Immune Response to SARS-CoV-2 Vaccines: Comparison
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COVID-19 vaccines have been developed to confer immunity against the SARS-CoV-2 infection. Prior to the pandemic of COVID-19 which started in March 2020, there was a well-established understanding about the structure and pathogenesis of previously known Coronaviruses from the SARS and MERS outbreaks. In addition to this, vaccines for various Coronaviruses were available for veterinary use. This knowledge supported the creation of various vaccine platforms for SARS-CoV-2. Before COVID-19 there are no reports of a vaccine being developed in under a year and no vaccine for preventing coronavirus infection in humans had ever been developed. Approximately nine different technologies are being researched and developed at various levels in order to design an effective COVID-19 vaccine. As the spike protein of SARS-CoV-2 is responsible for generating substantial adaptive immune response, mostly all the vaccine candidates have been targeting the whole spike protein or epitopes of spike protein as a vaccine candidate.

  • COVID-19
  • SARS-CoV-2
  • mRNA vaccine
  • adenoviral vectored vaccine
  • inactivated vaccine
  • subunit vaccine
  • adjuvants

1. Immune Response Generated by SARS-CoV-2 Infection

Coronaviruses are characterized by their large, protruding spike proteins that form a 100-nanometer crown, or corona, around the virus [50][1]. The envelope is comprised of four structural proteins, envelope (E), spike (S), membrane (M), and nucleoprotein (N), a lipid bilayer obtained from the host’s cell membrane, as well as a variable number of nonstructural proteins. SARS-CoV-2 recognizes and the class I fusion spike proteins attach to angiotensin-converting enzyme 2 (ACE2) commonly found in the respiratory epithelial cells of the host [51,52][2][3]. This allows for the viral capsid to fuse with the host cells and inject its nucleic acid into the host cells. The S2 subunit plays a vital role by permitting viral and cellular membranes to fuse and the S1–S2 junction is cleaved by the serine transmembrane protease serine 2 (TMPRSS2) found in the host [52][3]. In cats and ferrets, SARS-CoV-2 replicates well, but not in dogs, pigs, chickens, or ducks with cats having recently been shown to be especially susceptible to an experimental airborne illness [53][4]. Recent research has shown that the same receptor may be involved in infection in both cats and ferrets and is mediated by the transmembrane spike (S) [54][5]. Following attachment to the cell surface, the virus may enter the cells through endocytosis [55][6]. In vitro and in vivo research has been conducted regarding the translation and budding processes of SARS-CoV-1 and MERS viruses [56][7]. Different intercellular sensors, such as RIG I/MDA5/MAVS/TRAF3/IRF3/IRF7 and various TLRs/TRIF/MyD88/IkB/NF-kB/MAPK/AP-1 pathways, detect SARS-CoV-1 infection [57][8]. RIG I and IRF3/7 pathways are involved in type 1 interferon responses and may be inhibited by SARS proteins resulting in reduced antiviral response while boosting NF-kB activation, pro-inflammatory cytokine production, and necroptosis [57][8]. These signaling events have been implicated in hyper inflammation, increased cellular death, and cytokine storms [50][1].
The innate immune system possesses immunological memory, dubbed “trained memory”, which can influence the severity of the illnesses. The complex pathogenicity of COVID-19 and the disease’s virulence are linked to viral activation of the cytoplasmic NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome [58][9]. Macrophage and epithelial cell activation leads to the production of pro-inflammatory cytokines such as interleukin (IL)-1 and IL-18, which contribute to the pathogenic inflammation that causes COVID-19 symptoms to be so severe [59][10].
Toll-like receptors TLR3, TLR7, TLR8, and TLR9 detect mRNA, which leads to the induction of the NF-kB inflammatory pathway and a large number of pro-inflammatory cytokines that play a key role in the initiation of virus-induced inflammation [60,61][11][12]. Aside from heightened levels of acute-phase reactants and cytokine storm, little is known about the innate immune response. Presently, the majority of reports have concentrated on serious consequences and adaptive immune responses.
SARS-CoV-2 viral proteins attack a number of innate immune signaling proteins. Nsp13, Nsp15, and open reading frame ORF9b target the interferon (IFN) pathway, while Nsp13 and Orf9c target the NF-B pathway. SARS-CoV-2 Orf6 hampers NUP98-RAE1, an interferon-inducible mRNA nuclear export complex [62][13]. SARS-CoV-2 replication proteins Orf3b and Orf9c are canonical.

