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Trivalent inactivated vaccines (TIV) against influenza are given to 350 million people every year. Most of these are non-adjuvanted vaccines whose immunogenicity and protective efficacy are considered suboptimal. Commercially available non-adjuvanted TIV are known to elicit mainly a humoral immune response, whereas the induction of cell-mediated immune responses is negligible. Recently, a cationic liposomal adjuvant (dimethyldioctadecylammonium/trehalose 6,6'-dibehenate, CAF01) was developed. CAF01 has proven to enhance both humoral and cell-mediated immune responses to a number of different experimental vaccine candidates. In this study, we compared the immune responses in ferrets to a commercially available TIV with the responses to the same vaccine mixed with the CAF01 adjuvant. Two recently circulating H1N1 viruses were used as challenge to test the vaccine efficacy. CAF01 improved the immunogenicity of the vaccine, with increased influenza-specific IgA and IgG levels. Additionally, CAF01 promoted cellular-mediated immunity as indicated by interferon-gamma expressing lymphocytes, measured by flow cytometry. CAF01 also enhanced the protection conferred by the vaccine by reducing the viral load measured in nasal washes by RT-PCR. Finally, CAF01 allowed for dose-reduction and led to higher levels of protection compared to TIV adjuvanted with a squalene emulsion. The data obtained in this human-relevant challenge model supports the potential of CAF01 in future influenza vaccines.

Adjuvants are important components of vaccine formulations. Their functions include the delivery of antigen, recruitment of specific immune cells to the site of immunization, activation of these cells to create an inflammatory microenvironment, and maturation of antigen-presenting cells for enhancement of antigen-uptake and -presentation in secondary lymphoid tissues. Adjuvants include a large family of molecules and substances, many of which were developed empirically and without knowledge of their specific mechanisms of action. The discovery of pattern recognition receptors including Toll-like-, nucleotide-binding oligomerization domain (NOD)- and mannose-receptors, has significantly advanced the field of adjuvant research. It is now clear that effective adjuvants link innate and adaptive immunity by signaling through a combination of pathogen recognition receptors (PRRs). Research in our lab is focused towards the development of novel adjuvants and immunomodulators that can be used to improve neonatal vaccines for humans and animals. Using a neonatal pig model for pertussis, we are currently analyzing the effectiveness of host defence peptides (HDPs), bacterial DNA and polyphosphazenes as vaccine adjuvants.

The so called "first generation adjuvants" have been based on aluminium salts and they were added to vaccines composition to enhance immune response to vaccine antigen. Formerly produced vaccines contained inactivated or attenuated microorganisms, which were able to promote all necessary signals for high immune response. Nevertheless there was also produced immune response and also adverse events to antigens, which were not necessary for protection. Vaccinology has been further developed with possibility to produce recombinant and subunit antigens, which were needed for protection against infection. It was necessary to intensify targeted immune response against recombinant antigen, for fast and long term protection. Such need stimulated research for development of "adjuvanted systems of the second generation", which were tailored to particular antigen. Former adjuvants were based on stimulation of adaptive immunity. Contrary the first the second generation of adjuvanted systems is based on Pathogen-Associated Molecular Patterns (PAMP). By binding to Toll-like receptors (mostly TLR-4) as a part of innate immunity, they are able to influence adaptive immunity including humoral and also cellular arm of immune system. Licensed vaccines with second generation of adjuvant systems are Cervarix and Fendrix vaccines and in development are vaccines against malaria and genital herpes. Also for pre-pandemic vaccines is used new generation of adjuvanted systems.

The aluminium compounds, originally identified as adjuvants over 70 years ago, remain unique in their widespread application to human vaccines. Given this history, it is surprising that the physicochemical interactions between aluminium compounds and antigens are relatively poorly understood. This has clearly been a contributing factor to vaccine failures, for example, through inappropriate selection of aluminium species or buffers. Similarly, the mechanism(s) of action of aluminium adjuvants are relatively unstudied, although it appears that these agents fail to fit within the current principles underlying activation of the immune response. This review aims to examine recent developments in our understanding of the physicochemical and biological aspects of research into aluminium adjuvants.

Recent advances in immunobiology have led to a greater understanding of the healthy immune system and the complex pathogenesis of human immunodeficiency virus (HIV) infection. Knowledge of the mechanisms underlying the decrease in CD4+ T cells is rapidly evolving as a result of new assays, genetic advances, and recombinant DNA technologies. Studying the immune responses of long-term non-progressors is also providing insight into the immunopathology of HIV. Trials using highly active antiretroviral therapy and immune modulators have shown that it may be possible to reverse damage to the immune system and increase CD4+ T-cell numbers. Current and future findings might provide the knowledge necessary to identify effective HIV drugs and vaccines with acceptable toxicity profiles and to determine whether it will be possible to fully restore immune system function in patients with HIV disease.

Progressing tumors in man and mouse are often infiltrated by dendritic cells (DCs). Deficient antitumor immunity could be related to a lack of tumor-associated antigen (TAA) presentation by tumor-infiltrating DCs (TIDCs) or to a functional defect of TIDCs. Here we investigated the phenotype and function of TIDCs in transplantable and transgenic mouse tumor models. Although TIDCs could encompass various known DC subsets, most had an immature phenotype. We observed that TIDCs were able to present TAA in the context of major histocompatibility complex class I but that they were refractory to stimulation with the combination of lipopolysaccharide, interferon gamma, and anti-CD40 antibody. We could revert TIDC paralysis, however, by in vitro or in vivo stimulation with the combination of a CpG immunostimulatory sequence and an anti-interleukin 10 receptor (IL-10R) antibody. CpG or anti-IL-10R alone were inactive in TIDCs, whereas CpG triggered activation in normal DCs. In particular, CpG plus anti-IL-10R enhanced the TAA-specific immune response and triggered de novo IL-12 production. Subsequently, CpG plus anti-IL-10R treatment showed robust antitumor therapeutic activity exceeding by far that of CpG alone, and elicited antitumor immune memory.

The structurally related neuropeptides VIP and PACAP are released within the lymphoid organs following antigenic stimulation, and modulate the function of inflammatory cells through specific receptors. In activated macrophages, VIP and PACAP inhibit the production of pro-inflammatory agents (cytokines, chemokines, and nitric oxide), and stimulate the production of the anti-inflammatory cytokine IL-10. These events are mediated through the VIP/PACAP effects on de novo expression or nuclear translocation of several transcription factors, i.e., NFkappaB, CREB, c-Jun, JunB, and IRF-1. The in vivo administration of VIP/PACAP results in a similar pattern of cytokine and chemokine modulation, which presumably mediates the protective effect of VIP/PACAP in septic shock. In addition, VIP/PACAP reduce the expression of the co-stimulatory molecules B7.1/B7.2, and the subsequent stimulatory activity of macrophages for T-helper cells. In T-cells expressing specific VIP/PACAP receptors, VIP and PACAP inhibit the expression of FasL through effects on NFkappaB, NFAT, and Egr2/3. The reduction of FasL expression has several biological consequences: inhibition of antigen-induced cell death in CD4 T-cells, inhibition of the FasL-mediated cytotoxicity of CD8 and CD4 effectors against direct and bystander targets, and promotion of long-term memory Th2 cells, through a positive effect on the survival of Th2, but not Th1, effectors. The various biological effects of VIP and PACAP are discussed within the range of a general anti-inflammatory model.