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1.
iScience ; : 105904, 2022.
Article in English | ScienceDirect | ID: covidwho-2165433

ABSTRACT

SUMMARY Spacing the first two doses of SARS-CoV-2 mRNA vaccines beyond 3-4 weeks raised initial concerns about vaccine efficacy. While studies have since shown that long-interval regimens induce robust antibody responses, their impact on B and T cell immunity is poorly known. Here, we compare in SARS-CoV-2 naïve donors B and T cell responses to two mRNA vaccine doses administered 3-4 versus 16 weeks apart. After boost, the longer interval results in higher magnitude and a more mature phenotype of RBD-specific B cells. While the two geographically distinct cohorts present quantitative and qualitative differences in T cell responses at baseline and after priming, the second dose led to convergent features with overall similar magnitude, phenotype and function of CD4+ and CD8+ T cell responses at post-boost memory time points. Therefore, compared to standard regimens, a 16-week interval has a favorable impact on the B cell compartment but minimally affects T cell immunity.

2.
Clin Transl Immunology ; 11(10): e1423, 2022.
Article in English | MEDLINE | ID: covidwho-2127656

ABSTRACT

Objectives: High-magnitude CD8+ T cell responses are associated with mild COVID-19 disease; however, the underlying characteristics that define CD8+ T cell-mediated protection are not well understood. The antigenic breadth and the immunodominance hierarchies of epitope-specific CD8+ T cells remain largely unexplored and are essential for the development of next-generation broad-protective vaccines. This study identified a broad spectrum of conserved SARS-CoV-2 CD8+ T cell epitopes and defined their respective immunodominance and phenotypic profiles following SARS-CoV-2 infection. Methods: CD8+ T cells from 51 convalescent COVID-19 donors were analysed for their ability to recognise 133 predicted and previously described SARS-CoV-2-derived peptides restricted by 11 common HLA class I allotypes using heterotetramer combinatorial coding, which combined with phenotypic markers allowed in-depth ex vivo profiling of CD8+ T cell responses at quantitative and phenotypic levels. Results: A comprehensive panel of 49 mostly conserved SARS-CoV-2-specific CD8+ T cell epitopes, including five newly identified low-magnitude epitopes, was established. We confirmed the immunodominance of HLA-A*01:01/ORF1ab1637-1646 and B*07:02/N105-113 and identified B*35:01/N325-333 as a third epitope with immunodominant features. The magnitude of subdominant epitope responses, including A*03:01/N361-369 and A*02:01/S269-277, depended on the donors' HLA-I context. All epitopes expressed prevalent memory phenotypes, with the highest memory frequencies in severe COVID-19 donors. Conclusion: SARS-CoV-2 infection induces a predominant CD8+ T memory response directed against a broad spectrum of conserved SARS-CoV-2 epitopes, which likely contributes to long-term protection against severe disease. The observed immunodominance hierarchy emphasises the importance of T cell epitopes derived from nonspike proteins to the overall protective and cross-reactive immune response, which could aid future vaccine strategies.

3.
Int J Mol Sci ; 23(22)2022 Nov 19.
Article in English | MEDLINE | ID: covidwho-2116160

ABSTRACT

Facing the COVID-19 pandemic, anti-SARS-CoV-2 vaccines were developed at unprecedented pace, productively exploiting contemporary fundamental research and prior art. Large-scale use of anti-SARS-CoV-2 vaccines has greatly limited severe morbidity and mortality. Protection has been correlated with high serum titres of neutralizing antibodies capable of blocking the interaction between the viral surface protein spike and the host SARS-CoV-2 receptor, ACE-2. Yet, vaccine-induced protection subsides over time, and breakthrough infections are commonly observed, mostly reflecting the decay of neutralizing antibodies and the emergence of variant viruses with mutant spike proteins. Memory CD8 T cells are a potent weapon against viruses, as they are against tumour cells. Anti-SARS-CoV-2 memory CD8 T cells are induced by either natural infection or vaccination and can be potentially exploited against spike-mutated viruses. We offer here an overview of current research about the induction of anti-SARS-CoV-2 memory CD8 T cells by vaccination, in the context of prior knowledge on vaccines and on fundamental mechanisms of immunological memory. We focus particularly on how vaccination by two doses (prime/boost) or more (boosters) promotes differentiation of memory CD8 T cells, and on how the time-length of inter-dose intervals may influence the magnitude and persistence of CD8 T cell memory.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Pandemics , COVID-19/prevention & control , CD8-Positive T-Lymphocytes , Vaccination , Antibodies, Neutralizing
4.
Front Cell Infect Microbiol ; 12: 988604, 2022.
Article in English | MEDLINE | ID: covidwho-2115342

