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1.
Front Cell Infect Microbiol ; 11: 624483, 2021.
Article in English | MEDLINE | ID: covidwho-1574395

ABSTRACT

The immune response type organized against viral infection is determinant in the prognosis of some infections. This work has aimed to study Th polarization in acute COVID-19 and its possible association with the outcome through an observational prospective study. Fifty-eight COVID-19 patients were recruited in the Medicine Department of the hospital "12 de Octubre," 55 patients remaining after losses to follow-up. Four groups were established according to maximum degree of disease progression. T-helper cell percentages and phenotypes, analyzed by flow cytometer, and serum cytokines levels, analyzed by Luminex, were evaluated when the microbiological diagnosis (acute phase) of the disease was obtained. Our study found a significant reduction of %Th1 and %Th17 cells with higher activated %Th2 cells in the COVID-19 patients compared with reference population. A higher percent of senescent Th2 cells was found in the patients who died than in those who survived. Senescent Th2 cell percentage was an independent risk factor for death (OR: 13.88) accompanied by the numbers of total lymphocytes (OR: 0.15) with an AUC of 0.879. COVID-19 patients showed a profile of pro-inflammatory serum cytokines compared to controls, with higher levels of IL-2, IL-6, IL-15, and IP-10. IL-10 and IL-13 were also elevated in patients compared to controls. Patients who did not survive presented significantly higher levels of IL-15 than those who recovered. No significant differences were observed according to disease progression groups. The study has shown that increased levels of IL-15 and a high Th2 response are associated with a fatal outcome of the disease.


Subject(s)
COVID-19/immunology , SARS-CoV-2/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Helper-Inducer/immunology , Adult , Aged , COVID-19/blood , COVID-19/pathology , Cytokines/blood , Disease Progression , Female , Humans , Immunity , Male , Middle Aged , Multivariate Analysis , Prospective Studies , Th1 Cells/immunology , Th17 Cells/immunology , Th2 Cells/immunology
2.
Biomed Pharmacother ; 144: 112282, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1517062

ABSTRACT

Six months after the publication of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) sequence, a record number of vaccine candidates were listed, and quite a number of them have since been approved for emergency use against the novel coronavirus disease 2019 (COVID-19). This unprecedented pharmaceutical feat did not only show commitment, creativity and collaboration of the scientific community, but also provided a swift solution that prevented global healthcare system breakdown. Notwithstanding, the available data show that most of the approved COVID-19 vaccines protect only a proportion of recipients against severe disease but do not prevent clinical manifestation of COVID-19. There is therefore the need to probe further to establish whether these vaccines can induce sterilizing immunity, otherwise, COVID-19 vaccination would have to become a regular phenomenon. The emergence of SARS-CoV-2 variants could further affect the capability of the available COVID-19 vaccines to prevent infection and protect recipients from a severe form of the disease. These notwithstanding, data about which vaccine(s), if any, can confer sterilizing immunity are unavailable. Here, we discuss the immune responses to viral infection with emphasis on COVID-19, and the specific adaptive immune response to SARS-CoV-2 and how it can be harnessed to develop COVID-19 vaccines capable of conferring sterilizing immunity. We further propose factors that could be considered in the development of COVID-19 vaccines capable of stimulating sterilizing immunity. Also, an old, but effective vaccine development technology that can be applied in the development of COVID-19 vaccines with sterilizing immunity potential is reviewed.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , T-Lymphocytes, Helper-Inducer/immunology , COVID-19 Vaccines/administration & dosage , Humans , SARS-CoV-2/drug effects , T-Lymphocytes, Helper-Inducer/drug effects , Viral Vaccines/administration & dosage , Viral Vaccines/immunology
3.
J Virol ; 95(15): e0053021, 2021 07 12.
Article in English | MEDLINE | ID: covidwho-1486507

