a variety of HPV subtypes is described. The development of the HPV vaccine and its ultimate incorporation into our National Immunisation Schedule is reviewed.     

Screening for human papillomavirus infection in asymptomatic women in Hungary

BACKGROUND: A multicentre epidemiological survey was carried out in order to determine the prevalence of, and risk factors for, persistent cervical human papillomavirus (HPV) infection in women in Hungary. METHODS and RESULTS: A total of 728 women were examined for the prevalence of HPV. The estimated overall rate of HPV infection was 17%. In univariate analysis the strongest predictors were young age (< or =24 years), unmarried family status, smoking, a pathological Papanicolaou (Pap) smear, having a condyloma and previous gynaecological cancer in the family (age and marital status being the most important predictors). In multiple regression analysis, young age (< or =24 years)(odds ratio = 1.86, 95% confidence interval = 1.19-2.90, P < 0.01), smoking (1.78, 1.17-2.71, P < 0.05), an abnormal Pap smear (6.92, 2.68-17.84, P < 0.001), having a condyloma (4.22, 1.42-12.58, P < 0.01) and living in a region where the unemployment rate is relatively high (1.56, 1.24-2.82, P < 0.01) were associated risk factors for HPV infection. CONCLUSIONS: The prevalence of HPV infection in young women in Hungary is high. Screening for HPV is suggested only in women with an unfavourable gynaecological history who are < or =24 years old.     

Structural differences among cost-effectiveness models of human papillomavirus vaccines

In this article we compare previously published cost-effectiveness studies of human papillomavirus (HPV) vaccines along a defined subset of key model structural assumptions relating to HPV infection and disease, cervical cancer screening and HPV vaccination. For each structural aspect examined, we summarize assumptions from each study, provide a critical review and discuss the impact upon results. Considerable variation was observed across HPV vaccine cost-effectiveness models in a number of influential assumptions. Holding constant factors for which current data are lacking, the combined impact of assumptions made for the remaining parameters examined would appear to tend toward underestimation of the cost-effectiveness of HPV vaccination within existing studies. However, uncertainty concerning parameters, such as the duration of vaccine protection and acquired immunity following HPV infection, and the relationship between age and HPV virulence, complicates precise estimation of the cost-effectiveness of HPV vaccination and rigorous evaluation of the validity of existing modeling results.     

Development of prophylactic vaccines for genital and neonatal herpes

Over five decades numerous conventional candidate live attenuated and killed vaccines have failed to prevent genital herpes in clinical trials. However, a vaccine consisting of recombinant glycoprotein D from herpes simplex virus (HSV)-2 and deacylated monophosphoryl lipid A adjuvant has recently shown partial efficacy against clinical disease transmitted from HSV-1 and -2 seronegative women (73-74%). Comparisons between the efficacy of this vaccine and previous failed candidates and their effects on the immune system should help guide development of better vaccines through selection of appropriate HSV proteins, adjuvants or cytokines and newer vaccine vectors, such as DNA vaccines, recombinant viral vaccines and specific HSV mutants.     

Induction of cross-neutralizing antibodies by sequential immunization with heterologous papillomavirus L1VLPs and its implications for HPV prophylactic vaccines

Sequential immunization with antigens from different strains of HIV-1, influenza viruses or dengue viruses induced cross-neutralizing antibodies and enhanced the antibody responses against previous antigens. The characteristics of neutralizing antibodies induced by sequential immunization with different types of human papillomavirus (HPV) L1 virus-like particles (L1VLPs) are unclear. In this study, mice were primed with one or two types (HPV-16 or HPV16/18) of L1VLPs, then boosted sequentially with HPV6/18/45/11/31/58 or HPV6/45/11/31/58 L1VLPs, and sera were analyzed with HPV pseudovirus-based neutralization assay. The results showed that neutralizing activities against earlier immunized vaccine types were enhanced gradually by subsequent immunizations, and low levels of neutralizing activities against nonvaccine types (HPV33/35/52/59/68) were also observed. After absorbing the immune sera with vaccine-type (HPV16/18/45) L1VLPs, neutralizing activities against tested priming and boosting types (HPV16/18/58) decreased significantly, and that against nonvaccine type (HPV-33) was also partially eliminated. Moreover, neutralizing activities against vaccine types (HPV16/58) were significantly reduced after absorbing with nonvaccine-type VLPs (HPV33/52). These data suggest that cross-neutralizing epitopes exist among different HPV L1VLPs. The cross-neutralizing activities against nonvaccine types and the enhanced neutralizing activities against earlier immunized vaccine types may result from sequential boosting with these cross-neutralizing epitopes. These observations support early vaccination with more types of L1VLPs derived from HPVs that cause a serious threat to the population.     

Characterization of human papillomavirus infection in north Taiwan

The detection of human papillomavirus (HPV) is very important for the evaluation of preventative strategies for cervical cancer. The major objective of this study was to characterize the prevalence of different genotypes of HPV in north Taiwan to contribute to the epidemiological knowledge of HPV infections. Papanicolaou (Pap) cervical smears were collected from 10,543 women aged between 14 and 87 years. The polymerase chain reaction (PCR) and DNA array hybridization techniques were used to genotype 51 different HPV strains. HPV was detected in 1,577 women, which gave an overall HPV prevalence rate of 15%. Forty‐eight different genotypes were found in these patients, which included 9.7% that were high‐risk HPV (HR‐HPV) genotypes. The most common types of HR‐HPV in patients, in descending order of frequency, were HPV 52, 16, 58, 56, 39, 51, 18, 68, 31, 33, 59, 45, and 35. HPV 52 was the most frequent type in every age group. The four most common HR‐HPV types were found in 56.6% of the patients infected with HR‐HPV. In cases that were infected with multiple HPV genotypes, 69.2% had at least one HR‐HPV genotype. The rate of infection with HR‐HPV was higher in the younger age groups than the older ones. In conclusion, 48 HPV genotypes were identified from a large study of cervical screening samples and the prevalence of HPV genotypes in different age groups was very diverse. The formulation of a public health strategy for HPV vaccination should take into account the prevalence of various HR‐HPV/LR‐HPV genotypes. J. Med. Virol. 82:1416–1423, 2010. © 2010 Wiley‐Liss, Inc.