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has been prominent around the world since it was first discovered, affecting more than 100 million people. Although the symptoms of most infected patients are not serious, there is still a considerable proportion of patients who need hospitalization and even develop fatal symptoms such as cytokine storms, acute respiratory distress syndrome and so on. Cytokine storm is usually described as a collection of clinical manifestations caused by overactivation of the immune system, which plays an important role in tissue injury and multiorgan failure. The immune system of healthy individuals is composed of two interrelated parts, the innate immune system and the adaptive immune system. Innate immunity is the body's first line of defense against viruses; it can quickly perceive viruses through pattern recognition receptors and activate related inflammatory pathways to clear pathogens. The adaptive immune system is activated by specific antigens and is mainly composed of CD4+ T cells, CD8+ T cells and B cells, which play different roles in viral infection. Here, we discuss the immune response after SARS-CoV-2 infection. In-depth study of the recognition of and response of innate immunity and adaptive immunity to SARS-CoV-2 will help to prevent the development of critical cases and aid the exploration of more targeted treatments.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Immunity, Innate , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes
5.
Int J Mol Sci ; 23(21)2022 Nov 07.
Article in English | MEDLINE | ID: covidwho-2110123

ABSTRACT

Since the start of COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more than 6 million people have lost their lives worldwide directly or indirectly. Despite intensified efforts to clarify the immunopathology of COVID-19, the key factors and processes that trigger an inflammatory storm and lead to severe clinical outcomes in patients remain unclear. As an inflammatory storm factor, IL-33 is an alarmin cytokine, which plays an important role in cell damage or infection. Recent studies have shown that serum IL-33 is upregulated in COVID-19 patients and is strongly associated with poor outcomes. Increased IL-33 levels in severe infections may result from an inflammatory storm caused by strong interactions between activated immune cells. However, the effects of IL-33 in COVID-19 and the underlying mechanisms remain to be fully elucidated. In this review, we systematically discuss the biological properties of IL-33 under pathophysiological conditions and its regulation of immune cells, including neutrophils, innate lymphocytes (ILCs), dendritic cells, macrophages, CD4+ T cells, Th17/Treg cells, and CD8+ T cells, in COVID-19 phagocytosis. The aim of this review is to explore the potential value of the IL-33/immune cell pathway as a new target for early diagnosis, monitoring of severe cases, and clinical treatment of COVID-19.


Subject(s)
COVID-19 , Humans , Pandemics , SARS-CoV-2 , CD8-Positive T-Lymphocytes , Interleukin-33 , Cytokines/metabolism
6.
Front Bioinform ; 1: 622992, 2021.
Article in English | MEDLINE | ID: covidwho-2089804

ABSTRACT

Predictive models for vaccine design have become a powerful and necessary resource for the expeditiousness design of vaccines to combat the ongoing SARS-CoV-2 global pandemic. Here we use the power of these predicted models to assess the sequence diversity of circulating SARS-CoV-2 proteomes in the context of an individual's CD8 T-cell immune repertoire to identify potential. defined regions of immunogenicity. Using this approach of expedited and rational CD8 T-cell vaccine design, it may be possible to develop a therapeutic vaccine candidate with the potential for both global and local coverage.

