Current Drug Targets - Infectious Disorders - Volume 1, Issue 3, 2001

The history of vaccine devolvement spans a relatively short period of time in comparison to the history of human civilization. However, monumental advances in the field of vaccines have been made in effort to combat infectious disease. These advances have led to a reduction, and in one case the complete eradication, of the burden of some infectious diseases of the world. Throughout the history of vaccine development, milestone discoveries can be identified that have shaped the field of vaccine development, as we know it. These milestones include the first official use of a vaccine by Edward Jenner, the attenuation principals observed by Pasteur, the development of cell culture for the propagation of viruses, and the production of first recombinant protein based vaccine for hepatitis B. As vaccine development progresses into the 21st century, it will be important to build on the experience and knowledge generated in the past, in an effort to surpass the limitations that currently hamper the development of new and more effective vaccine technologies. Presented here is an overview on the history of vaccine development and its influence on the positioning of current trends and future considerations. Keywords: infectious disease, vaccine development

Vaccination of individuals has been practiced for many years and has been one of the most effective methods of controlling infectious diseases. Unfortunately, even with this success, society continues to suffer multi-billion dollar economic losses annually due to infectious diseases. These losses occur in all animal species as well as in humans. In order to further reduce these losses, academicians and companies are employing the multidisciplinary approach to develop better and safer vaccines. These include capitali- zing on advances in molecular biology, chemistry, pharmacy, immunology, genomics, proteomics, and fermentation. Thus, we are moving from a more empirical approach to vaccine production to a more focused, and, hopefully, more logical approach to identification and production of protective antigens. Furthermore, formulation and delivery of these antigens is playing a major role in revolutionizing how we deliver vaccines to induce the most appropriate immune response and ensure protection. The current review summarizes some of these advances and speculates as to how future vaccines will be produced and delivered for the benefit of society.

Vaccination remains the single most valuable tool in the prevention of infectious disease. Nevertheless, there exists a need to improve the performance of existing vaccines such that fewer boosts are needed or to develop novel vaccines. For the development of effective vaccines for humans, a great need exists for safe and effective adjuvants. A number of novel adjuvants have been reported in recent years including: i) bacterial toxins such as cholera toxin, CT, and the Escherichia coli heat-labile enterotoxin, LT ii) less toxic derivatives of CT and LT iii) endogenous human immuno- modulators, such as IL-2, IL-12, GM-CSF iv) hormones v) lipopeptides vi) saponins, such as QS-21 vii) synthetic oligonucleotides containing CpG motifs (CpG ODN) viii) lipid A derivatives, such as monophosphoryl lipid A, MPL and ix) muramyl dipeptide (MDP) derivatives. Herein, we will review recent findings using these novel adjuvant systems.

New generation vaccines, particularly those based on recombinant proteins and DNA, are likely to be less reactogenic than traditional vaccines, but are also less immunogenic. Therefore, there is an urgent need for the development of new and improved vaccine adjuvants. Adjuvants can be broadly separated into two classes, based on their principal mechanisms of action vaccine delivery systems and “immunostimulatory adjuvants”. Vaccine delivery systems are generally particulate e.g. emulsions, microparticles, iscoms and liposomes, and mainly function to target associated antigens into antigen presenting cells (APC), including macrophages and dendritic cells. This review will focus on recent developments in vaccine delivery systems. Immunostimulatory adjuvants are predominantly derived from pathogens and often represent pathogen associated molecular patterns (PAMP) e.g. LPS, MPL, CpG DNA, which activate cells of the innate immune system. Once activated, cells of innate immunity drive and focus the acquired immune response. In some studies, delivery systems and immunostimulatory agents have been combined for more effective delivery of the immunostimulatory adjuvant into APC. A rational approach to the development of new and more effective vaccine adjuvants will require much further work to better define the mechanisms of action of existing adjuvants. The discovery of more potent adjuvants may allow the development of vaccines against infectious agents such as HIV which do not naturally elicit protective immunity. New adjuvants and delivery system combinations may also allow vaccines to be delivered mucosally.

