Current Drug Targets - Volume 5, Issue 1, 2004

After clean water and good hygiene, vaccines are one of the most cost effective methods for improving public health. Vaccines can be used prophylactically and / or therapeutically in the treatment of infectious diseases as well as some cancers and also demonstrate potential in the treatment of autoimmune disorders. The requirements of regulatory authorities, however, demand that modern vaccines are rationally designed and thoroughly tested, indicating a move away from empirical approaches. This move has been accompanied by our increased understanding of the events, both molecular and cellular, that are necessary for immunity. As our knowledge of the mechanisms that underlie successful immune states increases, we are also learning how to induce immune responses that are appropriate for a particular disease state. In this issue of Current Drug Targets, articles are gathered together from six groups of researchers who are involved in the design of vaccines and other therapeutics against a diverse range of infectious diseases and cancers. Lin-fa Wang and Meng Yu open the issue with a review of the use of phage display libraries which can be used to identify those smallest of antigenic structures, epitopes, that are necessary for recognition by the effector molecules and cells of the immune system. The second review by Cameron Turtle and Derek Hart introduces the dendritic cell which in recent years has been increasingly recognised as being pivotal in determining the outcome of immune responses. The emphasis here is on the use of dendritic cells in cancer treatments but their importance in other vaccine applications is also made apparent. Joseph Torresi and his colleagues are next and review hepatitis C virus which has perhaps been unrecognised by the world at large as the causative agent of an epidemic which is second only to HIV. The strategies that viruses can adopt to avoid elimination by the immune system are made clear here, as well as some of the strategies that vaccinologists are using to counter this virus. Michael Batzloff, Sri Sriprakash and Michael Good follow our introduction to infectious diseases with an account of syndromes that are caused by streptococci and the vaccine strategies that are being brought to bear against this bacterium. The treatment of “strep throat” in developed countries where antibiotics are readily available may be thought to be trivial but the sequelae of streptococcal infections in developed and in less developed communities are serious indeed. HIV is of course known around the world but again no vaccine exists for its prevention or treatment. Ivan Stratov, Robert deRose, Damian Purcell and Stephen Kent are part of a large group that is deeply involved in finding a solution for HIV AIDS. As with Torresi's review of HCV, this account of the vaccine strategies which are being pursued against HIV make it clear that consideration of the pitfalls that can accompany inappropriate immune responses - in this case antibody that may enhance infection, must be made for vaccine strategies to be successful. The reviews so far, although using cutting edge technologies recently added to the arsenal of the vaccine designer, are all focused on inducing an active immune response. That is, the host responds with an immune response to inoculation with an antigen. The final review by Damon Eisen, Helen Liley and Robyn Minchinton describes the use of an alternative to conventional vaccines. This last article is appropriate because it describes a poorly appreciated protective system, that of innate immunity, and brings to our attention strategies which could be used to enhance the traditional armoury of active immunisation.

Antigenic epitopes are the part (contact points) of an antigen involved in specific interaction with the antigen-binding site (the paratope) of an antibody or a T-cell receptor. Detailed analysis of epitopes is important both for the understanding of immunological events and for the development of more effective vaccine and diagnostic tools for various diseases. Identification and characterization of epitopes is a complex process. Although various methods have been developed in this area, there still lacks a simple common approach which can be applied to all epitopes. Since its first introduction more than a decade ago, phage display technology has made a major impact in this area of research. With the exponential growth in this area, it is impractical to review the entire literature detailing all possible applications. Instead, this review aims to focus on specific applications related to the discovery and identification of epitopes which have potential as vaccine candidates or can be used in disease diagnosis.

Despite rapid advances in cancer therapeutics, relapsed disease due to failed immunosurveillance remains a major problem in many cancers. Dendritic cells are recognized as key to the induction of immune responses to cancer and intensive study is underway to facilitate their use in cancer immunotherapy. In initial clinical trials, dendritic cell preparations were, with the benefit of hindsight, largely sub-optimal, yet encouraging results have been seen. The challenge now is to expand our knowledge of the interactions between tumors and the immune system, through basic scientific research and coordinated large-scale clinical studies. This review focuses on the anti-tumor immune response, human dendritic cell biology and the results of recent clinical studies of dendritic cell immunotherapy for cancer.

