scholarly journals Evidence for Deleterious Original Antigenic Sin in SARS-CoV-2 Immune Response

2021 ◽  
Author(s):  
Sanjana R Sen ◽  
Emily C Sanders ◽  
Alicia M Santos ◽  
Keertna Bhuvan ◽  
Derek Y Tang ◽  
...  
Keyword(s):  
Disease Severity ◽  
Influenza A ◽  
Influenza Infection ◽  
Strong Association ◽  
Cross Reactivity ◽  
Single Amino Acid ◽  
Epitope Region ◽  
Previous Infection ◽  
Epitope Sequence ◽  
Original Antigenic Sin

A previous report demonstrated the strong association between the presence of antibodies binding to an epitope region from SARS-CoV-2 nucleocapsid, termed Ep9, and COVID-19 disease severity. Patients with anti-Ep9 antibodies (Abs) had hallmarks of original antigenic sin (OAS), including early IgG upregulation and cytokine-associated injury. Thus, the immunological memory of a previous infection was hypothesized to drive formation of suboptimal anti-Ep9 Abs in severe COVID-19 infections. This study identifies a putative original antigen capable of stimulating production of cross-reactive, anti-Ep9 Abs. From bioinformatics analysis, 21 potential original epitope regions were identified. Binding assays with patient blood samples directly show cross-reactivity between Abs binding to Ep9 and only one homologous potential antigen, a sequence derived from the neuraminidase protein of H3N2 Influenza A virus. This cross-reactive binding affinity is highly virus strain specific and sensitive to even single amino acid changes in epitope sequence. The neuraminidase protein is not present in the influenza vaccine, and the anti-Ep9 Abs likely resulted from the widespread influenza infection in 2014. Therefore, OAS from a previous infection could underlie some cases of COVID-19 disease severity and explain the diversity observed in disease outcomes.

scholarly journals From influenza infection to anti-ADAMTS13 autoantibodies via cross-reactivity

2018 ◽  
Vol 7 (4) ◽  
pp. 113-120
Author(s):  
Darja Kanduc
Keyword(s):  
Immune Responses ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Influenza A ◽  
Influenza Infection ◽  
Cross Reactivity ◽  
Influenza Viruses ◽  
Thrombocytopenic Purpura ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Autoantibodies (AAbs) against von Willebrand factor (vWF)-cleaving protease ADAMTS13 causally relate to thrombotic thrombocytopenic purpura (TTP). How anti-ADAMTS13 AAbs are generated is unknown. Starting from reports according to which influenza infection can trigger TTP by the production of ADAMTS13 AAbs, this study explores influenza viruses and ADAMTS13 protein for common peptide sequences that might underlie anti-influenza immune responses able to cross-react with ADAMTS13. Results document that numerous peptides are shared between influenza A and B viruses and ADAMTS13, thus supporting the hypothesis of cross-reactivity as a mechanism driving the generation of anti-ADAMTS13 AAbs.

scholarly journals A single amino acid substitution in PB1 of pandemic H1N1 with A/Ann Arbor/6/60 master donor virus mutations as a novel live-attenuated influenza virus vaccine

2022 ◽  
Author(s):  
Aitor Nogales ◽  
John Steel ◽  
Wen-Chun Liu ◽  
Anice C Lowen ◽  
Laura Rodriguez ◽  
...  
Keyword(s):  
Amino Acid ◽  
Guinea Pigs ◽  
Influenza A ◽  
Protective Efficacy ◽  
Influenza Infection ◽  
The United States ◽  
Single Amino Acid ◽  
Temperature Sensitive ◽  
Ann Arbor ◽  
The U.S

