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1.
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
2.
Open Forum Infect Dis ; 9(10): ofac490, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2062949

ABSTRACT

Although numerous studies have evaluated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using cycle threshold (Ct) values as a surrogate of viral ribonucleic acid (RNA) load, few studies have used standardized, quantitative methods. We validated a quantitative SARS-CoV-2 digital polymerase chain reaction assay normalized to World Health Organization International Units and correlated viral RNA load with symptoms and disease severity.

3.
Methods Mol Biol ; 2574: 309-366, 2022.
Article in English | MEDLINE | ID: covidwho-2059679

ABSTRACT

Paired- and single-chain T cell receptor (TCR) sequencing are now commonly used techniques for interrogating adaptive immune responses. TCRs targeting the same epitope frequently share motifs consisting of critical contact residues. Here we illustrate the key features of tcrdist3, a new Python package for distance-based TCR analysis through a series of three interactive examples. In the first example, we illustrate how tcrdist3 can integrate sequence similarity networks, gene-usage plots, and background-adjusted CDR3 logos to identify TCR sequence features conferring antigen specificity among sets of peptide-MHC-multimer sorted receptors. In the second example, we show how the TCRjoin feature in tcrdist3 can be used to flexibly query receptor sequences of interest against bulk repertoires or libraries of previously annotated TCRs based on matching of similar sequences. In the third example, we show how the TCRdist metric can be leveraged to identify candidate polyclonal receptors under antigenic selection in bulk repertoires based on sequence neighbor enrichment testing, a statistical approach similar to TCRNET and ALICE algorithms, but with added flexibility in how the neighborhood can be defined.


Subject(s)
Antigens , Receptors, Antigen, T-Cell , Algorithms , Epitopes
4.
Sci Adv ; 8(34): eade3956, 2022 Aug 26.
Article in English | MEDLINE | ID: covidwho-2001756

ABSTRACT

Improved adenovirus-based COVID-19 vaccines provide an important tool to combat the ever-evolving virus.

6.
Cell Rep Med ; 3(8): 100697, 2022 08 16.
Article in English | MEDLINE | ID: covidwho-1915084

ABSTRACT

The current strategy to detect immunodominant T cell responses focuses on the antigen, employing large peptide pools to screen for functional cell activation. However, these approaches are labor and sample intensive and scale poorly with increasing size of the pathogen peptidome. T cell receptors (TCRs) recognizing the same epitope frequently have highly similar sequences, and thus, the presence of large sequence similarity clusters in the TCR repertoire likely identify the most public and immunodominant responses. Here, we perform a meta-analysis of large, publicly available single-cell and bulk TCR datasets from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals to identify public CD4+ responses. We report more than 1,200 αßTCRs forming six prominent similarity clusters and validate histocompatibility leukocyte antigen (HLA) restriction and epitope specificity predictions for five clusters using transgenic T cell lines. Collectively, these data provide information on immunodominant CD4+ T cell responses to SARS-CoV-2 and demonstrate the utility of the reverse epitope discovery approach.


Subject(s)
COVID-19 , SARS-CoV-2 , CD4-Positive T-Lymphocytes/chemistry , Epitopes/analysis , Humans , Receptors, Antigen, T-Cell/genetics , T-Cell Antigen Receptor Specificity
7.
PLoS One ; 17(5): e0268237, 2022.
Article in English | MEDLINE | ID: covidwho-1910639

ABSTRACT

COVID-19 remains a challenge worldwide, and testing of asymptomatic individuals remains critical to pandemic control measures. Starting March 2020, a total of 7497 hospital employees were tested at least weekly for SARS CoV-2; the cumulative incidence of asymptomatic infections was 5.64%. Consistently over a 14-month period half of COVID-19 infections (414 of 820, total) were detected through the asymptomatic screening program, a third of whom never developed any symptoms during follow-up. Prompt detection and isolation of these cases substantially reduced the risk of potential workplace and outside of workplace transmission. COVID-19 vaccinations of the workforce were initiated in December 2020. Twenty-one individuals tested positive after being fully vaccinated (3.9 per 1000 vaccinated). Most (61.9%) remained asymptomatic and in majority (75%) the virus could not be sequenced due to low template RNA levels in swab samples. Further routine testing of vaccinated asymptomatic employees was stopped and will be redeployed if needed; routine testing for those not vaccinated continues. Asymptomatic SARS-CoV-2 testing, as a part of enhanced screening, monitors local dynamics of the COVID-19 pandemic and can provide valuable data to assess the ongoing impact of COVID-19 vaccination and SARS-CoV-2 variants, inform risk mitigation, and guide adaptive, operational planning including titration of screening strategies over time, based on infection risk modifiers such as vaccination.


