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1.
Nat Microbiol ; 9(8): 2073-2083, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38890491

RESUMEN

Influenza exposures early in life are believed to shape future susceptibility to influenza infections by imprinting immunological biases that affect cross-reactivity to future influenza viruses. However, direct serological evidence linked to susceptibility is limited. Here we analysed haemagglutination-inhibition titres in 1,451 cross-sectional samples collected between 1992 and 2020, from individuals born between 1917 and 2008, against influenza B virus (IBV) isolates from 1940 to 2021. We included testing of 'future' isolates that circulated after sample collection. We show that immunological biases are conferred by early life IBV infection and result in lineage-specific cross-reactivity of a birth cohort towards future IBV isolates. This translates into differential estimates of susceptibility between birth cohorts towards the B/Yamagata and B/Victoria lineages, predicting lineage-specific birth-cohort distributions of observed medically attended IBV infections. Our data suggest that immunological measurements of imprinting could be important in modelling and predicting virus epidemiology.


Asunto(s)
Anticuerpos Antivirales , Reacciones Cruzadas , Virus de la Influenza B , Gripe Humana , Humanos , Virus de la Influenza B/inmunología , Reacciones Cruzadas/inmunología , Gripe Humana/inmunología , Gripe Humana/virología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Estudios Transversales , Femenino , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Masculino , Pruebas de Inhibición de Hemaglutinación , Cohorte de Nacimiento , Adulto , Persona de Mediana Edad , Susceptibilidad a Enfermedades/inmunología
2.
J Virol ; 98(6): e0160423, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38780249

RESUMEN

The global burden of disease caused by influenza B virus (IBV) is substantial; however, IBVs remain overlooked. Understanding host-pathogen interactions and establishing physiologically relevant models of infection are important for the development and assessment of therapeutics and vaccines against IBV. In this study, we assessed an upper respiratory tract (URT)-restricted model of mouse IBV infection, comparing it to the conventional administration of the virus to the total respiratory tract (TRT). We found that URT infections caused by different strains of IBV disseminate to the trachea but resulted in limited dissemination of IBV to the lungs. Infection of the URT did not result in weight loss or systemic inflammation even at high inoculum doses and despite robust viral replication in the nose. Dissemination of IBV to the lungs was enhanced in mice lacking functional type I IFN receptor (IFNAR2), but not IFNγ. Conversely, in mice expressing the IFN-inducible gene Mx1, we found reduced IBV replication in the lungs and reduced dissemination of IBV from the URT to the lungs. Inoculation of IBV in both the URT and TRT resulted in seroconversion against IBV. However, priming at the TRT conferred superior protection from a heterologous lethal IBV challenge compared to URT priming, as determined by improved survival rates and reduced viral replication throughout the respiratory tract. Overall, our study establishes a URT-restricted IBV infection model, highlights the critical role of IFNs in limiting dissemination of IBV to the lungs, and also demonstrates that the lack of viral replication in the lungs may impact protection from subsequent infections. IMPORTANCE: Our study investigated how influenza B virus (IBV) spreads from the nose to the lungs of mice and the impact this has on disease and protection from re-infection. We found that when applied to the nose only, IBV does not spread very efficiently to the lungs in a process controlled by the interferon response. Priming immunity at the nose only resulted in less protection from re-infection than priming immunity at both the nose and lungs. These insights can guide the development of potential therapies targeting the interferon response as well as of intranasal vaccines against IBV.


Asunto(s)
Virus de la Influenza B , Pulmón , Infecciones por Orthomyxoviridae , Replicación Viral , Animales , Ratones , Virus de la Influenza B/fisiología , Virus de la Influenza B/inmunología , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/virología , Pulmón/virología , Pulmón/inmunología , Modelos Animales de Enfermedad , Interferones/metabolismo , Interferones/inmunología , Proteínas de Resistencia a Mixovirus/metabolismo , Proteínas de Resistencia a Mixovirus/genética , Receptor de Interferón alfa y beta/genética , Receptor de Interferón alfa y beta/deficiencia , Ratones Endogámicos C57BL , Interacciones Huésped-Patógeno/inmunología , Infecciones del Sistema Respiratorio/virología , Infecciones del Sistema Respiratorio/inmunología , Femenino , Interferón gamma/metabolismo , Tráquea/virología
3.
Clin Transl Immunology ; 13(5): e1509, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38737448