7.
Front Immunol ; 13: 942192, 2022.
Article in English | MEDLINE | ID: covidwho-2080137

ABSTRACT

The cellular immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in response to full mRNA COVID-19 vaccination could be variable among healthy individuals. Studies based only in specific antibody levels could show an erroneous immune protection at long times. For that, we analyze the antibody levels specific to the S protein and the presence of SARS-CoV-2-specific T cells by ELISpot and AIM assays in intensive care unit (ICU) workers with no antecedents of COVID-19 and vaccinated with two doses of mRNA COVID-19 vaccines. All individuals were seronegative for the SARS-CoV-2 protein S before vaccination (Pre-v), but 34.1% (14/41) of them showed pre-existing T lymphocytes specific for some viral proteins (S, M and N). One month after receiving two doses of COVID-19 mRNA vaccine (Post-v1), all cases showed seroconversion with high levels of total and neutralizing antibodies to the spike protein, but six of them (14.6%) had no T cells reactive to the S protein. Specifically, they lack of specific CD8+ T cells, but maintain the contribution of CD4+ T cells. Analysis of the immune response against SARS-CoV-2 at 10 months after full vaccination (Post-v10), exhibited a significant reduction in the antibody levels (p<0.0001) and protein S-reactive T cells (p=0.0073) in all analyzed individuals, although none of the individuals become seronegative and 77% of them maintained a competent immune response. Thus, we can suggest that the immune response to SARS-CoV-2 elicited by the mRNA vaccines was highly variable among ICU workers. A non-negligible proportion of individuals did not develop a specific T cell response mediated by CD8+ T cells after vaccination, that may condition the susceptibility to further viral infections with SARS-CoV-2. By contrast, around 77% of individuals developed strong humoral and cellular immune responses to SARS-CoV-2 that persisted even after 10 months. Analysis of the cellular immune response is highly recommended for providing exact information about immune protection against SARS-CoV-2.


Subject(s)
COVID-19 , Viral Vaccines , Humans , Antibodies, Neutralizing , CD8-Positive T-Lymphocytes , COVID-19/prevention & control , COVID-19 Vaccines , Intensive Care Units , RNA, Messenger/genetics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vaccination , T-Lymphocytes
8.
Immunity ; 55(7): 1299-1315.e4, 2022 07 12.
Article in English | MEDLINE | ID: covidwho-2076210

ABSTRACT

As the establishment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory in children remains largely unexplored, we recruited convalescent COVID-19 children and adults to define their circulating memory SARS-CoV-2-specific CD4+ and CD8+ T cells prior to vaccination. We analyzed epitope-specific T cells directly ex vivo using seven HLA class I and class II tetramers presenting SARS-CoV-2 epitopes, together with Spike-specific B cells. Unvaccinated children who seroconverted had comparable Spike-specific but lower ORF1a- and N-specific memory T cell responses compared with adults. This agreed with our TCR sequencing data showing reduced clonal expansion in children. A strong stem cell memory phenotype and common T cell receptor motifs were detected within tetramer-specific T cells in seroconverted children. Conversely, children who did not seroconvert had tetramer-specific T cells of predominantly naive phenotypes and diverse TCRαß repertoires. Our study demonstrates the generation of SARS-CoV-2-specific T cell memory with common TCRαß motifs in unvaccinated seroconverted children after their first virus encounter.


Subject(s)
COVID-19 , SARS-CoV-2 , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Epitopes, T-Lymphocyte , Humans , Immunologic Memory , Receptors, Antigen, T-Cell , Receptors, Antigen, T-Cell, alpha-beta/genetics , Spike Glycoprotein, Coronavirus
9.
Medical Journal of Malaysia ; 77(Supplement 1):31-34, 2022.
Article in English | EMBASE | ID: covidwho-2057521