ABSTRACT

Elicitation of lung tissue-resident memory CD8 T cells (TRMs) is a goal of T cell-based vaccines against respiratory viral pathogens, such as influenza A virus (IAV). C-C chemokine receptor type 2 (CCR2)-dependent monocyte trafficking plays an essential role in the establishment of CD8 TRMs in lungs of IAV-infected mice. Here, we used a combination adjuvant-based subunit vaccine strategy that evokes multifaceted (TC1/TC17/TH1/TH17) IAV nucleoprotein-specific lung TRMs to determine whether CCR2 and monocyte infiltration are essential for vaccine-induced TRM development and protective immunity to IAV in lungs. Following intranasal vaccination, neutrophils, monocytes, conventional dendritic cells (DCs), and monocyte-derived dendritic cells internalized and processed vaccine antigen in lungs. We found that basic leucine zipper ATF-like transcription factor 3 (BATF3)-dependent DCs were essential for eliciting T cell responses, but CCR2 deficiency enhanced the differentiation of CD127hi, KLRG-1lo, OX40+ve CD62L+ve, and mucosally imprinted CD69+ve CD103+ve effector and memory CD8 T cells in lungs and airways of vaccinated mice. Mechanistically, increased development of lung TRMs induced by CCR2 deficiency was linked to dampened expression of T-bet but not altered TCF-1 levels or T cell receptor signaling in CD8 T cells. T1/T17 functional programming, parenchymal localization of CD8/CD4 effector and memory T cells, recall T cell responses, and protective immunity to a lethal IAV infection were unaffected in CCR2-deficient mice. Taken together, we identified a negative regulatory role for CCR2 and monocyte trafficking in mucosal imprinting and differentiation of vaccine-induced TRMs. Mechanistic insights from this study may aid the development of T-cell-based vaccines against respiratory viral pathogens, including IAV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). IMPORTANCE While antibody-based immunity to influenza A virus (IAV) is type and subtype specific, lung- and airway-resident memory T cells that recognize conserved epitopes in the internal viral proteins are known to provide heterosubtypic immunity. Hence, broadly protective IAV vaccines need to elicit robust T cell memory in the respiratory tract. We have developed a combination adjuvant-based IAV nucleoprotein vaccine that elicits strong CD4 and CD8 T cell memory in lungs and protects against H1N1 and H5N1 strains of IAV. In this study, we examined the mechanisms that control vaccine-induced protective memory T cells in the respiratory tract. We found that trafficking of monocytes into lungs might limit the development of antiviral lung-resident memory T cells following intranasal vaccination. These findings suggest that strategies that limit monocyte infiltration can potentiate vaccine-induced frontline T-cell immunity to respiratory viruses, such as IAV and SARS-CoV-2.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunity, Mucosal , Immunologic Memory , Influenza A virus/immunology , Influenza Vaccines/immunology , Orthomyxoviridae Infections/immunology , Receptors, CCR2/immunology , T-Lymphocytes, Helper-Inducer/immunology , Animals , Influenza A virus/genetics , Influenza Vaccines/genetics , Influenza Vaccines/pharmacology , Lung/immunology , Mice , Mice, Knockout , Orthomyxoviridae Infections/genetics , Orthomyxoviridae Infections/prevention & control , Receptors, CCR2/genetics
4.
Viruses ; 13(10)2021 10 13.
Article in English | MEDLINE | ID: covidwho-1470992

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the coronavirus disease 2019 (COVID-19) pandemic, severely affecting public health and the global economy. Adaptive immunity plays a crucial role in fighting against SARS-CoV-2 infection and directly influences the clinical outcomes of patients. Clinical studies have indicated that patients with severe COVID-19 exhibit delayed and weak adaptive immune responses; however, the mechanism by which SARS-CoV-2 impedes adaptive immunity remains unclear. Here, by using an in vitro cell line, we report that the SARS-CoV-2 spike protein significantly inhibits DNA damage repair, which is required for effective V(D)J recombination in adaptive immunity. Mechanistically, we found that the spike protein localizes in the nucleus and inhibits DNA damage repair by impeding key DNA repair protein BRCA1 and 53BP1 recruitment to the damage site. Our findings reveal a potential molecular mechanism by which the spike protein might impede adaptive immunity and underscore the potential side effects of full-length spike-based vaccines.


Subject(s)
Adaptive Immunity/immunology , COVID-19/pathology , DNA Repair/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , V(D)J Recombination/genetics , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , BRCA1 Protein/antagonists & inhibitors , CD4 Lymphocyte Count , CD8-Positive T-Lymphocytes/immunology , COVID-19 Vaccines/immunology , Cell Line , DNA Damage/genetics , HEK293 Cells , Humans , Immunity, Humoral/immunology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes, Helper-Inducer/immunology , Tumor Suppressor p53-Binding Protein 1/antagonists & inhibitors
5.
J Exp Med ; 218(12)2021 12 06.
Article in English | MEDLINE | ID: covidwho-1467277

ABSTRACT

Adaptive immunity is a fundamental component in controlling COVID-19. In this process, follicular helper T (Tfh) cells are a subset of CD4+ T cells that mediate the production of protective antibodies; however, the SARS-CoV-2 epitopes activating Tfh cells are not well characterized. Here, we identified and crystallized TCRs of public circulating Tfh (cTfh) clonotypes that are expanded in patients who have recovered from mild symptoms. These public clonotypes recognized the SARS-CoV-2 spike (S) epitopes conserved across emerging variants. The epitope of the most prevalent cTfh clonotype, S864-882, was presented by multiple HLAs and activated T cells in most healthy donors, suggesting that this S region is a universal T cell epitope useful for booster antigen. SARS-CoV-2-specific public cTfh clonotypes also cross-reacted with specific commensal bacteria. In this study, we identified conserved SARS-CoV-2 S epitopes that activate public cTfh clonotypes associated with mild symptoms.