RESUMEN

Objectives: Seasonal influenza viruses cause roughly 650 000 deaths annually despite available vaccines. CD8+ T cells typically recognise influenza-derived peptides from internal structural and non-structural influenza proteins and are an attractive avenue for future vaccine design as they could reduce the severity of disease following infection with diverse influenza strains. CD8+ T cells recognise peptides presented by the highly polymorphic Human Leukocyte Antigens class I molecules (HLA-I). Each HLA-I variant has distinct peptide binding preferences, representing a significant obstacle for designing vaccines that elicit CD8+ T cell responses across broad populations. Consequently, the rational design of a CD8+ T cell-mediated vaccine would require the identification of highly immunogenic peptides restricted to a range of different HLA molecules. Methods: Here, we assessed the immunogenicity of six recently published novel influenza-derived peptides identified by mass-spectrometry and predicted to bind to the prevalent HLA-B*18:01 molecule. Results: Using CD8+ T cell activation assays and protein biochemistry, we showed that 3/6 of the novel peptides were immunogenic in several HLA-B*18:01+ individuals and confirmed their HLA-B*18:01 restriction. We subsequently compared CD8+ T cell responses towards the previously identified highly immunogenic HLA-B*18:01-restricted NP219 peptide. Using X-ray crystallography, we solved the first crystal structures of HLA-B*18:01 presenting immunogenic influenza-derived peptides. Finally, we dissected the first TCR repertoires specific for HLA-B*18:01 restricted pathogen-derived peptides, identifying private and restricted repertoires against each of the four peptides. Conclusion: Overall the characterisation of these novel immunogenic peptides provides additional HLA-B*18:01-restricted vaccine targets derived from the Matrix protein 1 and potentially the non-structural protein and the RNA polymerase catalytic subunit of influenza viruses.

5.
Expert Rev Vaccines ; 23(1): 39-48, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38037386

RESUMEN

INTRODUCTION: Influenza B viruses (IBV) cause a significant health and economic burden annually. Due to lower antigenic drift rate, less extensive antigenic diversity, and lack of animal reservoirs, the development of highly effective universal vaccines against IBV might be in reach. Current seasonal influenza vaccines are formulated to induce antibodies against the Hemagglutinin (HA) protein, but their effectiveness is reduced by mismatch between vaccine and circulating strains. AREAS COVERED: Given antibodies against the Neuraminidase (NA) have been associated with protection during influenza infection, there is considerable interest in the development of NA-based influenza vaccines. This review summarizes insights into the role of NA-based immunity against IBV and highlights knowledge gaps that should be addressed to inform the design of next-generation influenza B vaccines. We discuss how antibodies recognize broadly cross-reactive epitopes on the NA and the lack of understanding of IBV NA antigenic evolution which would benefit vaccine development in the future. EXPERT OPINION: Demonstrating NA antibodies as correlates of protection for IBV in humans would be paramount. Determining the extent of IBV NA antigenic evolution will be informative. Finally, it will be critical to determine optimal strategies for incorporating the appropriate NA antigens in existing clinically approved vaccine formulations.


Asunto(s)
Vacunas contra la Influenza , Gripe Humana , Infecciones por Orthomyxoviridae , Animales , Humanos , Virus de la Influenza B , Neuraminidasa , Antígenos Virales , Anticuerpos Antivirales , Glicoproteínas Hemaglutininas del Virus de la Influenza , Infecciones por Orthomyxoviridae/prevención & control
6.
Clin Transl Immunology ; 12(8): e1460, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37564999

RESUMEN

Objectives: There is an increasing appreciation for the need to study mucosal antibody responses in humans. Our aim was to determine the utility of different types of samples from the human respiratory tract, specifically nasopharyngeal (NP) swabs obtained for diagnostic purposes and bronchoalveolar lavage (BAL) obtained in outpatient and inpatient settings. Methods: We analysed antibody levels in plasma and NP swabs from 67 individuals with acute influenza as well as plasma and BAL from individuals undergoing bronchoscopy, including five control subjects as well as seven moderately and seven severely ill subjects with a respiratory viral infection. Levels of α2-macroglobulin were determined in BAL and plasma to assess plasma exudation. Results: IgG and IgA were readily detectable in BAL and NP swabs, albeit at different ratios, while IgM levels were low. The total amount of antibody recovered from NP swabs varied greatly between study participants. Accordingly, the levels of influenza HA-specific antibodies varied, and individuals with lower amounts of total Ig in NP swabs had undetectable levels of HA-specific Ig. Similarly, the total amount of antibody recovered from BAL varied between study participants. However, severely ill patients showed evidence of increased plasma exudation, which may confound analysis of their BAL samples for mucosal antibodies. Conclusion: Nasopharyngeal swabs collected for diagnostic purposes may have utility in assessing antibodies from the human nasal mucosa, but variability in sampling should be accounted for. BAL samples can be utilised to study antibodies from the lower respiratory tract, but the possibility of plasma exudation should be excluded.

