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T and B Cells Immune Response and the importance of vaccines Against SARS-CoV-2
1 School of Biological Science and Engineering, Yachay Tech University, Hacienda San José s/n, San Miguel de Urcuquí 100119, Ecuador; [email protected].
2 School of Biological Science and Engineering, Yachay Tech University, Hacienda San José s/n, San Miguel de Urcuquí 100119, Ecuador; [email protected].
3 School of Biological Science and Engineering, Yachay Tech University, Hacienda San José s/n, San Miguel de Urcuquí 100119, Ecuador
* Correspondence: [email protected]
Available from: http://dx.doi.org/10.21931/RB/2022.07.01.36
SARS-CoV-2 has become a global pandemic because it is a severe respiratory syndrome that attacks many people worldwide and can lead to death depending on the severity. In recent years, the study of the acquired immune response (T cells) and innate (B cells) has increased to better treat the disease from the quantitative cell count. A picture has begun to emerge revealing that CD4+ T cells, CD8+ T cells, and neutralizing antibodies contribute to the control of SARS-CoV-2 in COVID-19 cases. This work studies the three fundamental components of the adaptive immune system: B cells (the source of antibodies), CD4+T cells, and CD8+T cells and their function against SARS-CoV2. The importance of vaccines and the different types of existing vaccines are discussed. Implications of covid-19 variants on Immunity and vaccine types are also analyzed to understand how the action of the immune system will help treat the disease.
Keywords. Vaccine, B cells, CD4+, CD8+, SARS-CoV-2
Coronaviruses have been present within the human population for generations
1 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now the third of Betacoronavirus genus transferred to humans in the last twenty years. It has reported the highest contagiousness but the lowest mortality rate 2.It emerged in China in December 2019. From that point on, it would mark the beginning of a pandemic that would affect millions of people worldwide due to its high transmissibility 3.
COVID-19, resulting disease from SARS-CoV-2, presents common clinical manifestations for most patients, which are fever, cough, and a grave "flu" that can evolve into acute respiratory distress syndrome (ARDS), pneumonia, renal failure, and death
4. It has also been demonstrated that it can present post-COVID-19 complications, such as myocardial inflammation, arrhythmia, pneumothorax, and pleural effusion 5. A meta-analysis carried out in January 2021 has shown that SARS-CoV-2 is highly contagious when symptoms appear, but this contagiousness decreases to almost zero after ten days in mild-moderately ill patients. The same study suggests that it has a mean incubation period of 6.38 days, a time that can be considered relatively short if we take into account that the adaptive response takes between 15 and 21 days 6. Once the virus enters the body and the innate immune response fails, the second line of defense, the adaptive immune system, is put into action thanks to the dendritic cells, which carry the virus antigen to the CD4+ T cells (helper T cells) 7. These cells are responsible for triggering the humoral and cellular responses. This first response is in charge of defending the extracellular space through the action of antibodies produced by B cells 8. The second one is focused on killing the virus in the intracellular space through the activity of CD8+ T cells (cytotoxic T cells). These cells are of particular interest in this review because after people get infected with SARS-CoV-2, they tend to generate CD8+ T cells that can target more than 15 distinct fragments of coronavirus proteins inside the infected cells giving them more protection to new variants. In contrast to B cells antibodies, which target the spike protein on the virus's surface, a protein that is capable of mutations 9.
T Cells Response
Knowing about the adaptive response to certain diseases is essential for creating vaccines; in this case, it is necessary to understand how this response works against SARS-CoV-2. The first step for such an understanding is quantifying the virus-specific CD4+ and CD8+ T cells
10. CD4+ and CD8+ T cells primarily react to the spike protein on the coronavirus to initiate antiviral immunity[UdMO1] 11. In addition, depending on the patient and the severity of SARS-Cov-2, the immune response of T cells can range from optimal to suboptimal[UdMO2] 12. Over the years, the population of naïve T cells has declined. Still, conversely, antigen-experienced memory T cells become an essential part of the T cell population due to their memory system 13,14. The older the person, the better the immune response to previously exposed pathogens.