Subject(s)
COVID-19/immunology , Epitopes, T-Lymphocyte/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes, Helper-Inducer/immunology , Adult , Antibodies, Viral/immunology , Female , HLA Antigens/immunology , Humans , Lymphocyte Activation , Male
6.
Front Immunol ; 12: 729837, 2021.
Article in English | MEDLINE | ID: covidwho-1450810

ABSTRACT

We have developed a dual-antigen COVID-19 vaccine incorporating genes for a modified SARS-CoV-2 spike protein (S-Fusion) and the viral nucleocapsid (N) protein with an Enhanced T-cell Stimulation Domain (N-ETSD) to increase the potential for MHC class II responses. The vaccine antigens are delivered by a human adenovirus serotype 5 platform, hAd5 [E1-, E2b-, E3-], previously demonstrated to be effective in the presence of Ad immunity. Vaccination of rhesus macaques with the hAd5 S-Fusion + N-ETSD vaccine by subcutaneous prime injection followed by two oral boosts elicited neutralizing anti-S IgG and T helper cell 1-biased T-cell responses to both S and N that protected the upper and lower respiratory tracts from high titer (1 x 106 TCID50) SARS-CoV-2 challenge. Notably, viral replication was inhibited within 24 hours of challenge in both lung and nasal passages, becoming undetectable within 7 days post-challenge.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Coronavirus Nucleocapsid Proteins/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adenoviruses, Human/genetics , Adenoviruses, Human/immunology , Adenoviruses, Human/metabolism , Administration, Oral , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 Vaccines/administration & dosage , Cytokines/blood , Immunization, Secondary/methods , Immunoglobulin G/blood , Lung/virology , Macaca mulatta , Nose/virology , Phosphoproteins/immunology , Protein Domains/immunology , T-Lymphocytes, Helper-Inducer/immunology , Vaccination , Virus Replication/immunology
7.
Immunobiology ; 226(5): 152134, 2021 09.
Article in English | MEDLINE | ID: covidwho-1373079

ABSTRACT

COVID-19 (CoronaVirus disease 2019) is caused by the SARS-CoV-2 virus (severe acute respiratory syndrome corona virus 2). SARS-CoV-2 virus is highly contagious and affects the human respiratory tract resulting in symptoms such as high fever, body ache, cough, dysfunctions of tastebuds and smelling sense of body. The objective of the present study involves immunoinformatic analysis to predict COVID-19 protein for vaccine construct based on the genomic information SARS-CoV-2 virus. At present, as per WHO estimates, around 133 COVID-19 novel vaccines under development. Three amino acid sequences of SARS-CoV-2 were retrieved from the NCBI database for the analysis of vaccine construct. This study involves computational and immunoinformatic methods. The Immunoinformatic tools used in the present study are NetCTL server, IFN epitope server, Toxin PRED, BCPred, CTL + HTL + ADJUVANTS + LINKERS, AlgPredserver, VaxiJenserver, ProtParam to predict vaccine construct. The secondary and tertiary structure prediction is done by PSIPRED, I-TASSER, Galaxy refine, prosA + Ramachandran. Finally, docking of the vaccine constructs and ligand was done with the help of Cluspro 2.0. C-ImmSimm webserver to simulate the potential vaccine construct. The present study demonstrated three potential Vaccine constructs for the SARS-CoV-2 virus, which were docked with TLR8 (Toll-likereceptor8). Interestingly from these, all constructs one having a high potential for the inhibition effect of the SARS-CoV-2virus. Immunological simulation data shows significant elevated amount of memory B cell; also, the high response was seen in TH(Helper) and TC(cytotoxic) cell population from the vaccine construct proposed in the current study. Hence, these constructs are suitable vaccine candidates that might be useful in developing a novel vaccine.


Subject(s)
COVID-19 Vaccines , COVID-19/prevention & control , SARS-CoV-2/immunology , Vaccines, Subunit , Amino Acid Sequence , Antigens, Viral/immunology , B-Lymphocytes/immunology , Computational Biology , Computer Simulation , Epitopes/immunology , Genome, Viral , SARS-CoV-2/genetics , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Helper-Inducer/immunology , Toll-Like Receptor 8/immunology
8.
Sci Rep ; 11(1): 15431, 2021 07 29.
Article in English | MEDLINE | ID: covidwho-1332853