ABSTRACT

Introduction: Although CD4 and CD8 T-cells are the main subset of T-lymphocytes, their roles in COVID-19 infection and severity remain unclear. This study aimed to determine the role of increased CD4/CD8 T-cells ratio as a risk factor for cases of 28-days in-hospital mortality in COVID-19 patients. Material(s) and Method(s): This study employed a prospective cohort design. Inclusion criteria were confirmed COVID-19 cases with a positive polymerase chain reaction report. CD4 and CD8 T-cells absolute counts were measured by flow cytometry. The CD4/CD8 ratio was calculated by dividing the absolute count of CD4 by that of CD8 T-cells. Result(s): A total of 85 subjects were followed for 28 days. The mean age of the subjects was 52.64 years, and majority of them were females (51.8%). Twenty-eight (32.9%) subjects died within 28 days of follow-up. Receiver operating characteristics analysis obtained an area under curve of 0.68 with the cut-off value 1.26 with p = 0.005. Kaplan-Meier's analysis obtained Hazard Ratio 2.91 (95%CI 1.377-6.161;p = 0.0052). Conclusion(s): Subjects with an increase in CD4/CD8 T-cells ratio >1.26 had a 2.91-times risk of 28 days in-hospital mortality. Copyright © 2022, Malaysian Medical Association. All rights reserved.

10.
Viruses ; 14(9)2022 08 28.
Article in English | MEDLINE | ID: covidwho-2006222

ABSTRACT

BACKGROUND: The adaptive antiviral immune response requires interaction between CD8+ T cells, dendritic cells, and Th1 cells for controlling SARS-CoV-2 infection, but the data regarding the role of CD8+ T cells in the acute phase of COVID-19 and post-COVID-19 syndrome are still limited. METHODS: . Peripheral blood samples collected from patients with acute COVID-19 (n = 71), convalescent subjects bearing serum SARS-CoV-2 N-protein-specific IgG antibodies (n = 51), and healthy volunteers with no detectable antibodies to any SARS-CoV-2 proteins (HC, n = 46) were analyzed using 10-color flow cytometry. RESULTS: Patients with acute COVID-19 vs. HC and COVID-19 convalescents showed decreased absolute numbers of CD8+ T cells, whereas the frequency of CM and TEMRA CD8+ T cells in acute COVID-19 vs. HC was elevated. COVID-19 convalescents vs. HC had increased naïve and CM cells, whereas TEMRA cells were decreased compared to HC. Cell-surface CD57 was highly expressed by the majority of CD8+ T cells subsets during acute COVID-19, but convalescents had increased CD57 on 'naïve', CM, EM4, and pE1 2-3 months post-symptom onset. CXCR5 expression was altered in acute and convalescent COVID-19 subjects, whereas the frequencies of CXCR3+ and CCR4+ cells were decreased in both patient groups vs. HC. COVID-19 convalescents had increased CCR6-expressing CD8+ T cells. Moreover, CXCR3+CCR6- Tc1 cells were decreased in patients with acute COVID-19 and COVID-19 convalescents, whereas Tc2 and Tc17 levels were increased compared to HC. Finally, IL-27 negatively correlated with the CCR6+ cells in acute COVID-19 patients. CONCLUSIONS: We described an abnormal CD8+ T cell profile in COVID-19 convalescents, which resulted in lower frequencies of effector subsets (TEMRA and Tc1), higher senescent state (upregulated CD57 on 'naïve' and memory cells), and higher frequencies of CD8+ T cell subsets expressing lung tissue and mucosal tissue homing molecules (Tc2, Tc17, and Tc17.1). Thus, our data indicate that COVID-19 can impact the long-term CD8+ T cell immune response.


