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1.
Int J Biol Sci ; 18(1): 386-408, 2022.
Article in English | MEDLINE | ID: covidwho-1607858

ABSTRACT

Responding to the coronavirus disease 2019 (COVID-19) pandemic has been an unexpected and unprecedented global challenge for humanity in this century. During this crisis, specialists from the laboratories and frontline clinical personnel have made great efforts to prevent and treat COVID-19 by revealing the molecular biological characteristics and epidemic characteristics of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, SARS-CoV-2 has severe consequences for public health, including human respiratory system, immune system, blood circulation system, nervous system, motor system, urinary system, reproductive system and digestive system. In the review, we summarize the physiological and pathological damage of SARS-CoV-2 to these systems and its molecular mechanisms followed by clinical manifestation. Concurrently, the prevention and treatment strategies of COVID-19 will be discussed in preclinical and clinical studies. With constantly unfolding and expanding scientific understanding about COVID-19, the updated information can help applied researchers understand the disease to build potential antiviral drugs or vaccines, and formulate creative therapeutic ideas for combating COVID-19 at speed.


Subject(s)
COVID-19/pathology , COVID-19/therapy , Immunotherapy/methods , SARS-CoV-2 , Animals , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19 Vaccines , Cytokines/metabolism , Female , Humans , Immune System , Immunity, Innate , Immunologic Memory , Male , Mice
2.
JCI Insight ; 6(24)2021 12 22.
Article in English | MEDLINE | ID: covidwho-1598468

ABSTRACT

mRNA vaccines for SARS-CoV-2 have shown exceptional clinical efficacy, providing robust protection against severe disease. However, our understanding of transcriptional and repertoire changes following full vaccination remains incomplete. We used scRNA-Seq and functional assays to compare humoral and cellular responses to 2 doses of mRNA vaccine with responses observed in convalescent individuals with asymptomatic disease. Our analyses revealed enrichment of spike-specific B cells, activated CD4+ T cells, and robust antigen-specific polyfunctional CD4+ T cell responses following vaccination. On the other hand, although clonally expanded CD8+ T cells were observed following both vaccination and natural infection, CD8+ T cell responses were relatively weak and variable. In addition, TCR gene usage was variable, reflecting the diversity of repertoires and MHC polymorphism in the human population. Natural infection induced expansion of CD8+ T cell clones that occupy distinct clusters compared to those induced by vaccination and likely recognize a broader set of viral antigens of viral epitopes presented by the virus not seen in the mRNA vaccine. Our study highlights a coordinated adaptive immune response in which early CD4+ T cell responses facilitate the development of the B cell response and substantial expansion of effector CD8+ T cells, together capable of contributing to future recall responses.


Subject(s)
/immunology , COVID-19/immunology , Immunity, Cellular/immunology , Immunity, Humoral/immunology , /therapeutic use , Adaptive Immunity/genetics , Adaptive Immunity/immunology , Adult , Aged , Antigens, Viral , B-Lymphocytes , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , COVID-19/prevention & control , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Carrier State , Convalescence , Epitopes , Female , Humans , Immunity, Cellular/genetics , Immunity, Humoral/genetics , Immunogenicity, Vaccine , Immunologic Memory , Male , Middle Aged , RNA-Seq , SARS-CoV-2 , Single-Cell Analysis , Spike Glycoprotein, Coronavirus/immunology , Th1 Cells , Th17 Cells , Vaccines, Synthetic/immunology , Vaccines, Synthetic/therapeutic use , Young Adult , /therapeutic use
3.
Front Immunol ; 12: 760249, 2021.
Article in English | MEDLINE | ID: covidwho-1581341