T cells are easier to induce a response against new pathogens in children. For this reason, it has been observed that children who become infected are not significantly affected by the disease
13. Furthermore, CD4+T cells stimulate B cells to produce viral-specific antibodies and cytotoxic CD8+T cells to target virus-infected cells 11. In addition, activated CD4+ and CD8+ T cells have been found to help both clearances of the acute infection caused by the disease and protective immunity against reinfection by establishing immunological memory against the pathogen 15.
CD4+ T cells are central organizers of antiviral immune responses. Furthermore, some of the functions of CD4+ T cells in SARS-CoV-2 infection are their ability to differentiate into various helper and effector cell types. This serves different actions: helps CD8+ T cells, instructs B cells, recruits innate cells, has direct antiviral activities, and facilitates tissue repair
16 (Figure 1). In situations of uncontrolled immune or inflammatory responses, CD4+ T cells can cause pathology 17. Different studies have made it possible to find CD4+ T cells that are reactive against SARS-CoV-2 in patients who have not suffered from the disease, which is suggested according to Bacher. P., et al (2020) arise in response to infection by the common cold coronavirus (CCCoV) 12. In addition, a correlation between the reappearance of CD4+ T cells and the patient's recovery has been observed when the patient has a severe SARS-CoV-2 infection 18. This suggests that the patient's cells have already acquired some immunity against SARS-CoV-2 and give them protection against the disease, which causes them to recover.
Figure 1. In the image, we can see CD4+ T cell response during COVID-19; we can see how the virus enters the organism. Later we can see how a naïve T cell acts, the cell has interaction with the interferon type I and types II[UdMO1] , after the contact, we can see that there is a proliferation of T [UdMO2] FH cells which can activate the antiviral response system, or they can join Germinal Centre T cells, to generate the activation of Germinal-center B cells.
Through the literature, it can be known that CD8+ T cells have an essential role in eliminating viral infections
19. Activated CD8+ T cells have been found to display a wide range of cytotoxic molecules, which appear in the blood of infected patients before they recover from the disease 20. In SARS-CoV-2 infections, the presence of virus-specific CD8+T cells has been associated with better COVID-19 outcomes (19). This is because immunodominance is one of the main characteristics of the responses of CD8+ T cells in viral infections. According to Peng (2022), they knew how CD8+ T cells could better attack the disease of interest in this case SARS-CoV-2. Peng et al. 2020, knowing that CD8+ T attack SARS-CoV-2 will be essential for the design of vaccines to obtain optimal responses from CD8+ T cells 22. Furthermore, circulating SARS-CoV-2-specific CD8+T cells are less consistently observed than CD4+ T cells 23.
Furthermore, Activated T cells directed toward spike (S), nucleo-capsid (N), membrane (M), and other types of open reading frames can be detected in approximately 70% of acute and convalescent COVID-19 patients
10. This is possible observed utilizing human leukocyte antigen (HLA) class I and II predicted peptide "mega pools" to stimulate peripheral blood mononuclear cells (PBMCs) of the patient 24 (Figure 2)
Figure 2. CD8+ T cell response during COVID-19; first we can see how the virus enters the organism. Later, it can be observed how the naive cells interact with interferon I and III, which produces the activation and clonal expansion of T cells, which is a central event in the production of specific immune responses. Finally, memory T cells and effector T cells are produced.