Subject(s)
COVID-19 , Interleukin-27 , Antiviral Agents/metabolism , CD8-Positive T-Lymphocytes , COVID-19/complications , Humans , Immunoglobulin G , SARS-CoV-2
11.
Transfusionsmedizin ; 12(03):148-155, 2022.
Article in English | Web of Science | ID: covidwho-2004808

ABSTRACT

An entire spectrum of disruptions, but also some lightning fast innovations, were brought on by the SARS-CoV-2 pandemic. This focused review looks at the pandemic from the vantage point of cellular therapy;specifically four aspects are considered: How do risks of cell therapy patients with SARS-CoV-2 infection and COVID differ from the general population? Do recipients of cellular therapies, here specifically recipients of autologous and allogeneic stem cell transplants and CAR-T-cells, meaningfully respond to SARS-CoV-2 vaccines? What effects does the pandemic have on donor availability and cell therapy supply chains and hence, on the accessibility of cellular therapies? What cell therapies, if any, are therapeutically beneficial in severe COVID? Briefly, the excessive risk of an unfavorable, frequently lethal course of cell therapy patients with SARS-CoV-2 infection was confirmed. The vaccine frequently, albeit not with the same regularity as in healthy vaccinees, induces presumably clinically meaningful humoral and/or cellular immunity. Creative solutions have quantitatively maintained access to cellular therapeutics. SARS-CoV-2-specific T-cell products for adoptive immune transfer were developed, although an opportunity for their clinical evaluation did not arise. Clinical trials with mesenchymal stromal cells for severe COVID are being pursued world-wide;the question of efficacy currently remains unanswered, but initial data fuel considerable optimism of the scene. Some of the insights and innovations from the SARS-CoV-2-pandemic can possibly be generalized and may thus prevail.

12.
Vaccine X ; 12: 100202, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1966901

ABSTRACT

Encouraging protection results from current mRNA-based SARS-CoV-2 vaccine platforms are primarily due to the induction of SARS- CoV-2- specific B cell antibody and CD4 + T cell. Even though, current mRNA vaccine platforms are adept in inducing SARS-CoV2-specific CD8 + T cell, much less is known about CD8 T cells contribution to the overall vaccine protection. Our allogeneic cellular vaccine, based on a secreted form of the heat-shock protein gp96-Ig, achieves high frequencies of polyclonal CD8 + T cell responses to tumor and infectious antigens through antigen cross-priming in vivo. We and others have shown that gp96-Ig, in addition to antigen-specific CD8 + T cell anti-tumor and anti-pathogen immunity, primes antibody responses as well. Here, we generated a cell-based vaccine that expresses SARS-Cov-2 Spike (S) protein and simultaneously secretes gp96-Ig and OX40L-Fc fusion proteins. We show that co-secretion of gp96-Ig-S peptide complexes and the OX40L-Fc costimulatory fusion protein in allogeneic cell lines results in enhanced activation of S protein-specific IgG antibody responses. These findings were further strengthened by the observation that this vaccine platform induces T follicular helper cells (TFH) and protein-S -specific CD8 + T cells. Thus, a cell-based gp96-Ig vaccine/OX40-L fusion protein regimen provides encouraging translational data that this vaccine platform induces pathogen-specific CD8+, CD4 + T and B cell responses, and may cohesively work as a booster for FDA-approved vaccines. Our vaccine platform can be rapidly engineered and customized based on other current and future pathogen sequences.

13.
Cytokine ; 158: 155980, 2022 10.
Article in English | MEDLINE | ID: covidwho-1966481

ABSTRACT

SARS-CoV-2 easily infects human monocytes, macrophages and possibly dendritic cells (DCs), causing dysfunctions of these important antigen presenting cells (APCs). Observed DC dysfunctions facilitate improper antigen presentation, which obviously results T cell anergy, exhaustion and apoptosis, thus, may be contributing significantly in SARS-CoV-2 infection associated lymphopenia. Neem Leaf Glycoprotein or NLGP has enormous role in altered DC functions, thereby, offering optimum T cell mediated cytotoxicity, as experienced from cancer system. Such NLGP guided correction of altered DCs might also be effective to generate proper SARS-CoV-2-specific effector and central memory T cells.