ABSTRACT

Background: The humoral and cellular immune responses to SARS-COV-2 vaccination remain to be elucidated in hemodialysis (HD) patients and kidney transplant recipients (KTRs), considering their baseline immunosuppressed status. The aim of our study was to assess the associations of vaccine-induced antibody responses with circulating lymphocytes sub-populations and their respective patterns of alterations in maintenance HD patients and KTRs. Materials and Methods: We included 34 HD patients and 54 KTRs who received two doses of the mRNA-vaccine BNT162b2. Lymphocyte subpopulations were analyzed by flow cytometry before vaccination (T0), before the second vaccine dose (T1) and 2 weeks after the second dose (T2). The anti-SARS-CoV2 antibody response was assessed at T1 and at T2. Results: 31 HD patients (91.8%) and 16 KTRs (29.6%) became seropositive at T2. HD patients who became seropositive following the first dose displayed higher CD19+ B lymphocytes compared to their seronegative HD counterparts. A positive correlation was established between CD19+ B cells counts and antibody titers at all time-points in both groups (p < 0.001). KTRs showed higher naïve CD4+CD45RA+ T helper cells compared to HD patients at baseline and T2 whereas HD patients displayed higher memory CD45RO+ T cells compared to KTRs at T2. The naïve CD4+CD45RA to memory CD4+CD45RO+ T helper cells fraction was negatively associated with antibody production in both groups. Conclusions: Our study provides a potential conceptual framework for monitoring vaccination efficacy in HD patients and KTRs considering the correlation established between CD19+ B cells, generation of memory CD4+ T helper cells and anti SARS-CoV2 antibody response to vaccination.


Subject(s)
Antibody Formation/immunology , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Immunity, Humoral , Immunocompromised Host , Immunologic Memory , B-Lymphocytes/metabolism , Biomarkers , CD4-Positive T-Lymphocytes/metabolism , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/immunology , Female , Humans , Immunophenotyping , Kidney Transplantation , Lymphocyte Count , Male , Renal Dialysis , SARS-CoV-2/immunology
4.
Front Immunol ; 12: 565625, 2021.
Article in English | MEDLINE | ID: covidwho-1574690

ABSTRACT

Sub-Saharan Africa has generally experienced few cases and deaths of coronavirus disease 2019 (COVID-19). In addition to other potential explanations for the few cases and deaths of COVID-19 such as the population socio-demographics, early lockdown measures and the possibility of under reporting, we hypothesize in this mini review that individuals with a recent history of malaria infection may be protected against infection or severe form of COVID-19. Given that both the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Plasmodium falciparum (P. falciparum) merozoites bind to the cluster of differentiation 147 (CD147) immunoglobulin, we hypothesize that the immunological memory against P. falciparum merozoites primes SARS-CoV-2 infected cells for early phagocytosis, hence protecting individuals with a recent P. falciparum infection against COVID-19 infection or severity. This mini review therefore discusses the potential biological link between P. falciparum infection and COVID-19 infection or severity and further highlights the importance of CD147 immunoglobulin as an entry point for both SARS-CoV-2 and P. falciparum into host cells.


Subject(s)
Basigin/immunology , COVID-19 , Immunologic Memory , Malaria, Falciparum , Plasmodium falciparum/immunology , SARS-CoV-2/immunology , Africa South of the Sahara/epidemiology , COVID-19/epidemiology , COVID-19/immunology , Humans , Malaria, Falciparum/epidemiology , Malaria, Falciparum/immunology , Merozoites/immunology , Severity of Illness Index
5.
Nat Rev Immunol ; 20(8): 460-461, 2020 08.
Article in English | MEDLINE | ID: covidwho-1550299
6.
Nat Immunol ; 22(8): 942-944, 2021 08.
Article in English | MEDLINE | ID: covidwho-1550320
7.
Genome Med ; 13(1): 164, 2021 10 14.
Article in English | MEDLINE | ID: covidwho-1542128