7.
Sci Adv ; 9(29): eadg5301, 2023 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-37478181

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection of vaccinated individuals is increasingly common with the circulation of highly immune evasive and transmissible Omicron variants. Here, we report the dynamics and durability of recalled spike-specific humoral immunity following Omicron BA.1 or BA.2 breakthrough infection, with longitudinal sampling up to 8 months after infection. Both BA.1 and BA.2 infections robustly boosted neutralization activity against the infecting strain while expanding breadth against BA.4, although neutralization activity was substantially reduced for the more recent XBB and BQ.1.1 strains. Cross-reactive memory B cells against both ancestral and Omicron spike were predominantly expanded by infection, with limited recruitment of de novo Omicron-specific B cells or antibodies. Modeling of neutralization titers predicts that protection from symptomatic reinfection against antigenically similar strains will be durable but is undermined by new emerging strains with further neutralization escape.


Asunto(s)
Anticuerpos Neutralizantes , Infección Irruptiva , COVID-19 , Humanos , SARS-CoV-2
8.
Clin Transl Immunology ; 12(6): e1456, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37383182

RESUMEN

Objectives: Influenza causes significant morbidity and mortality, especially in high-risk populations. Although current vaccination regimens are the best method to combat annual influenza disease, vaccine efficacy can be low in high-risk groups, such as haematopoietic stem cell transplant (HSCT) recipients. Methods: We comprehensively assessed humoral immunity, antibody landscapes, systems serology and influenza-specific B-cell responses, together with their phenotypes and isotypes, to the inactivated influenza vaccine (IIV) in HSCT recipients in comparison to healthy controls. Results: Inactivated influenza vaccine significantly increased haemagglutination inhibition (HAI) titres in HSCT recipients, similar to healthy controls. Systems serology revealed increased IgG1 and IgG3 antibody levels towards the haemagglutinin (HA) head, but not to neuraminidase, nucleoprotein or HA stem. IIV also increased frequencies of total, IgG class-switched and CD21loCD27+ influenza-specific B cells, determined by HA probes and flow cytometry. Strikingly, 40% of HSCT recipients had markedly higher antibody responses towards A/H3N2 vaccine strain than healthy controls and showed cross-reactivity to antigenically drifted A/H3N2 strains by antibody landscape analysis. These superior humoral responses were associated with a greater time interval after HSCT, while multivariant analyses revealed the importance of pre-existing immune memory. Conversely, in HSCT recipients who did not respond to the first dose, the second IIV dose did not greatly improve their humoral response, although 50% of second-dose patients reached a seroprotective HAI titre for at least one of vaccine strains. Conclusions: Our study demonstrates efficient, although time-dependent, immune responses to IIV in HSCT recipients, and provides insights into influenza vaccination strategies targeted to immunocompromised high-risk groups.

9.
Immunity ; 56(5): 909-913, 2023 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-37105169

RESUMEN

Immunological imprinting generically refers to the effects prior exposures have on subsequent immune responses to, and eventually protection against, antigenically related viruses. Here, Koutsakos and Ellebedy explain different concepts and terms around imprinting and the fundamental immunological principles behind it. They also discuss the potential role imprinting may have in the context of COVID-19 vaccines.


Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Humanos
10.
ERJ Open Res ; 9(2)2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36891079