Subject(s)
Azadirachta , COVID-19 , Neoplasms , CD8-Positive T-Lymphocytes , Dendritic Cells , Humans , Plant Leaves , Plant Proteins , SARS-CoV-2
14.
Front Aging ; 2: 714239, 2021.
Article in English | MEDLINE | ID: covidwho-1933921

ABSTRACT

As people around the world continue to live longer, maintaining a good quality of life is of increasing importance. The COVID-19 pandemic revealed that the elderly are disproportionally vulnerable to infectious diseases and Immunosenescence plays a critical role in that. An ageing immune system influences the conventional activity of T cells which are at the forefront of eliminating harmful foreign antigens. With ageing, unconventional end-stage T cells, that exhibit a senescent phenotype, amass. These senescent T cells deviate from T cell receptor (TCR) signaling toward natural killer (NK) activity. The transition toward innate immune cell function from these adaptor T cells impacts antigen specificity, contributing to increased susceptibility of infection in the elderly. The mechanism by which senescent T cells arise remains largely unclear however in this review we investigate the part that bystander activation plays in driving the change in function of T cells with age. Cytokine-induced bystander activation may offer a plausible explanation for the induction of NK-like activity and senescence in T cells. Further understanding of these specific NK-like senescent T cells allows us to identify the benefits and detriments of these cells in health and disease which can be utilized or regulated, respectively. This review discusses the dynamic of senescent T cells in adopting NK-like T cells and the implications that has in an infectious disease context, predominately in the elderly.

15.
Front Immunol ; 13: 891524, 2022.
Article in English | MEDLINE | ID: covidwho-1933678

ABSTRACT

Since the start of the COVID-19 pandemic, mutations have led to the emergence of new SARS-CoV-2 variants, and some of these have become prominent or dominant variants of concern. This natural course of development can have an impact on how protective the previously naturally or vaccine induced immunity is. Therefore, it is crucial to understand whether and how variant specific mutations influence host immunity. To address this, we have investigated how mutations in the recent SARS-CoV-2 variants of interest and concern influence epitope sequence similarity, predicted binding affinity to HLA, and immunogenicity of previously reported SARS-CoV-2 CD8 T cell epitopes. Our data suggests that the vast majority of SARS-CoV-2 CD8 T cell recognized epitopes are not altered by variant specific mutations. Interestingly, for the CD8 T cell epitopes that are altered due to variant specific mutations, our analyses show there is a high degree of sequence similarity between mutated and reference SARS-CoV-2 CD8 T cell epitopes. However, mutated epitopes, primarily derived from the spike protein, in SARS-CoV-2 variants Delta, AY.4.2 and Mu display reduced predicted binding affinity to their restriction element. These findings indicate that the recent SARS-CoV-2 variants of interest and concern have limited ability to escape memory CD8 T cell responses raised by vaccination or prior infection with SARS-CoV-2 early in the pandemic. The overall low impact of the mutations on CD8 T cell cross-recognition is in accordance with the notion that mutations in SARS-CoV-2 are primarily the result of receptor binding affinity and antibody selection pressures exerted on the spike protein, unrelated to T cell immunity.


Subject(s)
COVID-19 , SARS-CoV-2 , CD8-Positive T-Lymphocytes , Epitopes, T-Lymphocyte/genetics , Humans , Pandemics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
16.
Aging Cell ; 21(8): e13668, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1932252

ABSTRACT

A variety of intrinsic and extrinsic factors contribute to the altered efficiency of CTLs in elderly organisms. In particular, the efficacy of antiviral CD8+ T cells responses in the elderly has come back into focus since the COVID-19 pandemic outbreak. However, the exact molecular mechanisms leading to alterations in T cell function and the origin of the observed impairments have not been fully explored. Therefore, we investigated whether intrinsic changes affect the cytotoxic ability of CD8+ T cells in aging. We focused on the different subpopulations and time-resolved quantification of cytotoxicity during tumor cell elimination. We report a surprising result: Killing kinetics of CD8+ T cells from elderly mice are much faster than those of CD8+ T cells from adult mice. This is true not only in the total CD8+ T cell population but also for their effector (TEM ) and central memory (TCM ) T cell subpopulations. TIRF experiments reveal that CD8+ T cells from elderly mice possess comparable numbers of fusion events per cell, but significantly increased numbers of cells with granule fusion. Analysis of the cytotoxic granule (CG) content shows significantly increased perforin and granzyme levels and turns CD8+ T cells of elderly mice into very efficient killers. This highlights the importance of distinguishing between cell-intrinsic alterations and microenvironmental changes in elderly individuals. Our results also stress the importance of analyzing the dynamics of CTL cytotoxicity against cancer cells because, with a simple endpoint lysis analysis, cytotoxic differences could have easily been overlooked.


