Human prophylactic vaccine adjuvants and their determinant role in new vaccine formulations

Adjuvants have been considered for a long time to be an accessory and empirical component of vaccine formulations. However, accumulating evidence of their crucial role in initiating and directing the immune response has increased our awareness of the importance of adjuvant research in the past decade. Nevertheless, the importance of adjuvants still is not fully realized by many researchers working in the vaccine field, who are involved mostly in the search for better target antigens. The choice of a proper adjuvant can be determinant for obtaining the best results for a given vaccine candidate, but it is restricted due to intellectual property and know-how issues. Consequently, in most cases the selected adjuvant continues to be the aluminum salt, which has a record of safety, but predominantly constitutes a delivery system (DS). Ideally, new strategies should combine immune potentiators (IP) and DS by mixing both compounds or by obtaining structures that contain both IP and DS. In addition, the term immune polarizer has been introduced as an essential concept in the vaccine design strategies. Here, we review the theme, with emphasis on the discussion of the few licensed new adjuvants, the need for safe mucosal adjuvants and the adjuvant/immunopotentiating activity of conjugation. A summary of toxicology and regulatory issues will also be discussed, and the Finlay Adjuvant Platform is briefly summarized.

Human prophylactic vaccine adjuvants and their determinant role in new vaccine formulations.

Adjuvants have been considered for a long time to be an accessory and empirical component of vaccine formulations. However, accumulating evidence of their crucial role in initiating and directing the immune response has increased our awareness of the importance of adjuvant research in the past decade. Nevertheless, the importance of adjuvants still is not fully realized by many researchers working in the vaccine field, who are involved mostly in the search for better target antigens. The choice of a proper adjuvant can be determinant for obtaining the best results for a given vaccine candidate, but it is restricted due to intellectual property and know-how issues. Consequently, in most cases the selected adjuvant continues to be the aluminum salt, which has a record of safety, but predominantly constitutes a delivery system (DS). Ideally, new strategies should combine immune potentiators (IP) and DS by mixing both compounds or by obtaining structures that contain both IP and DS. In addition, the term immune polarizer has been introduced as an essential concept in the vaccine design strategies. Here, we review the theme, with emphasis on the discussion of the few licensed new adjuvants, the need for safe mucosal adjuvants and the adjuvant/immunopotentiating activity of conjugation. A summary of toxicology and regulatory issues will also be discussed, and the Finlay Adjuvant Platform is briefly summarized.

Immunotherapy of malignant gliomas using autologous and allogeneic tissue cells.

Immunotherapy of brain tumors is rapidly emerging as a potential clinical option [1-3]. The quality and magnitude of immune responses evoked by the new generation anti-tumor vaccines is in general highly dependent on the source or choice of peptide antigens, and as well, a suitable immunopotentiator. Poorly immunogenic antigens, such as those present in tumor cell lysates, may not reliably provide stimulation like recombinant or DNA-encoded protein antigens might be expected to. In addition, the efficacy of the vaccine may depend on inherent counteracting measures of the tumor which dampen immune surveillance and immune effector activity triggered by immunization [4]. Our body has many means of limiting an immune response to our own (self) proteins. In particular, patients with gliomas exhibit a broad suppression of cell-mediated immunity [5-8]. Unfortunately, for most tumor vaccines the induction of local or systemic immune effector cells does not necessarily translate into objective clinical responses or increased survival [9]. Here we review immunotherapeutic approaches against gliomas and recent pre-clinical and clinical initiatives based on cellular or active immunization of the patient's immune system using autologous and allogeneic tissues or cultured cells. Available evidence shows that single modality cancer therapies likely remain suboptimal. Combination regimens targeting the immune system at multiple coordinated levels must be developed, and possibly combined with strategies to inhibit immune suppressive factors if significant clinical benefit is to be achieved.

Vaccination of dogs with six different candidate leishmaniasis vaccines composed of a chimerical recombinant protein containing ribosomal and histone protein epitopes in combination with different adjuvants.