Subject(s)
COVID-19 , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Testing , COVID-19 Vaccines , Humans , Pandemics/prevention & control , SARS-CoV-2 , Workforce
8.
Nat Commun ; 13(1): 2774, 2022 05 19.
Article in English | MEDLINE | ID: covidwho-1900484

ABSTRACT

Respiratory tract infection with SARS-CoV-2 results in varying immunopathology underlying COVID-19. We examine cellular, humoral and cytokine responses covering 382 immune components in longitudinal blood and respiratory samples from hospitalized COVID-19 patients. SARS-CoV-2-specific IgM, IgG, IgA are detected in respiratory tract and blood, however, receptor-binding domain (RBD)-specific IgM and IgG seroconversion is enhanced in respiratory specimens. SARS-CoV-2 neutralization activity in respiratory samples correlates with RBD-specific IgM and IgG levels. Cytokines/chemokines vary between respiratory samples and plasma, indicating that inflammation should be assessed in respiratory specimens to understand immunopathology. IFN-α2 and IL-12p70 in endotracheal aspirate and neutralization in sputum negatively correlate with duration of hospital stay. Diverse immune subsets are detected in respiratory samples, dominated by neutrophils. Importantly, dexamethasone treatment does not affect humoral responses in blood of COVID-19 patients. Our study unveils differential immune responses between respiratory samples and blood, and shows how drug therapy affects immune responses during COVID-19.


Subject(s)
COVID-19 , Antibodies, Viral , Humans , Immunity , Immunoglobulin G , Immunoglobulin M , Respiratory System , SARS-CoV-2 , Severity of Illness Index , Spike Glycoprotein, Coronavirus
9.
Vaccines (Basel) ; 10(5)2022 May 20.
Article in English | MEDLINE | ID: covidwho-1875823

ABSTRACT

Longitudinal data comparing SARS-CoV-2 serology in individuals following infection and vaccination over 12 months are limited. This study compared the magnitude, decay, and variability in serum IgG, IgA, and neutralizing activity induced by natural infection (n = 218) or mRNA vaccination in SARS-CoV-2 naïve (n = 143) or experienced (n = 122) individuals over time using enzyme-linked immunosorbent assays and an in vitro virus neutralization assay. Serological responses were found to be highly variable after natural infection compared with vaccination but durable through 12 months. Antibody levels in vaccinated, SARS-CoV-2 naïve individuals peaked by 1 month then declined through 9 months, culminating in non-detectable SARS-CoV-2-specific serum IgA. Individuals with both infection and vaccination showed SARS-CoV-2-specific IgG and IgA levels that were more robust and slower to decline than the other groups; neutralizing activity remained highest in this group at 9 months past vaccination. These data reinforce the benefit of vaccination after SARS-CoV-2 recovery.