Hepatitis C virus (HCV) accounts for the majority of cases of transfusion acquired hepatitis and hepatitis transmitted by injecting drug use. The patients who do not clear the infection become chronic carriers of HCV and form a reservoir of infection within human populations. Furthermore, these carriers are at serious risk of developing cirrhosis of the liver and hepatocellular carcinoma. The disease is of major concern in developing as well as in developed countries and yet there are no vaccines against HCV, treatment is confined to the use of chemotherapy which is expensive and not always effective. The major obstacle in vaccine development is a limited understanding of the type of immune response that is necessary for viral clearance and the occurrence of various genotypes and quasispecies of HCV. The problems are further compounded by difficulties in growing the virus in vitro and the lack of a suitable and economical animal model. In this review we describe the virus, the strategies that it uses to evade the immune response and the tactics that may be useful in designing successful vaccine candidates.

Group A streptococcus (GAS) is responsible for a number of diseases ranging from uncomplicated pharyngitis through to life-treating invasive and post-infectious diseases such as necrotizing fasciitis and rheumatic heart disease. GAS associated diseases occur globally and are serious problems in many developing nations and indigenous populations of many developed nations. This, and the resurgence in industrialized countries, and increased virulence of GAS in the 1980s highlight the need of cost-effective control strategies. Here we highlight the GAS diseases that are still a problem in many populations and discuss potentially useful strategies to combat GAS infections and disease.

The HIV / AIDS pandemic is a global emergency and a preventive HIV vaccine is urgently needed. HIV has, however, proved a difficult pathogen to vaccinate against. This is largely because HIV has a very high mutation rate and can escape immune responses, it has a latent stage where it can rest silently integrated into host DNA, and neutralising antibodies that can neutralise diverse field strains have so far proved difficult to induce. There is however, considerable evidence now that HIV-specific CD4 and CD8 T cells can provide partial control of HIV replication and delay or prevent disease. Technologies to quantify and analyse HIV-specific T cells have advanced recently, and in particular ELISpot, intracellular cytokine staining and tetramer studies have provided clear analyses of the ability of HIV vaccines to induce T cell responses. The use of pools of overlapping HIV peptides as in vitro antigens has also provided a standardised reagent for accurate measurement of T cell responses. HIV protein vaccines have not induced broad neutralising antibodies or T cell responses and failed to protect humans in the only phase III efficacy trial yet completed. Viral vectors, such as canarypox, engineered to express HIV genes, have induced HIV-specific CD8 T cell responses in a minority of subjects in phase II trials and are proceeding to human efficacy trials. Currently, the most effective method of inducing CD8+ CTL immunity in non-human primates utilises priming with naked plasmid DNA and then boosting with recombinant viral vectors both encoding various parts of the HIV genome. Such vaccines have induced non-sterilising immunity to virulent Simian / Human immunodeficiency virus exposure in macaques and have entered phase I trials. Multiple other approaches are also being evaluated in what has become a global effort for a vaccine to prevent AIDS. Although an HIV vaccine is still a long way off, there is reason to be optimistic that a vaccine to prevent AIDS will eventually be developed.

Vaccines have been described as “weapons of mass protection”. The eradication of many diseases is testament to their utility and effectiveness. Nevertheless, many vaccine preventable diseases remain prevalent because of political and economic barriers. Additionally, the effects of immaturity and old age, therapies that incapacitate the adaptive immune system and the multitude of strategies evolved by pathogens to evade immediate or sustained recognition by the mammalian immune system are barriers to the effectiveness of existing vaccines or development of new vaccines. In the front line of defence against the pervasiness of infection are the elements of the innate immune system. Innate immunity is under studied and poorly appreciated. However, in the first days after entry of a pathogen into the body, our entire protective response is dependant upon the various elements of our innate immune repertoire. In spite of its place as our initial defence against infection, attention is only now turning to strategies which enhance or supplement innate immunity. This review examines the need for and potential of innate immune therapies.