ABSTRACT

BACKGROUND: The receptor-binding domain (RBD) variants of SARS-CoV-2 could impair antibody-mediated neutralization of the virus by host immunity; thus, prospective surveillance of antibody escape mutants and understanding the evolution of RBD are urgently needed. METHODS: Using the single B cell cloning technology, we isolated and characterized 93 RBD-specific antibodies from the memory B cells of four COVID-19 convalescent individuals in the early stage of the pandemic. Then, global RBD alanine scanning with a panel of 19 selected neutralizing antibodies (NAbs), including several broadly reactive NAbs, was performed. Furthermore, we assessed the impact of single natural mutation or co-mutations of concern at key positions of RBD on the neutralization escape and ACE2 binding function by recombinant proteins and pseudoviruses. RESULTS: Thirty-three amino acid positions within four independent antigenic sites (1 to 4) of RBD were identified as valuable indicators of antigenic changes in the RBD. The comprehensive escape mutation map not only confirms the widely circulating strains carrying important immune escape RBD mutations such as K417N, E484K, and L452R, but also facilitates the discovery of new immune escape-enabling mutations such as F486L, N450K, F490S, and R346S. Of note, these escape mutations could not affect the ACE2 binding affinity of RBD, among which L452R even enhanced binding. Furthermore, we showed that RBD co-mutations K417N, E484K, and N501Y present in B.1.351 appear more resistant to NAbs and human convalescent plasma from the early stage of the pandemic, possibly due to an additive effect. Conversely, double mutations E484Q and L452R present in B.1.617.1 variant show partial antibody evasion with no evidence for an additive effect. CONCLUSIONS: Our study provides a global view of the determinants for neutralizing antibody recognition, antigenic conservation, and RBD conformation. The in-depth escape maps may have value for prospective surveillance of SARS-CoV-2 immune escape variants. Special attention should be paid to the accumulation of co-mutations at distinct major antigenic sites. Finally, the new broadly reactive NAbs described here represent new potential opportunities for the prevention and treatment of COVID-19.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 , Immune Evasion , Mutation , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Adult , Aged , B-Lymphocytes/immunology , COVID-19/genetics , COVID-19/immunology , Female , Humans , Immunologic Memory , Male , Middle Aged , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
8.
PLoS One ; 16(11): e0258743, 2021.
Article in English | MEDLINE | ID: covidwho-1511818

ABSTRACT

BCG vaccination is known to induce innate immune memory, which confers protection against heterologous infections. However, the effect of BCG vaccination on the conventional adaptive immune cells subsets is not well characterized. We investigated the impact of BCG vaccination on the frequencies of T cell subsets and common gamma c (γc) cytokines in a group of healthy elderly individuals (age 60-80 years) at one month post vaccination as part of our clinical study to examine the effect of BCG on COVID-19. Our results demonstrate that BCG vaccination induced enhanced frequencies of central (p<0.0001) and effector memory (p<0.0001) CD4+ T cells and diminished frequencies of naïve (p<0.0001), transitional memory (p<0.0001), stem cell memory (p = 0.0001) CD4+ T cells and regulatory T cells. In addition, BCG vaccination induced enhanced frequencies of central (p = 0.0008), effector (p<0.0001) and terminal effector memory (p<0.0001) CD8+ T cells and diminished frequencies of naïve (p<0.0001), transitional memory (p<0.0001) and stem cell memory (p = 0.0034) CD8+T cells. BCG vaccination also induced enhanced plasma levels of IL-7 (p<0.0001) and IL-15 (p = 0.0020) but diminished levels of IL-2 (p = 0.0033) and IL-21 (p = 0.0020). Thus, BCG vaccination was associated with enhanced memory T cell subsets as well as memory enhancing γc cytokines in elderly individuals, suggesting its ability to induce non-specific adaptive immune responses.


Subject(s)
BCG Vaccine/immunology , Cytokines/immunology , Immunologic Memory/immunology , Interleukin Receptor Common gamma Subunit/immunology , Aged , Aged, 80 and over , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Female , Humans , Interleukins/immunology , Male , Middle Aged , Mycobacterium tuberculosis/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Vaccination/methods
9.
Front Immunol ; 12: 769059, 2021.
Article in English | MEDLINE | ID: covidwho-1505989

ABSTRACT

The prognosis of severe COVID-19 patients has motivated research communities to uncover mechanisms of SARS-CoV-2 pathogenesis also on a regional level. In this work, we aimed to understand the immunological dynamics of severe COVID-19 patients with different degrees of illness, and upon long-term recovery. We analyzed immune cellular subsets and SARS-CoV-2-specific antibody isotypes of 66 COVID-19 patients admitted to the Hospital Clínico Universidad de Chile, which were categorized according to the WHO ten-point clinical progression score. These included 29 moderate patients (score 4-5) and 37 severe patients under either high flow oxygen nasal cannula (18 patients, score 6), or invasive mechanical ventilation (19 patients, score 7-9), plus 28 convalescent patients and 28 healthy controls. Furthermore, six severe patients that recovered from the disease were longitudinally followed over 300 days. Our data indicate that severe COVID-19 patients display increased frequencies of plasmablasts, activated T cells and SARS-CoV-2-specific antibodies compared to moderate and convalescent patients. Remarkably, within the severe COVID-19 group, patients rapidly progressing into invasive mechanical ventilation show higher frequencies of plasmablasts, monocytes, eosinophils, Th1 cells and SARS-CoV-2-specific IgG than patients under high flow oxygen nasal cannula. These findings demonstrate that severe COVID-19 patients progressing into invasive mechanical ventilation show a distinctive type of immunity. In addition, patients that recover from severe COVID-19 begin to regain normal proportions of immune cells 100 days after hospital discharge and maintain high levels of SARS-CoV-2-specific IgG throughout the study, which is an indicative sign of immunological memory. Thus, this work can provide useful information to better understand the diverse outcomes of severe COVID-19 pathogenesis.