RESUMEN

Background: COPD patients are more susceptible to viral respiratory infections and their sequelae, and have intrinsically weaker immune responses to vaccinations against influenza and other pathogens. Prime-boost, double-dose immunisation has been suggested as a general strategy to overcome weak humoral response to vaccines, such as seasonal influenza vaccination, in susceptible populations with weak immunity. However, this strategy, which may also provide fundamental insights into the nature of weakened immunity, has not been formally studied in COPD. Methods: We conducted an open-label study of seasonal influenza vaccination in 33 vaccine-experienced COPD patients recruited from established cohorts (mean age 70 (95% CI 66.9-73.2) years; mean forced expiratory volume in 1 s/forced vital capacity ratio 53.4% (95% CI 48.0-58.8%)). Patients received two sequential standard doses of the 2018 quadrivalent influenza vaccine (15 µg haemagglutinin per strain) in a prime-boost schedule 28 days apart. We measured strain-specific antibody titres, an accepted surrogate of likely efficacy, and induction of strain-specific B-cell responses following the prime and boost immunisations. Results: Whereas priming immunisation induced the expected increase in strain-specific antibody titres, a second booster dose was strikingly ineffective at further increasing antibody titres. Similarly, priming immunisation induced strain-specific B-cells, but a second booster dose did not further enhance the B-cell response. Poor antibody responses were associated with male gender and cumulative cigarette exposure. Conclusions: Prime-boost, double-dose immunisation does not further improve influenza vaccine immunogenicity in previously vaccinated COPD patients. These findings underscore the need to design more effective vaccine strategies for COPD patients for influenza.

11.
Immunity ; 56(4): 879-892.e4, 2023 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-36958334

RESUMEN

Although the protective role of neutralizing antibodies against COVID-19 is well established, questions remain about the relative importance of cellular immunity. Using 6 pMHC multimers in a cohort with early and frequent sampling, we define the phenotype and kinetics of recalled and primary T cell responses following Delta or Omicron breakthrough infection in previously vaccinated individuals. Recall of spike-specific CD4+ T cells was rapid, with cellular proliferation and extensive activation evident as early as 1 day post symptom onset. Similarly, spike-specific CD8+ T cells were rapidly activated but showed variable degrees of expansion. The frequency of activated SARS-CoV-2-specific CD8+ T cells at baseline and peak inversely correlated with peak SARS-CoV-2 RNA levels in nasal swabs and accelerated viral clearance. Our study demonstrates that a rapid and extensive recall of memory T cell populations occurs early after breakthrough infection and suggests that CD8+ T cells contribute to the control of viral replication in breakthrough SARS-CoV-2 infections.


Asunto(s)
COVID-19 , Humanos , SARS-CoV-2 , Linfocitos T CD8-positivos , Infección Irruptiva , ARN Viral , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunación
12.
PLoS Pathog ; 18(10): e1010891, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36206307

RESUMEN

Although antibody-inducing split virus vaccines (SV) are currently the most effective way to combat seasonal influenza, their efficacy can be modest, especially in immunologically-naïve individuals. We investigated immune responses towards inactivated whole influenza virus particle vaccine (WPV) formulations, predicated to be more immunogenic, in a non-human primate model, as an important step towards clinical testing in humans. Comprehensive analyses were used to capture 46 immune parameters to profile how WPV-induced responses differed to those elicited by antigenically-similar SV formulations. Naïve cynomolgus macaques vaccinated with either monovalent or quadrivalent WPV consistently induced stronger antibody responses and hemagglutination inhibition (HI) antibody titres against vaccine-matched viruses compared to SV formulations, while acute reactogenic effects were similar. Responses in WPV-primed animals were further increased by boosting with the same formulation, conversely to modest responses after priming and boosting with SV. 28-parameter multiplex bead array defined key antibody features and showed that while both WPV and SV induced elevated IgG responses against A/H1N1 nucleoprotein, only WPV increased IgG responses against A/H1N1 hemagglutinin (HA) and HA-Stem, and higher IgA responses to A/H1N1-HA after each vaccine dose. Antibodies to A/H1N1-HA and HA-Stem that could engage FcγR2a and FcγR3a were also present at higher levels after one dose of WPV compared to SV and remained elevated after the second dose. Furthermore, WPV-enhanced antibody responses were associated with higher frequencies of HA-specific B-cells and IFN-γ-producing CD4+ T-cell responses. Our data additionally demonstrate stronger boosting of HI titres by WPV following prior infection and support WPV administered as a priming dose irrespective of the follow up vaccine for the second dose. Our findings thus show that compared to SV vaccination, WPV-induced humoral responses are significantly increased in scope and magnitude, advocating WPV vaccination regimens for priming immunologically-naïve individuals and also in the event of a pandemic outbreak.