10.
Clin Infect Dis ; 2021 Dec 10.
Article in English | MEDLINE | ID: covidwho-1852985

ABSTRACT

BACKGROUND: Following SARS-CoV-2 infection or vaccination there is significant variability between individuals in protective antibody levels against SARS-CoV-2, and within individuals against different virus variants. However, host demographic or clinical characteristics that predict variability in cross-reactive antibody levels are not well-described. These data could inform clinicians, researchers, and policy makers on the populations most likely to require vaccine booster shots. METHODS: In an institutional review board-approved prospective observational cohort study of staff at St. Jude Children's Research Hospital, we identified participants with plasma samples collected after SARS-CoV-2 infection, after mRNA vaccination, and after vaccination following infection, and quantitated IgG levels by ELISA to the spike receptor binding domain (RBD) from five important SARS-CoV-2 variants (Wuhan Hu-1, B.1.1.7, B.1.351, P.1 and B.1.617.2). We used regression models to identify factors that contributed to cross-reactive IgG against one or multiple viral variants. RESULTS: Following infection, a minority of the cohort generated cross-reactive antibodies, IgG antibodies that bound all tested variants. Those that did had increased disease severity, poor metabolic health, and were of a particular ancestry. Vaccination increased the levels of cross-reactive IgG levels in all populations including immunocompromised, elderly and persons with poor metabolic health. Younger people with a healthy weight mounted the highest responses. CONCLUSIONS: Our findings provide important new information on individual antibody responses to infection/vaccination that could inform clinicians on the populations that may require follow-on immunization.

11.
mSphere ; 7(3): e0017922, 2022 06 29.
Article in English | MEDLINE | ID: covidwho-1854243

ABSTRACT

To understand reinfection rates and correlates of protection for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we established eight different longitudinal cohorts in 2020 under the umbrella of the PARIS (Protection Associated with Rapid Immunity to SARS-CoV-2)/SPARTA (SARS SeroPrevalence And Respiratory Tract Assessment) studies. Here, we describe the PARIS/SPARTA cohorts, the harmonized assays and analysis that are performed across the cohorts, as well as case definitions for SARS-CoV-2 infection and reinfection that have been established by the team of PARIS/SPARTA investigators. IMPORTANCE Determining reinfection rates and correlates of protection against SARS-CoV-2 infection induced by both natural infection and vaccination is of high significance for the prevention and control of coronavirus disease 2019 (COVID-19). Furthermore, understanding reinfections or infection after vaccination and the role immune escape plays in these scenarios will inform the need for updates of the current SARS-CoV-2 vaccines and help update guidelines suitable for the postpandemic world.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19 Vaccines , Humans , Reinfection , Seroepidemiologic Studies
12.
Immunity ; 55(5): 749-780, 2022 05 10.
Article in English | MEDLINE | ID: covidwho-1838899

ABSTRACT

The lungs are constantly exposed to inhaled debris, allergens, pollutants, commensal or pathogenic microorganisms, and respiratory viruses. As a result, innate and adaptive immune responses in the respiratory tract are tightly regulated and are in continual flux between states of enhanced pathogen clearance, immune-modulation, and tissue repair. New single-cell-sequencing techniques are expanding our knowledge of airway cellular complexity and the nuanced connections between structural and immune cell compartments. Understanding these varied interactions is critical in treatment of human pulmonary disease and infections and in next-generation vaccine design. Here, we review the innate and adaptive immune responses in the lung and airways following infection and vaccination, with particular focus on influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The ongoing SARS-CoV-2 pandemic has put pulmonary research firmly into the global spotlight, challenging previously held notions of respiratory immunity and helping identify new populations at high risk for respiratory distress.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/prevention & control , Humans , Immunity, Innate , Immunity, Mucosal , Lung , Vaccination
13.
Front Pediatr ; 9: 752993, 2021.
Article in English | MEDLINE | ID: covidwho-1779952

ABSTRACT

Objectives: Studies of household transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) focused on households with children are limited. We investigated household secondary attack rate (SAR), transmission dynamics, and contributing factors in households with children. Materials and Methods: In this prospective case-ascertained study in Los Angeles County, California, all households members were enrolled if ≥1 member tested positive for SARS-CoV-2 by polymerase chain reaction (PCR). Nasopharyngeal PCRs, serology, and symptom data were obtained over multiple visits. Results: A total of 489 individuals in 105 households were enrolled from June to December 2020. The majority (77.3%) reported a household annual income of <$50,000, and most (92.9%) were of Hispanic/Latinx ethnicity. Children <18 years old accounted for 46.9% index cases, of whom 45.3% were asymptomatic. Household index cases were predominantly children during low community transmission and adults during the high community transmission period (χ2 = 7.647, p = 0.0036. The mean household SAR was 77.0% (95% CI: 69.4-84.6%). Child and adult index cases both efficiently transmitted SARS-CoV-2 within households [81.9%, (95% CI: 72.1-91.9%) vs. 72.4% (95% CI: 59.8-85.1%), p = 0.23]. Household income and pets were significantly associated with higher SAR in the multivariable analysis of household factors (p = 0.0013 and 0.004, respectively). Conclusions: The SAR in households with children in an urban setting with a large ethnic minority population is much higher than previously described. Children play important roles as index cases. SAR was disproportionately impacted by household income. Vaccination and public health efforts need special focus on children and vulnerable communities to help mitigate SARS-CoV-2 spread.

