RESUMEN
Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with increasing ability to evade neutralizing antibodies have emerged. Thus, earlier interest in defining the correlates of protection from infection, mainly mediated by humoral immunity, has shifted to correlates of protection from disease, which require a more comprehensive analysis of both humoral and cellular immunity. In this review, we summarized the evidence that supports the role of SARS-CoV-2-specific T cells induced by infection, by vaccination or by their combination (defined as hybrid immunity) in disease protection. We then analyzed the different epidemiological and virological variables that can modify the magnitude, function, and anatomical localization of SARS-CoV-2-specific T cells and their influence in the possible ability of T cells to protect the host from severe COVID-19 development.
Asunto(s)
COVID-19 , SARS-CoV-2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Humanos , Inmunidad Humoral , Pandemias , Linfocitos T , VacunaciónRESUMEN
Individuals with potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not necessarily develop PCR or antibody positivity, suggesting that some individuals may clear subclinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1-3. Here we hypothesize that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-2 (refs. 4-11), would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T cells, including those against the early transcribed replication-transcription complex (RTC)12,13, in intensively monitored healthcare workers (HCWs) who tested repeatedly negative according to PCR, antibody binding and neutralization assays (seronegative HCWs (SN-HCWs)). SN-HCWs had stronger, more multispecific memory T cells compared with a cohort of unexposed individuals from before the pandemic (prepandemic cohort), and these cells were more frequently directed against the RTC than the structural-protein-dominated responses observed after detectable infection (matched concurrent cohort). SN-HCWs with the strongest RTC-specific T cells had an increase in IFI27, a robust early innate signature of SARS-CoV-2 (ref. 14), suggesting abortive infection. RNA polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA polymerase was preferentially targeted (among the regions tested) by T cells from prepandemic cohorts and SN-HCWs. RTC-epitope-specific T cells that cross-recognized HCoV variants were identified in SN-HCWs. Enriched pre-existing RNA-polymerase-specific T cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T cells as targets for vaccines against endemic and emerging Coronaviridae.
Asunto(s)
Infecciones Asintomáticas , COVID-19/inmunología , COVID-19/virología , ARN Polimerasas Dirigidas por ADN/inmunología , Células T de Memoria/inmunología , SARS-CoV-2/inmunología , Seroconversión , Proliferación Celular , Estudios de Cohortes , ARN Polimerasas Dirigidas por ADN/metabolismo , Evolución Molecular , Femenino , Personal de Salud , Humanos , Masculino , Proteínas de la Membrana/inmunología , Células T de Memoria/citología , Complejos Multienzimáticos/inmunología , SARS-CoV-2/enzimología , SARS-CoV-2/crecimiento & desarrollo , Transcripción Genética/inmunologíaRESUMEN
Memory T cells induced by previous pathogens can shape susceptibility to, and the clinical severity of, subsequent infections1. Little is known about the presence in humans of pre-existing memory T cells that have the potential to recognize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we studied T cell responses against the structural (nucleocapsid (N) protein) and non-structural (NSP7 and NSP13 of ORF1) regions of SARS-CoV-2 in individuals convalescing from coronavirus disease 2019 (COVID-19) (n = 36). In all of these individuals, we found CD4 and CD8 T cells that recognized multiple regions of the N protein. Next, we showed that patients (n = 23) who recovered from SARS (the disease associated with SARS-CoV infection) possess long-lasting memory T cells that are reactive to the N protein of SARS-CoV 17 years after the outbreak of SARS in 2003; these T cells displayed robust cross-reactivity to the N protein of SARS-CoV-2. We also detected SARS-CoV-2-specific T cells in individuals with no history of SARS, COVID-19 or contact with individuals who had SARS and/or COVID-19 (n = 37). SARS-CoV-2-specific T cells in uninfected donors exhibited a different pattern of immunodominance, and frequently targeted NSP7 and NSP13 as well as the N protein. Epitope characterization of NSP7-specific T cells showed the recognition of protein fragments that are conserved among animal betacoronaviruses but have low homology to 'common cold' human-associated coronaviruses. Thus, infection with betacoronaviruses induces multi-specific and long-lasting T cell immunity against the structural N protein. Understanding how pre-existing N- and ORF1-specific T cells that are present in the general population affect the susceptibility to and pathogenesis of SARS-CoV-2 infection is important for the management of the current COVID-19 pandemic.