Asunto(s)
Subtipo H1N1 del Virus de la Influenza A , Vacunas contra la Influenza , Gripe Humana , Animales , Humanos , Hemaglutininas , Anticuerpos Antivirales , Vacunación , Pruebas de Inhibición de Hemaglutinación , Vacunas de Productos Inactivados , Macaca fascicularis , Virión , Inmunoglobulina A , Inmunoglobulina G , Nucleoproteínas
13.
Immunity ; 55(7): 1316-1326.e4, 2022 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-35690062

RESUMEN

Vaccination against SARS-CoV-2 protects from infection and improves clinical outcomes in breakthrough infections, likely reflecting residual vaccine-elicited immunity and recall of immunological memory. Here, we define the early kinetics of spike-specific humoral and cellular immunity after vaccination of seropositive individuals and after Delta or Omicron breakthrough infection in vaccinated individuals. Early longitudinal sampling revealed the timing and magnitude of recall, with the phenotypic activation of B cells preceding an increase in neutralizing antibody titers. While vaccination of seropositive individuals resulted in robust recall of humoral and T cell immunity, recall of vaccine-elicited responses was delayed and variable in magnitude during breakthrough infections and depended on the infecting variant of concern. While the delayed kinetics of immune recall provides a potential mechanism for the lack of early control of viral replication, the recall of antibodies coincided with viral clearance and likely underpins the protective effects of vaccination against severe COVID-19.


Asunto(s)
COVID-19 , Vacunas Virales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Humanos , SARS-CoV-2 , Vacunación
15.
Immunol Cell Biol ; 100(8): 636-652, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35713361

RESUMEN

Special AT-binding protein 1 (SATB1) is a chromatin-binding protein that has been shown to be a key regulator of T-cell development and CD4+ T-cell fate decisions and function. The underlying function for SATB1 in peripheral CD8+ T-cell differentiation processes is largely unknown. To address this, we examined SATB1-binding patterns in naïve and effector CD8+ T cells demonstrating that SATB1 binds to noncoding regulatory elements linked to T-cell lineage-specific gene programs, particularly in naïve CD8+ T cells. We then assessed SATB1 function using N-ethyl-N-nitrosourea-mutant mice that exhibit a point mutation in the SATB1 DNA-binding domain (termed Satb1m1Anu/m1Anu ). Satb1m1Anu/m1Anu mice exhibit diminished SATB1-binding, naïve, Satb1m1Anu/m1Anu CD8+ T cells exhibiting transcriptional and phenotypic characteristics reminiscent of effector T cells. Upon activation, the transcriptional signatures of Satb1m1Anu/m1Anu and wild-type effector CD8+ T cells converged. While there were no overt differences, primary respiratory infection of Satb1m1Anu/m1Anu mice with influenza A virus (IAV) resulted in a decreased proportion and number of IAV-specific CD8+ effector T cells recruited to the infected lung when compared with wild-type mice. Together, these data suggest that SATB1 has a major role in an appropriate transcriptional state within naïve CD8+ T cells and ensures appropriate CD8+ T-cell effector gene expression upon activation.


Asunto(s)
Virus de la Influenza A , Proteínas de Unión a la Región de Fijación a la Matriz , Animales , Linfocitos T CD8-positivos , Diferenciación Celular , Activación de Linfocitos , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Ratones
16.
Nat Immunol ; 23(5): 768-780, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35314848

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination elicit CD4+ T cell responses to the spike protein, including circulating follicular helper T (cTFH) cells that correlate with neutralizing antibodies. Using a novel HLA-DRB1*15:01/S751 tetramer to track spike-specific CD4+ T cells, we show that primary infection or vaccination induces robust S751-specific CXCR5- and cTFH cell memory responses. Secondary exposure induced recall of CD4+ T cells with a transitory CXCR3+ phenotype, and drove expansion of cTFH cells transiently expressing ICOS, CD38 and PD-1. In both contexts, cells exhibited a restricted T cell antigen receptor repertoire, including a highly public clonotype and considerable clonotypic overlap between CXCR5- and cTFH populations. Following a third vaccine dose, the rapid re-expansion of spike-specific CD4+ T cells contrasted with the comparatively delayed increase in antibody titers. Overall, we demonstrate that stable pools of cTFH and memory CD4+ T cells established by infection and/or vaccination are efficiently recalled upon antigen reexposure and may contribute to long-term protection against SARS-CoV-2.