ABSTRACT

Currently, no approved vaccine is available against the Middle East respiratory syndrome coronavirus (MERS-CoV), which causes severe respiratory disease. The spike glycoprotein is typically considered a suitable target for MERS-CoV vaccine candidates. A computational strategy can be used to design an antigenic vaccine against a pathogen. Therefore, we used immunoinformatics and computational approaches to design a multi-epitope vaccine that targets the spike glycoprotein of MERS-CoV. After using numerous immunoinformatics tools and applying several immune filters, a poly-epitope vaccine was constructed comprising cytotoxic T-cell lymphocyte (CTL)-, helper T-cell lymphocyte (HTL)-, and interferon-gamma (IFN-γ)-inducing epitopes. In addition, various physicochemical, allergenic, and antigenic profiles were evaluated to confirm the immunogenicity and safety of the vaccine. Molecular interactions, binding affinities, and the thermodynamic stability of the vaccine were examined through molecular docking and dynamic simulation approaches, during which we identified a stable and strong interaction with Toll-like receptors (TLRs). In silico immune simulations were performed to assess the immune-response triggering capabilities of the vaccine. This computational analysis suggested that the proposed vaccine candidate would be structurally stable and capable of generating an effective immune response to combat viral infections; however, experimental evaluations remain necessary to verify the exact safety and immunogenicity profile of this vaccine.


Subject(s)
Epitopes/immunology , Middle East Respiratory Syndrome Coronavirus/immunology , Vaccines/immunology , Computational Biology , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Epitopes, B-Lymphocyte/genetics , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/genetics , Epitopes, T-Lymphocyte/immunology , Humans , Immunogenicity, Vaccine/immunology , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Models, Molecular , Molecular Docking Simulation , Phylogeny , Protein Binding , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Helper-Inducer/immunology , Vaccines/pharmacology , Vaccines, DNA , Vaccines, Subunit/immunology , Viral Vaccines/immunology
9.
J Virol ; 95(15): e0053021, 2021 07 12.
Article in English | MEDLINE | ID: covidwho-1218208

ABSTRACT

Elicitation of lung tissue-resident memory CD8 T cells (TRMs) is a goal of T cell-based vaccines against respiratory viral pathogens, such as influenza A virus (IAV). C-C chemokine receptor type 2 (CCR2)-dependent monocyte trafficking plays an essential role in the establishment of CD8 TRMs in lungs of IAV-infected mice. Here, we used a combination adjuvant-based subunit vaccine strategy that evokes multifaceted (TC1/TC17/TH1/TH17) IAV nucleoprotein-specific lung TRMs to determine whether CCR2 and monocyte infiltration are essential for vaccine-induced TRM development and protective immunity to IAV in lungs. Following intranasal vaccination, neutrophils, monocytes, conventional dendritic cells (DCs), and monocyte-derived dendritic cells internalized and processed vaccine antigen in lungs. We found that basic leucine zipper ATF-like transcription factor 3 (BATF3)-dependent DCs were essential for eliciting T cell responses, but CCR2 deficiency enhanced the differentiation of CD127hi, KLRG-1lo, OX40+ve CD62L+ve, and mucosally imprinted CD69+ve CD103+ve effector and memory CD8 T cells in lungs and airways of vaccinated mice. Mechanistically, increased development of lung TRMs induced by CCR2 deficiency was linked to dampened expression of T-bet but not altered TCF-1 levels or T cell receptor signaling in CD8 T cells. T1/T17 functional programming, parenchymal localization of CD8/CD4 effector and memory T cells, recall T cell responses, and protective immunity to a lethal IAV infection were unaffected in CCR2-deficient mice. Taken together, we identified a negative regulatory role for CCR2 and monocyte trafficking in mucosal imprinting and differentiation of vaccine-induced TRMs. Mechanistic insights from this study may aid the development of T-cell-based vaccines against respiratory viral pathogens, including IAV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). IMPORTANCE While antibody-based immunity to influenza A virus (IAV) is type and subtype specific, lung- and airway-resident memory T cells that recognize conserved epitopes in the internal viral proteins are known to provide heterosubtypic immunity. Hence, broadly protective IAV vaccines need to elicit robust T cell memory in the respiratory tract. We have developed a combination adjuvant-based IAV nucleoprotein vaccine that elicits strong CD4 and CD8 T cell memory in lungs and protects against H1N1 and H5N1 strains of IAV. In this study, we examined the mechanisms that control vaccine-induced protective memory T cells in the respiratory tract. We found that trafficking of monocytes into lungs might limit the development of antiviral lung-resident memory T cells following intranasal vaccination. These findings suggest that strategies that limit monocyte infiltration can potentiate vaccine-induced frontline T-cell immunity to respiratory viruses, such as IAV and SARS-CoV-2.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunity, Mucosal , Immunologic Memory , Influenza A virus/immunology , Influenza Vaccines/immunology , Orthomyxoviridae Infections/immunology , Receptors, CCR2/immunology , T-Lymphocytes, Helper-Inducer/immunology , Animals , Influenza A virus/genetics , Influenza Vaccines/genetics , Influenza Vaccines/pharmacology , Lung/immunology , Mice , Mice, Knockout , Orthomyxoviridae Infections/genetics , Orthomyxoviridae Infections/prevention & control , Receptors, CCR2/genetics
10.
Eur J Immunol ; 51(6): 1325-1333, 2021 06.
Article in English | MEDLINE | ID: covidwho-1159066

