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Virus-Like Particles-Based COVID-19 Vaccines
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Virus-like particles (VLPs) are a versatile, safe, and highly immunogenic vaccine platform. The use of a very flexible vaccine platform in COVID-19 vaccine development is an important feature that cannot be ignored. Incorporating the spike protein and its variations into VLP vaccines is a desirable strategy as the morphology and size of VLPs allows for better presentation of several different antigens. 

virus-like particles vaccines COVID-19 SARS-CoV-2
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Entry Collection: COVID-19
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Update Time: 18 Feb 2022
Table of Contents

    1. Introduction

    The SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is the causative agent of COVID-19 (Coronavirus Disease 2019) [1][2][3] and is responsible for the recent pandemic, which has already reported 248,467,363 cases and 5,027,183 deaths worldwide as of 5 November 2021 [4]. As new cases continue to increase worldwide, it is urgent to develop inexpensive and versatile vaccines to handle emerging variants that can affect pre-existing natural immunity and the efficacy of already approved vaccines [5]. According to the World Health Organization, 129 COVID-19 vaccines are under clinical trials, and eight are approved for emergency or definitive use worldwide, including inactivated, mRNA, and viral vector vaccines (Table 1) [6][7]. Although we already have these available vaccines, there is still a need for improved versions of COVID-19 vaccines. Hence, adapting vaccines to variants of concern (VOCs) along with decreasing vaccine costs will be the goals for the next step towards eradication. A technology that has the potential to address some of these issues is the virus-like particles (VLPs) vaccine platform, as it is adaptable, resembles viral structures, is highly immunogenic, and can be less expensive than other platforms.
    Table 1. Summary of WHO COVID-19 approved vaccines.
    Name Platform Adjuvant Dosage Efficacy * References
    Inactivated Alum 2 doses 83.5% (95% CI, 65.4–92.1) [8][9][10][11]
    Inactivated Alum 2 doses 72.8% (95% CI, 58.1–82.4) [12][13]
    (Bharat Biotech)
    Inactivated Alum 2 doses 77.8% (95% CI, 65.2–86.4) [14][15]
    Viral vector No 2 doses 74.0% (95% CI, 65.3–80.5) [16][17][18]
    (Oxford/AstraZeneca formulation)
    Viral vector No 2 doses 74.0% (95% CI, 65.3–80.5) [16][17][18]
    (Johnson &Johnson-Janssen)
    Viral vector No 1 dose 66.9% (95% CI, 59.0–73.4) [19][20][21][22]
    mRNA No 2 doses 94.1% (95% CI, 89.3–96.8) [23][24]
    mRNA No 2 doses 95% (95% CI, 90.3–97.6) [25][26]
    * Against symptomatic COVID-19.
    The VLPs are noninfectious nanoscale particles composed of single or multiple self-assembling viral or nonviral proteins, which mimic a native viral particle [27]. These particles, when used as immunogens, are captured and processed by antigen-presenting cells (APCs) and presented by both MHC-I and MHC-II to T helper and cytotoxic T lymphocytes (Figure 1A). The structural repetitiveness and particle size of VLPs enhance recognition and direct activation of B cells. [28][29][30][31]. Taken altogether, these properties lead to robust humoral and cellular immune responses, which are exciting for vaccination against infectious diseases [32][33][34][35][36][37][38].
    VLPs are classified according to their structural composition (nonenveloped-neVLPs or enveloped-eVLPs) and to the native virus components (homologous or heterologous) [39] (Figure 1B). Homologous VLPs comprise particles that self-assemble using proteins derived from the native virus only [40]. On the other hand, heterologous VLPs contain proteins from different sources to increase immunogenicity [41]. Moreover, available bioinformatics tools can help to optimize the rational design of new and pre-existing VLPs to achieve the best immunogenic performance [32][42][43][44][45][46].
    Figure 1. The adaptive immune response generated by VLPs immunization and VLPs classification. (A) After immunization, VLPs are phagocytized by dendritic cells or macrophages. Then, they are carried out to lymphatic vessels, where the antigenic regions will be processed and presented by class II MHC molecules (CD4+ T cells) and, through cross-presentation, by class I (CD8+ T cells). Immunological pathway activation by immunization with VLPs will activate robust cellular (cytokines) and humoral (B cell-antibodies) immune responses. (B) VLPs are classified as nonenveloped (neVLPs) or enveloped VLPs (eVLPs) based on the absence or presence of a lipidic membrane, respectively. These particles can also be classified as homologous or heterologous VLPs according to their composition. Homologous VLPs are assembled using proteins from the native pathogen only (blue), and heterologous VLPs can be assembled using proteins or peptides from different sources (black and blue).

