Vaccines: Frontiers in Design and Development Chapter Abstracts
Chapter 1
Driving Forces in the Development of Innovative Vaccines
Philippe Moingeon
Abstract
Schematically, four frontiers to the development of innovative vaccine can be identified, including:
(i) The knowledge frontier: our current understanding of innate immune mechanisms, antigen processing and presentation, immune memory, and pathogen-host interface provides the ground for rational approaches to vaccine and adjuvant design. (ii) The technology frontier: vaccine development is facilitated by genome mining as a mean to identify target antigens, new protein expression systems, rationally-designed adjuvants and vector systems, needleless administration devices, as well as new tools to monitor immune responses. (iii) The target frontier: the (re) emergence of old and new infectious pathogens creates a need for new prophylactic vaccines. Therapeutic vaccines are being developed against a variety of targets, including chronic infectious diseases, allergies, cancers, as well as metabolic and neurodegenerative diseases. (iv) The development frontier: vaccine development faces a more stringent regulatory environment. Societal acceptance, as well as production and distribution issues (e.g. large-scale manufacturing of biologicals, cost containment, availability to developing countries) have also to be taken into account.
In order to cope with these challenges, all actors involved in vaccine development (ie research institutions, industries, government agencies, funding entities) have to align in support of global public health strategies. Collectively, such combined and coordinated efforts should lead in the forthcoming decade to an increased vaccine coverage against a growing number of infectious and non infectious diseases, both in industrialized and in developing countries.
Chapter 2
Immunological Basis for the Rational Design of New Vaccines
Laleh Majlessi and Claude Leclerc
Abstract
Vaccines constitute highly powerful tools for preventing infectious diseases. Smallpox eradication and the remarkable decrease in poliomyelitis or measles throughout the world represent the most significant successes of vaccination. However, infectious diseases remain the leading cause of death in both industrialized and developing countries. Thus, both the development of new vaccines to prevent diseases for which no vaccine is available and the improvement in terms of efficacy and safety of existing vaccines remain a priority. An efficient vaccine against a pathogen has to (i) generate protective immune responses in a large proportion of individuals, against all pathogen serotypes, (ii) establish immunological memory, (iii) be effective in newborns, adults and elderly, (iv) be safe and stable (v) be economically feasible. To fulfill these criteria, strong modifications will be required in the methods that have been used so far to design vaccine candidates. In particular, modern vaccinology can strongly benefit from the latest progress in molecular biology, microbiology and immunology. In this review, we discuss some essential features of the immune system and potential implications of our increasing knowledge of pathogen genomes and the physiology of immune system for the development of new strategies for vaccination.
Chapter 3
Targeting Innate Immunity With Adjuvants: Can Accurate Danger Signals Drive More Protective Immune Responses?
Nicolas Burdin
Abstract
Innate immunity was largely ignored for decades as it was thought to be a simplistic first line of defence providing non-specific microbicidal activity and acute inflammation signals to delay the growth of infectious agents, while giving more time for antigen-specific lymphocytes (adaptive immunity) to develop and then eradicate pathogens. It is now clear that the level of protection conferred by B and T cells in response to pathogen insults largely depends on the quality and accuracy of the initial "danger" signals perceived by innate immune cells at the site of entry of infectious agents. Pathogen-derived compounds capable of activating innate immune cells are being characterized at a molecular level and their mechanisms of action deciphered. Synthetic homologues of these microbial agents are currently being evaluated and developed for clinical applications as vaccine adjuvants or therapeutic agents. This chapter reviews the immunostimulatory properties of some of these molecules, including antimicrobial peptides, toll like-receptor agonists, synthetic ligands for non conventional T cells and the possible opportunity of targeting regulatory T cells with some of the above adjuvants. Benefits and expected limitations of using these novel pathogen-mimicking adjuvants are also discussed.