ABSTRACT

T follicular helper (Tfh) cells play an essential role in regulating the GC reaction and, consequently, the generation of high-affinity antibodies and memory B cells. Therefore, Tfh cells are critical for potent humoral immune responses against various pathogens and their dysregulation has been linked to autoimmunity and cancer. Tfh cell differentiation is a multistep process, in which cognate interactions with different APC types, costimulatory and coinhibitory pathways, as well as cytokines are involved. However, it is still not fully understood how a subset of activated CD4+ T cells begins to express the Tfh cell-defining chemokine receptor CXCR5 during the early stage of the immune response, how some CXCR5+ pre-Tfh cells enter the B-cell follicles and mature further into GC Tfh cells, and how Tfh cells are maintained in the memory compartment. In this review, we discuss recent advances on how antigen and cognate interactions are important for Tfh cell differentiation and long-term persistence of Tfh cell memory, and how this is relevant to the current understanding of COVID-19 pathogenesis and the development of potent SARS-CoV-2 vaccines.


Subject(s)
Antigens, Viral/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Cell Differentiation/immunology , Immunologic Memory , SARS-CoV-2/immunology , T-Lymphocytes, Helper-Inducer/immunology , Animals , COVID-19/pathology , COVID-19/prevention & control , COVID-19 Vaccines/therapeutic use , Humans , T-Lymphocytes, Helper-Inducer/pathology
12.
Emerg Microbes Infect ; 10(1): 629-637, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1124369

ABSTRACT

COVID-19 vaccines emerging from different platforms differ in efficacy, duration of protection, and side effects. To maximize the benefits of vaccination, we explored the utility of employing a heterologous prime-boost strategy in which different combinations of the four types of leading COVID-19 vaccine candidates that are undergoing clinical trials in China were tested in a mouse model. Our results showed that sequential immunization with adenovirus vectored vaccine followed by inactivated/recombinant subunit/mRNA vaccine administration specifically increased levels of neutralizing antibodies and promoted the modulation of antibody responses to predominantly neutralizing antibodies. Moreover, a heterologous prime-boost regimen with an adenovirus vector vaccine also improved Th1-biased T cell responses. Our results provide new ideas for the development and application of COVID-19 vaccines to control the SARS-CoV-2 pandemic.


Subject(s)
Adenovirus Vaccines/immunology , Antibodies, Viral/blood , COVID-19 Vaccines/immunology , Immunization, Secondary/methods , Vaccines, Subunit/immunology , Vaccines, Synthetic/immunology , Adenovirus Vaccines/administration & dosage , Animals , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Interferon-gamma/blood , Lymphocyte Count , Mice , Mice, Inbred BALB C , SARS-CoV-2/immunology , T-Lymphocytes/immunology , T-Lymphocytes, Helper-Inducer/immunology , Vaccination/adverse effects , Vaccines, Subunit/administration & dosage , Vaccines, Synthetic/administration & dosage
13.
Nat Commun ; 12(1): 1403, 2021 03 03.
Article in English | MEDLINE | ID: covidwho-1117351

ABSTRACT

SARS-CoV-2 vaccines are advancing into human clinical trials, with emphasis on eliciting high titres of neutralising antibodies against the viral spike (S). However, the merits of broadly targeting S versus focusing antibody onto the smaller receptor binding domain (RBD) are unclear. Here we assess prototypic S and RBD subunit vaccines in homologous or heterologous prime-boost regimens in mice and non-human primates. We find S is highly immunogenic in mice, while the comparatively poor immunogenicity of RBD is associated with limiting germinal centre and T follicular helper cell activity. Boosting S-primed mice with either S or RBD significantly augments neutralising titres, with RBD-focussing driving moderate improvement in serum neutralisation. In contrast, both S and RBD vaccines are comparably immunogenic in macaques, eliciting serological neutralising activity that generally exceed levels in convalescent humans. These studies confirm recombinant S proteins as promising vaccine candidates and highlight multiple pathways to achieving potent serological neutralisation.