Subject(s)
COVID-19 , Neoplasms , Animals , CD8-Positive T-Lymphocytes , Cytotoxicity, Immunologic , Granzymes , Humans , Membrane Glycoproteins , Mice , Pandemics , Perforin , Pore Forming Cytotoxic Proteins
17.
Front Immunol ; 13: 918611, 2022.
Article in English | MEDLINE | ID: covidwho-1924110

ABSTRACT

The primary goal of vaccines that protect against respiratory viruses appears to be the induction of neutralizing antibodies for a long period. Although this goal need not be changed, recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have drawn strong attention to another arm of acquired immunity, CD8+ T cells, which are also called killer T cells. Recent evidence accumulated during the coronavirus disease 2019 (COVID-19) pandemic has revealed that even variants of SARS-CoV-2 that escaped from neutralizing-antibodies that were induced by either infection or vaccination could not escape from CD8+ T cell-mediated immunity. In addition, although traditional vaccine platforms, such as inactivated virus and subunit vaccines, are less efficient in inducing CD8+ T cells, newly introduced platforms for SARS-CoV-2, namely, mRNA and adenoviral vector vaccines, can induce strong CD8+ T cell-mediated immunity in addition to inducing neutralizing antibodies. However, CD8+ T cells function locally and need to be at the site of infection to control it. To fully utilize the protective performance of CD8+ T cells, it would be insufficient to induce only memory cells circulating in blood, using injectable vaccines; mucosal immunization could be required to set up CD8+ T cells for the optimal protection. CD8+ T cells might also contribute to the pathology of the infection, change their function with age and respond differently to booster vaccines in comparison with antibodies. Herein, we overview cutting-edge ideas on CD8+ T cell-mediated immunity that can enable the rational design of vaccines for respiratory viruses.


Subject(s)
COVID-19 , Viral Vaccines , Antibodies, Neutralizing , CD8-Positive T-Lymphocytes , COVID-19/prevention & control , Humans , SARS-CoV-2
18.
Front Immunol ; 13: 835830, 2022.
Article in English | MEDLINE | ID: covidwho-1902993

ABSTRACT

CD8+ T cells have key protective roles in many viral infections. While an overall Th1-biased cellular immune response against SARS-CoV-2 has been demonstrated, most reports of anti-SARS-CoV-2 cellular immunity have evaluated bulk T cells using pools of predicted epitopes, without clear delineation of the CD8+ subset and its magnitude and targeting. In recently infected persons (mean 29.8 days after COVID-19 symptom onset), we confirm a Th1 bias (and a novel IL-4-producing population of unclear significance) by flow cytometry, which does not correlate to antibody responses against the receptor binding domain. Evaluating isolated CD8+ T cells in more detail by IFN-γ ELISpot assays, responses against spike, nucleocapsid, matrix, and envelope proteins average 396, 901, 296, and 0 spot-forming cells (SFC) per million, targeting 1.4, 1.5, 0.59, and 0.0 epitope regions respectively. Nucleocapsid targeting is dominant in terms of magnitude, breadth, and density of targeting. The magnitude of responses drops rapidly post-infection; nucleocapsid targeting is most sustained, and vaccination selectively boosts spike targeting. In SARS-CoV-2-naïve persons, evaluation of the anti-spike CD8+ T cell response soon after vaccination (mean 11.3 days) yields anti-spike CD8+ T cell responses averaging 2,463 SFC/million against 4.2 epitope regions, and targeting mirrors that seen in infected persons. These findings provide greater clarity on CD8+ T cell anti-SARS-CoV-2 targeting, breadth, and persistence, suggesting that nucleocapsid inclusion in vaccines could broaden coverage and durability.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Nucleocapsid/immunology , SARS-CoV-2/physiology , Antibodies, Viral/metabolism , Broadly Neutralizing Antibodies/metabolism , Cells, Cultured , Enzyme-Linked Immunospot Assay , Humans , Molecular Targeted Therapy , Peptides/genetics , Peptides/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , United States , Vaccination
19.
Hum Vaccin Immunother ; 18(5): 2048622, 2022 11 30.
Article in English | MEDLINE | ID: covidwho-1900981

