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Shafqat, A.;  Arabi, T.; Sabbah, B.; Abdulkader, H.; Shafqat, S.; Razak, A.; Kashir, J.; Alkattan, K.; Yaqinuddin, A. Understanding COVID-19 Vaccines Today: Are T-cells Key Players?. Encyclopedia. Available online: https://encyclopedia.pub/entry/24166 (accessed on 03 July 2024).
Shafqat A,  Arabi T, Sabbah B, Abdulkader H, Shafqat S, Razak A, et al. Understanding COVID-19 Vaccines Today: Are T-cells Key Players?. Encyclopedia. Available at: https://encyclopedia.pub/entry/24166. Accessed July 03, 2024.
Shafqat, Areez, Tarek Arabi, Belal Sabbah, Humzah Abdulkader, Shameel Shafqat, Adhil Razak, Junaid Kashir, Khaled Alkattan, Ahmed Yaqinuddin. "Understanding COVID-19 Vaccines Today: Are T-cells Key Players?" Encyclopedia, https://encyclopedia.pub/entry/24166 (accessed July 03, 2024).
Shafqat, A.,  Arabi, T., Sabbah, B., Abdulkader, H., Shafqat, S., Razak, A., Kashir, J., Alkattan, K., & Yaqinuddin, A. (2022, June 17). Understanding COVID-19 Vaccines Today: Are T-cells Key Players?. In Encyclopedia. https://encyclopedia.pub/entry/24166
Shafqat, Areez, et al. "Understanding COVID-19 Vaccines Today: Are T-cells Key Players?." Encyclopedia. Web. 17 June, 2022.
Understanding COVID-19 Vaccines Today: Are T-cells Key Players?
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This entry is adapted from the peer-reviewed paper 10.3390/vaccines10060904

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has heavily mutated since the beginning of the coronavirus-2019 (COVID-19) pandemic. In this regard, the so-called variants of concern (VOCs) feature mutations that confer increased transmissibility and evasion of antibody responses. The VOCs have caused significant spikes in COVID-19 cases, raising significant concerns about whether COVID-19 vaccines will protect against current and future variants. In this research, whereas the protection COVID-19 vaccines offer against the acquisition of infection appears compromised, the protection against severe COVID-19 is maintained. From an immunologic standpoint, this is likely underpinned by the maintenance of T-cell responses against VOCs. Therefore, the role of T-cells is essential to understanding the broader adaptive immune response to COVID-19, which has the potential to shape public policies on vaccine protocols and inform future vaccine design.

SARS-CoV-2 variants of concern COVID-19 vaccines T-cells

1. Introduction

Since the beginning of the COVID-19 pandemic, a concerted effort from the scientific community has resulted in highly effective vaccines against the ancestral Wuhan strain. However, concerns subsequently arose about their efficacy against SARS-CoV-2 variants of concern (VOCs): VOCs acquired mutations in epitopes targeted by neutralizing antibodies (nAbs), resulting in the evasion of humoral responses. However, clinical trials evaluating COVID vaccines against the VOCs have yielded excellent protection from the severe disease. While humoral responses are essential in neutralizing viruses extracellularly, cellular responses comprising T-cells recognize and eliminate virus-infected cells. Therefore, although antibodies are crucial in preventing infection, cellular responses ameliorate disease severity, albeit this basic model does not consider other functions of antibodies, such as opsonization and antibody-mediated cellular cytotoxicity.

2. Importance of T-cell Responses in Immunity to Human Coronaviruses (HCoVs)

SARS-CoV-2 is an enveloped single-stranded, positive-sense RNA virus with a large genome of approximately 30 kb, one of the largest among RNA viruses [1]. It belongs to the family of betacoronaviruses that includes the closely related SARS-CoV-1 and MERS-CoV-2 viruses that, although limited in incidence and prevalence globally, also cause severe respiratory infection in humans. On the other hand, the endemic common cold coronaviruses (CCCoVs) are highly prevalent—more than 90% of adults test positive for prior exposure, and seropositivity is near-ubiquitous in childhood—and include two betacoronaviruses, HKU-1 and OC43, and two alphacoronaviruses, 293E and NL63 [2][3].
Studying the humoral and cellular responses to other HCoVs provides an insight into the trajectory of long-term protective immunity against SARS-CoV-2. It also provides key data for characterizing the origin and nature of pre-existing cross-reactive immunity to SARS-CoV-2, which is detected in many COVID-19 and uninfected individuals (discussed below). The high rate of reinfection 12 months after initial CCoV infection suggests that sterilizing humoral immunity is absent, but the mild clinical symptoms of reinfection point to control by cellular responses that limit disease severity [4][5]. Similarly, cellular responses against SARS-CoV-1 remain robust even 17 years after the initial infection despite the waning of antibody responses [6]. Analyses of MERS-CoV have yielded similar results [7]; a recent study demonstrated that even seronegative individuals display cellular responses against MERS-CoV [8].
In summary, cell-mediated immunity to HCoVs, SARS-CoV-1, and MERS-CoV appears to be more robust and sustained than humoral responses. This is also seemingly the case for SARS-CoV-2: nAbs provide 87% protection against infection for 6 months [9], with sterilizing immunity remaining stable for 10 months, but waning afterward [10]. A study modeled the decay of nAb titers to reveal a significant decline over 250 days, which predisposes to reinfection [11]. Breakthrough infections in vaccinated individuals are also an issue. People double vaccinated with the BNT162b2 mRNA vaccine were seemingly protected from reinfection for 6 months, but serum nAbs then waned [12].