Asunto(s)
COVID-19 , SARS-CoV-2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Epítopos/metabolismo , Humanos , Receptores CXCR5/metabolismo , Linfocitos T Colaboradores-Inductores
18.
Methods Mol Biol ; 2380: 201-209, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34802133

RESUMEN

Generation of effective immune protection against viral infection and vaccination depends greatly on a successful engagement and stimulation of adaptive immune B cells and a specialized CD4+ T cell subset called T follicular helper cells (TFH cells). Since TFH cells primarily reside in lymphoid tissues, they can be challenging to study in human settings. However, a counterpart of these cells, circulating TFH (cTFH) cells, can be detected in peripheral blood. Assessment of cTFH cells serves as an informative marker of humoral responses following viral infection and vaccination and can be predictive of antibody titers. Here, we describe a comprehensive flow cytometry detection method for dissecting cTFH subsets and activation, together with the assessment of antibody-secreting cells (ASCs), from a small volume of human whole blood. This approach allows the investigation of cellular events that underpin successful immune responses following influenza and SARS-CoV-2 infection/vaccination in humans and is applicable to other viral disease settings.


Asunto(s)
Linfocitos B/inmunología , COVID-19 , Gripe Humana , Células T Auxiliares Foliculares/inmunología , COVID-19/inmunología , Humanos , Gripe Humana/inmunología
19.
J Leukoc Biol ; 111(2): 355-365, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34730247

RESUMEN

Vaccination remains the most effective mechanism to reduce the impact of COVID-19. Induction of neutralizing antibodies is a strong correlate of protection from infection and severe disease. An understanding of the cellular events that underpin the generation of effective neutralizing antibodies is therefore key to the development of efficacious vaccines that target emerging variants of concern. Analysis of the immune response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and vaccination has identified circulating T follicular helper cells (cTFH ) as a robust correlate of the neutralizing antibody response. Here, we discuss the analysis of cTFH cells and their lymphoid counterparts in human humoral immune responses during COVID-19, and in response to vaccination with SARS-CoV-2 spike. We discuss the phenotypic heterogeneity of cTFH cells and the utility of cTFH subsets as informative biomarkers for development of humoral immunity. We posit that the analysis of the most effective cTFH will be critical to inducing durable immunity to new variants of SARS-CoV-2.


Asunto(s)
Vacunas contra la COVID-19/administración & dosificación , COVID-19/inmunología , Inmunidad Celular , Inmunidad Humoral , SARS-CoV-2/inmunología , Células T Auxiliares Foliculares/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , COVID-19/prevención & control , COVID-19/virología , Humanos
20.
Proc Natl Acad Sci U S A ; 118(41)2021 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-34607957

RESUMEN

Morbidity and mortality rates from seasonal and pandemic influenza occur disproportionately in high-risk groups, including Indigenous people globally. Although vaccination against influenza is recommended for those most at risk, studies on immune responses elicited by seasonal vaccines in Indigenous populations are largely missing, with no data available for Indigenous Australians and only one report published on antibody responses in Indigenous Canadians. We recruited 78 Indigenous and 84 non-Indigenous Australians vaccinated with the quadrivalent influenza vaccine into the Looking into InFluenza T cell immunity - Vaccination cohort study and collected blood to define baseline, early (day 7), and memory (day 28) immune responses. We performed in-depth analyses of T and B cell activation, formation of memory B cells, and antibody profiles and investigated host factors that could contribute to vaccine responses. We found activation profiles of circulating T follicular helper type-1 cells at the early stage correlated strongly with the total change in antibody titers induced by vaccination. Formation of influenza-specific hemagglutinin-binding memory B cells was significantly higher in seroconverters compared with nonseroconverters. In-depth antibody characterization revealed a reduction in immunoglobulin G3 before and after vaccination in the Indigenous Australian population, potentially linked to the increased frequency of the G3m21* allotype. Overall, our data provide evidence that Indigenous populations elicit robust, broad, and prototypical immune responses following immunization with seasonal inactivated influenza vaccines. Our work strongly supports the recommendation of influenza vaccination to protect Indigenous populations from severe seasonal influenza virus infections and their subsequent complications.


Asunto(s)
Anticuerpos Antivirales/sangre , Pueblos Indígenas/estadística & datos numéricos , Vacunas contra la Influenza/inmunología , Gripe Humana/prevención & control , Activación de Linfocitos/inmunología , Australia , Linfocitos B/inmunología , Humanos , Inmunoglobulina G/sangre , Memoria Inmunológica/inmunología , Gripe Humana/inmunología , Gripe Humana/virología , Recuento de Linfocitos , Vacunación Masiva , Riesgo , Células T Auxiliares Foliculares/inmunología , Linfocitos T/inmunología
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