Team:Slovenia/Background/Modern vaccines

Vaccines are the single most important application of immunology. Vaccination has saved more lives than any other medical treatment in human history. Generally, typical vaccine is a suspension of microorganisms or parts of microorganisms that induce immune response in the host, either upon injection or via exposure to another portal of entry. Vaccination confers artificially acquired active immunity. A prophylactic vaccine is a vaccine designed to prevent disease. It may be administered prior to exposure to pathogen, or after exposure to pathogen but prior to the occurrence of disease.

An ideal vaccine should have the following properties:
1. safety, ideally 100%; this is a potential problem with attenuated microbial vaccines,
2. effective in all individuals,
3. effective against wide range of different microbial strains,
4. offers long lasting protection without repeated vaccinations,
5. stable and simple to store, which is especially important in third world countries,
6. simple to apply (preferably oral or mucosal application),
7. cheap to manufacture, thus being broadly affordable.

There are in principle two types of vaccines:
1. '''whole microbes''', which can be either attenuated or killed. This is traditionally the most successfull type of vaccines. Microbes represent the whole spectrum of antigens and additionally provide microbial adjuvants, that activate innate immune response. Those compounds may, however, be absent from some microbes, which avoid recognition by the immune surveillance such as H. pylori. Attenuated vaccines represent potential danger, particularly in immunocompromised individiuals.

2. '''subunit vaccines''', which are isolated or synthetic microbial components, such as proteins or polysaccharides. Genomic information of most microbial pathogens provides a platform to identify the candidate vaccine antigens, in the process called 'reverse vaccinology'. 3D models or structures of antigens provided by structural genomics additionally allow more accurate prediction of the B-cell epitopes of immunodominant antigens, which enable us to design multiepitope vaccines comprising several epitopes from different antigens. Those antigens typically require addition of adjuvants that increase the immune response. Typical adjuvants used for vaccination are aluminium oxides and TLR agonists (CpG, MPLA, poly(I:C)), which trigger production of costimulatory molecules that are required for the development of adaptive immune response. Recent progress in understanding the molecular mechanism of effective adjuvants provides another important step towards more effective vaccines.

Generally, an effective vaccine should induce an innate immune response, high titters of neutralizing antibodies, strong cellular immune response, including activation of T helper cells and cytotoxic T lymphocytes (CTLs), as well as mucosal immune response. This should lead to a long lasting protection against infections. The consequence of the progress in basic immunology resulted in understanding of a cooperation between innate and adaptive immunity.

Defined essential signals are required to induce effective T- and B-cell responses and subsequent establishing of memory T- and B-cell repertoires, which is the aim of vaccination. Briefly, these signals are: antigen recognition and APC activation, antigen presentation and costimulation.

The role of costimulation in T-cell activation explains an old observation that protein antigens fail to elicit T-cell dependent immune response unless these antigens are administered with substances that activate dendritic cells, macrophages and other APCs. This has been called the 'dirty little secret of immunologists', and today we know that this effect was due to adjuvants. The term is derived from the latin adjuvare, meaning to help, because these compounds can increase and/or modulate the intrinsic immunogenicity of an antigen by inducing the expression of costimulators on APCs and by stimulating the APCs to secrete cytokines that activate T cells. Adjuvants convert inert protein antigens into mimics of pathogenic microbes (Guy B. 2007).

Most adjuvants actually belong to pathogen-associated molecular patterns (PAMPs), molecules that are recognized by innate immune cells by specific pathogen recognition receptors (PRRs). Among PRRs, TLRs play a crucial role in early steps of immune response to infection. TLRs are expressed at the surface or in the endosomes of different APC subtypes and they respond to specific bacterial, viral, fungal or protozoan signals. This activates APCs, modulates and shapes the adaptive response, for instance, by shifting the balance towards Th1 or Th2 cells. Importantly, TLRs do not only trigger APC activation, but they also have a role in antigen presentation. The presence of both antigen and TLR is required for optimal antigen presentation and activation: TLRs control the generation of T-cell receptor (TCR) ligands (peptides, derived from processing of pathogen antigens, bound to MHC class 2 molecules) from the phagosome, which ensures that the contents derived from microbial pathogens are preferentially presented to T-cells by the activated APC. This means that antigen and TLR-agonists should be co-delivered in order to be present in the same phagosome cargo and induce optimal antigen presentation and stimulation of the subsequent T-cell response (Blander J.M., 2007).

The identification of chemical nature of TLR agonists led to the design of synthetic ligands that can trigger TLRs more precisely and safely than pathogen-derived ligands, which were selected by their ability to bind receptors and activate downstream signaling pathways. Different PRR agonists can synergize and/or balance each other's immunomodulatory activity. It is known, that we can induce sinergy by combining agonists that act on MyD88-dependent and MyD88-independent pathways. A vaccine that stimulates complementary TLR pathways can thus broaden the Th cell response that is induced.

Perfect example of sinergy is the live attenuated yellow fever vaccine 17D (YF-17D), that is one of the most effective vaccines available. Immunological mechanisms, by which YF-17D acts were recently revealed by Querec et. al. This vaccine activates multiple TLRs on dendritic cells to elicit a broad spectrum of innate and adaptive immune respones. Specifically it activates multiple DC subsets via TLRs 2, 7 ,8 and 9. The adaptive immune response is charactereized by a mixed T helper cell Th1/Th2 cytokine profile and antigen-specific CD8⁺ T-cells.

TLR agonists, that polarize immune response towards Th1 are LPS (TLR 4 agonist), flagellin (TLR 5 agonist), dsRNA (TLR 3 agonist), ssRNA (TLR 7 and TLR 8 agonist) and unmethyated DNA (TLR 9 agonist). Contrary, Th2 inducers are triacyl lipopeptides (TLR 1-2 agonist) and diacyl lipopeptide (TLR 2-6 agonist).

Rational design of modern vaccines is the promising way to find the optimal and safe formulation of adjuvants and antigens, that will work synergisticly and elicit desired immune response. New vaccines have more defined composition and always include adjuvants, that mimic and compensate lacking pathogen's properties, that are needed to induce immune response.



Schematic diagram of human Toll-like receptors, their ligands, adaptor molecules and cellular localization (Kanzler H., 2007)