3. T-cell Contributions to Resolution of SARS-CoV-2 Infection and Memory

The limited understanding of the duration of infection and vaccine-induced protection against reinfection and breakthrough infection, respectively, has resulted in the implementation of vaccine booster doses at spaced intervals to enhance nAb titers. However, although conventional vaccines primarily aim to trigger humoral responses, the potential role of cellular immunity in the context of protection against COVID-19 disease progression should not be overlooked.
Though humoral responses are certainly important mediators in sterilizing immunity, their contribution to the resolution of SARS-CoV-2 infection is likely dispensable. For instance, patients with X-linked agammaglobulinemia and those receiving targeted anti-CD20 immunotherapy recover from COVID-19 without complications [13][14]. In contrast, robust CD4+ and CD8+ responses—the majority of which are directed against the S protein—are detected in convalescent COVID-19 patients [15][16] and are much more variable in acute severe COVID-19 [17]. Furthermore, CD4+ responses—not the antibody response—appear to be the best predictor of COVID-19 severity [17]. The early induction of T-cell responses is a major determinant of mild COVID-19, whereas delayed recruitment is associated with severe disease [18]. Lastly, asymptomatic individuals or those who recover from mild COVID-19 exhibit robust T-cell responses to SARS-CoV-2, despite remaining seronegative [16]. These findings show that while nAbs contributions pertain to the protection against SARS-CoV-2 infection, optimal T-cell responses ensure a favorable clinical outcome by clearing the infection.
Moreover, Dan et al. assessed immunologic memory 8 months post-SARS-CoV-2 infection [19]: nAb titers declined significantly over the 8 months, with approximately 25% of subjects becoming seronegative during this time. In contrast, cellular responses are more durable: 90% and 70% of individuals exhibited CD4+ and CD8+ responses, respectively, with most CD4+ cells adopting a follicular helper (TFH) phenotype. Furthermore, memory B-cells were detected in 100% of subjects after 8 months and even increased over time, being higher at 6 months than 1-month post-symptom onset [19]. Therefore, while nAb responses decay significantly over time, cellular and memory responses remain comparatively more stable.
Regarding vaccination, immunologic memory 6 months after the second dose of the mRNA-1273 Moderna vaccine features measurable CD4+ and CD8+ memory T-cell responses in 100% of individuals, with a significant portion of CD4+ memory assuming a TFH phenotype [20]. An interesting comparative study evaluated the phenotypes of immunologic memory 6 months after vaccination by the BNT162b2 Pfizer, mRNA-1273 Moderna, Ad26.COV2.S Janssen, and NVX-CoV2373 Novavax vaccines. At 6 months after vaccination, although the mRNA vaccines featured significant reductions in antibody titers, T-cell and B-cell memory responses remained stable with 100% of individuals being positive for CD4+ memory T-cells [21].
Despite these encouraging results, these studies evaluated immunologic memory to SARS-CoV-2 in the blood. However, immunological memory is active at infection sites, draining lymph nodes (LNs), and secondary lymphoid organs. In this research, a recent study characterized tissue-level immunologic memory 6 months after SARS-CoV-2 infection to reveal abundant tissue-resident memory T and B-cells mainly in the lungs and lung-draining LNs with abundant germinal center reactions in the latter [22]. These results demonstrate that SARS-CoV-2 infection elicits a robust and coordinated cellular memory response [22].
Therefore, while cellular responses are essential to combating SARS-CoV-2 infection and ameliorating disease severity, they are also crucial in immunological memory against SARS-CoV-2. These immunologic responses attenuate clinical severity upon reinfection. Interestingly, recent studies have associated SARS-CoV-2 reactive memory T-cells with a reduced risk against reinfection, suggesting a potential role of T-cells in protecting against the acquisition of COVID-19 [23][24]. This could have major public health implications, particularly for vaccine boosting intervals, since only considering serology may underestimate infection- or vaccine-induced protective immunity. However, the lack of protection against reinfection/breakthrough infection with VOCs, despite the presence of robust cellular memory, argues against a role of T-cells in the protection against the acquisition of infection and is more consistent with a predominant role of nAbs in sterilizing immunity.