Asunto(s)
Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Neumonía Viral/inmunología , Síndrome Respiratorio Agudo Grave/inmunología , Linfocitos T/inmunología , Betacoronavirus/química , COVID-19 , Estudios de Casos y Controles , Infecciones por Coronavirus/virología , Proteínas de la Nucleocápside de Coronavirus , Reacciones Cruzadas/inmunología , Humanos , Epítopos Inmunodominantes/inmunología , Proteínas de la Nucleocápside/química , Proteínas de la Nucleocápside/inmunología , Pandemias , Fosfoproteínas , Neumonía Viral/virología , SARS-CoV-2RESUMEN
The responses of CD8+ T cells to hepatotropic viruses such as hepatitis B range from dysfunction to differentiation into effector cells, but the mechanisms that underlie these distinct outcomes remain poorly understood. Here we show that priming by Kupffer cells, which are not natural targets of hepatitis B, leads to differentiation of CD8+ T cells into effector cells that form dense, extravascular clusters of immotile cells scattered throughout the liver. By contrast, priming by hepatocytes, which are natural targets of hepatitis B, leads to local activation and proliferation of CD8+ T cells but not to differentiation into effector cells; these cells form loose, intravascular clusters of motile cells that coalesce around portal tracts. Transcriptomic and chromatin accessibility analyses reveal unique features of these dysfunctional CD8+ T cells, with limited overlap with those of exhausted or tolerant T cells; accordingly, CD8+ T cells primed by hepatocytes cannot be rescued by treatment with anti-PD-L1, but instead respond to IL-2. These findings suggest immunotherapeutic strategies against chronic hepatitis B infection.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Reactividad Cruzada/inmunología , Virus de la Hepatitis B/inmunología , Hepatocitos/inmunología , Hepatocitos/virología , Animales , Antígeno B7-H1/antagonistas & inhibidores , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular , Cromatina/metabolismo , Femenino , Hepatitis B/tratamiento farmacológico , Hepatitis B/inmunología , Hepatitis B/virología , Humanos , Tolerancia Inmunológica , Interleucina-2/inmunología , Interleucina-2/uso terapéutico , Macrófagos del Hígado/inmunología , Activación de Linfocitos , Masculino , Ratones , Transcriptoma/genéticaRESUMEN
The emergence of new SARS-CoV-2 lineages able to escape antibodies elicited by infection or vaccination based on the Spike protein of the Wuhan isolates has reduced the ability of Spike-specific antibodies to protect previously infected or vaccinated individuals from infection. Therefore, the role played by T cells in the containment of viral replication and spread after infection has taken a more central stage. In this brief review, we will discuss the role played by T cells in the protection from COVID-19, with a particular emphasis on the kinetics of the T cell response and its localization at the site of primary infection.
Asunto(s)
COVID-19 , SARS-CoV-2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Humanos , Cinética , Glicoproteína de la Espiga del Coronavirus , Linfocitos T , VacunaciónRESUMEN
BACKGROUND & AIMS: Chronic hepatitis B virus (HBV) infection is characterized by the presence of defective viral envelope proteins (hepatitis B surface antigen [HBsAg]) and the duration of infection-most patients acquire the infection at birth or during the first years of life. We investigated the effects of these factors on patients' lymphocyte and HBV-specific T-cell populations. METHODS: We collected blood samples and clinical data from 243 patients with HBV infection (3-75 years old) in the United Kingdom and China. We measured levels of HBV DNA, HBsAg, hepatitis B e antigen, and alanine aminotransferase; analyzed HBV genotypes; and isolated peripheral blood mononuclear cells (PBMCs). In PBMCs from 48 patients with varying levels of serum HBsAg, we measured 40 markers on nature killer and T cells by mass cytometry. PBMCs from 189 patients with chronic infection and 38 patients with resolved infections were incubated with HBV peptide libraries, and HBV-specific T cells were identified by interferon gamma enzyme-linked immune absorbent spot (ELISpot) assays or flow cytometry. We used multivariate linear regression and performed variable selection using the Akaike information criterion to identify covariates associated with HBV-specific responses of T cells. RESULTS: Although T- and natural killer cell phenotypes and functions did not change with level of serum HBsAg, numbers of HBs-specific T cells correlated with serum levels of HBsAg (r = 0.3367; P < .00001). After we performed the variable selection, the multivariate linear regression model identified patient age as the only factor significantly associated with numbers of HBs-specific T cells (P = .000115). In patients younger than 30 years, HBs-specific T cells constituted 28.26% of the total HBV-specific T cells; this value decreased to 7.14% in patients older than 30 years. CONCLUSIONS: In an analysis of immune cells from patients with chronic HBV infection, we found that the duration of HBsAg exposure, rather than the quantity of HBsAg, was associated with the level of anti-HBV immune response. Although the presence of HBs-specific T cells might not be required for the clearance of HBV infection in all patients, strategies to restore anti-HBV immune responses should be considered in patients younger than 30 years.