ABSTRACT

We report a Human Immune System (HIS)-humanized mouse model ("DRAGA": HLA-A2.HLA-DR4.Rag1KO.IL-2 RγcKO.NOD) for COVID-19 research. DRAGA mice express transgenically HLA-class I and class-II molecules in the mouse thymus to promote human T cell development and human B cell Ig-class switching. When infused with human hematopoietic stem cells from cord blood reconstitute a functional human immune system, as well as human epi/endothelial cells in lung and upper respiratory airways expressing the human ACE2 receptor for SARS-CoV-2. The DRAGA mice were able to sustain SARS-CoV-2 infection for at least 25 days. Infected mice showed replicating virus in the lungs, deteriorating clinical condition, and human-like lung immunopathology including human lymphocyte infiltrates, microthrombi and pulmonary sequelae. Among the intra-alveolar and peri-bronchiolar lymphocyte infiltrates, human lung-resident (CD103+) CD8+ and CD4+ T cells were sequestered in epithelial (CD326+) lung niches and secreted granzyme B and perforin, suggesting anti-viral cytotoxic activity. Infected mice also mounted human IgG antibody responses to SARS-CoV-2 viral proteins. Hence, HIS-DRAGA mice showed unique advantages as a surrogate in vivo human model for studying SARS-CoV-2 immunopathological mechanisms and testing the safety and efficacy of candidate vaccines and therapeutics.


Subject(s)
COVID-19 , HLA-DR4 Antigen , Animals , B-Lymphocytes , CD8-Positive T-Lymphocytes , Disease Models, Animal , Endothelial Cells , HLA-A2 Antigen/genetics , Humans , Mice , Mice, Inbred NOD , Mice, Transgenic , SARS-CoV-2
20.
Clin Immunol ; 237: 108991, 2022 04.
Article in English | MEDLINE | ID: covidwho-1866980

ABSTRACT

Many studies have been performed in severe COVID-19 on immune cells in the circulation and on cells obtained by bronchoalveolar lavage. Most studies have tended to provide relative information rather than a quantitative view, and it is a combination of approaches by various groups that is helping the field build a picture of the mechanisms that drive severe lung disease. Approaches employed to date have not revealed information on lung parenchymal T cell subsets in severe COVID-19. Therefore, we sought to examine early and late T cell subset alterations in the lungs and draining lymph nodes in severe COVID-19 using a rapid autopsy protocol and quantitative imaging approaches. Here, we have established that cytotoxic CD4+ T cells (CD4 + CTLs) increase in the lungs, draining lymph nodes and blood as COVID-19 progresses. CD4 + CTLs are prominently expanded in the lung parenchyma in severe COVID-19. In contrast CD8+ T cells are not prominent, exhibit increased PD-1 expression, and no obvious increase is seen in the number of Granzyme B+ CD8+ T cells in the lung parenchyma in severe COVID-19. Based on quantitative evidence for re-activation in the lung milieu, CD4 + CTLs may be as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19.


Subject(s)
CD4-Positive T-Lymphocytes , COVID-19 , CD8-Positive T-Lymphocytes , Humans , Lung , T-Lymphocyte Subsets , T-Lymphocytes, Cytotoxic
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