Subject(s)
COVID-19 Vaccines/therapeutic use , SARS-CoV-2/pathogenicity , Animals , Antibodies, Neutralizing/immunology , Antibody Formation/physiology , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Humans , Macaca , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , Viral Vaccines/therapeutic use
14.
Nat Commun ; 12(1): 1162, 2021 02 19.
Article in English | MEDLINE | ID: covidwho-1091489

ABSTRACT

The durability of infection-induced SARS-CoV-2 immunity has major implications for reinfection and vaccine development. Here, we show a comprehensive profile of antibody, B cell and T cell dynamics over time in a cohort of patients who have recovered from mild-moderate COVID-19. Binding and neutralising antibody responses, together with individual serum clonotypes, decay over the first 4 months post-infection. A similar decline in Spike-specific CD4+ and circulating T follicular helper frequencies occurs. By contrast, S-specific IgG+ memory B cells consistently accumulate over time, eventually comprising a substantial fraction of circulating the memory B cell pool. Modelling of the concomitant immune kinetics predicts maintenance of serological neutralising activity above a titre of 1:40 in 50% of convalescent participants to 74 days, although there is probably additive protection from B cell and T cell immunity. This study indicates that SARS-CoV-2 immunity after infection might be transiently protective at a population level. Therefore, SARS-CoV-2 vaccines might require greater immunogenicity and durability than natural infection to drive long-term protection.


Subject(s)
Antibodies, Viral/immunology , Antibody Formation , COVID-19/immunology , Immunity, Cellular , Immunologic Memory , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Humans , Immunoglobulin G/immunology , Longitudinal Studies , Models, Theoretical , Neutralization Tests , T-Lymphocytes, Helper-Inducer/immunology
15.
Immunol Rev ; 299(1): 108-117, 2021 01.
Article in English | MEDLINE | ID: covidwho-1072592

ABSTRACT

Humoral immunity is a critical component of the coordinated response required to resolve viral infections and mediate protection following pathogen clearance or vaccination. A better understanding of factors shaping the memory B cell response will allow tailored development of efficient preventative vaccines against emerging acute viral infections, therapeutic vaccines, and immunotherapies for chronic viral infections. Here, we use recent data obtained by profiling antigen-specific B cell responses in hepatitis B as a framework to explore lessons that can be learnt from different viral infections about the diverse influences on humoral immunity. Hepatitis B provides a paradigm where successful B cell responses in resolved or vaccinated individuals can be contrasted to the failed response in chronic infection, while also exemplifying the degree to which B cell responses within infected individuals can differ to two antigens from the same virus. Drawing on studies in other human and murine infections, including emerging data from COVID-19, we consider the influence of antigen quantity and structure on the quality of the B cell response, the role of differential CD4 help, the importance of germinal center vs extrafollicular responses and the emerging concept that responses residing in non-lymphoid organs can participate in B cell memory.


Subject(s)
Antibodies, Viral/metabolism , B-Lymphocytes/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Hepatitis B virus/physiology , Hepatitis B/immunology , SARS-CoV-2/physiology , T-Lymphocytes, Helper-Inducer/immunology , Antibody Formation , Antigens, Viral/immunology , Humans , Immunity, Humoral , Immunodominant Epitopes/immunology , Immunologic Memory
16.
Front Immunol ; 11: 596964, 2020.
Article in English | MEDLINE | ID: covidwho-1067653

ABSTRACT

We designed the killed swine influenza A virus (SwIAV) H1N2 antigen (KAg) with polyriboinosinic:polyribocytidylic acid [(Poly(I:C)] adsorbed corn-derived Nano-11 particle based nanovaccine called Nano-11-KAg+Poly(I:C), and evaluated its immune correlates in maternally derived antibody (MDA)-positive pigs against a heterologous H1N1 SwIAV infection. Immunologically, in tracheobronchial lymph nodes (TBLN) detected enhanced H1N2-specific cytotoxic T-lymphocytes (CTLs) in Nano-11-KAg+Poly(I:C) vaccinates, and in commercial vaccinates detected CTLs with mainly IL-17A+ and early effector phenotypes specific to both H1N2 and H1N1 SwAIV. In commercial vaccinates, activated H1N2- and H1N1-specific IFNγ+&TNFα+, IL-17A+ and central memory T-helper/Memory cells, and in Nano-11-KAg+Poly(I:C) vaccinates H1N2-specific central memory, IFNγ+ and IFNγ+&TNFα+, and H1N1-specific IL-17A+ T-helper/Memory cells were observed. Systemically, Nano-11-KAg+Poly(I:C) vaccine augmented H1N2-specific IFNγ+ CTLs and H1N1-specific IFNγ+ T-helper/Memory cells, and commercial vaccine boosted H1N2- specific early effector CTLs and H1N1-specific IFNγ+&TNFα+ CTLs, as well as H1N2- and H1N1-specific T-helper/Memory cells with central memory, IFNγ+&TNFα+, and IL-17A+ phenotypes. Remarkably, commercial vaccine induced an increase in H1N1-specific T-helper cells in TBLN and naive T-helper cells in both TBLN and peripheral blood mononuclear cells (PBMCs), while H1N1- and H1N2-specific only T-helper cells were augmented in Nano-11-KAg+Poly(I:C) vaccinates in both TBLN and PBMCs. Furthermore, the Nano-11-KAg+Poly(I:C) vaccine stimulated robust cross-reactive IgG and secretory IgA (SIgA) responses in lungs, while the commercial vaccine elicited high levels of serum and lung IgG and serum hemagglutination inhibition (HI) titers. In conclusion, despite vast genetic difference (77% in HA gene identity) between the vaccine H1N2 and H1N1 challenge viruses in Nano-11-KAg+Poly(I:C) vaccinates, compared to over 95% identity between H1N1 of commercial vaccine and challenge viruses, the virus load and macroscopic lesions in the lungs of both types of vaccinates were comparable, but the Nano-11-KAg+Poly(I:C) vaccine cleared the virus from the nasal passage better. These data suggested the important role played by Nano-11 and Poly(I:C) in the induction of polyfunctional, cross-protective cell-mediated immunity against SwIAV in MDA-positive pigs.


