宫颈癌治疗性疫苗临床研究进展

宫颈癌的发生与高危型人乳头瘤病毒( human papillomavirus,HPV)的持续感染有关.随着对HPV及其致病机制的深入研究,已经开发了多种用于宫颈癌生物免疫治疗的疫苗,有些已进入临床试验.此文对已进入临床试验阶段的宫颈癌疫苗的设计策略和临床试验进展做一综述.     

宫颈癌治疗性疫苗研究进展

宫颈癌为妇女最常见的恶性肿瘤之一,其与人乳头瘤病毒(human papillomavirus,HPV)感染密切相关.随着对HPV及其致病机理研究的深入和免疫学的发展,利用免疫学方法治疗HPV引发的疾病显示良好的前景.目前,有关HPV治疗性疫苗的研究已取得较大进展,这些疫苗包括病毒/细菌载体疫苗、肽疫苗、蛋白疫苗、DNA疫苗、细胞疫苗等.此文就HPV治疗性疫苗的研究进展做一综述.     

Update on human papillomavirus vaccines for cervical cancer

Cervical cancer is a leading cause of cancer related mortality in women, particularly in developing countries. As a result of several recent advances in molecular biology, the causal association between human papillomavirus (HPV) infection and cervical cancer has been firmly established and the oncogenic potential of certain HPV types has been clearly demonstrated. In recognition of the causal association of cervical cancer with a sexually transmitted viral infection, substantial interest has arisen to develop effective prophylactic and therapeutic vaccines. Prophylactic strategies currently under investigation focus on the induction of effective humoral immune responses that are potentially protective against subsequent HPV infection. Using recombinant techniques to express the L1 major capsid protein, papillomavirus-like particles (VLPs) have been synthesized in order to induce neutralizing antibody responses and impressive immunoprophylactic effects have been demonstrated in both animals and humans. For the treatment of existing HPV infection, techniques to improve cellular immunity by enhancing viral antigen recognition are being studied. For this purpose, the oncogenic proteins E6 and E7 of HPV-16 and -18 are the focus of current clinical trials for cervical cancer patients. The development of successful HPV-specific vaccines may offer an attractive and cost-effective alternative to existing screening and treatment programs for cervical cancer.     

Therapeutic vaccines for cervical cancer: dendritic cell-based immunotherapy

Human papillomavirus (HPV) infection represents the most important risk factor for the development of cervical dysplasia and cervical cancer. Several lines of evidence suggest that cell-mediated immune responses are important in controlling both HPV infections and HPV-associated neoplasia. Since HPV E6 and E7 oncoproteins are expressed in these lesions and are necessary for the maintenance of the malignant phenotype, these proteins might be potential tumor-specific target antigens for immunotherapy of cervical cancer. The gold standard treatment for locally advanced cervical cancer is primary radiation therapy combined with chemotherapy. A potential drawback of this potentially curative treatment is a profound and long lasting negative effect on the immune system. Treatment-induced immunosuppression combined with tumor-induced subversion of the immune system may therefore impose severe limitations on the efficacy of conventional vaccination strategies in late stage cervical cancer patients. The recognition of dendritic cells (DC) as powerful antigen-presenting cells capable of inducing primary T cell responses in vitro and in vivo, has recently generated widespread interest in DC-based immunotherapy of several human malignancies. Here, we review various therapeutic HPV vaccines being developed and implemented in human clinical trials, with a particular emphasis on the use of autologous DC pulsed with full-length HPV 16 or 18 E7 oncoproteins as a novel strategy to induce HPV E7-specific and tumor-specific T cell responses in cervical cancer patients following conventional treatment.     

Toward oligosaccharide- and glycopeptide-based HIV vaccines

The human immunodeficiency virus (HIV) is the causative agent of acquired immune deficiency syndrome (AIDS), and HIV type 1 (HIV-1) is responsible for the current global pandemic of HIV and AIDS. There is widespread agreement that the best hope to contain this pandemic is the development of an effective HIV-1 vaccine. The major difficulty in HIV vaccine design, however, is in identifying novel epitopes for inducing broadly neutralizing antibodies. Accumulating data have implied that the HIV-1 carbohydrates, which are a strong defense against host immune attack, can also serve as targets for vaccines. This notion was reinforced by the characterization of a novel oligomannose cluster on HIV-1 glycoprotein gp120 as the epitope of the broadly neutralizing antibody 2G12. This review describes the current status and prospective of the progress toward a carbohydrate-based HIV vaccine. Recent research on the design, synthesis and antigenicity of HIV-1 oligosaccharides and glycopeptide immunogens is also discussed.     