The immune system has numerous ways to detect and avoid the return of infectious pathogens. B cells are a crucial subset of B lymphocytes that play a critical role in the innate immune response against bacterial and viral diseases
25–27. It selects B cells to produce antibodies that bind to the virus. It also extracts a store of memory B cells that jumps into action if the virus attacks again 28. These pathogen-specific B cells are induced to differentiate and secrete their antigen receptors into the blood in the form of antibodies 29. B cells are just as crucial as T cells within the immune system because they produce antibodies that will trap specific invading viruses. Antibodies circulate throughout the body and bind to the pathogen that triggers the response wherever it occurs It is essential to highlight that one of the immune system's most effective protection methods is the secretion of high-affinity antibodies. As the infection progresses in our body, the antibodies improve heir affinity for the antigen, and the isotope class changes (immunoglobulin [Ig ]M, IgG, IgA, IgE) 30. When all three immunoglobulin classes (i.e. IgG, IgM, and IgA) are found, the maximum neutralisation activity against SARS-CoV-2 is achieved. Tis is a measure of the ability of the antibodies to work together in a synergistic manne 31.
The isotype is the part of the antibody that does not bind antigen directly but triggers other immune effector functionalities, such as activating the complement cascade or binding to receptors on immune cells to guide responses to pathogens
32,33. During the process of an immune response, B cells that find their cognate antigen are activated and move to the center of the B cell follicle. Here the B cells form structures known as germinal centers 34. Persistent antibody evolution occurs in germinal centers. This process requires that B cells are exposed to antigens trapped in immune complexes on follicular dendritic cells 35. Improvements in B-cell affinity occur in specialized; transient microanatomical constructs called germinal centers (GCs), which develop in secondary lymphoid organs, for example, lymph nodes and the spleen. GCs are developed after the immune challenge and are essential for immunological memory production 36. The GC B cell response gives rise to affinity-matured memory B cells and long-lived plasma cells (Figure 3). There is an increase in the number of SARS-CoV-2-specific memory B cells over time following mild infection.
Figure 3. This is a figure. The germinal center (GC) reaction. The B cells proliferate faster once the GC response is initiated in a secondary lymphoid organ. In addition, some cells will change from immune response cells to pre-GC memory B cells. The remaining B cells initiate and participate in the GC reaction where iterative cycles of proliferation, mutation, and selection increase the average antigen-binding strength of the B cell receptors (affinity maturation). Some B cells will differentiate throughout the response into short-lived plasmablasts (secreting the now affinity-matured Abs), long-lived plasmablasts, and memory B cells.
Spike and nucleocapsid are the primary antigens tested for seroconversion
37. In COVID-19 cases, the Spike protein targets >90% of neutralizing antibodies, some of them targeting the N-terminus 38,39(Figure 4). The study developed by Gaebler et al. (2021) demonstrates that during the first six months after infection, the anti-SARS-CoV-2 memory B cell response evolves. This process occurs with the accumulation of somatic Ig mutations and the production of antibodies with greater amplitude and neutralizing rate 29. Neutralizing antibodies are crucial for virus clearance and to achieve protection against SARS-CoV-2. Tey may achieve this in several ways including interfering with virion binding to receptors, blocking virus uptake into host cells, and preventing uncoating of viral genomes in endosome or causing aggregation of virus particles 40.
Figure 4. Monoclonal neutralizing antibodies. A functioning system of monoclonal antibodies binds to the virus's spike protein. The spike protein is a homo-trimer, with each monomer composed of two subunits (S1 and S2). S1 contains the N-terminal domain (NTD) and the receptor binding domain (RBD) which mediates the ACE2 interaction, while S2 mediates membrane fusion.These neutralizing antibodies prevent SARS-CoV-2 from binding to ACE2, resulting in decreased effectiveness of the virus.