14.
Nat Immunol ; 23(5): 781-790, 2022 05.
Article in English | MEDLINE | ID: covidwho-1778617

ABSTRACT

Although mRNA vaccine efficacy against severe coronavirus disease 2019 remains high, variant emergence has prompted booster immunizations. However, the effects of repeated exposures to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens on memory T cells are poorly understood. Here, we utilize major histocompatibility complex multimers with single-cell RNA sequencing to profile SARS-CoV-2-responsive T cells ex vivo from humans with one, two or three antigen exposures, including vaccination, primary infection and breakthrough infection. Exposure order determined the distribution between spike-specific and non-spike-specific responses, with vaccination after infection leading to expansion of spike-specific T cells and differentiation to CCR7-CD45RA+ effectors. In contrast, individuals after breakthrough infection mount vigorous non-spike-specific responses. Analysis of over 4,000 epitope-specific T cell antigen receptor (TCR) sequences demonstrates that all exposures elicit diverse repertoires characterized by shared TCR motifs, confirmed by monoclonal TCR characterization, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and current vaccination protocols continue to expand and differentiate spike-specific memory.


Subject(s)
COVID-19 , SARS-CoV-2 , CD8-Positive T-Lymphocytes , Humans , Phenotype , Receptors, Antigen, T-Cell/genetics , Spike Glycoprotein, Coronavirus/genetics , Vaccines, Synthetic , mRNA Vaccines
15.
Cell Rep Med ; 3(3): 100562, 2022 03 15.
Article in English | MEDLINE | ID: covidwho-1705044

ABSTRACT

Robust T cell responses have been associated with milder outcomes in many infections. T cells also establish long-term memory pools and, as they are predominantly directed toward epitopes encompassing conserved peptides, can respond to SARS-CoV-2 variants, including Omicron. Here, we discuss epitope-specific CD8+ and CD4+ T cell responses toward SARS-CoV-2 infection and vaccination, their subsequent persistence into long-term memory, and ongoing work to determine their role in limiting disease severity.


Subject(s)
COVID-19 , SARS-CoV-2 , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , COVID-19/prevention & control , Epitopes , Humans , Immunologic Memory , Vaccination
16.
Nat Immunol ; 23(2): 177-185, 2022 02.
Article in English | MEDLINE | ID: covidwho-1671601

ABSTRACT

Children and adolescents exhibit a broad range of clinical outcomes from SARS-CoV-2 infection, with the majority having minimal to mild symptoms. Additionally, some succumb to a severe hyperinflammatory post-infectious complication called multisystem inflammatory syndrome in children (MIS-C), predominantly affecting previously healthy individuals. Studies characterizing the immunological differences associated with these clinical outcomes have identified pathways important for host immunity to SARS-CoV-2 and innate modulators of disease severity. In this Review, we delineate the immunological mechanisms underlying the spectrum of pediatric immune response to SARS-CoV-2 infection in comparison with that of adults.


Subject(s)
COVID-19/complications , COVID-19/immunology , Immunity, Innate , SARS-CoV-2/immunology , Systemic Inflammatory Response Syndrome/immunology , Adolescent , Adolescent Development , Age Factors , Asymptomatic Diseases , COVID-19/diagnosis , COVID-19/virology , Child , Child Development , Comorbidity , Host-Pathogen Interactions , Humans , Risk Factors , SARS-CoV-2/pathogenicity , Severity of Illness Index , Systemic Inflammatory Response Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/virology
17.
Cell Host Microbe ; 30(1): 83-96.e4, 2022 01 12.
Article in English | MEDLINE | ID: covidwho-1634725