Subject(s)
COVID-19/immunology , Eosinophils/immunology , Plasma Cells/immunology , SARS-CoV-2/physiology , Th1 Cells/immunology , Aged , Antibodies, Viral/blood , Convalescence , Disease Progression , Female , Humans , Immunity, Cellular , Immunoglobulin G/blood , Immunologic Memory , Male , Middle Aged , Severity of Illness Index
10.
Emerg Microbes Infect ; 10(1): 578-588, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1490460

ABSTRACT

Mycobacterium tuberculosis (M. tuberculosis) is the pathogen which causes tuberculosis (TB), a significant human public health threat. Co-infection of M. tuberculosis and the human immunodeficiency virus (HIV), emergence of drug resistant M. tuberculosis, and failure to develop highly effective TB vaccines have limited control of the TB epidemic. Trained immunity is an enhanced innate immune response which functions independently of the adaptive/acquired immune system and responds non-specifically to reinfection with invading agents. Recently, several studies have found trained immunity has the capability to control and eliminate M. tuberculosis infection. Over the past decades, however, the consensus was adaptive immunity is the only protective mechanism by which hosts inhibit M. tuberculosis growth. Furthermore, autophagy plays an essential role in the development of trained immunity. Further investigation of trained immunity, M. tuberculosis infection, and the role of autophagy in this process provide new possibilities for vaccine development. In this review, we present the general characteristics of trained immunity and autophagy. We additionally summarize several examples where initiation of trained immunity contributes to the prevention of M. tuberculosis infection and propose future directions for research in this area.


Subject(s)
Autophagy , Immunity, Innate , Mycobacterium tuberculosis/immunology , Tuberculosis Vaccines/immunology , Tuberculosis/immunology , Tuberculosis/prevention & control , Adaptive Immunity , Animals , Humans , Immunologic Memory , Vaccination
11.
Front Immunol ; 12: 741639, 2021.
Article in English | MEDLINE | ID: covidwho-1497078

ABSTRACT

Children have reduced severity of COVID-19 compared to adults and typically have mild or asymptomatic disease. The immunological mechanisms underlying these age-related differences in clinical outcomes remain unexplained. Here, we quantify 23 immune cell populations in 141 samples from children and adults with mild COVID-19 and their PCR-negative close household contacts at acute and convalescent time points. Children with COVID-19 displayed marked reductions in myeloid cells during infection, most prominent in children under the age of five. Recovery from infection in both children and adults was characterised by the generation of CD8 TCM and CD4 TCM up to 9 weeks post infection. SARS-CoV-2-exposed close contacts also had immunological changes over time despite no evidence of confirmed SARS-CoV-2 infection on PCR testing. This included an increase in low-density neutrophils during convalescence in both exposed children and adults, as well as increases in CD8 TCM and CD4 TCM in exposed adults. In comparison to children with other common respiratory viral infections, those with COVID-19 had a greater change in innate and T cell-mediated immune responses over time. These findings provide new mechanistic insights into the immune response during and after recovery from COVID-19 in both children and adults.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , SARS-CoV-2/physiology , Adolescent , Adult , Child , Child, Preschool , Cohort Studies , Convalescence , Environmental Exposure , Family Characteristics , Female , Humans , Immunity, Cellular , Immunologic Memory , Infant , Male , Middle Aged , Young Adult
12.
J Infect Dis ; 224(8): 1305-1315, 2021 10 28.
Article in English | MEDLINE | ID: covidwho-1493821

