Figure 2.

Simplified model of vaccine stimulation of the immune system. (A) Immune stimulation by live-attenuated viruses and/or vectored viral immunogens. After immunization, live-attenuated and vectored viral particles are endocytosed by antigen-presenting cells (APCs). The live-attenuated viruses can activate cell membrane pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) 2 and 6 (a). Upon entry, the live-attenuated viruses expose the nucleic acid and transcribe their genes, which, in turn, are sensed by endosomal TLRs (b). Activation of TLRs initiates signaling pathways culminating in the caspase pathway activation and production of pro-inflammatory and antiviral cytokines and chemokines (c). Immune stimulation by vectored viral immunogens may induce, via NOD-like receptor family pyrin domain-containing (NLRP) 3 pathway, inflammasome activation (a*) and cytokine production (b*). The transcribed vector-encoded transgene generates the immunogenic proteins (blue circles), which can then be proteosome-processed and associated with class I major histocompatibility complex (MHC-I) (c*) or with class II major histocompatibility complex (MHC-II) in endocytic vesicles (d*). MHC-I molecules loaded with transgenic epitopes translocate to the cell membrane, where they are recognized by antigen-specific CD8⁺ T cells (e*). Consequently, the infected cell is killed, and releases antigens in the extracellular space. In the same way, MHC-II molecules loaded with transgenic epitopes and translocated to the cell membrane are recognized by CD4⁺ helper T cells, which secrete cytokines and chemokines and further activate antigen-specific CD8⁺ T cells and B cells. Finally, stimulated B cells maturate into antibody-secreting plasma cells and/or memory B cells, as well as a portion of the stimulated T cells, which become memory cells (not shown). Overall, live immunogens are able to equally stimulate both humoral and cell-associated immune responses). (B) Immune stimulation by non-live (inert) inactivated vaccines, protein subunits, and virus-like particles. Immunization with antigens, inoculated together with the adjuvants that are added to vaccine formulations induces cytokine production from local cells. Cytokines in turn activate and/or attract APCs to the immunization site. In addition, the antigens may directly activate APCs through binding to cell membrane TLRs (a). The inactivated viruses are phagocytized by APCs and nucleic-acid traces inside the phagosomes and may activate endosomal TLRs (b), leading to the production of cytokines and chemokines (in a smaller amount, compared to (A) (c). The antigens contained in the inert vaccines in protein subunit formulations and in virus-like particles, after the entry in the call, are also degraded inside the endocytic vesicles, loaded onto MHC-II molecules (a*), and presented to CD4⁺ T cells (b*). Activation of CD4⁺ T lymphocytes leads to production of cytokines and chemokines, which induce the activation of antigen-specific B cells (c*), which maturate into antibody-secreting plasma cells (d*) and/or memory B cells. In general, inert antigens, such as nonlive inactivated vaccines, protein subunits, and virus-like particles, induce potent humoral responses and low-to-moderate T-cell responses. Activation of CD8⁺ T cells by inert antigens occurs through alternative pathways that are not depicted in this figure. The stimulation processes described and depicted in steps (a), (b), and (c) is reported less frequently and is less potent than stimulation by live immunogens (A), as depicted in (B) panel).