Human papillomavirus vaccines for the prevention and treatment of cervical cancer

The identification of human papillomavirus (HPV) as a cause of cervical cancer and its precursor lesions indicates that HPV vaccines can potentially be used to prevent or treat cervical cancer and other HPV-associated malignancies. Prophylactic HPV vaccines aim to prevent infection by producing neutralizing antibodies against HPV capsid proteins L1 and L2. However, because HPV-infected basal keratinocytes and HPV-transformed cells generally do not express L1 or L2, therapeutic HPV vaccines are being developed to treat established HPV infections and HPV-associated malignancies by targeting non-structural early viral antigens of HPV, such as E6 and E7 (two viral oncogenic proteins required for the induction and maintenance of malignant cancer). Results from preclinical HPV vaccine studies have led to several HPV vaccine clinical trials. If these prophylactic and therapeutic HPV vaccines prove as successful in patients as they have in animal models, HPV vaccines may have a role in the control of HPV infection and HPV-associated disease.     

Recombinant vaccines against leptospirosis

Leptospirosis is an important neglected infectious disease that occurs in urban environments, as well as in rural regions worldwide. Rodents, the principal reservoir hosts of pathogenic Leptospira spp., and other infected animals shed the bacteria in their urine. During occupational or even recreational activities, humans that come into direct contact with infected animals or with a contaminated environment, particularly water, are at risk of infection. Prevention of urban leptospirosis is largely dependent on sanitation measures that are often difficult to implement, especially in developing countries. Vaccination with inactivated whole-cell preparations (bacterins) has limited efficacy due to the wide antigenic variation of the pathogen. Intensive efforts towards developing improved recombinant vaccines are ongoing. During the last decade, many reports on the evaluation of recombinant vaccines have been published. Partial success has been obtained with some surface-exposed protein antigens. The combination of protective antigens and new adjuvants or delivery systems may result in the much-needed effective vaccine.     

Anti-idiotype-based vaccines against biological toxins

Biological toxins produced by living organisms represent one of the major sources of contamination of stored grain and agricultural products, and other food sources. The majority of these biological toxins are highly lethal, nonproteinaceous low-molecular-weight chemical compounds which exert their potent toxicity through a variety of mechanisms. Because of their small size, they generally do not induce a significantly high affinity protective antibody response upon toxin exposure, even when conjugated to large protein carriers which enhance their immunogenicity. Moreover, the very toxic nature of biological toxins precludes their use as immunogens in the induction of protective immunity. To circumvent this difficulty, an attempt was made to develop antibody (anti-idiotype)-based vaccines against a protein synthesis inhibitor, the trichothecene mycotoxin T-2, and the sodium channel blockers tetrodotoxin and saxitoxin. Protective monoclonal antitoxin antibodies were first generated and then used to induce specific monoclonal anti-idiotype antibodies. Specific anti-idiotype antibodies were assessed for their ability to induce in vivo protective immunity against toxicity.     

Novel cancer vaccines

The intellectual property literature concerning novel cancer vaccine strategies for the period of 1998 and 2000 is reviewed. Nearly 400 citations have been identified and the majority of the citations described herein involve the identification of new tumour associated antigens and novel strategies of cancer vaccine formulations. Significant progresses have been made during this period in the identification of new tumour associated antigens (TAAs), the refinement of gene and DNA vaccination techniques, the development of dendritic cell-based immunotherapy and the use of cytokines and CpG-containing oligodeoxynucleotides as vaccine adjuvants. In addition, encouraging results have been obtained from vaccination studies of animal tumour models and a large number of novel cancer vaccines are currently under development or at early stages of clinical evaluation. Although the availability of cancer vaccines for clinical use in patient management remains a challenge to the cancer research community, we can be cautiously optimistic that vaccination has the potential to become an important treatment option for cancer patients in the foreseeable future.     