Chapter 4
Mucosal Immunity and Vaccine Design
Cecil Czerkinsky, Ali M. Harandi and Jan Holmgren
Abstract
The mucosal immune system consists of an integrated network of lymphoid cells which works in concert with innate host factors to promote host defence. Mucosal immunisation can be used both to protect mucosal surfaces against colonization and invasion by microbial pathogens and to provide a means to prevent local and systemic inflammatory immune responses to non degraded food and airborne antigens or allergens. The latter property has recently been utilized in attempts to suppress auto- and allo-reactive responses associated with organ specific autoimmune diseases and to prevent graft rejection.
However, in practice induction of productive immunity as well as induction of peripheral immune suppression by the mucosal route of administration require both large amounts of antigens and even so have relatively short-lasting effects. To circumvent these limitations and to bypass the powerful natural mechanical and physico-chemical barrier function of mucosal epithelia, major efforts have been devoted to the development of delivery systems and adjuvants/immunomodulators to formulate efficient mucosal vaccines.
Among the most studied vector/delivery systems and adjuvants for mucosal immunization, cholera toxin (CT) and the closely related E. coli heat-labile enterotoxin (LT) have proven to be very useful tools to study mucosal immune responses induced by various routes. Because of the inherent toxicity of CT and LT which precludes their use in humans, detoxified derivatives of these toxins with retained adjuvant activity have been generated. The clinically most advanced of these derivatives is the completely non-toxic, recombinantly produced cholera toxin B-subunit (CTB). CTB is a protective component of a widely registered oral vaccine against cholera. CTB has also in preclinical studies proved to be a very promising vector for either giving rise to anti-infective immunity or for inducing peripheral anti-inflammatory tolerance to chemically or genetically linked foreign antigens administered mucosally. Promising advances have recently been made in the design of another class of efficient mucosal adjuvants based on CpG-motif containing bacterial DNA or synthetic oligo-deoxynucleotides, as well as various imidazoquinoline compounds binding to different Toll-like receptors on mucosal antigen-presenting cells.
Chapter 5
Immunization Using the Skin: New Approaches
Gregory M. Glenn, David C. Flyer, Mohammad Al-Khalili and Larry R. Ellingsworth
Abstract
The skin has a large component of immune cells, and is well equipped to detect invasion by pathogens and orchestrate vaccine responses. Notably, the gold standard, yet crude skin immunization technique is responsible for eradication of smallpox worldwide. Vaccine delivery into the skin must overcome the natural barriers to delivery and result in effective, functional immune responses. There is currently a great deal of preclinical data suggesting that this may happen for human vaccines. Clinical testing of this concept has confirmed the preclinical observations that adjuvants can be delivered to safely induce strong immune responses and various approaches to optimizing vaccine delivery to the skin are discussed.
Chapter 6
Cellular Vaccines: Current Status
Alessandra Nardin and Jean-Pierre Abastado
Abstract
Cellular vaccines represent a novel generation of vaccines specifically designed for immunotherapy of cancer and chronic infectious diseases. Similarly to classical vaccines, they comprise both antigenic and adjuvant activities. However, these two components are engineered to provide the immunogenicity required to overcome a potential immunodeficit associated with the disease, so that a sustained, protective immune response can be elicited. Dendritic cells which were differentiated, activated, and loaded ex vivo with tumor-derived antigens have been shown to represent a safe vaccine, inducing immune and clinical responses following injection in some cancer patients. Given the numerous methods used to prepare dendritic cells, the definition of common criteria for assessing their potency is one of the main technological challenges. Vaccination with killed autologous or allogeneic tumor cells constitutes another approach for eliciting immunity to relevant tumor-rejection antigens, many of which are still unknown. Although this may seem a less technologically-demanding strategy as it does not require the preparation of viable, active cells, it remains critical to provide an effective adjuvant together with the antigen. We review here the current methods for preparing cell-based vaccines and discuss the new technological avenues that are being explored in this field.