Influenza A viruses (IAV) remain emerging threats to human public health. Live-attenuated influenza vaccines (LAIV) are one of the most effective prophylactic options to prevent disease caused by influenza infections. However, licensed LAIV remain restricted for use in 2- to 49-year old healthy and non-pregnant people. Therefore, development of LAIV with increased safety, immunogenicity, and protective efficacy is highly desired. The United States (U.S.) licensed LAIV is based on the master donor virus (MDV) A/Ann Arbor/6/60 H2N2 backbone, which was generated by adaptation of the virus to growth at low temperatures. Introducing the genetic signature of the U.S. MDV into the backbone of other IAV strains resulted in varying levels of attenuation. While the U.S. MDV mutations conferred an attenuated phenotype to other IAV strains, the same amino acid changes did not significantly attenuate the pandemic A/California/04/09 H1N1 (pH1N1) strain. To attenuate pH1N1, we replaced the conserved leucine at position 319 with glutamine (L319Q) in PB1 and analyzed the in vitro and in vivo properties of pH1N1 viruses containing either PB1 L319Q alone or in combination with the U.S. MDV mutations using two animal models of influenza infection and transmission, ferrets and guinea pigs. Our results demonstrated that L319Q substitution in the pH1N1 PB1 alone or in combination with the mutations of the U.S. MDV resulted in reduced pathogenicity (ferrets) and transmission (guinea pigs), and an enhanced temperature sensitive phenotype. These results demonstrate the feasibility of generating an attenuated MDV based on the backbone of a contemporary pH1N1 IAV strain.

scholarly journals Universal protection against influenza infection by a multidomain antibody to influenza hemagglutinin

Science ◽  
2018 ◽  
Vol 362 (6414) ◽  
pp. 598-602 ◽  
Author(s):  
Nick S. Laursen ◽  
Robert H. E. Friesen ◽  
Xueyong Zhu ◽  
Mandy Jongeneelen ◽  
Sven Blokland ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Influenza Infection ◽  
Cross Reactivity ◽  
Broadly Neutralizing Antibodies ◽  
Adeno Associated Virus ◽  
Influenza Hemagglutinin ◽  
Influenza Virus Hemagglutinin ◽  
Single Domain Antibodies

Broadly neutralizing antibodies against highly variable pathogens have stimulated the design of vaccines and therapeutics. We report the use of diverse camelid single-domain antibodies to influenza virus hemagglutinin to generate multidomain antibodies with impressive breadth and potency. Multidomain antibody MD3606 protects mice against influenza A and B infection when administered intravenously or expressed locally from a recombinant adeno-associated virus vector. Crystal and single-particle electron microscopy structures of these antibodies with hemagglutinins from influenza A and B viruses reveal binding to highly conserved epitopes. Collectively, our findings demonstrate that multidomain antibodies targeting multiple epitopes exhibit enhanced virus cross-reactivity and potency. In combination with adeno-associated virus–mediated gene delivery, they may provide an effective strategy to prevent infection with influenza virus and other highly variable pathogens.

scholarly journals Previous Influenza Infection Exacerbates Allergen Specific Response and Impairs Airway Barrier Integrity in Pre-Sensitized Mice

2021 ◽  
Vol 22 (16) ◽  
pp. 8790
Author(s):  
Kevin Looi ◽  
Alexander N. Larcombe ◽  
Kara L. Perks ◽  
Luke J. Berry ◽  
Graeme R. Zosky ◽  
...  
Keyword(s):  
Lung Function ◽  
Post Infection ◽  
Influenza A ◽  
Influenza Infection ◽  
Specific Ige ◽  
Specific Response ◽  
Barrier Integrity ◽  
Cellular Inflammation ◽  
Downstream Effects ◽  
Previous Infection