B and T Cell Immune Response

More than 80% of individuals with SARS-CoV-2 infection have a conventional respiratory virus-like clinical course that is mild to severe and self-limiting [50][1]. SARS-CoV-2 spike proteins bind to the cluster of differentiation 147 (CD147) and infect human T-cell lines and this pathway may even be implicated in inducing T-cell death [63][14]. CD147 is found in a variety of tissues and cells and is involved in cell proliferation, apoptosis, tumor cell migration, metastasis, and differentiation, particularly in hypoxic environments [64][15]. CD147 Ig0-Ig1–Ig2 is a second isoform of CD147 that has been identified. CD147 dysregulation has been linked to many varieties of cancer and regulates the production of matrix metalloproteinase (MMP) and vascular endothelial growth factor (VEGF), as well as signals for tumor cell invasion and metastasis [65][16]. COVID-19 treatment may be prevented by hindering the SARS-CoV-2 spike binding and subsequent infection by blocking CD147 protein with meplazumab [64][15].
In order to proliferate, viruses attach to cells that express specific receptors and then are able to enter the cells. In order to combat these viruses, class I major histocompatibility complex (MHC) proteins present viral peptides to CD8+ cytotoxic T. The virus-infected tissue cells are lysed by CD8+ cytotoxic T lymphocytes. Other antigen-presenting cells such as dendritic cells and macrophages present viral particles via MHC-Class-II to CD4+ T lymphocytes [66][17]. These CD4+ T cells, or helper T-cells, can interact with B cells which can identify viruses directly and produce virus-specific antibodies. Within the first week, after the onset of symptoms, the IgM isotype primary virus-specific antibody response is detected [67][18]. This can generate lifelong immunity through the production of IgG isotype antibodies that follow the early IgM response.
T- and B-cell responses to viral determinants, as well as identification of virus-infected cells, are crucial to outhe researchers' knowledge of various antiviral immune events. The S1 and S2 subunits of the Coronavirus spike protein are broken at the S1/S2 border and the S2′ cleavage site. SARS-CoV-2 spike proteins polybasic furin cleavage sequence (PRRARS) differs by four-amino-acid insertion from those in other SARS. T- and B-cell epitopes have been identified that demonstrate immunodominance [68][19]. SARS-CoV-2 is the third SARS-like virus to cause an outbreak, and thus shares many similarities with SARS-CoV-1 and MERS-CoV. These similarities may have resulted in those populations affected by the 2002 and 2012 outbreaks having some immune protection from COVID-19. Potential T-cell and B-cell epitopes of SARS-CoV-2 have been predicted using a bioinformatics technique based on their resemblance to SARS-CoV possible T-cell and B-cell epitopes, though only SARS-CoV T-cell epitopes and 16% of known SARS-CoV B-cell epitopes map to SARS-CoV-2 [69,70][20][21]. The conserved B- and T-cell epitopes shared between SARS-CoV and SARS-CoV-2 show the potential to lead to vaccination strategies that direct the immune response to these conserved regions. This immunity not only builds on existing research, but may result in cross-protective immunity against other varieties of coronavirus and future strains that may be mutated [69][20]. SARS-CoV-2 structural proteins show significant genetic similarities with SARS-CoV but not to MERS-CoV. Reactivity of SARS-specific memory T-cells was found to persist for 9- to 11-years post-infection and was specific to the S, N, and M proteins in SARS-type viruses with no cross-reactivity with MERS [71][22].

