# Tailored Nanoparticles as Vaccine Components
## 2 Forms of Antigen in a Vaccine  
In principle, the best immune response is elicited by a vaccine that is as similar as possible to the actual pathogen and that mimics its route and mechanism of infection [5]. Thus, many successful vaccines against viruses and bacteria consist of inactivated (killed) or attenuated (chemically or genetically disabled) pathogens [5; 15]. Such formulations have drawbacks, though: their development (e.g., by a repeated passage in non-human host organisms or cell lines) might take many years, and their production can be difficult and time-consuming [5; 28]. For these reasons, vaccines have been developed that present the most important epitopes, or their genetic information, to the immune system by other means. Subunit vaccines use purified antigen molecules such as proteins or bacterial cell wall polysaccharides [29], though the latter can only induce antibodies but not CTL [30]. Nucleotide vaccines do not contain actual antigen molecules but instead RNA or DNA that encodes them, leaving it to the cells in the vicinity of the injected vaccine to produce the antigenic protein; macrophages and/or dendritic cells then process the antigen and initiate an immune response [1]. Since in an infection, the immune system usually encounters whole pathogens, i.e., particles that may contain many copies of the antigens on its surface or in its interior [17], the innate immune response is naturally optimized for particulate antigens. Compared to soluble antigens, they are phagocytosed better by the immune cells and give stronger responses. Particulate antigens such as whole bacteria more strongly activate the intracellular signaling pathways of the innate immune cells, such as the inflammosome and the calcineurin/NFAT pathway, resulting in better cytokine production and immune stimulation. Starting the humoral adaptive immune response, in turn, requires endocytosis of antigen by B cells, which is more efficient with particulate antigens since the crosslinking (induced proximity) of several B cell receptor molecules by a multivalent particulate antigen yields stronger B cell activation with better antigen presentation to T helper cells [17]. Pathogens have used such strong immune reactions to particulate antigens for their own purpose, namely to subvert the immune response directed against them. For example, hepatitis B virus (HBV) triggers infected cells to produce virus-like entities called subviral particles (SVPs) of about 25 nm diameter (compared to 42 nm for the HBV virion) that display the viral surface antigen (sAg) but contain no viral genome. SVPs vastly outnumber the real virions, and being highly immunogenic, they deflect the immune response, enabling chronic HBV infection [31]. Because of their strong immunogenicity, these SVPs have indeed been used as carriers for vaccine epitopes from other pathogens [7] as a kind of natural vaccine nanoparticle. The HBsAg SVPs are glycosylated lipoprotein particles stabilized by a network of intramolecular and intermolecular disulfide bonds, and they allow targeted modifications of both the glycan content and the level of disulfide bonding. HBsAg SVPs accept and present foreign antigenic sequences to yield a chimeric particulate delivery platform that led to the development of the Mosqurix vaccine against malaria and other potential preclinical vaccines against infectious diseases [7]. In the development of vaccines with all-synthetic components, it makes sense to use synthetic nanoparticles (NPs) to emulate the strong immunogenicity of polyvalent bacteria, viruses, and SVPs [3; 5; 6; 8; 16; 21; 32; 33].