In this study we assessed the effects of antigen exposure in mice pre-sensitized with allergen following viral infection on changes in lung function, cellular responses and tight junction expression. Female BALB/c mice were sensitized to ovalbumin and infected with influenza A before receiving a second ovalbumin sensitization and challenge with saline, ovalbumin (OVA) or house dust mite (HDM). Fifteen days post-infection, bronchoalveolar inflammation, serum antibodies, responsiveness to methacholine and barrier integrity were assessed. There was no effect of infection alone on bronchoalveolar lavage cellular inflammation 15 days post-infection; however, OVA or HDM challenge resulted in increased bronchoalveolar inflammation dominated by eosinophils/neutrophils or neutrophils, respectively. Previously infected mice had higher serum OVA-specific IgE compared with uninfected mice. Mice previously infected, sensitized and challenged with OVA were most responsive to methacholine with respect to airway resistance, while HDM challenge caused significant increases in both tissue damping and tissue elastance regardless of previous infection status. Previous influenza infection was associated with decreased claudin-1 expression in all groups and decreased occludin expression in OVA or HDM-challenged mice. This study demonstrates the importance of the respiratory epithelium in pre-sensitized individuals, where influenza-infection-induced barrier disruption resulted in increased systemic OVA sensitization and downstream effects on lung function.

scholarly journals Metabolite profiles associated with disease progression in influenza infection

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0247493
Author(s):  
Chris H. Wendt ◽  
Sandra Castro-Pearson ◽  
Jennifer Proper ◽  
Sarah Pett ◽  
Timothy J. Griffin ◽  
...  
Keyword(s):  
Disease Progression ◽  
Influenza A ◽  
Influenza Infection ◽  
Conditional Logistic Regression ◽  
Strong Association ◽  
Composite Endpoint ◽  
Composite Outcome ◽  
Influenza A H1n1 ◽  
Develop Disease Progression ◽  
The Individual

Background We performed metabolomic profiling to identify metabolites that correlate with disease progression and death. Methods We performed a study of adults hospitalized with Influenza A(H1N1)pdm09. Cases (n = 32) were defined by a composite outcome of death or transfer to the intensive care unit during the 60-day follow-up period. Controls (n = 64) were survivors who did not require transfer to the ICU. Four hundred and eight metabolites from eight families were measured on plasma sample at enrollment using a mass spectrometry based Biocrates platform. Conditional logistic regression was used to summarize the association of the individual metabolites and families with the composite outcome and its major two components. Results The ten metabolites with the strongest association with disease progression belonged to five different metabolite families with sphingolipids being the most common. The acylcarnitines, glycerides, sphingolipids and biogenic metabolite families had the largest odds ratios based on the composite endpoint. The tryptophan odds ratio for the composite is largely associated with death (OR 17.33: 95% CI, 1.60–187.76). Conclusions Individuals that develop disease progression when infected with Influenza H1N1 have a metabolite signature that differs from survivors. Low levels of tryptophan had a strong association with death. Registry ClinicalTrials.gov Identifier: NCT01056185

scholarly journals Age-specific differences in the dynamics of protective immunity to influenza

2018 ◽  
Author(s):  
Sylvia Ranjeva ◽  
Rahul Subramanian ◽  
Vicky J. Fang ◽  
Gabriel M. Leung ◽  
Dennis K. M. Ip ◽  
...  
Keyword(s):  
Protective Immunity ◽  
Influenza A ◽  
Influenza Infection ◽  
Age Groups ◽  
Virus Infections ◽  
Influenza A Viruses ◽  
Individual Level ◽  
Antibody Titers ◽  
Original Antigenic Sin ◽  
Changes Over Time

AbstractInfluenza A viruses evolve rapidly to escape host immunity, such that individuals can be infected multiple times with the same subtype. The form and duration of protective immunity after each influenza infection are poorly understood. Here, we quantify the dynamics of protective immunity against influenza A virus infections by fitting individual-level mechanistic models to longitudinal serology from children and adults in a household cohort study. We find that most protection in children is explained by antibody titers measured by the hemagglutination inhibition (HI) assay. In contrast, in adults, HI antibody titers explain a smaller fraction of protection. Protection against circulating strains wanes to approximately 50% of peak levels 3.5-7 years after infection in both age groups, and wanes faster against influenza A(H3N2) than A(H1N1)pdm09. Protection against H3N2 lasts longer in adults than in children. Our results suggest that the focus of influenza antibody responses changes over time from the highly mutable hemagglutinin head to other epitopes, consistent with the immunological theory of original antigenic sin, and that this change of focus might affect protection. Additionally, we estimate that imprinting, or primary infection with a subtype of one phylogenetic group, has little to no effect on the risk of non-medically attended influenza infections in adults. We also find no evidence of long-term cross-protection between subtypes. This work underscores the need for longitudinal data on multiple components of the immune response to better understand the development of immunity and differences in susceptibility within populations.