    2. SARS-CoV-2, VOCs, and Structural Vaccinology

    The SARS-CoV-2 positive-sense single-stranded RNA genome (29 kb in length) encodes four structural and 16 non-structural proteins [3]. The structural proteins are the membrane (M), envelope (E), spike (S), and nucleocapsid (N) proteins, as seen in other coronaviruses (Figure 2A).
    Figure 2. SARS-CoV-2 structural proteins and the different states of the Spike protein. (A) Schematic representation of the SARS-CoV-2 viral particle. The structure of the SARS-CoV-2 viral particle is composed of four structural proteins: Membrane (M), Envelope (E), Nucleocapsid (N), and Spike (S). The S protein is found in two different states on viral particles: open state (minor population) and closed state (major population). In addition, during the membrane fusion process (host cell entry), the S protein can be found in the fusion state (fusion S). (B) Schematic representation of the binding of open-state S (PDB ID 7498) to the ACE2 receptor present in the host cell. The illustrations were made in free software (CellPaint 2.0 [47] and 3D Protein Imager [48]). The binding figure was made using the crystal structure of ACE2 bound to Spike available at the Protein Data Bank (PDB ID 7A98).
    Among these structural proteins, the main target for vaccine development is the SARS-CoV-2 S protein, which gives the characteristic crown-shaped structure of coronaviruses [49][50]. S is a highly glycosylated [51] homotrimer transmembrane protein (UNIPROT ID P0DTC2) composed of 1273 amino acids per chain. Known human sarbecoviruses (SARS-CoV-2 and SARS-CoV-1) and the alphacoronavirus NL63 invade the host cell through an interaction between the S protein and its receptor, the angiotensin-converting enzyme 2 (ACE2) [51][52][53][54][55] (Figure 2B). In general, the S protein consists of two major regions in addition to the signal peptide (SP) (1–12): the S1 subunit (13–685), and the S2 subunit (686–1273), which contains the transmembrane region (TM) (1214–1234) followed by the cytoplasmic domain (CD) (1235–1273) (Figure 3A). The S protein and the ACE2 receptor binding are mediated by the receptor-binding motif (RBM; 437–508), located in the receptor-binding domain (RBD; 319–541) [56] (Figure 3A, purple and cyan, respectively). The fusion machinery in S2 is composed of two fusion peptides (816–837 and 835–855) and two heptad regions (920–970 and 1163–1202). The first site of cleavage targeted by host proteases, such as furin and TMPRSS2, is located in the S1/S2 interface (685–686) [57][58][59] (Figure 3A, red). Removing the S1/S2 site promotes conformational changes that open the second cleavage site at S2 (815–816). The subsequent cleavage of the S2 site promotes the projection of needle-shaped fusion peptides into the host membrane [60][61], leading to cell fusion in 60–120 s in feline coronavirus [62]. The S protein presents a closed and open conformation [45][63] (Figure 3B, upper and bottom panel, respectively). With one or more RBDs projected outward, the open state constitutes the major conformation population of viable virions [63]. The increased exposure and steric freedom enable stronger interactions with the ACE2 receptor [45][64]. Therefore, mutations that stabilize this open conformation lead to positive selection, making the virus more transmissible [65][66][67].
    Figure 3. Structure and domain organization of the SARS-CoV-2 Spike (S) protein. (A) The S structure comprises a cytoplasmic domain (CD, white), a transmembrane domain (TM, black), and an ectodomain, which is divided into two subunits, S1 (gray) and S2 (dark gray). The magnification shows the several disulfide bridges (DB, yellow) and the glycosylation sites (GlcNAc, green) through the S protein ectodomain. It is highlighted in red, the S1/S2 interface. The receptor-binding domain (RBD, in cyan) and the receptor-binding motif (RBM, magenta) are also shown in S1. (B) As mentioned in Figure 2, the S protein shows two conformers on viable viruses (closed and open state). The upper panel shows the S protein in the closed state (trimeric and monomeric state). The bottom panel shows the S protein in the open state (trimeric and monomeric state). Illustrations were made in PyMol [68] using the wild-type structures available from Zhang et al. [69][70].


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      Prates-Syed, W.A. Virus-Like Particles-Based COVID-19 Vaccines. Encyclopedia. Available online: (accessed on 08 December 2022).
      Prates-Syed WA. Virus-Like Particles-Based COVID-19 Vaccines. Encyclopedia. Available at: Accessed December 08, 2022.
      Prates-Syed, Wasim Aluisio. "Virus-Like Particles-Based COVID-19 Vaccines," Encyclopedia, (accessed December 08, 2022).
      Prates-Syed, W.A. (2022, February 15). Virus-Like Particles-Based COVID-19 Vaccines. In Encyclopedia.
      Prates-Syed, Wasim Aluisio. ''Virus-Like Particles-Based COVID-19 Vaccines.'' Encyclopedia. Web. 15 February, 2022.