The outer casing, an integral component of the model, features an inner wall coated with a mirror-reflective film (Figures 1A–C). This film visually amplifies a single virus (Figure 1D) and a small patch of plasma membrane into multiple virions and a large continuous plasma membrane, creating a realistic scenario that mimics virus-cell interactions. The bottom tray of the model represents the plasma membrane and, when flipped over, reveals a detailed visualization of the viral replication cycle (Figure 1E) (Samji, 2009; Kumar and Sakharam, 2024) and antigenic shift processes (Figure 1E) (Zhang et al., 2023; Luczo and Spackman, 2024).

The core of the IAV model features a genome comprising eight RNA segments and associated proteins, including nucleoproteins (NPs) and RNA-dependent RNA polymerases (RdRps)—the latter comprising PA, PB1, and PB2 proteins (Zhu et al., 2023). Together, these proteins which are symbolized by kneaded super-light clay (Linyi Yilanzi Stationery Co., Ltd.), a type of paper clay, with designated colors, bind to the RNAs, symbolized by rolled formable iron wires, to form ribonucleoprotein (RNP) complexes (Figure 2A). The viral envelope is depicted as a two-layered structure: an inner layer of matrix protein 1 (M1) (Peukes et al., 2021) and an outer lipoprotein layer (Figure 2B). The two structures that comprise the hemisphere are both crafted from clay. There are several methods for preparing the hemispherical viral envelope, with the molding method being the most straightforward. To begin, select a sphere, such as a bowl, to serve as the mold and wrap its exterior in plastic wrap. Next, drape a rolled-out sheet of paper clay evenly over the form. Press the clay to conform to the shape of the mold, trimming any excess material along the rim. Allow the formed hemisphere to air-dry completely before gently removing it from the mold. Alternatively, if a suitable mold is not available, the assembly method can be employed. Start by cutting the flat paper clay into petal shapes (Figure 2B). The edges of these shapes are then raised and carefully joined together. Smooth the seams to create a hemisphere, which is then left to air-dry. Appropriate magnets, such as 5-mm-diameter Neodymium beads (from Pan’an County Leilei Buck Ball Toys Co., Ltd.), are embedded within the docking edges of the two hemispheres. This allows the two hemispheres to be securely fixed together using magnetic attraction, forming a spherical viral particle. Embedded within the envelope are two types of spikes: hemagglutinin (HA) (Russell et al., 2018) and neuraminidase (NA) (Wen and Wan, 2019) (Figures 2C,D). Specific holes are punched in the hemispherical envelope to facilitate the insertion of both the HA and NA proteins into their corresponding transmembrane regions, allowing for the possibility of replacing them with mutant forms. Each encoded protein spike may undergo structural changes due to viral mutations. For example, in studying the shift and drift processes of the H7N9 virus, we have created multiple models of the H9N2 IAV NA, H7N9 IAV NA, H9N2 IAV HA, mutant H9N2 IAV HA, and H7N9 IAV HA proteins using kneaded clay.

Beyond structural insights, the model also replicates the viral life cycle (Samji, 2009). By bringing the simulated virion close to the tray, the HA spike is shown to interact with and bind to the sialic acid receptor on the plasma membrane (via magnetic attraction), simulating the initial infection process of IAV (Figure 2E). Subsequent stages of the infection process are illuminated by diagrams displayed beneath the tray (Figure 1C). After HA binds to the sialic acid receptor, the virus undergoes invagination and is internalized into the cell. The viral matrix protein 2 (M2) ion channel then lowers the pH within the viral envelope, triggering a conformational change in HA, which facilitates fusion between the viral envelope and the plasma membrane, ultimately releasing the viral nucleocapsid into the cytoplasm (Manzoor et al., 2017). The nucleocapsid is transported to the nucleus via nuclear pores, where transcription and replication of viral RNA occur. The resulting mRNA moves to the cytoplasm, enabling the synthesis of viral proteins. These newly synthesized components then assemble into progeny viruses, which are subsequently released from the cell.

The model is especially useful for explaining the antigenic variation of IAV, which is classified into subtypes based on the unique characteristics of its HA and NA antigens. Due to the segmented nature of its genome (comprising eight RNA segments), IAV can undergo “reassortment” when two viruses from different host species co-infect the same cell. This process can produce antigenically novel strains, a phenomenon termed antigenic shift (Scholtissek, 1995). For instance, the model simulates the creation of the H7N9 avian influenza virus: a domestic duck transmits an H7N3 virus to an intermediate host (a chicken) carrying the H9N2 subtype, while a wild bird transmits a different H7N9 virus to the same chicken. The reassortment of genes from these strains results in the novel H7N9 virus (Figures 2F,G). Conversely, antigenic drift involves continuous or minor variations within a specific subtype, which can alter the structure of an antigen, subsequently reducing antibody-binding affinity and weakening the immune response (Yewdell, 2011). Both antigenic shift and drift can lead to changes in the shape of the HA antigen, which can be simulated in the model by altering the type of antigen. This modification renders pre-existing antibodies ineffective (Figure 2H) (Treanor, 2004).

Preventing influenza requires a proactive, science-based approach (Cowling and Okoli, 2024). Vaccination remains the most effective strategy. Each year, flu vaccines are tailored to include three or four strains of the virus, which may vary annually. Upon vaccination, the body generates antibodies targeting the HA antigens of the virus contained in the vaccine. These antibodies block the virus from binding to and infecting host cells (Figure 3A). The model illustrates how a viral antigen and a specific antibody attract each other through magnetic forces. However, if the HA gene mutates, the encoded antigen may also change shape, rendering previously effective antibodies unable to bind and allowing the mutated virus to infect host cells. As demonstrated in the model, the antibody stimulated by the vaccine is unable to bind to the mutant antigens, as these antigens do not incorporate the magnetic beads (Figure 2H).

For antiviral treatment, oseltamivir is the drug of choice. Once metabolized in the body, it is converted to the active compound oseltamivir carboxylic acid, a potent and selective inhibitor of the influenza NA enzyme. By inhibiting NA, this drug prevents the release of progeny virions from infected cells, thereby curbing virus spread (Figures 1E, 3B) (Jackson et al., 2011). Similarly, amantadine blocks the M2 ion channel, preventing the release of viral nucleic acids into the cytoplasm and thereby exhibiting antiviral activity (Figures 1E, 3B) (Jackson et al., 2011). The interaction between drugs and their targets is also modeled using magnetic forces to simulate attraction.