Chimerical protein "Q", composed of antigenic ribosomal and histone sequences, in combination with live BCG is a promising canine leishmaniasis vaccine candidate; one of the few vaccine candidates that have been tested successfully in dogs. Unfortunately, live BCG is not an appropriate adjuvant for commercial application due to safety problems in dogs. In order to find a safe adjuvant with similar efficacy to live BCG, muramyl dipeptide, aluminium hydroxide, Matrix C and killed Propionibacterium acnes in combination with either E. coli- or baculovirus-produced recombinant JPCM5_Q protein were tested. Groups of five or seven dogs were vaccinated with six different adjuvant-antigen combinations and challenged with a high dose intravenous injection of Leishmania infantum JPC strain promastigotes. All candidate vaccines proved to be safe, and both humoral and cellular responses to the recombinant proteins were detected at the end of the prime-boost vaccination scheme. However, clinical and parasitological data obtained during the 10 month follow-up period indicated that protection was not induced by either of the six candidate vaccines. Although no direct evidence was obtained, our data suggest that live BCG may have a significant protective effect against challenge with L. infantum in dogs.

Veterinary vaccine development from an industrial perspective.

Veterinary vaccines currently available in Europe and in other parts of the world are developed by the veterinary pharmaceutical industry. The development of a vaccine for veterinary use is an economic endeavour that takes many years. There are many obstacles along the path to the successful development and launch of a vaccine. The industrial development of a vaccine for veterinary use usually starts after the proof of concept that is based on robust academic research. A vaccine can only be made available to the veterinary community once marketing authorisation has been granted by the veterinary authorities. This review gives a brief description of the regulatory requirements which have to be fulfilled before a vaccine can be admitted to the market. Vaccines have to be produced in a quality controlled environment to guarantee delivery of a product of consistent quality with well defined animal and consumer safety and efficacy characteristics. The regulatory and manufacturing legislative framework in which the development takes place is described, as well as the trend in developments in production systems. Recent developments in bacterial, viral and parasite vaccine research and development are also addressed and the development of novel adjuvants that use the expanding knowledge of immunology and disease pathology are described.

Vaccine immunopotentiators of the future.

Vaccine adjuvants or immunopotentiators comprise a diverse group of molecules or formulations. Despite a wealth of different candidates, there is a need for better vaccine adjuvants in both veterinary and human medicine. For human vaccines, the immunopotentiator choice has been limited to aluminum salts, until recently. By contrast, a whole range of adjuvants is employed for inactivated veterinary vaccines, due to less stringent safety and regulatory requirements and proven superior vaccine performance. This review highlights recent developments and future trends in immunopotentiators.

Expression of chicken interleukin-2 by turkey herpesvirus increases the immune response against Marek's disease virus but fails to increase protection against virulent challenge.

As Marek's disease virus continues to evolve towards greater virulence, more efficacious vaccines will be required in the future. We expressed chicken interleukin-2 (IL-2) from a turkey herpesvirus (HVT) in an attempt to increase the efficacy of HVT as a vaccine against Marek's disease. The recombinant IL-2/HVT was safe for in ovo vaccination, although it replicated less in the birds compared with the parent HVT strain. Expression of IL-2 increased the neutralizing antibody response against HVT but did not increase the protection against virulent Marek's disease virus challenge.

Vaccine adjuvant technology: from theoretical mechanisms to practical approaches.

Poorly immunogenic antigens depend on vaccine adjuvants to evoke an immune response. In addition, adjuvants largely determine the magnitude, quality, time of onset and the duration of immune responses to co-administered antigens. As late as 1989, Janeway aptly called adjuvants: "the immunologist's dirty little secret". This statement reflected the ignorance on the mechanisms of action of most known adjuvants. Yet, rational vaccine design involves a logical choice of adjuvant based on a knowledge of their mode of action and their effects on product efficacy and safety. However, even today the key processes critical for immune induction in general and those evoked by vaccine adjuvants in particular are being disputed among immunologists. This paper presents the four most important concepts likely to explain some of the mechanisms of vaccine adjuvants. They include: (i) the geographical concept of immune reactivity; (ii) the depot concept; (iii) the hypothesis of pathogen-structure recognition, and (iv) the damage/endogenous danger theory. These paradigms are based on observations gathered in mammalian species, largely in murine models. In aquatic animals the processes underlying immune induction will at least partly overlap those in mammals. However, due to inherent species differences, certain pathways may be different. Rational vaccine design, a difficult goal in mammals, is further hampered in aquatic animals by the lack of immunological tools in these species. Extensive trial and error-based approaches have yielded adjuvant candidates for various fish species, with acceptable safety and proven efficacy, some of which are presented.