References

  1. Cao, C.; Cai, Z.; Xiao, X.; Rao, J.; Chen, J.; Hu, N.; Yang, M.; Xing, X.; Wang, Y.; Li, M.; et al. The architecture of the SARS-CoV-2 RNA genome inside virion. Nat. Commun. 2021, 12, 3917.
  2. Gorse, G.J.; Patel, G.B.; Vitale, J.N.; O’Connor, T.Z. Prevalence of antibodies to four human coronaviruses is lower in nasal secretions than in serum. Clin. Vaccine Immunol. 2010, 17, 1875–1880.
  3. Moss, P. The T cell immune response against SARS-CoV-2. Nat. Immunol. 2022, 23, 186–193.
  4. Edridge, A.W.D.; Kaczorowska, J.; Hoste, A.C.R.; Bakker, M.; Klein, M.; Loens, K.; Jebbink, M.F.; Matser, A.; Kinsella, C.M.; Rueda, P.; et al. Seasonal coronavirus protective immunity is short-lasting. Nat. Med. 2020, 26, 1691–1693.
  5. Tan, H.-X.; Lee, W.S.; Wragg, K.M.; Nelson, C.; Esterbauer, R.; Kelly, H.G.; Amarasena, T.; Jones, R.; Starkey, G.; Wang, B.Z.; et al. Adaptive immunity to human coronaviruses is widespread but low in magnitude. Clin. Transl. Immunol. 2021, 10, e1264.
  6. Le Bert, N.; Tan, A.T.; Kunasegaran, K.; Tham, C.Y.L.; Hafezi, M.; Chia, A.; Chng, M.H.Y.; Lin, M.; Tan, N.; Linster, M.; et al. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature 2020, 584, 457–462.
  7. Zhao, J.; Abeer, N.A.; Salim, A.B.; Waleed, A.A.; Ahmad, A.B.; Atef, M.N.; Laila, A.L.; Mohammed, G.A.; Al Gethamy Manal, M.; Ashraf, M.D.; et al. Recovery from the Middle East respiratory syndrome is associated with antibody and T cell responses. Sci. Immunol. 2017, 2, eaan5393.
  8. Mok, C.K.P.; Zhu, A.; Zhao, J.; Lau, E.H.Y.; Wang, J.; Chen, Z.; Zhuang, Z.; Wang, Y.; Alshukairi, A.N.; Baharoon, S.A.; et al. T-cell responses to MERS coronavirus infection in people with occupational exposure to dromedary camels in Nigeria: An observational cohort study. Lancet Infect. Dis. 2021, 21, 385–395.
  9. Hall, V.J.; Foulkes, S.; Charlett, A.; Atti, A.; Monk, E.J.M.; Simmons, R.; Wellington, E.; Cole, M.J.; Saei, A.; Oguti, B.; et al. SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: A large, multicentre, prospective cohort study (SIREN). Lancet 2021, 397, 1459–1469.
  10. Murchu, E.O.; Byrne, P.; Carty, P.G.; De Gascun, C.; Keogan, M.; O’Neill, M.; Harrington, P.; Ryan, M. Quantifying the risk of SARS-CoV-2 reinfection over time. Rev. Med. Virol. 2022, 32, e2260.
  11. Khoury, D.S.; Cromer, D.; Reynaldi, A.; Schlub, T.E.; Wheatley, A.K.; Juno, J.A.; Subbarao, K.; Kent, S.J.; Triccas, J.A.; Davenport, M.P. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat. Med. 2021, 27, 1205–1211.
  12. Hall, V.; Foulkes, S.; Insalata, F.; Kirwan, P.; Saei, A.; Atti, A.; Wellington, E.; Khawam, J.; Munro, K.; Cole, M.; et al. Protection against SARS-CoV-2 after Covid-19 Vaccination and Previous Infection. N. Engl. J. Med. 2022, 386, 1207–1220.
  13. Soresina, A.; Moratto, D.; Chiarini, M.; Paolillo, C.; Baresi, G.; Focà, E.; Bezzi, M.; Baronio, B.; Giacomelli, M.; Badolato, R. Two X-linked agammaglobulinemia patients develop pneumonia as COVID-19 manifestation but recover. Pediatr. Allergy Immunol. 2020, 31, 565–569.