scholarly journals Association between plasma glycocalyx component levels and poor prognosis in severe influenza type A (H1N1)

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiao Huang ◽  
Feng Lu ◽  
Huanhuan Tian ◽  
Haoran Hu ◽  
Fangyu Ning ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Disease Severity ◽  
Plasma Levels ◽  
Influenza A ◽  
Strong Association ◽  
H1n1 Influenza ◽  
Endothelial Glycocalyx ◽  
Inflammatory Factors ◽  
Severe Influenza ◽  
Influenza A H1n1

AbstractInfluenza A virus infection causes a series of diseases, but the factors associated with disease severity are not fully understood. Disruption of the endothelial glycocalyx contributes to acute lung injury in sepsis, but has not been well studied in H1N1 influenza. We aim to determine whether the plasma glycocalyx components levels are predictive of disease severity in H1N1 influenza. This prospective observational study included 53 patients with influenza A (H1N1) during the influenza season, and 30 healthy controls in our hospital. Patients were grouped by severity and survival. We collected clinical data and blood samples at admission. Inflammatory factors (tumor necrosis factor-α, interleukin-6, interleukin-10) and endothelial glycocalyx components (syndecan-1, hyaluronan, heparan sulfate) were measured. The plasma levels of syndecan-1, hyaluronan, and heparan sulfate were significantly higher in patients with severe influenza A (H1N1) than in mild cases. Syndecan-1 and hyaluronan were positively correlated with disease severity, which was indicated by the APACHE II and SOFA scores and lactate levels, and negatively correlated with albumin levels. At a cutoff point ≥ 173.9 ng/mL, syndecan-1 had a 81.3% sensitivity and 70.3% specificity for predicting of 28-day mortality. Kaplan–Meier analysis demonstrated a strong association between syndecan-1 levels and 28-day mortality (log-rank 11.04, P = 0.001). Elevated plasma levels of syndecan-1 has a potential role in systemic organ dysfunction and may be indicative of disease severity in patients with influenza A (H1N1).

scholarly journals Immunoglobulin G, A and M response to influenza vaccination in different age groups: effects of priming and boosting

1986 ◽  
Vol 96 (3) ◽  
pp. 513-522 ◽  
Author(s):  
Walter E. P. Beyer ◽  
Jos T. M. Van Der Logt ◽  
Ruud van Beek ◽  
Nic Masurel
Keyword(s):  
Antibody Response ◽  
Influenza Vaccine ◽  
Influenza A ◽  
Influenza Infection ◽  
Age Groups ◽  
Antibody Responses ◽  
Trivalent Influenza Vaccine ◽  
Antibody Capture ◽  
The Mean ◽  
Original Antigenic Sin

SUMMARYFifty volunteers, treated with an inactivated trivalent influenza vaccine containing A/Bangkok/1/79 (H3N2), A/Brazil/11/78 (H1N1) and B/Singapore/222/79 virus, were subdivided according to the estimated first exposure to influenza in their lifetime (priming) and the presence of antibodies against the vaccine components in the pre-vaccination sera. The isotypic antibody response (IgG, IgA, IgM) was determined by means of an antibody capture haemadsorption immunosorbent technique. For all three vaccine components, previously seropositive subjects produced antibodies of the IgG- and IgA-class more frequently than previously seronegative persons. Subjects primed to one of the influenza A subtypes showed more IgG and IgA responses in comparison with those unprimed (prime-effect). In contrast, IgM antibodies occurred in only 19 and 11% of primed, but in 59 and 54% of unprimed subjects, for A (H3N2) and A (HlNl), respectively. The incidence of IgM titre rises was not influenced by the prevaccination state. However, the mean magnitude of anti-A(H1N1)-IgM titre rises was greater in those previously seronegative. The concepts of primary and reinfection and of ‘original antigenic sin’ are discussed, and it is suggested that age and, if possible, serological state prior to antigen-exposure should be taken into account when studying isotypic antibody responses after influenza infection or vaccination.