ABSTRACT

BACKGROUND: A notable feature of coronavirus disease 2019 (COVID-19) is that children are less susceptible to severe disease. Children are known to experience more infections with endemic human coronaviruses (HCoVs) compared to adults. Little is known whether HCoV infections lead to cross-reactive anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. METHODS: We investigated the presence of cross-reactive anti-SARS-CoV-2 IgG antibodies to spike 1 (S1), S1-receptor-binding domain (S1-RBD), and nucleocapsid protein (NP) by enzyme-linked immunosorbent assays, and neutralizing activity by a SARS-CoV-2 pseudotyped virus neutralization assay, in prepandemic sera collected from children (n = 50) and adults (n = 45), and compared with serum samples from convalescent COVID-19 patients (n = 16). RESULTS: A significant proportion of children (up to 40%) had detectable cross-reactive antibodies to SARS-CoV-2 S1, S1-RBD, and NP antigens, and the anti-S1 and anti-S1-RBD antibody levels correlated with anti-HCoV-HKU1 and anti-HCoV-OC43 S1 antibody titers in prepandemic samples (P < .001). There were marked increases of anti-HCoV-HKU1 and - OC43 S1 (but not anti-NL63 and -229E S1-RBD) antibody titers in serum samples from convalescent COVID-19 patients (P < .001), indicating an activation of cross-reactive immunological memory to ß-coronavirus spike. CONCLUSIONS: We demonstrated cross-reactive anti-SARS-CoV-2 antibodies in prepandemic serum samples from children and young adults. Promoting this cross-reactive immunity and memory response derived from common HCoV may be an effective strategy against SARS-COV-2 and future novel coronaviruses.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , Immunoglobulin G/blood , SARS-CoV-2/immunology , Adolescent , Adult , Antibodies, Viral/immunology , COVID-19/blood , COVID-19/virology , Child , Child, Preschool , Convalescence , Coronavirus 229E, Human/immunology , Coronavirus Envelope Proteins/immunology , Coronavirus OC43, Human/immunology , Cross Reactions , Enzyme-Linked Immunosorbent Assay , Female , HEK293 Cells , Humans , Immunoglobulin G/immunology , Immunologic Memory , Male , Middle Aged , Spike Glycoprotein, Coronavirus/immunology , Young Adult
13.
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
14.
Front Immunol ; 12: 758154, 2021.
Article in English | MEDLINE | ID: covidwho-1477831

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has severely impacted daily life all over the world. Any measures to slow down the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to decrease disease severity are highly requested. Recent studies have reported inverse correlations between plasma levels of vitamin D and susceptibility to SARS-CoV-2 infection and COVID-19 severity. Therefore, it has been proposed to supplement the general population with vitamin D to reduce the impact of COVID-19. However, by studying the course of COVID-19 and the immune response against SARS-CoV-2 in a family with a mutated, non-functional vitamin D receptor, we here demonstrate that vitamin D signaling was dispensable for mounting an efficient adaptive immune response against SARS-CoV-2 in this family. Although these observations might not directly be transferred to the general population, they question a central role of vitamin D in the generation of adaptive immunity against SARS-CoV-2.


Subject(s)
B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Familial Hypophosphatemic Rickets/genetics , Receptors, Calcitriol/genetics , SARS-CoV-2/immunology , Adaptive Immunity/genetics , Adaptive Immunity/immunology , COVID-19/immunology , Familial Hypophosphatemic Rickets/immunology , Female , Humans , Immunologic Memory/immunology , Lymphocyte Count , Vitamin D/blood , Vitamin D/therapeutic use
15.
Sci Rep ; 11(1): 20738, 2021 10 20.
Article in English | MEDLINE | ID: covidwho-1475484

ABSTRACT

Monoclonal antibodies that target SARS-CoV-2 with high affinity are valuable for a wide range of biomedical applications involving novel coronavirus disease (COVID-19) diagnosis, treatment, and prophylactic intervention. Strategies for the rapid and reliable isolation of these antibodies, especially potent neutralizing antibodies, are critical toward improved COVID-19 response and informed future response to emergent infectious diseases. In this study, single B cell screening was used to interrogate antibody repertoires of immunized mice and isolate antigen-specific IgG1+ memory B cells. Using these methods, high-affinity, potent neutralizing antibodies were identified that target the receptor-binding domain of SARS-CoV-2. Further engineering of the identified molecules to increase valency resulted in enhanced neutralizing activity. Mechanistic investigation revealed that these antibodies compete with ACE2 for binding to the receptor-binding domain of SARS-CoV-2. These antibodies may warrant further development for urgent COVID-19 applications. Overall, these results highlight the potential of single B cell screening for the rapid and reliable identification of high-affinity, potent neutralizing antibodies for infectious disease applications.


