Vaccinology in the COVID-19 Pandemic Era: Comparison
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Different approaches have been used in parallel to make COVID-19 vaccines, including the use of nucleic acid-based vectors, whole virus (live-attenuated and inactivated), viral vectors (replicating and nonreplicating), adjuvant recombinant protein nanoparticles, and virus-like particles (VLPs). Among the protective antigens of SARS-CoV-2, the attention has mainly focused on the native S protein, which is able to induce potent neutralizing antibodies, even if its presentation to the immune system differs substantially between the different categories of vaccines. However, new evidence is being raised about potential roles for other, more conserved non-spike viral antigens, such as nucleocapsid (N) proteins, which might represent an innovation in the fight against emerging SARS-CoV-2 variants and a source for universal vaccines providing long-lasting immunity.

  • COVID-19
  • recombinant vaccines
  • pandemic

1. Introduction

Many vaccines approved for emergency use against COVID-19 contain biomaterial and nanoparticles that facilitate the delivery and action of the vaccine within host cells [138]; indeed, the mRNA vaccines developed by pharmaceutical companies consist of lipid nanoparticles containing the nucleic acid sequence encoding the S protein, or in recombinant Ad vectors, containing the S antigen–encoding sequence in the Ad DNA [1][2][3][4][5][6][7][8][9][10][11]. The main nanoparticles used to enhance the delivery of the vaccine into the host cells are shown in Table 1.
Table 1. Main nanoparticles for COVID-19 vaccines.
Vaccine Brand NameType of NanoparticleTechnologyRole of Nanoparticles
mRNA-1273

ModernaTX, Inc., Cambridge (MA), United States		Lipid nanoparticles containing cholesterol, DSPC, and PEG2000mRNARNA carrier for safe and efficient transport in vivo [12]
NVX-CoV2373Virus-like nanoparticles containing saponin-based adjuvantsProtein subunitThermostable, higher binding affinity toward the human ACE2 receptor [13]
BNT162b2

Pfizer/BioNtech		Lipid nanoparticles containing an ionizable cationic lipid/phosphatidylcholine/cholesterol/PEG–lipidmRNARNA carrier for safe and efficient transport in vivo [1][7][8]
ARCT-021

Arcturus Therapeutics Ltd.		Lipid nanoparticles containing ionizable lipid with a thioester to link the amine-bearing headgroup to lipid tails via two additional ester groups.mRNARNA carrier for safe and efficient transport in vivo [14]
Chula Cov19

Chulalongkorn University		Novel lipid nanoparticles containing cationic lipidsmRNARNA carrier for safe and efficient transport in vivo [9]
CVnCoV

CureVac AG		Lipid nanoparticles containing ionizable lipid ALC-0315mRNARNA carrier for safe and efficient transport in vivo [10]

2. Whole Virus Vaccines

Whole virus vaccines contain attenuated or inactivated forms of SARS-CoV-2 that can stimulate a protective immune response without causing the disease. The immunogenic profile of these two types of vaccines is clearly different. Whereas live-activated vaccines can stimulate both cellular and humoral immune responses, inactivated vaccines can only stimulate humoral response to SARS-CoV-2 [151]. However, use of live-activated forms of the virus raises several problems that limit the use of these platforms, such as postvaccination viral mutations inducing increases in toxicity and adverse reactions secondary to proliferation of the virus in the nasal cavity [162].
Among inactivated vaccines, 10 candidates have been approved for emergency use authorization (EUA), while 21 candidates were still in the evaluation stage as of 8 February 2022 [173]. The approved vaccines are BBIBP-CorV (89 countries), CoronaVac (53 countries), BBV152 (13 countries), KoviVac (3 countries), inactivated Vero Cells (2 countries), Qaz-COVID-in (2 countries), KConecaVac (2 countries), ERUCOV-VAC (Turkey), FAKHRAVAC (MIVAC; Iran), and COVIran Barekat (Iran). On the other hand, a single live-attenuated vaccine is in a phase 1 clinical trial in the UK [173].

