**1. Rationale for the Development of Capsid-Like Particle-Based Vaccines**

The development of vaccines remains the most effective method for preventing and controlling the spread of infectious diseases [1,2]. Traditional live-attenuated vaccines, such as those targeting measles [3], rubella [4] and smallpox [5] are highly immunogenic and can induce potent and long-lived antibody responses even after a single immunization [6]. This was originally ascribed to the ability of the attenuated virus to replicate in the host after vaccination. The high immunogenicity of live-attenuated viruses comes with a cost of increased safety risks and challenging manufacturing processes [7,8]. In contrast, modern recombinant subunit vaccines (i.e., based on a soluble protein antigen) show high safety, but in general fail to induce similar long-lasting antibody responses in humans [6,9–12]. Within recent years, several virus-like particle (VLP) based vaccines have been tested in clinical trials, of which vaccines targeting Hepatitis B (HBV) (Recombivax HB® and Engerix-B®), Human papillomavirus (HPV) (Cervarix®, Gardasil®, and Gardasil 9®) and Hepatitis E (HEV) (Hecolin®) have been licensed [13]. Notably, the HPV vaccine stands as a unique example of a recombinant subunit vaccine with comparable immunogenicity to live-attenuated vaccines, even after a single dose [14–16]. This vaccine is formed by the self-assembly of the HPV major capsid protein into capsid-like particles (CLP), the structure of which is thought to be key to its high potency [17]. CLPs constitute a subclass of VLPs and are rigid, non-lipid, protein-based particles. A large number of studies have jointly established a strong causal link between the high immunogenicity of CLPs and their structural similarities to native viruses. Of these properties, their size (20–200 nm in diameter) and repetitive

surface geometry are considered the most important [18–26]. Moreover, it has long been recognized that the immunogenicity of a vaccine antigen can be significantly increased if it is delivered to the immune system in a similar multivalent, repetitive and particulate format [27,28]. Consequently, several strategies have been pursued, exploiting CLPs as scaffolds for the presentation of heterologous antigens, including self-antigens.

Here, we will review key attributes of various CLP-based vaccine technologies in terms of their ability to facilitate a highly immunogenic epitope display. Additionally, practical aspects of the conjugation systems, such as their versatility, manufacturability and scalability will be discussed. In this context, we highlight the Tag/Catcher-AP205 platform as a particularly versatile and effective technology and provide a rationale for further development of this technology for vaccine design.