Implications of Variants on Immunity and Vaccines
Variants occur through naturally occurring nucleotide changes in the viral genome during replication, and these changes develop faster in RNA viruses than in DNA viruses
41. Variants of concern (VOC) of SARS-CoV-2 pose a threat because divergent strains with an accumulation of mutations in different S domains can evade infection or neutralizing antibodies induced by vaccination 42,43. These VOC include the Alpha Variant (B.1.1.7) lineage initially detected in the United Kingdom and spread worldwide 44. The Beta Variant (B.1.351) and Gamma Variant (P.1) lineages were detected in South Africa and Brazil 45. These variants have several mutations and deletions compared to previously circulating viruses located in the receptor-binding domain (RBD). In December 2020, the Delta Variant (B.1.617.2) was detected 42. This variant caused infections throughout the world, but the countries most affected by this variant were the United States 46 and India 47,48. In November 2021, the Omicron Variant (B.1.1.529) was detected, causing many infections around the world 49(Figure 5).
Figure 5. SARS-CoV-2 variants. The N501Y substitution is common to the Alpha, Beta, Gamma, and Omicron variant strains. The E484K/Q/A and K417T/N substitutions are present in the Beta, Gamma, and Omicron strains, while the L452R substitution is unique to the Delta variant.
Genomic surveillance of SARS-CoV-2 variants has primarily focused on mutations in the spike glycoprotein, which mediates attachment to cells and targets neutralizing antibodies because the spike is the major viral antigen in the current vaccines. Adequate protection may still occur despite a few changes at antigenic sites in SARS-CoV-2 variants because current vaccines provoke an immune response to the entire spike protein
50. The generation of powerful and long-lasting antibodies through the induction of long-lived memory B cells and plasma cells is the key to a vaccine's effectiveness. The antibody response provides a continuous supply of high-affinity antibodies that circulate and test our bloodstream and mucosal surface 51.
A recent study identified a new monoclonal antobody (S2X259) with broadly neutralizing effects targeting a highly conserved RBD region called antigenic site II
52. This region is usually inaccessible because of the RBD confirmation, and therefore a low fraction of antibodies generally targets this site in infected individuals. S2X259 reacted with 29 of 30 S of SARS-CoV-2 and its new variants. Alterations did not hinder the binding of this antibody in the RBD, which are present in the Alpha, Beta, and Gamma variants. The antibody binds to the epitope is conserved in all circulating SARS-CoV-2 variants. Therefore, the study demonstrated its broad applicability as a broadly neutralizing antibody for SARS-CoV-2 variants.
Importance of vaccines
For some time now, vaccines have become a preventive, routine, and effective measure to reduce the eradication rate or eradication of certain viral diseases
53. Furthermore, vaccines help in the creation of acquired immunity. Viral vector vaccines use a modified version of a virus, which is different from the target virus for which they carry important instructions to our cells. Also, vaccines prevent disease among vaccinated people. In addition, vaccines reduce infections even among people who are not vaccinated through herd immunity. Herd immunity happens if a sufficient proportion of the population is immunized or is immune to the virus 54. Pharmaceutical companies can use the knowledge obtained in the realization of vaccines against SARS-CoV it is necessary to explain the importance of SARS-CoV before mention as “tool” to develop vaccines against SARS-CoV-2: “SARS-CoV have significant similarities in their genomic sequences because they come from the same family and share a common cell receptor (ACE2) 55,56 . By sharing a receptor, it helps in the develop and obtain vaccines against SARS-CoV-2. Since it has been observed that SARS-CoV-2 and SARS-CoV-2 spike mRNA vaccines have been shown to mediate protection against severe disease, which can occur as early as ten days after the first vaccination when neutralizing antibodies are barely detectable 57,58. Therefore, vaccine-induced CD8+ T cells may be the primary protection mediators at this early stage 58.
The first two members of the Betacoronavirus genus, MERS and SARS, left us with experience and specific knowledge when designing vaccines to combat this type of virus. This facilitated the rapid response from scientists to start the development of the SARS-CoV-2 vaccines
(62). As we can observe in Table 1, scientists were based on 5 different leading platforms: RNA, DNA, Non-Replicant Viral Vector, Inactivated Viral Products, and Recombinant to develop the vaccines Protein Subunit. However, not all types of vaccines trigger the same immune responses in the body. Such is the case of LNP encapsulated mRNA and Inactivated vaccines, capable only of triggering the humoral immune response, representing a clear disadvantage if antibodies fail to detect emerging variants 8.