32. DNA- and RNA-Based Vaccines

In DNA- and RNA-based vaccines, the genetic material from SARS-CoV-2 is used to elicit a protective immune response without causing disease. Both vaccine platforms can induce mainly B- and T-cell responses, with different risk profiles; indeed, DNA vaccines carry the risk of the integration of genetic material within the host DNA; RNA vaccines do not carry this risk but need to be stored at lower temperatures compared with DNA vaccines [151]. As of 8 February 2022, there was 1 DNA-based candidate (ZycoV-D) approved for EUA in a single country (India), while 16 candidates were in the clinical evaluation stage [173]. On the other side, three RNA-based candidates have been used as authorized vaccines for emergency use worldwide: BNT162b2 (137 countries), mRNA-1273 (85 countries), and TAK-919 (Japan); furthermore, 32 RNA-based candidates are currently in the clinical evaluation stage [173].

43. Viral Vector Vaccines

Viral vector vaccines do not contain antigens by themselves but use the translation mechanisms of the host cells to produce them. Those developed against SARS-CoV-2 are made of modified viral vectors that deliver genes encoding the surface spike proteins; there are two main types of viral vector vaccines: replicating viral vector vaccines enter the host cells and replicate to generate whole viral particles which produce the SARS-CoV-2 spike protein; and nonreplicating viral vector vaccines directly generate viral antigens within the host cells [184]. As of 8 February 2022, six nonreplicating viral vectors had been approved for EUA worldwide: AZD1222 (137 countries), Ad26.COV2.S (106 countries), Gam-COVID-Vac (74 countries), Covishield (47 countries), Sputnik Light (26 countries), and Ad5-nCoV (10 countries). Another 28 nonreplicating viral vectors are at the clinical trial stage. On the contrary, only eight replicating viral vectors are at the clinical trial stage [173].

54. Protein Subunit Vaccines

There are two main types of protein subunit vaccines against SARS-CoV-2: polysaccharide and conjugate vaccines. Polysaccharide vaccines contain polysaccharides of the SARS-CoV-2 cell wall, while conjugate candidates are bound to a polysaccharide chain with a carrier protein to induce a booster effect in the immune system response [195]. Most protein subunit vaccines contain harmless recombinant spike proteins; however, the emergence of variants of concern (VOCs) has stimulated research in order to identify potential new antigenic targets. In this regard, a recent study showed the potential role of intraviral nucleocapsid (N) protein use as a novel vaccine strategy to target multiple SARS-CoV-2 variants and thus lead to universal long-lasting immunity [206]. In fact, in contrast to the spike protein, the N-protein is relatively conserved within a single strain and among different strains across evolutionary stages. Interestingly, anti-N immunoglobulins have been detected in patients with SARS-CoV and SARS-CoV-2 infections [206][217].
In any case, protein subunit vaccines represent a promising solution for vaccines against COVID-19 as they can also be produced by large-scale microbial fermentation in developing countries, do not require storage at cold temperatures, and are safe when used in combination with adjuvants [228][239]. These vaccines represent a valuable source for large-scale vaccination programs in low- and middle-income countries (LMICs).
To date, 13 protein subunit vaccines have been authorized for emergency use against SARS-CoV-2: NVX-CoV2373 (34 countries), CIGB-66 (6 countries), FINLAY-FR-2 (4 countries), COVOVAX (3 countries), RBD Dimer (3 countries), MVC-COV-1901 (2 countries), FINLAY-FR-1A (Cuba), BECOV2A (India), EpiVacCorona-N (Russia), CHO cell (United Arab Emirates), Razi Corv Pars (Iran), and Covax-19 (Iran) [173]. Furthermore, 60 protein subunit vaccines are currently at the clinical trial stage [173].

65. Virus-like Particles (VLPs)

Several VLP platforms can be used to produce eVLPs and neVLPs to generate potentially long-lasting immune responses against SARS-CoV-2. To improve the self-assembly of VLP multimers, most candidates were developed combining the N protein and the highly immunogenic spike protein. To address issues related to the fast, large-scale production of VLPs, heterologous VLPs are preferred over homologous molecules. As of 8 February 2022, only five vaccine candidates were at the clinical trial stage, with no VLP approved for EUA against SARS-CoV-2 [173].

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