Asunto(s)
Antígenos de Superficie de la Hepatitis B/inmunología , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Linfocitos T/inmunología , Adolescente , Adulto , Factores de Edad , Antivirales/uso terapéutico , Células Cultivadas , Niño , Preescolar , ADN Viral/aislamiento & purificación , Femenino , Antígenos de Superficie de la Hepatitis B/sangre , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/aislamiento & purificación , Hepatitis B Crónica/sangre , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Humanos , Células Asesinas Naturales/inmunología , Masculino , Persona de Mediana Edad , Cultivo Primario de Células , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND & AIMS: Knowledge about the regulation of anti-HBV humoral immunity during natural HBV infection is limited. We recently utilized dual fluorochrome-conjugated HBsAg to demonstrate, in patients with chronic HBV (CHB) infection, the functional impairment of their HBsAg-specific B cells. However, the features of their HBcAg-specific B cells are unknown. Here we developed a method to directly visualize, select and characterize HBcAg-specific B cells in parallel with HBsAg-specific B cells. METHODS: Fluorochrome-conjugated HBcAg reagents were synthesized and utilized to directly detect ex vivo HBcAg-specific B cells in 36 patients with CHB. The frequency, phenotype, functional maturation and transcriptomic profile of HBcAg-specific B cells was studied by flow cytometry, in vitro maturation assays and NanoString-based detection of expression of immune genes, which we compared with HBsAg-specific B cells and total B cells. RESULTS: HBcAg-specific B cells are present at a higher frequency than HBsAg-specific B cells in patients with CHB and, unlike HBsAg-specific B cells, they mature efficiently into antibody-secreting cells in vitro. Their phenotypic and transcriptomic profiles show that HBcAg-specific B cells are preferentially IgG+ memory B cells. However, despite their phenotypic and functional differences, HBcAg- and HBsAg-specific B cells from patients with CHB share an mRNA expression pattern that differs from global memory B cells and is characterized by high expression of genes indicative of cross-presentation and innate immune activity. CONCLUSIONS: During chronic HBV infection, a direct relation exists between serological detection of anti-HBs and anti-HBc antibodies, and the quantity and function of their respective specific B cells. However, the transcriptomic analysis performed in HBsAg- and HBcAg-specific B cells suggests additional roles of HBV-specific B cells beyond the production of antibodies. LAY SUMMARY: Protection of viral infection necessitates the production of antibodies that are generated by specialized cells of the immune system called B cells. During chronic HBV infection, antibodies against the internal part of the virus (core or HBcAg) are detectable while the antibodies directed against the virus envelope (surface or HBsAg) are not present. Here we developed a method that allows us to directly visualize ex vivo the B cells specific for these 2 viral components, highlighting their differences and similarities, and showing how 2 components of the same virus can have different impacts on the function of antiviral B cells.