scholarly journals Enhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
A. Vuorela ◽  
T. L. Freitag ◽  
K. Leskinen ◽  
H. Pessa ◽  
T. Härkönen ◽  
...  
Keyword(s):  
T Cell ◽  
Influenza A ◽  
Strong Association ◽  
Cell Epitope ◽  
Cell Receptor ◽  
Cross Reactivity ◽  
Cell Immunity ◽  
Increased Risk ◽  
Influenza A H1n1

AbstractNarcolepsy type 1 (NT1) is a chronic neurological disorder having a strong association with HLA-DQB1*0602, thereby suggesting an immunological origin. Increased risk of NT1 has been reported among children or adolescents vaccinated with AS03 adjuvant-supplemented pandemic H1N1 influenza A vaccine, Pandemrix. Here we show that pediatric Pandemrix-associated NT1 patients have enhanced T-cell immunity against the viral epitopes, neuraminidase 175–189 (NA175–189) and nucleoprotein 214–228 (NP214–228), but also respond to a NA175–189-mimic, brain self-epitope, protein-O-mannosyltransferase 1 (POMT1675–689). A pathogenic role of influenza virus-specific T-cells and T-cell cross-reactivity in NT1 are supported by the up-regulation of IFN-γ, perforin 1 and granzyme B, and by the converging selection of T-cell receptor TRAV10/TRAJ17 and TRAV10/TRAJ24 clonotypes, in response to stimulation either with peptide NA175–189 or POMT1675–689. Moreover, anti-POMT1 serum autoantibodies are increased in Pandemrix-vaccinated children or adolescents. These results thus identify POMT1 as a potential autoantigen recognized by T- and B-cells in NT1.

scholarly journals A High-throughput Anti-SARS-CoV-2 IgG Testing Platform for COVID-19

2020 ◽  
Author(s):  
Jinwei Du ◽  
Eric Chu ◽  
Dayu Zhang ◽  
Chuanyi M Lu ◽  
Aiguo Zhang ◽  
...  
Keyword(s):  
High Throughput ◽  
Influenza A ◽  
High Sensitivity ◽  
Cross Reactivity ◽  
Antibody Detection ◽  
Influenza B ◽  
Serum Samples ◽  
Igg Antibody ◽  
Percent Agreement ◽  
Previous Infection

Background: Serology tests for detecting the antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can identify previous infection and help to confirm the presence of current infection. Objective: The aim of this study was to evaluate the performances of a newly developed high throughput immunoassay for anti-SARS-CoV-2 IgG antibody detection. Results: Clinical agreement studies were performed in 77 COVID-19 patient serum samples and 226 negative donor serum/plasma samples. Positive percent agreement (PPA) was 42.86% (95% CI: 9.90% to 81.59%), 55.56% (95% CI: 21.20% to 86.30%), and 96.72% (95% CI: 88.65% to 99.60%) for samples collected on 0-7 days, 8-14 days, and ≥15 days from symptom onset, respectively. Negative Percent Agreement (NPA) was 98.23% (95% CI: 95.53% to 99.52%). No cross-reactivity was observed to patient samples positive for IgG antibodies against the following pathogens: HIV, HAV, HBV, RSV, CMV, EBV, Rubella, Influenza A, and Influenza B. Hemoglobin (200 mg/dL), bilirubin (2 mg/dL) and EDTA (10 mM) showed no significant interfering effect on this assay. Conclusion: An anti-SARS-CoV-2 IgG antibody assay with high sensitivity and specificity has been developed. With the high throughput, this assay will speed up the anti-SARS-CoV-2 IgG testing.

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