Subject(s)
Influenza A virus/immunology , Influenza Vaccines/administration & dosage , Influenza Vaccines/immunology , Nanoparticles , Orthomyxoviridae Infections/veterinary , Poly I-C , Swine Diseases/prevention & control , Vaccines, Inactivated , Animals , Antibodies, Viral/immunology , Antigens, Viral/immunology , Cross Reactions , Cytokines/metabolism , Immunity, Cellular , Immunologic Memory , Influenza Vaccines/chemistry , Nanoparticles/chemistry , Poly I-C/chemistry , Swine , Swine Diseases/immunology , Swine Diseases/virology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , Viral Load
17.
Sci Rep ; 11(1): 3238, 2021 02 05.
Article in English | MEDLINE | ID: covidwho-1065946

ABSTRACT

The rampant spread of COVID-19, an infectious disease caused by SARS-CoV-2, all over the world has led to over millions of deaths, and devastated the social, financial and political entities around the world. Without an existing effective medical therapy, vaccines are urgently needed to avoid the spread of this disease. In this study, we propose an in silico deep learning approach for prediction and design of a multi-epitope vaccine (DeepVacPred). By combining the in silico immunoinformatics and deep neural network strategies, the DeepVacPred computational framework directly predicts 26 potential vaccine subunits from the available SARS-CoV-2 spike protein sequence. We further use in silico methods to investigate the linear B-cell epitopes, Cytotoxic T Lymphocytes (CTL) epitopes, Helper T Lymphocytes (HTL) epitopes in the 26 subunit candidates and identify the best 11 of them to construct a multi-epitope vaccine for SARS-CoV-2 virus. The human population coverage, antigenicity, allergenicity, toxicity, physicochemical properties and secondary structure of the designed vaccine are evaluated via state-of-the-art bioinformatic approaches, showing good quality of the designed vaccine. The 3D structure of the designed vaccine is predicted, refined and validated by in silico tools. Finally, we optimize and insert the codon sequence into a plasmid to ensure the cloning and expression efficiency. In conclusion, this proposed artificial intelligence (AI) based vaccine discovery framework accelerates the vaccine design process and constructs a 694aa multi-epitope vaccine containing 16 B-cell epitopes, 82 CTL epitopes and 89 HTL epitopes, which is promising to fight the SARS-CoV-2 viral infection and can be further evaluated in clinical studies. Moreover, we trace the RNA mutations of the SARS-CoV-2 and ensure that the designed vaccine can tackle the recent RNA mutations of the virus.


Subject(s)
COVID-19 Vaccines , Deep Learning , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Allergens , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , COVID-19 Vaccines/toxicity , Codon Usage , Computational Biology , Drug Design , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/immunology , Humans , Immunogenicity, Vaccine , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Mutation , Protein Conformation , RNA, Viral , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Solubility , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Helper-Inducer/immunology , Vaccines, Subunit/chemistry , Vaccines, Subunit/immunology
18.
Cytokine ; 140: 155439, 2021 04.
Article in English | MEDLINE | ID: covidwho-1032441

ABSTRACT

BACKGROUND: Immunodeficiency has pivotal role in the pathogenesis of coronavirus disease 2019 (COVID-19). Several studies have indicated defects in the immune system of COVID-19 patients at different disease stages. Therefore, this study investigated whether alters in immune responses of COVID-19 patients may be considered as predicting factors for disease outcome. METHODS: The percentages of innate and adoptive immune cells in the recovered and dead patients with COVID-19, and healthy subjects were determined by flow cytometry. The levels of pro- and anti-inflammatory cytokines and other immune factors were also measured by enzyme-linked immunosorbent assay. RESULTS: At the first day of hospitalization, the frequencies of CD56dim CD16+ NK cells and CD56bright CD16dim/- NK cells in patients who died during treatment were significantly increased compared to recovered and healthy individuals (P < 0.0001). The recovered and dead patients had a significant increase in monocyte number in comparison with healthy subjects (P < 0.05). No significant change was observed in Th1 cell numbers between the recovered and dead patients while Th2, Th17 cell, and Treg percentages in death cases were significantly lower than healthy control and those recovered, unlike exhausted CD4 + and CD8 + T cells and activated CD4 + T cells (P < 0.0001-0.05). The activated CD8 + T cell was significantly higher in the recovered patients than healthy individuals (P < 0.0001-0.05). IL-1α, IL-1ß, IL-6, and TNF-α levels in patients were significantly increased (P < 0.0001-0.01). However, there were no differences in TNF-α and IL-1ß levels between dead and recovered patients. Unlike TGF-ß1 level, IL-10 was significantly increased in recovered patients (P < 0.05). Lymphocyte numbers in recovered patients were significantly increased compared to dead patients, unlike ESR value (P < 0.001-0.01). CRP value in recovered patients significantly differed from dead patients (P < 0.001). CONCLUSION: Changes in frequencies of some immune cells and levels of some immune factors may be considered as predictors of mortality in COVID-19 patients.