Asunto(s)
Linfocitos B/inmunología , Antígenos del Núcleo de la Hepatitis B/inmunología , Antígenos de Superficie de la Hepatitis B/inmunología , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Proteínas de la Nucleocápside/inmunología , Proteínas del Envoltorio Viral/inmunología , Adolescente , Adulto , Niño , Estudios de Cohortes , ADN Viral/sangre , ADN Viral/inmunología , Femenino , Anticuerpos contra la Hepatitis B/sangre , Hepatitis B Crónica/sangre , Hepatitis B Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Transcriptoma , Adulto JovenRESUMEN
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is often associated with hepatitis B virus (HBV) infection. Cells of most HBV-related HCCs contain HBV-DNA fragments that do not encode entire HBV antigens. We investigated whether these integrated HBV-DNA fragments encode epitopes that are recognized by T cells and whether their presence in HCCs can be used to select HBV-specific T-cell receptors (TCRs) for immunotherapy. METHODS: HCC cells negative for HBV antigens, based on immunohistochemistry, were analyzed for the presence of HBV messenger RNAs (mRNAs) by real-time polymerase chain reaction, sequencing, and Nanostring approaches. We tested the ability of HBV mRNA-positive HCC cells to generate epitopes that are recognized by T cells using HBV-specific T cells and TCR-like antibodies. We then analyzed HBV gene expression profiles of primary HCCs and metastases from 2 patients with HCC recurrence after liver transplantation. Using the HBV-transcript profiles, we selected, from a library of TCRs previously characterized from patients with self-limited HBV infection, the TCR specific for the HBV epitope encoded by the detected HBV mRNA. Autologous T cells were engineered to express the selected TCRs, through electroporation of mRNA into cells, and these TCR T cells were adoptively transferred to the patients in increasing numbers (1 × 104-10 × 106 TCR+ T cells/kg) weekly for 112 days or 1 year. We monitored patients' liver function, serum levels of cytokines, and standard blood parameters. Antitumor efficacy was assessed based on serum levels of alpha fetoprotein and computed tomography of metastases. RESULTS: HCC cells that did not express whole HBV antigens contained short HBV mRNAs, which encode epitopes that are recognized by and activate HBV-specific T cells. Autologous T cells engineered to express TCRs specific for epitopes expressed from HBV-DNA in patients' metastases were given to 2 patients without notable adverse events. The cells did not affect liver function over a 1-year period. In 1 patient, 5 of 6 pulmonary metastases decreased in volume during the 1-year period of T-cell administration. CONCLUSIONS: HCC cells contain short segments of integrated HBV-DNA that encodes epitopes that are recognized by and activate T cells. HBV transcriptomes of these cells could be used to engineer T cells for personalized immunotherapy. This approach might be used to treat a wider population of patients with HBV-associated HCC.
Asunto(s)
Carcinoma Hepatocelular/terapia , ADN Viral , Virus de la Hepatitis B/genética , Inmunoterapia Adoptiva/métodos , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/terapia , Recurrencia Local de Neoplasia/genética , Linfocitos T/inmunología , Transcriptoma/inmunología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/secundario , Carcinoma Hepatocelular/virología , Línea Celular Tumoral , Electroporación , Epítopos de Linfocito T/biosíntesis , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Antígenos de la Hepatitis B/genética , Antígenos de la Hepatitis B/inmunología , Humanos , Inmunoterapia Adoptiva/efectos adversos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Trasplante de Hígado , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Biosíntesis de Proteínas , ARN Viral/genética , Receptores de Antígenos de Linfocitos T , Integración Viral , alfa-Fetoproteínas/metabolismoRESUMEN
The natural killer (NK) group 2 member D (NKG2D) is an activating immune receptor expressed on NK cells, cytotoxic T cells and a subset of other T cells. It has an important role in the recognition and lysis of a variety of infected and tumor cells. Despite significant gains in our understanding of NKG2D, the relevance of NKG2D and its ligands in human diseases has only recently started to emerge. Here, we present an overview of the recent advances in NKG2D biology, discuss the expression of NKG2D ligands in cancer patients and evaluate the diagnostic and prognostic potential of NKG2D ligands.
Asunto(s)
Células Asesinas Naturales/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Animales , Línea Celular Tumoral , Humanos , Ligandos , Neoplasias/inmunología , Neoplasias/patología , SolubilidadRESUMEN
SARS-CoV-2 infections manifest with a broad spectrum of presentations, ranging from asymptomatic infections to severe pneumonia and fatal outcomes. This review centers on asymptomatic infections, a widely reported phenomenon that has substantially contributed to the rapid spread of the pandemic. In such asymptomatic infections, we focus on the role of innate, humoral, and cellular immunity. Notably, asymptomatic infections are characterized by an early and robust innate immune response, particularly a swift type 1 IFN reaction, alongside a rapid and broad induction of SARS-CoV-2-specific T cells. Often, antibody levels tend to be lower or undetectable after asymptomatic infections, suggesting that the rapid control of viral replication by innate and cellular responses might impede the full triggering of humoral immunity. Even if antibody levels are present in the early convalescent phase, they wane rapidly below serological detection limits, particularly following asymptomatic infection. Consequently, prevalence studies reliant solely on serological assays likely underestimate the extent of community exposure to the virus.