Table 1. Immune response according to each type of vaccine.
Almost all the COVID-19 vaccines approved worldwide were designed to require two doses to reach stronger protection against the disease
66. The first clinical trials revealed that a weak immune response was found after only one dose of the vaccine. Although it offers little protection against the virus, it can potentially lead to partial immunity, which drastically increases the risk that vaccine-resistant variants of SARS-CoV-2 emerge 67. On the other hand, the immune responses are more robust after completing the two-dose vaccine series and have shown sustained protection against new variants 66. One of the last documented examples is the delta variant, which has been reported a 33% protection after a single shot of a two-dose COVID-19 vaccine, while individuals who completed the two-dose vaccine series reported a 90% protection against this variant 66.
Lately, researchers have opted for a new strategy known as heterologous prime and boost. It gives a third dose (booster shot) of a different COVID-19 vaccine after 6 months of the second dose
(UPDATE). Studies have shown that persons over fifty years of age who took the booster shot had a 90% lower mortality rate from COVID-19 than those who did not 69. The reason behind this is that the neutralizing antibody responses were enhanced to such a level that they exceeded the estimated levels necessary to protect us from the virus 70. What remains uncertain is if this third dose will be enough to lengthen the protection gap or if this booster will become a standard measure to control population immunity 70.
An idea that has taken root in the population during the pandemic is that only by forming antibodies (humoral response) against SARS-CoV-2 will we be able to overcome the virus and the social consequences it has brought, but this is not entirely true. It is evident according to the literature data collected that, although at first, the researchers wanted to give a solution to COVID-19 by stimulating the generation of B antibodies through vaccines, with the arrival of new variants in increasingly shorter periods, they had to shift their focus to the cellular immune response
67. This decision is because the B antibodies bind like a lock-and-key to spike proteins on the surface of the virus. However, these spikes are very susceptible to mutations; consequently, the B antibodies could become obsolete 71, unlike what happened with the CD8+ T cells, which can target more than 15 distinct fragments of coronavirus proteins inside the infected cells. In this way, the next generation of COVID-19 vaccines will be dedicated to stimulating the cellular response more effectively provide more robust protection against emerging variants 9.
The SARS-CoV-2 virus population is constantly evolving and will likely remain a part of our lives for many years to come. This virus has revolutionized the world economically and socially. This virus has revolutionized the world economically and socially. In addition, the development of vaccines against COVID-19 is related to immunological memory. To prevent COVID-19 disease and avoid transmission, the vaccine must elicit high titers of neutralizing antibodies. Memory T cells can fight infection if they have a high amount of neutralizing antibodies. Almost all vaccines against COVID-19 attack the spike protein. Older people have a poor T-cell response, so they risk severe COVID-19. Therefore, the elderly should be vaccinated so that the immunization provided by the vaccine occurs long before the infection, which allows the response, expansion, and maturation of the adaptive immune system.
Although the characteristics and functions of the virus have been deciphered during the last two years, there is still to investigate the relationships of SARS-CoV-2 with the severity of the disease, immunological memory, protection, and vaccines. However, studies of antigen-specific CD4+T cells, CD8+T cells, B cells, and antibodies together in larger cohorts of acute patients, representing a range of disease severity, are needed to understand protective adaptive immune responses mechanisms COVID-19 further. In addition, the scientific community must continue to improve surveillance and monitoring strategies to prevent these occurrences from having such damaging effects in the future.
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Received: 2 January 2021 / Accepted: 13 February 2022 / Published: date. 15 February 2022
Citation: Ordoñez R , Solano D , Granizo G. T and B Cells Immune Response and the importance of vaccines Against SARS-CoV-2. Revis Bionatura 2022;7(1). 36. http://dx.doi.org/10.21931/RB/2022.07.01.36