2. mRNA Vaccines

mRNA vaccines have been considered for over three decades and are comprised of self-replicating RNA or messenger RNA that cause cells to express an antigen that can elicit cytotoxic T lymphocyte responses. mRNA shows specific benefits in inducing transient expression and production of specific antigenic proteins that give rise to MHC-1 presentation [72][23]. This has made RNA a popular choice in several COVID-19 vaccines, including the approved Pfizer–BioNTech and Moderna vaccines. These vaccines use RNA to induce the expression of SARS-CoV-2 spike protein which are then recognized and destroyed, allowing the body to build up memory immune cells. Nucleoside-modified messenger RNA is commonly used in RNA vaccines, although this is not necessarily always the case. The mRNA molecules are combined with lipid nanoparticles which improve the absorption of RNA into cells and protect the strand while in transport [73,74,75][24][25][26]. The first COVID-19 vaccines to be approved in the United Kingdom, the United States, and the European Union were RNA vaccines [76,77][27][28].
Severe allergic responses are uncommon. In December 2020, of the 1,893,360 people who received the first dose of the Pfizer–BioNTech COVID-19 vaccine, there were 21 cases of anaphylaxis [78][29]. In total, 10 occurrences of anaphylaxis were reported between December 2020 and January 2021 of the 4,041,396 Moderna COVID-19 vaccine dosages administered. The allergic symptoms were most likely caused by lipid nanoparticles (LNPs) [79][30].

3. Viral Vector Vaccines

Several COVID-19 vaccines use adenovirus vector carrying DNA that encodes an antigenic SARS-CoV-2 protein. This DNA is injected into the host’s cells and directs the cell to encode for an antigen that stimulates a systemic immune response.

4. Inactivated Vaccines

Inactivated vaccines use a dead version of the pathogen and are generally the quickest choice for antiviral immunizations. Inactivated viruses are promising because they exhibit numerous viral proteins for immune identification, have consistent expression of conformation-dependent antigenic epitopes, and can be mass-produced easily. Historically, inactivated viruses have been utilized for the production of vaccines and have been found to be useful in preventing viral infections such as polio [127][31]. To date, different chemical and physical strategies have been used to inactivate coronaviruses, including the use of formalin, formaldehyde, -propiolactone, and UV alone or a blend of these techniques [128][32]. Virus-neutralizing antibodies are primarily important for the protection against viral infection, a principle that remains true for the great majority of viral infections against which humans develop significant immune protection as a result of infection or vaccination. There are already many vaccine candidates that are being considered for their ability to induce the production of antibodies able to bind and neutralize the coronavirus spike protein [129][33]. Currently available inactivated vaccines serve to improve immunity by eliciting the production. Antibodies of this type frequently disrupt the virus from undergoing conformation changes or its interactions with cell entry receptors [130][34]. The mechanism of action by which the immune response is generated by inactivated vaccine is depicted in Figure 1. Adjuvants are necessary to induce an effective and strong immune response because these vaccines provide weaker immunity than live vaccines. Adjuvants are frequently required when inactivated vaccinations are delivered, and periodic booster doses are required to ensure long-term protection, which are the main disadvantages of inactivated vaccines.