  14. Montero-Escribano, P.; Matías-Guiu, J.; Gómez-Iglesias, P.; Porta-Etessam, J.; Pytel, V.; Matias-Guiu, J.A. Anti-CD20 and COVID-19 in multiple sclerosis and related disorders: A case series of 60 patients from Madrid, Spain. Mult. Scler. Relat. Disord. 2020, 42, 102185.
  15. Grifoni, A.; Weiskopf, D.; Ramirez, S.I.; Mateus, J.; Dan, J.M.; Moderbacher, C.R.; Rawlings, S.A.; Sutherland, A.; Premkumar, L.; Jadi, R.S.; et al. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell 2020, 181, 1489–1501.e15.
  16. Sekine, T.; Perez-Potti, A.; Rivera-Ballesteros, O.; Strålin, K.; Gorin, J.-B.; Olsson, A.; Llewellyn-Lacey, S.; Kamal, H.; Bogdanovic, G.; Muschiol, S.; et al. Robust T Cell Immunity in Convalescent Individuals with Asymptomatic or Mild COVID-19. Cell 2020, 183, 158–168.e14.
  17. Moderbacher, C.R.; Ramirez, S.I.; Dan, J.M.; Grifoni, A.; Hastie, K.M.; Weiskopf, D.; Belanger, S.; Abbott, R.K.; Kim, C.; Choi, J.; et al. Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity. Cell 2020, 183, 996–1012.e19.
  18. Sette, A.; Crotty, S. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell 2021, 184, 861–880.
  19. Dan Jennifer, M.; Mateus, J.; Kato, Y.; Kathryn, M.H.; Esther, D.Y.; Caterina, E.F.; Grifoni, A.; Sydney, I.R.; Haupt, S.; Frazier, A.; et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science 2021, 371, eabf4063.
  20. Mateus, J.; Dan Jennifer, M.; Zhang, Z.; Moderbacher, C.R.; Lammers, M.; Goodwin, B.; Sette, A.; Crotty, S.; Weiskopf, D. Low-dose mRNA-1273 COVID-19 vaccine generates durable memory enhanced by cross-reactive T cells. Science 2021, 374, eabj9853.
  21. Zhang, Z.; Mateus, J.; Coelho, C.H.; Dan, J.M.; Moderbacher, C.R.; Gálvez, R.I.; Cortes, F.H.; Grifoni, A.; Tarke, A.; Chang, J.; et al. Humoral and cellular immune memory to four COVID-19 vaccines. bioRxiv 2022. bioRxiv:2022.2003.2018.484953.
  22. Maya, M.L.P.; Rybkina, K.; Kato, Y.; Kubota, M.; Matsumoto, R.; Nathaniel, I.B.; Zhang, Z.; Kathryn, M.H.; Grifoni, A.; Weiskopf, D.; et al. SARS-CoV-2 infection generates tissue-localized immunological memory in humans. Sci. Immunol. 2021, 6, eabl9105.
  23. Wyllie, D.; Jones, H.E.; Mulchandani, R.; Trickey, A.; Taylor-Phillips, S.; Brooks, T.; Charlett, A.; Ades, A.E.; EDSAB-HOME investigators; Moore, P.; et al. SARS-CoV-2 responsive T cell numbers and anti-Spike IgG levels are both associated with protection from COVID-19: A prospective cohort study in keyworkers. medRxiv 2021. medRxiv:2020.2011.2002.20222778.
  24. Kundu, R.; Narean, J.S.; Wang, L.; Fenn, J.; Pillay, T.; Fernandez, N.D.; Conibear, E.; Koycheva, A.; Davies, M.; Tolosa-Wright, M.; et al. Cross-reactive memory T cells associate with protection against SARS-CoV-2 infection in COVID-19 contacts. Nat. Commun. 2022, 13, 80.
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Subjects: Infectious Diseases
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Areez Shafqat
,
Tarek Arabi
,
Belal Sabbah
,
Humzah Abdulkader
,
Shameel Shafqat
,
Adhil Razak
,
Junaid Kashir
,
Khaled AlKattan
,
Ahmed Yaqinuddin
View Times: 408
Entry Collection: COVID-19
Revisions: 3 times (View History)
Update Date: 21 Jun 2022
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