Subject(s)
Antibodies, Neutralizing/chemistry , B-Lymphocytes/virology , COVID-19/blood , COVID-19/immunology , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Monoclonal/immunology , Antibodies, Viral/immunology , B-Lymphocytes/immunology , Binding Sites/immunology , Biological Products , Female , HEK293 Cells , Humans , Immunoglobulin G/immunology , Immunoglobulin G/metabolism , Immunologic Memory , Mice , Mice, Inbred BALB C , Protein Binding , Spike Glycoprotein, Coronavirus , Vaccines
16.
J Clin Immunol ; 41(8): 1709-1722, 2021 11.
Article in English | MEDLINE | ID: covidwho-1474048

ABSTRACT

BACKGROUND: Data on immune responses to SARS-CoV-2 in patients with Primary Antibody Deficiencies (PAD) are limited to infected patients and to heterogeneous cohorts after immunization. METHODS: Forty-one patients with Common Variable Immune Deficiencies (CVID), six patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-receptor binding domain (RBD) antibody production, generation of Spike-specific memory B-cells, and Spike-specific T-cells before vaccination and one week after the second dose of BNT162b2 vaccine. RESULTS: The vaccine induced Spike-specific IgG and IgA antibody responses in all HD and in 20% of SARS-CoV-2 naive CVID patients. Anti-Spike IgG were detectable before vaccination in 4 out 7 CVID previously infected with SARS-CoV-2 and were boosted in six out of seven patients by the subsequent immunization raising higher levels than patients naïve to infection. While HD generated Spike-specific memory B-cells, and RBD-specific B-cells, CVID generated Spike-specific atypical B-cells, while RBD-specific B-cells were undetectable in all patients, indicating the incapability to generate this new specificity. Specific T-cell responses were evident in all HD and defective in 30% of CVID. All but one patient with XLA responded by specific T-cell only. CONCLUSION: In PAD patients, early atypical immune responses after BNT162b2 immunization occurred, possibly by extra-follicular or incomplete germinal center reactions. If these responses to vaccination might result in a partial protection from infection or reinfection is now unknown. Our data suggests that SARS-CoV-2 infection more effectively primes the immune response than the immunization alone, possibly suggesting the need for a third vaccine dose for patients not previously infected.


Subject(s)
Antibodies, Viral/blood , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunologic Deficiency Syndromes/immunology , SARS-CoV-2/immunology , Humans , Immunoglobulin G/blood , Immunologic Memory , Lymphocytes/immunology , Spike Glycoprotein, Coronavirus/immunology
17.
Front Immunol ; 12: 740708, 2021.
Article in English | MEDLINE | ID: covidwho-1470758

ABSTRACT

SARS-CoV-2 mRNA vaccines have demonstrated high efficacy and immunogenicity, but limited information is currently available on memory B cell generation and long-term persistence. Here, we investigated spike-specific memory B cells and humoral responses in 145 subjects, up to 6 months after the BNT162b2 vaccine (Comirnaty) administration. Spike-specific antibodies peaked 7 days after the second dose and significant antibody titers and ACE2/RBD binding inhibiting activity were still observed after 6 months, despite a progressive decline over time. Concomitant to antibody reduction, spike-specific memory B cells, mostly IgG class-switched, increased in the blood of vaccinees and persisted 6 months after vaccination. Following the in vitro restimulation, circulating memory B cells reactivated and produced spike-specific antibodies. A high frequency of spike-specific IgG+ plasmablasts, identified by computational analysis 7 days after boost, positively correlated with the generation of IgG+ memory B cells at 6 months. These data demonstrate that mRNA BNT162b2 vaccine elicits strong B cell immunity with spike-specific memory B cells that still persist 6 months after vaccination, playing a crucial role for a rapid response to SARS-CoV-2 virus encounter.