Long term protection against cervical infection with the human papillomavirus: review of currently available vaccines

Two vaccines against HPV are commercially available: an HPV-16/18 (bivalent) and an HPV-6/11/16/18 (quadrivalent) vaccine. Vaccination programs have been and will be implemented before the full duration of protection is known. Whether booster doses will be required is also unknown at this time. Meanwhile, predictions rely upon phase III studies and mathematical modelling. In a head to head study, the bivalent vaccine induced a higher, more sustained immune response than the quadrivalent vaccine. Immunogenicity of the bivalent vaccine against HPV-16 and HPV-18 has been demonstrated up to 8.4 years. For the quadrivalent vaccine, immunogenicity data up to 5 years show that the immune response against HPV-18 wanes after approximately 4 years. Efficacy against infection and cervical lesions associated with HPV-16/18 has been shown up to 8.4 and 5 years with the bivalent and quadrivalent vaccine, respectively. Cross-protection against non-vaccine types appears stronger with the bivalent vaccine. However, both vaccines may provide sufficient immunogenicity to confer long-term protection. Ongoing monitoring is essential.     

Development of vaccines against bovine tuberculosis

Bovine tuberculosis caused by Mycobacterium bovis remains an economically important problem in Great Britain with potential zoonotic consequences, and the incidence is rising exponentially. In 1997 an independent scientific review recommended that the best option for disease control in Great Britain was the development of a cattle vaccine. Bovine tuberculosis remains a significant problem in countries of the developing world. Indeed, more than 94% of the world's population live in countries in which the control of bovine tuberculosis in buffalos or cattle is limited or absent. Effective vaccination strategies would have a major impact in countries that cannot afford expensive test and slaughter-based control strategies. Here, we present a review of progress toward that goal, and discuss how this progress has shaped our research strategy for the development of a vaccine.     

Intranasal delivery of vaccines against HIV

HIV poses a serious health threat in the world. Mucosal transmission of HIV through the genitourinary tract may be the most important route of transmission. Intranasal immunisations induce vaginal and systemic immune responses. Various protein-, DNA- and RNA-based immunopotentiating adjuvants/delivery systems and live bacterial and viral vectors are available for intranasal immunisations, and these systems may differ in their ability to induce a specific type of immune response (e.g., a cytotoxic T cell versus an antibody response). As the protection against HIV may require both cytotoxic T cell and antibodies, a combination of adjuvants/delivery systems for combinations of mucosal and parenteral immunisations may be required in order to develop a protective anti-HIV vaccine.     

Intranasal delivery of vaccines against HIV

HIV poses a serious health threat in the world. Mucosal transmission of HIV through the genitourinary tract may be the most important route of transmission. Intranasal immunisations induce vaginal and systemic immune responses. Various protein-, DNA- and RNA-based immunopotentiating adjuvants/delivery systems and live bacterial and viral vectors are available for intranasal immunisations, and these systems may differ in their ability to induce a specific type of immune response (e.g., a cytotoxic T cell versus an antibody response). As the protection against HIV may require both cytotoxic T cell and antibodies, a combination of adjuvants/delivery systems for combinations of mucosal and parenteral immunisations may be required in order to develop a protective anti-HIV vaccine.     

DNA vaccines for cancer

Immunotherapy has become a potentially feasible strategy for the control of cancers; the goal of cancer vaccines is to achieve this via tumor antigen-specific humoral or cell-mediated immunity, as well as via innate immunity. DNA vaccines have become important immunotherapeutic agents for combating cancers due to their simplicity and safety, and their capacity for repeated administration. Continuing progress in our understanding of how professional antigen-presenting cells orchestrate immune responses provides a framework from which to design more effective DNA vaccines. To this end, innovative strategies to enhance DNA vaccine potency have been developed, including the modification of enhancement of antigen delivery, antigen processing, manipulation of apoptosis, and anti-angiogenic strategies. Furthermore, strategies for breaking immune tolerance to endogenous tumor-associated antigens have begun to be developed. These advances in DNA vaccine technology have led to significant results in preclinical tumor models, prompting the execution of a number of clinical trials of DNA vaccines for cancer. If these trials prove DNA vaccines to be clinically effective, they could lead to the development of a new generation of therapies for the treatment and/or prevention of cancer.