Chapter 7
Veterinary Applications of the Canarypox Vaccine Vector Technology: Recent Developments for Vaccines in Domestic Mammalian Species
Jean-Christophe Audonnet, Jules Minke and Hervé Poulet
Abstract
One of the most significant changes in the field of veterinary vaccines in the past few years has been the introduction of several recombinant vaccines based on the canarypox vector platform. The commercial success of this platform seems paradoxical when one looks at the published vaccine literature on "canarypox" or "ALVAC". Out of the approximately 150 references that can be found (as of February 2004) on the PubMed database, only 12 are directly related to veterinary vaccine applications. Yet, the innovative canarypox platform has clearly found commercial viability for a number of veterinary targets, mainly for companion animals (cats, dogs and horses), whereas the very same platform has not delivered new products for human vaccines. The registration of canarypox-based veterinary vaccines, both in Europe and in North America, reflects in fact the excellent properties of this vector (e.g. proven safety in the target species, ability to be combined with existing vaccine formulations, ability to be integrated into a marketing strategy and proven efficacy against infectious challenges in target species) as well as the advantages of the technology when compared to classical vaccines used in the field.
Chapter 8
Immunological Aspects of Vaccine Safety: Where Do We Go?
Paul-Henri Lambert and Michel Goldman
Abstract
All vaccines carry some risk of adverse events, but fortunately vaccine-related toxicity is usually rare, mild and transient. Some questions are often raised regarding the potential immunological impact of vaccination. It is likely that in some exceptional circumstances, an inappropriate vaccine-induced response to a targeted pathogen may occasionally lead to the enhancement of natural disease. Vaccine-induced immune complex mediated manifestations (e.g. vasculitis) are rarely reported and usually considered as the consequence of immunization. Much less data indicate that vaccines may influence the quality of the immune response to other antigens or to allergens and there is no reason to believe that they could induce a kind of "immunological overload". There is so far very little evidence that autoimmune diseases might be induced or triggered by vaccination. Despite their excellent safety record, vaccines often remain the target of unsubstantiated allegations of undesirable immunological effects. Although these are not justified, it is essential to consider immunological safety as a first priority in vaccine development, even in the earliest stages of research.
Chapter 9
Vaccines Against Nosocomial Infections
Philippe Moingeon and Jeffrey Almond
Abstract
Nosocomial infections (NI) are associated with opportunistic pathogens, usually transmitted in hospital settings to immunosuppressed or highly exposed individuals (e.g. patients undergoing surgery, or hospitalized in intensive care units). The most frequently encountered pathogens include Staphylococcus aureus, S. epidermidis, enterococci (E. faecium, E. faecalis), Clostridium difficile, Escherichia coli, Pseudomonas aeruginosa, Legionella pneumophila and the yeast, Candida albicans. The burden of nosocomial infection is significantly increasing in the context of growing antimicrobial resistance among such pathogens. Attempts to develop vaccines, and for some of the targets, passive immunotherapies are discussed in the present review. Such innovative immunoprophylactic or therapeutic approaches are facilitated by the identification of new potential targets from genomics studies. In addition, the molecular analysis of biofilm formation is yielding important information regarding virulence factors for some of these pathogens. This can potentially be used for vaccine design.
Chapter 10
TB Vaccine Development: Opportunity and Imperative
Anne S. De Groot, and Julie A. McMurry
Abstract
On the short list of the following health threats - HIV, tuberculosis, and bioterror pathogens- tuberculosis (TB) should be considered the most significant current threat to global health. TB is already widely distributed in the world's population and the pace of new infection and disease rate is accelerating in countries where endemic TB co-exists with an expanding HIV epidemic. Indeed, latent TB infection (LTBI) affects one third of the world's population - nearly 2 billion individuals. Therefore, the development of a TB vaccine to prevent disease or to curb the development of active disease from a latent state of infection, would have an enormous impact on developing world economies. However, no new TB vaccine has been licensed for human use since the late 1800's, when Bacille Calmette-Guerin (BCG), a live attenuated vaccine against TB, was first discovered. Developing a TB vaccine represents a significant challenge for vaccine developers as the correlates of TB immunity remain poorly defined and any new vaccine must be developed for use in a population that has already been immunized against TB with BCG. Fortunately, a philanthropic source of funding (the Bill and Melinda Gates Foundation) has succeeded in stirring new interest in TB vaccines. As a result of this impetus, a range of TB vaccine candidates are entering pre-clinical studies, and several phase I trials are expected to take place in the next few years. This chapter frames the opportunity for developing a new TB vaccine and describes several recent TB vaccine development efforts.