5. Subunit Vaccines

Protein-based subunit vaccines are another safe vaccine against SARS-CoV-2. To safely produce an immune response, these vaccines use innocuous fragments of proteins that resemble the COVID-19 S-proteins. Similar to other COVID-19 vaccine mechanisms, subunit vaccines induce immunological responses to the SARS-CoV-2 spike (S) protein. The S protein, prior to binding receptors on the cell membrane, is in a metastable pre-fusion conformation that undergoes significant rearrangement during virus–cell fusion. The immune responses generated by vaccine often target the pre-fusion S protein as this is more protective and limits transmission. The S-protein is comprised of an amino-terminal S1 receptor-binding domain (RBD) and a carboxy-terminal S2 subunit. The S1 subunit is a popular target during vaccine development as this is the main region implicated in allowing viral entry. A polyclonal antibody directed against various other epitopes of the S protein other than the RBD may be effective at hindering viral attachment, giving extra neutralizing activity, and/or preventing post-attachment fusion, for example. A vaccination that targets many epitopes might also reduce the risk of immunological escape through mutation. To boost the stability of the vaccines, proteins, which are frequently unstable, are packaged within nanoparticles and adsorbed onto adjuvants [134][35]. Genetically engineered subunit vaccines, otherwise known as recombinant protein vaccines, are constructed by incorporating pathogenic microorganism target genes with a vector which is then injected into an industrial organism in order to express the antigen of interest. These proteins are extracted from the organisms and used in vaccines to elicit an immunological response. These vaccines’ antigenicity is intimately linked to their expression mechanisms. Currently, yeasts, insect cells, mammalian cells, and bacteria are the most common methods used to express the antigen to generate subunit vaccines. Antigen-presenting cells with strong inherent adjuvant activity take up this form of the vaccine, such as the SARS-CoV nucleocapsid protein subunit vaccine. They effectively generate a T and B cell-mediated adaptive immune response. Recombinant protein vaccines provide a high level of inherent safety and stability. Furthermore, they can be manufactured in large quantities, making them ideal for mass immunization programs. However, recombinant protein vaccines have a number of drawbacks, including poor immunogenicity, a short immunization time, a dependency on immunization timing, and adjuvant type. Currently, COVID-19 recombinant protein vaccines use the SARS-CoV-2 surface S protein as the target antigen. The nucleocapsid protein, on the other hand, is immunogenic and has been employed in the production of COVID-19 recombinant protein vaccines. Although there is a risk of antibody-dependent enhancement (ADE) with recombinant protein, which occurs when antibodies bind pathogens but cannot prevent infection and thus the risk of worsening the severity of COVID-19 through ADE is a possible stumbling block for antibody-based vaccinations and therapies. Recombinant protein vaccines, in particular, have the ability to generate both mucosal and humoral immunity. Immunization efficacy can be improved by combining DNA vaccines and recombinant protein vaccines [135][36].

6. COVID-19 Vaccine Adjuvants

Immunologic adjuvants are substances used in combination with specific vaccine antigens that serve to enhance and prolong antigen-specific immune responses [140][37]. In viral infection, T-cell recruitment is the hallmark and favored immunological response. In the case of subunit vaccines for SARS-CoV-2, the T-cell response is the more significant marker of vaccine success, and adjuvants aid in eliciting a predominantly Th1-skewed immune response. The five most common COVID-19 subunit vaccine adjuvants are alum, beta defensin, MF59, matrix-M, and CpG. B-defensin adjuvanted multi-epitope subunit vaccines with 28 epitopes (three from replicase, three from NSp1, two from envelope, five from membrane, six from nucleocapsid, and nine from spike proteins) have been developed. The molecular docking revealed strong binding affinities for TLR3 and TLR8. These vaccines could protect against a wide range of diseases, particularly emerging variations of concern (VOC) [141][38]. A study with the full S-Matrix-M adjuvanted vaccination (NVXCoV2373) found a higher titer of S-protein antibodies and CD4+ and CD8+ T cells, follicular CD4+ Th, and germinal center B cells in mice spleen [142][39]. The safety, effectiveness, and tolerability of the S-AS03, S-CpG/alum, and placebo groups received 3, 9, and 30 g doses at 21-day intervals in a phase 1 subunit COVID-19 vaccine (SCB-2019). When opposed to AS03, CpG is a comparatively safe compound. S-AS03 and S-CpG/alum both cause the development of neutralizing antibodies (NA). S-AS03, on the other hand, developed a faster neutralizing antibody than the S-CpG/alum group, demonstrating the adjuvants’ differences. In the two adjuvanted groups, helper T-cell immune responses were generated, but this was not the case in S-protein specific to the non-adjuvanted S-trimer COVID-19 vaccination. The preferred options were 9 g S-trimer-AS03 and 30 g S-trimer-CpG/alum, according to this dose discovery restudyearch [143][40]. Yang et al. conducted a phase 1 and 2 subunit vaccination trial (2021). Adverse effects were mild to moderate in both phases 1 and 2. The seroconversion rates of NA in phase 2 were 76 percent and 72 percent in the 25 g and 50 g dosage groups, respectively, 14 days after the second treatment. After 14 days, seroconversion rates in the 25 g and 50 g groups were 97 percent and 93 percent, respectively, in the third dosage schedule. Three consecutive 25 g dosage shots were shown to be safe and efficacious when given at 14-day intervals [138][41]. Alum is used as an adjuvant in this vaccine.

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