Subject(s)
COVID-19/immunology , Cytokines/immunology , Immune System/immunology , Immunity/immunology , SARS-CoV-2/immunology , Survivors/statistics & numerical data , Adult , Aged , Aged, 80 and over , COVID-19/mortality , COVID-19/virology , Cytokines/blood , Female , Humans , Immune System/cytology , Male , Middle Aged , Monocytes/immunology , SARS-CoV-2/physiology , Survival Rate , T-Lymphocytes/immunology , T-Lymphocytes, Helper-Inducer/classification , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Regulatory/immunology
19.
Science ; 369(6508)2020 09 04.
Article in English | MEDLINE | ID: covidwho-981641

ABSTRACT

Coronavirus disease 2019 (COVID-19) is currently a global pandemic, but human immune responses to the virus remain poorly understood. We used high-dimensional cytometry to analyze 125 COVID-19 patients and compare them with recovered and healthy individuals. Integrated analysis of ~200 immune and ~50 clinical features revealed activation of T cell and B cell subsets in a proportion of patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses reaching >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable with that in uninfected individuals. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. Our analyses identified three immunotypes associated with poor clinical trajectories versus improving health. These immunotypes may have implications for the design of therapeutics and vaccines for COVID-19.


Subject(s)
B-Lymphocytes/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , T-Lymphocytes/immunology , Adaptive Immunity , Adult , Aged , Aged, 80 and over , Antibodies, Viral/blood , B-Lymphocyte Subsets/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19 , Cytokines/blood , Female , Humans , Immunologic Memory , Lymphocyte Activation , Male , Middle Aged , Pandemics , Plasma Cells/immunology , SARS-CoV-2 , Severity of Illness Index , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Helper-Inducer/immunology , Time Factors , Young Adult
20.
Front Immunol ; 11: 596553, 2020.
Article in English | MEDLINE | ID: covidwho-979020

ABSTRACT

The severity of SARS-CoV-2 infection has been related to uncontrolled inflammatory innate responses and impaired adaptive immune responses mostly due to exhausted T lymphocytes and lymphopenia. In this work we have characterized the nature of the lymphopenia and demonstrate a set of factors that hinder the effective control of virus infection and the activation and arming of effector cytotoxic T CD8 cells and showing signatures defining a high-risk population. We performed immune profiling of the T helper (Th) CD4+ and T CD8+ cell compartments in peripheral blood of 144 COVID-19 patients using multiparametric flow cytometry analysis. On the one hand, there was a consistent lymphopenia with an overrepresentation of non-functional T cells, with an increased percentage of naive Th cells (CD45RA+, CXCR3-, CCR4-, CCR6-, CCR10-) and persistently low frequency of markers associated with Th1, Th17, and Th1/Th17 memory-effector T cells compared to healthy donors. On the other hand, the most profound alteration affected the Th1 subset, which may explain the poor T cells responses and the persistent blood virus load. Finally, the decrease in Th1 cells may also explain the low frequency of CD4+ and CD8+ T cells that express the HLA-DR and CD38 activation markers observed in numerous patients who showed minimal or no lymphocyte activation response. We also identified the percentage of HLA-DR+CD4+ T cells, PD-1+CD+4/CD8+ T cells in blood, and the neutrophil/lymphocyte ratio as useful factors for predicting critical illness and fatal outcome in patients with confirmed COVID-19.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , SARS-CoV-2/immunology , T-Lymphocytes, Helper-Inducer/immunology , Th1 Cells/immunology , ADP-ribosyl Cyclase 1/immunology , ADP-ribosyl Cyclase 1/metabolism , Aged , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , COVID-19/virology , Cell Differentiation/immunology , Female , HLA-DR Antigens/immunology , HLA-DR Antigens/metabolism , Humans , Lymphocyte Activation/immunology , Male , Middle Aged , Prospective Studies , SARS-CoV-2/physiology , T-Lymphocytes, Helper-Inducer/metabolism , Th1 Cells/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism
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