Chapter 11
Development of a Vaccine Against Rotaviruses: Current Status
Duncan Steele, Roger Glass and Joseph Bresee
Abstract
Rotaviruses remain a major cause of morbidity and mortality in young children in developing countries and the development of a rotavirus vaccine is a high priority for the international community. Despite a setback for the reassortant rhesus rotavirus vaccine because of possible links to intussusception, the oral live, attenuated vaccine approach remains the strategy of choice and two candidates are in late-stage development and clinical evaluation. These vaccine candidates, which employ a different concept for protection against severe rotavirus disease, are being tested in large safety and efficacy trials designed to measure safety from an association with intussusception. The aim is to have a vaccine licensed within the next 12 to 24 months. Despite these advancements, challenges to the design of rotavirus vaccines and to the future usefulness and introduction of these vaccines remain. Several alternative live, attenuated vaccine candidates are in early-stage development and are building a partnership model with national vaccine manufacturers in emerging nations.
Chapter 12
Development of a Vaccine Against Human Papillomavirus (HPV)
Russell L. Basser, Stirling Edwards and Ian H. Frazer
Abstract
Human papillomavirus (HPV) is associated with a common and usually asymptomatic infection, and occurs especially after commencement of sexual activity. Pathology related to persistent HPV infection is a major cause of mortality and morbidity worldwide. While it has long been accepted as a major etiological agent in the development of cervical cancer and anogenital warts, it is increasingly recognised as having a critical role in the development of cancers involving other anogenital sites and distant locations, such as the head and neck. The pivotal discovery of how to produce virus-like particles (VLPs) of HPV capsid in the early 1990's have resulted in the development of a prophylactic vaccine. Early clinical trials of VLPs have demonstrated remarkable efficacy in preventing persistent HPV infection, and results from phase 3 trials are expected in the next 2 to 3 years. A variety of approaches to therapy for established HPV infection and its consequences are currently being pursued, but progress has been slow and, as yet, no controlled clinical data have been published. Successful development of prophylactic and therapeutic vaccines for HPV infection will have a profound impact on healthcare in both developed and developing countries.
Chapter 13
Development of Cancer Vaccines: Current Status
Pamela L. Beatty and Olivera J. Finn
Abstract
The pioneering work leading to the isolation and molecular characterization of tumor antigens has been fundamental to the design of cancer vaccines. It showed that tumor-specific epitopes were presented by tumor cells and cancer vaccine strategies could be developed to prime the immune system to recognize and destroy tumor cells while preserving normal cells. The current challenges to tumor immunologists working on therapeutic and prophylactic vaccines include making the right choices of antigen, delivery systems, adjuvants, and routes of administration, as well as overcoming evasion mechanisms imposed by the tumor. Studies of cancer vaccines in animal models and their testing in small clinical trials have shown promising results, prompting further improvements in their design according to the newest discoveries in immunology. This chapter will highlight various cancer vaccines that are under development as well as review several that are currently in clinical trials.
Chapter 14
Antigen-specific Immunotherapy for Allergies
Claude Andre
Abstract
Specific immunotherapy has been performed since the beginning of the 20th century with the objective of preventing the development of allergic reactions following contact of a sensitized organism with common allergens from the environment. This approach is effective for the treatment of rhinoconjunctivitis and allergic asthma, but is associated with rare adverse events that can sometimes be severe after injection. Immunotherapy is being developed along several lines in order to improve efficacy and safety. This includes sublingual administration of allergens in tablet form, preparation of major allergens by genetic recombination and immunomodulation based on the understanding of mechanisms responsible for allergy.
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