Replicating attenuated strains of intracellular bacteria like Salmonella typhimurium, Listeria monocytogenes or Mycobacterium bovis Bacille Calmette Guerin (BCG), and non-replicating virus-like-particles (VLP) consisting, for instance, of the VP1-surface component of polyoma virus offer great potential as heterologous carriers delivering foreign protein antigens for immune recognition. Moreover, attenuated S.typhimurium and L.monocytogenes strains hold also great promise as delivery vehicles for DNA vaccines. Polyoma virus-specific VLP consisting of VP1-pentamers are also of interest as carrier devices for eukaryotic expression plasmids. At first sight these different replicating and non-replicating types of vehicles have little in common, but from an immunological point of view viable bacteria and non-viable VLP are both well suited for evoking protective immune responses via several routes of vaccine administration. As these antigen carriers generate humoral and cell-mediated immunity, the heterologous antigens are not only targeted to appropriate pathways of major histocompatibility (MHC) class I and class II antigen processing and presentation, but also generate an adequate cytokine milieu for promoting antigen-specific responses. The most prominent advantage of these carrier devices is presented by their capacity to directly target antigenic proteins or DNA vaccines to immature dendritic cells (DC) along their maturation pathway. Mature DC are the key antigen presenting cell population which efficiently mediates antigen transport to organised lymphoid tissues for the initiation of T cell responses. In general, uptake of these diverse antigen delivery systems by antigen presenting cells (APC) finally lead to efficacious immune responses in the control of pathogenic microorganisms and tumours.

T lymphocytes play a major role in the recognition and subsequent elimination of tumors and intracellular pathogens. Induction of epitope-specific T cell responses can help in the clearance of diseases for which no conventional vaccines exist. However, the lack of simple methods to identify relevant T cell epitopes, the high mutation rate of many pathogens, and HLA polymorphism have made the development of efficient T cell epitope-based, or “epitope-driven” vaccines difficult to achieve. Our research over the past several years has applied bioinformatics tools in conjunction with T cell assays to identify naturally processed putative T cell epitopes from several pathogens. This strategy willaccelerate the development of new generation T cell epitope-based vaccines against various pathogens including viruses such as HIV and WNV, bacteria such as M.tb., and parasites such as plasmodium. This chapter will review the use of a bioinformatics-based approach to identify putative T cell epitopes. It will summarize the current state of knowledge regarding T cell-epitope-based vaccines and discuss several ways to improve their efficacy.

Significant effort and progress has occurred over the last several years in the development of vaccines against three main tropical parasitic diseases (malaria, leishmaniases and schistosomiasis). However, an effective vaccine is not yet available. The difficulties in developing a vaccine against parasitic disease are com- plicated not only by the necessity to identify (and produce) appropriate, protective antigens but also a lack of complete understanding of the types of immune responses needed for protection. Despite these hurdles, several candidate vaccines are under development for each disease at least one promising vaccine candidate exists that is in late stage clinical testing.This chapter will briefly review the current status of malaria, leishmaniasis and schistosomiasis vaccines.

Encapsulated bacteria such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae serogroup B (Hib) are a major cause of disease worldwide. Vaccine development against these organisms has targeted their capsular polysaccharides (CPS), as anti-capsular antibodies often protect against disease. The capsular polysaccharide vaccines that have been available against these organisms are neither immunogenic nor protective in young children and certain immunocompromised individuals. In general, polysaccharide (PS) antigens elicit a T-independent immune response, characterized by lack of memory, and poor immunogenicity at the extremes of life. Efforts to overcome the poor immunogenicity of CPS vaccines have led to development of conjugate vaccines. By conjugating CPS to carrier proteins it is possible to induce a T-dependent immune response against these antigens. Although conjugate vaccines have been successful against Hib disease, their applicability to multi-serotype / serogroup pathogens like the pneumococcus or the meningococcus is questioned. As a result, alternative vaccines including (1) surface proteins conserved across serotypes / serogroups, (2) peptides that mimic PS antigens and (3) DNA vaccines are presently under investigation. This review will highlight the potential and limitations of both CPS and CPS-conjugate vaccines against encapsulated bacteria as well as alternative strategies against PS antigens.