ABSTRACT

SARS-CoV-2 infection causes diverse outcomes ranging from asymptomatic infection to respiratory distress and death. A major unresolved question is whether prior immunity to endemic, human common cold coronaviruses (hCCCoVs) impacts susceptibility to SARS-CoV-2 infection or immunity following infection and vaccination. Therefore, we analyzed samples from the same individuals before and after SARS-CoV-2 infection or vaccination. We found hCCCoV antibody levels increase after SARS-CoV-2 exposure, demonstrating cross-reactivity. However, a case-control study indicates that baseline hCCCoV antibody levels are not associated with protection against SARS-CoV-2 infection. Rather, higher magnitudes of pre-existing betacoronavirus antibodies correlate with more SARS-CoV-2 antibodies following infection, an indicator of greater disease severity. Additionally, immunization with hCCCoV spike proteins before SARS-CoV-2 immunization impedes the generation of SARS-CoV-2-neutralizing antibodies in mice. Together, these data suggest that pre-existing hCCCoV antibodies hinder SARS-CoV-2 antibody-based immunity following infection and provide insight on how pre-existing coronavirus immunity impacts SARS-CoV-2 infection, which is critical considering emerging variants.


Subject(s)
Antibodies, Viral/immunology , Antibody Formation/immunology , COVID-19/immunology , Common Cold/immunology , Immunity, Humoral/immunology , SARS-CoV-2/immunology , Animals , Asymptomatic Infections , COVID-19/virology , Case-Control Studies , Cell Line , Common Cold/virology , Cross Reactions/immunology , Female , HEK293 Cells , Humans , Mice , Mice, Inbred C57BL , Spike Glycoprotein, Coronavirus/immunology
18.
J Interferon Cytokine Res ; 41(12): 477-481, 2021 12.
Article in English | MEDLINE | ID: covidwho-1585196
19.
Cell ; 185(4): 603-613.e15, 2022 02 17.
Article in English | MEDLINE | ID: covidwho-1588149

ABSTRACT

SARS-CoV-2 mRNA vaccines induce robust anti-spike (S) antibody and CD4+ T cell responses. It is not yet clear whether vaccine-induced follicular helper CD4+ T (TFH) cell responses contribute to this outstanding immunogenicity. Using fine-needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we evaluated the T cell receptor sequences and phenotype of lymph node TFH. Mining of the responding TFH T cell receptor repertoire revealed a strikingly immunodominant HLA-DPB1∗04-restricted response to S167-180 in individuals with this allele, which is among the most common HLA alleles in humans. Paired blood and lymph node specimens show that while circulating S-specific TFH cells peak one week after the second immunization, S-specific TFH persist at nearly constant frequencies for at least six months. Collectively, our results underscore the key role that robust TFH cell responses play in establishing long-term immunity by this efficacious human vaccine.


Subject(s)
COVID-19/immunology , COVID-19/virology , Immunity/immunology , SARS-CoV-2/immunology , T Follicular Helper Cells/immunology , Vaccination , Vaccines, Synthetic/immunology , mRNA Vaccines/immunology , Adult , B-Lymphocytes/immunology , BNT162 Vaccine/immunology , COVID-19/blood , Clone Cells , Cohort Studies , Cytokines/metabolism , Female , Germinal Center/immunology , HLA-DP beta-Chains/immunology , Humans , Immunodominant Epitopes/immunology , Jurkat Cells , Lymph Nodes/metabolism , Male , Middle Aged , Peptides/chemistry , Peptides/metabolism , Protein Multimerization , Receptors, Antigen, T-Cell/metabolism
20.
Cell host & microbe ; 2021.
Article in English | EuropePMC | ID: covidwho-1564429

ABSTRACT

A major unresolved question is whether prior immunity to endemic, human common cold coronaviruses (hCCCoV) impacts susceptibility to SARS-CoV-2 infection. Lin et al. analyze hCCCoV antibodies in the same individuals before and after SARS-CoV-2 infection, finding pre-existing betacoronavirus antibodies may hinder SARS-CoV-2 effective immunity following infection.

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