Subject(s)
B-Lymphocytes/immunology , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , SARS-CoV-2/immunology , Vaccines, Synthetic/administration & dosage , Adult , Aged , Antibodies, Viral/blood , Antigens, Viral/immunology , Female , Humans , Immunoglobulin G/blood , Immunologic Memory , Male , Middle Aged , Spike Glycoprotein, Coronavirus/immunology , Vaccination , Young Adult
18.
JCI Insight ; 6(18)2021 09 22.
Article in English | MEDLINE | ID: covidwho-1467778

ABSTRACT

The importance of the adaptive T cell response in the control and resolution of viral infection has been well established. However, the nature of T cell-mediated viral control mechanisms in life-threatening stages of COVID-19 has yet to be determined. The aim of the present study was to determine the function and phenotype of T cell populations associated with survival or death of patients with COVID-19 in intensive care as a result of phenotypic and functional profiling by mass cytometry. Increased frequencies of circulating, polyfunctional CD4+CXCR5+HLA-DR+ stem cell memory T cells (Tscms) and decreased proportions of granzyme B-expressing and perforin-expressing effector memory T cells were detected in recovered and deceased patients, respectively. The higher abundance of polyfunctional PD-L1+CXCR3+CD8+ effector T cells (Teffs), CXCR5+HLA-DR+ Tscms, and anti-nucleocapsid (anti-NC) cytokine-producing T cells permitted us to differentiate between recovered and deceased patients. The results from a principal component analysis show an imbalance in the T cell compartment that allowed for the separation of recovered and deceased patients. The paucity of circulating PD-L1+CXCR3+CD8+ Teffs and NC-specific CD8+ T cells accurately forecasts fatal disease outcome. This study provides insight into the nature of the T cell populations involved in the control of COVID-19 and therefore might impact T cell-based vaccine designs for this infectious disease.


Subject(s)
B7-H1 Antigen/immunology , CD4-Positive T-Lymphocytes/immunology , CD8 Antigens/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Immunity, Cellular , Receptors, CXCR3/immunology , Adult , COVID-19/mortality , COVID-19/pathology , Epitopes, T-Lymphocyte/immunology , Female , France/epidemiology , Humans , Immunologic Memory , Lymphocyte Activation , Male , SARS-CoV-2 , Survival Rate/trends
19.
Signal Transduct Target Ther ; 6(1): 368, 2021 10 13.
Article in English | MEDLINE | ID: covidwho-1467093

ABSTRACT

The long-term immunity and functional recovery after SARS-CoV-2 infection have implications in preventive measures and patient quality of life. Here we analyzed a prospective cohort of 121 recovered COVID-19 patients from Xiangyang, China at 1-year after diagnosis. Among them, chemiluminescence immunoassay-based screening showed 99% (95% CI, 98-100%) seroprevalence 10-12 months after infection, comparing to 0.8% (95% CI, 0.7-0.9%) in the general population. Total anti-receptor-binding domain (RBD) antibodies remained stable since discharge, while anti-RBD IgG and neutralization levels decreased over time. A predictive model estimates 17% (95% CI, 11-24%) and 87% (95% CI, 80-92%) participants were still 50% protected against detectable and severe re-infection of WT SARS-CoV-2, respectively, while neutralization levels against B.1.1.7 and B.1.351 variants were significantly reduced. All non-severe patients showed normal chest CT and 21% reported COVID-19-related symptoms. In contrast, 53% severe patients had abnormal chest CT, decreased pulmonary function or cardiac involvement and 79% were still symptomatic. Our findings suggest long-lasting immune protection after SARS-CoV-2 infection, while also highlight the risk of immune evasive variants and long-term consequences for COVID-19 survivors.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Immunologic Memory , Models, Immunological , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , COVID-19/diagnostic imaging , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prospective Studies , Tomography, X-Ray Computed
20.
Annu Rev Immunol ; 39: 667-693, 2021 04 26.
Article in English | MEDLINE | ID: covidwho-1457607

ABSTRACT

Traditionally, the innate and adaptive immune systems are differentiated by their specificity and memory capacity. In recent years, however, this paradigm has shifted: Cells of the innate immune system appear to be able to gain memory characteristics after transient stimulation, resulting in an enhanced response upon secondary challenge. This phenomenon has been called trained immunity. Trained immunity is characterized by nonspecific increased responsiveness, mediated via extensive metabolic and epigenetic reprogramming. Trained immunity explains the heterologous effects of vaccines, which result in increased protection against secondary infections. However, in chronic inflammatory conditions, trained immunity can induce maladaptive effects and contribute to hyperinflammation and progression of cardiovascular disease, autoinflammatory syndromes, and neuroinflammation. In this review we summarize the current state of the field of trained immunity, its mechanisms, and its roles in both health and disease.


Subject(s)
Immunologic Memory , Vaccines , Animals , Cell Differentiation , Humans , Immune System , Immunity, Innate
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