Asunto(s)
COVID-19 , Humanos , SARS-CoV-2 , Infecciones Asintomáticas , Anticuerpos Antivirales , Inmunidad InnataRESUMEN
Fluorescently conjugated antigen-bait systems have been extensively used to identify antigen-specific B cells and probe humoral immunity across different settings. Following this approach, we used HBV antigens to bind the B cell receptor (BCR), permitting antigen-specific B cell detection by flow cytometry. Fluorochromes can either be attached covalently via chemical conjugation to the antigen or attached non-covalently by biotinylating the antigen. Dual-staining antigen-baits (where an antigen is directly conjugated to two distinct fluorochromes) have now been used to identify HBsAg- and HBcAg-specific B cells with a high degree of reliability and specificity. This system can be used to detect and characterize cells ex vivo or adapted to isolate antigen-specific cells using fluorescence-activated cell sorting.
Asunto(s)
Linfocitos B , Citometría de Flujo , Colorantes Fluorescentes , Antígenos de Superficie de la Hepatitis B , Virus de la Hepatitis B , Hepatitis B Crónica , Humanos , Citometría de Flujo/métodos , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/virología , Virus de la Hepatitis B/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Antígenos de Superficie de la Hepatitis B/inmunología , Colorantes Fluorescentes/química , Coloración y Etiquetado/métodos , Receptores de Antígenos de Linfocitos B/metabolismo , Receptores de Antígenos de Linfocitos B/inmunología , Antígenos del Núcleo de la Hepatitis B/inmunologíaRESUMEN
The early and mid-career researchers (EMCRs) of scientific communities represent the forefront of research and the future direction in which a field takes. The opinions of this key demographic are not commonly aggregated to audit fields and precisely demonstrate where challenges lie for the future. To address this, we initiated the inaugural International Emerging Researchers Workshop for the global Hepatitis B and Hepatitis D scientific community (75 individuals). The cohort was split into small discussion groups and the significant problems, challenges, and future directions were assessed. Here, we summarise the outcome of these discussions and outline the future directions suggested by the EMCR community. We show an effective approach to gauging and accumulating the ideas of EMCRs and provide a succinct summary of the significant gaps remaining in the Hepatitis B and Hepatitis D field.
Asunto(s)
Hepatitis B , Hepatitis D , Humanos , Hepatitis B/virología , Hepatitis D/virología , Investigación Biomédica , Investigadores , Virus de la Hepatitis BRESUMEN
BACKGROUND: Hybrid immunity to SARS-CoV-2, resulting from both vaccination and natural infection, remains insufficiently understood in paediatric populations, despite increasing rates of breakthrough infections among vaccinated children. METHODS: We conducted a prospective longitudinal study to investigate the magnitude, specificity, and cytokine profile of antigen-specific T cell responses elicited by breakthrough SARS-CoV-2 infection in a cohort of mRNA-vaccinated children (n = 29) aged 5-11. This longitudinal analysis involved six distinct time points spanning a 16-month period post-vaccination, during which we analysed a total of 159 blood samples. All children who were followed for at least 12 months (n = 26) experienced a breakthrough infection. We conducted cytokine release assays using minimal blood samples, and we verified the cellular origin of these responses through intracellular cytokine staining. FINDINGS: After breakthrough infection, children who had received mRNA vaccines showed enhanced Th1 responses specific to Spike peptides. Additionally, their Spike-specific T cells exhibited a distinctive enrichment of CD4+ IFN-γ+IL10+ cells, a characteristic akin to adults with hybrid immunity. Importantly, vaccination did not impede the development of multi-specific T cell responses targeting Membrane, Nucleoprotein, and ORF3a/7/8 antigens. INTERPRETATION: Children, previously primed with a Spike-based mRNA vaccine and experiencing either symptomatic or asymptomatic breakthrough infection, retained the ability to enhance and diversify Th1/IL-10 antigen-specific T cell responses against multiple SARS-CoV-2 proteins. These findings mirror characteristics associated with hybrid cellular immunity in adults, known to confer resistance against severe COVID-19. FUNDING: This study was funded by the National Medical Research Council (NMRC) Singapore (COVID19RF-0019, MOH-000019, MOH-000535, OFLCG19May-0034 and MOH-OFYIRG19nov-0002).
Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/prevención & control , COVID-19/virología , SARS-CoV-2/inmunología , Niño , Estudios Longitudinales , Masculino , Femenino , Preescolar , Citocinas/metabolismo , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Estudios Prospectivos , Vacunación , Vacunas de ARNm/inmunología , Linfocitos T/inmunología , Células TH1/inmunologíaRESUMEN
The paucity of information on longevity of vaccine-induced immune responses and uncertainty of the correlates of protection hinder the development of evidence-based COVID-19 vaccination policies for new birth cohorts. Here, to address these knowledge gaps, we conducted a cohort study of healthy 5-12-year-olds vaccinated with BNT162b2. We serially measured binding and neutralizing antibody titers (nAbs), spike-specific memory B cell (MBC) and spike-reactive T cell responses over 1 year. We found that children mounted antibody, MBC and T cell responses after two doses of BNT162b2, with higher antibody and T cell responses than adults 6 months after vaccination. A booster (third) dose only improved antibody titers without impacting MBC and T cell responses. Among children with hybrid immunity, nAbs and T cell responses were highest in those infected after two vaccine doses. Binding IgG titers, MBC and T cell responses were predictive, with T cells being the most important predictor of protection against symptomatic infection before hybrid immunity; nAbs only correlated with protection after hybrid immunity. The stable MBC and T cell responses over time suggest sustained protection against symptomatic SARS-CoV-2 infection, even when nAbs wane. Booster vaccinations do not confer additional immunological protection to healthy children.
Asunto(s)
Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacuna BNT162 , COVID-19 , SARS-CoV-2 , Linfocitos T , Vacunación , Humanos , Niño , COVID-19/inmunología , COVID-19/prevención & control , SARS-CoV-2/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Preescolar , Femenino , Masculino , Vacuna BNT162/inmunología , Vacuna BNT162/administración & dosificación , Linfocitos T/inmunología , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Células B de Memoria/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Estudios de Cohortes , Inmunización Secundaria , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangreRESUMEN
There is little information on BNT162b2 vaccine-induced variant-specific immunogenicity, safety data and dynamics of breakthrough infections in pediatric populations. We addressed these questions using a prospective two dose BNT162b2 (10 mcg) vaccination cohort study of healthy children 5-11 years in Singapore. Follow up included blood samples at scheduled visits, daily vaccination symptom diary and confirmation of SARS-CoV-2 infection. Surrogate virus neutralization test (sVNT) and spike-specific T cell responses against SARS-CoV-2 variants were performed. The mean age of 127 participants was 8.27 years (SD 1.95) and 51.2% were males. The median sVNT level against original variant after 1 dose and 2 dose vaccination was 61.4% and 95.1% respectively (p < 0.0001). Neutralizing antibodies against the Omicron variant was the lowest, median 22.4% (IQR 16.5-30.8). However, T cell IFN-γ cytokine response against Omicron variant was high and remained so about 4 months after vaccination. Fever rate increased significantly from 4% (dose 1) to 11.5% (dose 2). The risk of Omicron breakthrough infection decreased by 7.8% for every 1% increase in sVNT inhibition level measured after dose 2 vaccination. BNT162b2 vaccines were safe, induced good T cell responses but poor neutralizing antibodies against Omicron in children. Low neutralizing antibody levels post-vaccination was predictive of subsequent breakthrough infection.
Asunto(s)
COVID-19 , Vacunas , Masculino , Humanos , Niño , Anciano de 80 o más Años , Femenino , Vacuna BNT162 , Infección Irruptiva , Estudios de Cohortes , Estudios Prospectivos , COVID-19/prevención & control , SARS-CoV-2 , Vacunación , Anticuerpos Neutralizantes , Anticuerpos AntiviralesRESUMEN
Solid organ transplant (SOT) recipients receive immunosuppressive drugs (ISDs) and are susceptible to developing severe COVID-19. Here, we analyze the Spike-specific T-cell response after 3 doses of mRNA vaccine in a group of SOT patients (n = 136) treated with different ISDs. We demonstrate that a combination of a calcineurin inhibitor (CNI), mycophenolate mofetil (MMF), and prednisone (Pred) treatment regimen strongly suppressed the mRNA vaccine-induced Spike-specific cellular response. Such defects have clinical consequences because the magnitude of vaccine-induced Spike-specific T cells was directly proportional to the ability of SOT patients to rapidly clear SARS-CoV-2 after breakthrough infection. To then compensate for the T-cell defects induced by immunosuppressive treatment and to develop an alternative therapeutic strategy for SOT patients, we describe production of 6 distinct SARS-CoV-2 epitope-specific ISD-resistant T-cell receptor (TCR)-T cells engineered using the mRNA electroporation method with reactivity minimally affected by mutations occurring in Beta, Delta, Gamma, and Omicron variants. This strategy with transient expression characteristics marks an improvement in the immunotherapeutic field and provides an attractive and novel therapeutic possibility for immunosuppressed COVID-19 patients.