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1. An effective vaccine needs to mimic as close as possible the 'real' biological entity from which it is derived (i.e. pathogen, cancer cell) in order to be recognized by the host immune system as real 'danger. This will eventually initiate the cascade of molecular and cellular events inducing several levels of cross-talk between the innate and adaptive immune systems for an effective immune response and immunological memory. However, most successful vaccines have been empirically derived, and the immunological mechanisms underlying the effective induction of long-term protective immunity remain largely unknown
2. Most of the current successful vaccines are based on live attenuated or inactivated pathogen 'particles carrying their own unique and specific antigens. The live attenuated vaccines are characterized by a limited viral replication in the host upon injection and carry the native pathogen-associated molecular signals (PAMS) (i.e. viral genetic material), which trigger the activation of the innate immune system binding to the pathogen recognition receptors (PRRs). Live attenuated vaccines replicate and reach host immune sites where they are taken up by dendritic cells (DCs) or other antigen-presenting cells (APCs), which migrate to lymphoid organs for presenting the antigens to T and B lymphocytes. They elicit immune responses similar to those from natural infections and often are effective after a single administration (3). However, such vaccines may cause mild-to-severe adverse effects in patients, often as consequence of the limited replication in the host.
3. On the contrary, the inactivated vaccines do not replicate and are safer than live attenuated vaccines; however, they are generally less effective, requiring multiple administrations to boost
the immune response antibody titer over time. The inactivated vaccines are made as whole cell or as subunit vaccines (i.e. individual viral proteins). In this framework, recent advances in
genomics and proteomics have provided essential tools to develop alternative non-replicating vaccine strategy, including recombinant proteins, synthetic peptides, DNA, and particulate
structures (i.e. virus-like particles).
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4. Inactivated as well as non-replicating vaccines activate innate responses only at their site of injection, and intradermal skin immunization seems to induce a more effective protective immune responses (4-6), considering the high number of DCs in the skin dermis (7). In contrast to safety advantages, the major drawback of vaccines based on selected antigens is the less effective processing and presentation to the immune system. Therefore, most formulations of non-living vaccines must include an adjuvant as 'danger signal to trigger a sufficient activation
of the innate system and, downstream, of the adaptive immune response
5. The innate immune system is at the interface between the vaccine antigen and the host's adaptive immune response; therefore, the evaluation of the molecular effects induced by
vaccines on PRRs biology is of high relevance. Studying molecular signatures that are induced rapidly after vaccination will identify causal elements of the adaptive immune response, which may be useful in ultimately predicting protective immune responses. Such prediction will enable the evaluation of the efficacy or immunogenicity of untested vaccines in the general population or the identification of unresponsive individuals to vaccination. Furthermore, the predictive signatures would uncover new correlates of protection and further decipher the biological mechanisms by which such molecular signatures modulate vaccine-induced immunity and protection.
6. In recent years, the field has seen a remarkable explosion of information about the components of innate immunity and their role in guiding and shaping the adaptive immune response. A significantly improved fund of knowledge has been accomplished regarding the PRRs, mainly the TLR family members, as well as the associated pathways and their role in the host responses upon exposure to a foreign antigen, in the form of vaccine or pathogen. In particular, many tiles have been added to the mosaic describing the molecular processing and
recognition of antigens by cells of the innate immune system and how this will impact on the nature as well as the duration (immune memory) of the adaptive T and B-cell immune responses.
7. The development of safer but less potent recombinant vaccines, to minimize the possible biological risks linked to traditional inactivated or killed vaccines, is boosting mandatory studies aimed to improve their immunogenic and protective activity. In this regard, the use of TLR or non-TLR PRR signaling to boost vaccine efficacy is heavily explored and documented in several established vaccines. To this aim, systems biology holds considerable promise for discovery and new insights into complex networking processes such as interaction between foreign vaccine
antigens, innate immunity, and the downstream adaptive immune response.8. Systems biology not only has the potential to accelerate the discovery of new regulators of innate immunity but also will provide more comprehensive insights into the kinetics of regulation
at the transcriptional, protein-protein interaction, and post-transcriptional levels. All this information will be of high impact on vaccine development, providing molecular prediction markers of the immunogenicity of a vaccine, uncovering new correlates of vaccine efficacy, as well as guiding the design of new vaccine antigens or formulations. Moreover, such system-level approaches could permit the identification of vaccine responders versus non-responders, allowing a better immunological coverage of the licensed vaccines.
1) Why are inactivated vaccines sometimes dangerous to humans?Dationte mav avnarionce low-level advarea afferte