Biology subjects

Kaplonek, P.

Publications and source records attributed to Kaplonek, P..

5 recordsLinked to original sources

bioRxiv2021

Comprehensive antibody profiling of mRNA vaccination in children

While children have been largely spared from COVID-19 disease, the emergence of viral variants of concern (VOC) with increased transmissibility, combined with fluctuating mask mandates and school re-openings have led to increased infections and disease among children. Thus, there is an urgent need to roll out COVID-19 vaccines to children of all ages. However, whether children respond equivalently to adults to mRNA vaccines and whether dosing will elicit optimal immunity remains unclear. Given the recent announcement of incomplete immunity induced by the pediatric dose of the BNT162b2 vaccine in young children, here we aimed to deeply profile and compare the vaccine-induced humoral immune response in 6-11 year old children receiving the pediatric (50g) or adult (100g) dose of the mRNA-1273 vaccine compared to adults and naturally infected children or children that experienced multi inflammatory syndrome in children (MIS-C) for the first time. Children elicited an IgG dominant vaccine induced immune response, surpassing adults at a matched 100g dose, but more variable immunity at a 50g dose. Irrespective of titer, children generated antibodies with enhanced Fc-receptor binding capacity. Moreover, like adults, children generated cross-VOC humoral immunity, marked by a decline of omicron receptor binding domain-binding, but robustly preserved omicron Spike-receptor binding, with robustly preserved Fc-receptor binding capabilities, in a dose dependent manner. These data indicate that while both 50g and 100g of mRNA vaccination in children elicits robust cross-VOC antibody responses, 100ug of mRNA in children results in highly preserved omicron-specific functional humoral immunity. One-Sentence SummarymRNA vaccination elicits robust humoral immune responses to SARS-CoV-2 in children 6-11 years of age.

immunology↗

bioRxiv2021

Longitudinal characterization of circulating neutrophils uncovers distinct phenotypes associated with disease severity in hospitalized COVID-19 patients

Multiple studies have identified an association between neutrophils and COVID-19 disease severity; however, the mechanistic basis of this association remains incompletely understood. Here we collected 781 longitudinal blood samples from 306 hospitalized COVID-19+ patients, 78 COVID-19- acute respiratory distress syndrome patients, and 8 healthy controls, and performed bulk RNA-sequencing of enriched neutrophils, plasma proteomics, cfDNA measurements and high throughput antibody profiling assays to investigate the relationship between neutrophil states and disease severity or death. We identified dynamic switches between six distinct neutrophil subtypes using non-negative matrix factorization (NMF) clustering. At days 3 and 7 post-hospitalization, patients with severe disease had an enrichment of a granulocytic myeloid derived suppressor cell-like state gene expression signature, while non-severe patients with resolved disease were enriched for a progenitor-like immature neutrophil state signature. Severe disease was associated with gene sets related to neutrophil degranulation, neutrophil extracellular trap (NET) signatures, distinct metabolic signatures, and enhanced neutrophil activation and generation of reactive oxygen species (ROS). We found that the majority of patients had a transient interferon-stimulated gene signature upon presentation to the emergency department (ED) defined here as Day 0, regardless of disease severity, which persisted only in patients who subsequently died. Humoral responses were identified as potential drivers of neutrophil effector functions, as enhanced antibody-dependent neutrophil phagocytosis and reduced NETosis was associated with elevated SARS-CoV-2-specific IgG1-to-IgA1 ratios in plasma of severe patients who survived. In vitro experiments confirmed that while patient-derived IgG antibodies mostly drove neutrophil phagocytosis and ROS production in healthy donor neutrophils, patient-derived IgA antibodies induced a predominant NETosis response. Overall, our study demonstrates neutrophil dysregulation in severe COVID-19 and a potential role for IgA-dominant responses in driving neutrophil effector functions in severe disease and mortality.

immunology↗

bioRxiv2021

Subtle immunological differences in mRNA-1273 and BNT162b2 COVID-19 vaccine induced Fc-functional profiles

The successful development of several COVID-19 vaccines has substantially reduced morbidity and mortality in regions of the world where the vaccines have been deployed. However, in the wake of the emergence of viral variants, able to evade vaccine induced neutralizing antibodies, real world vaccine efficacy has begun to show differences across the mRNA platforms, suggesting that subtle variation in immune responses induced by the BNT162b2 and mRNA1273 vaccines may provide differential protection. Given our emerging appreciation for the importance of additional antibody functions, beyond neutralization, here we profiled the postboost binding and functional capacity of the humoral response induced by the BNT162b2 and mRNA-1273 in a cohort of hospital staff. Both vaccines induced robust humoral immune responses to WT SARS-CoV-2 and VOCs. However, differences emerged across epitopespecific responses, with higher RBD- and NTD-specific IgA, as well as functional antibodies (ADNP and ADNK) in mRNA-1273 vaccine recipients. Additionally, RBD-specific antibody depletion highlighted the different roles of non-RBD-specific antibody effector function induced across the mRNA vaccines, providing novel insights into potential differences in protective immunity generated across these vaccines in the setting of newly emerging VOCs.

immunology↗

bioRxiv2021

Early cross-coronavirus reactive signatures of protective humoral immunity against COVID-19

The introduction of vaccines has inspired new hope in the battle against SARS-CoV-2. However, the emergence of viral variants, in the absence of potent antivirals, has left the world struggling with the uncertain nature of this disease. Antibodies currently represent the strongest correlate of immunity against COVID-19, thus we profiled the earliest humoral signatures in a large cohort of severe and asymptomatic COVID-19 individuals. While a SARS-CoV-2-specific immune response evolved rapidly in survivors of COVID-19, non-survivors exhibited blunted and delayed humoral immune evolution, particularly with respect to S2-specific antibody evolution. Given the conservation of S2 across {beta}-coronaviruses, we found the early development of SARS-CoV-2-specific immunity occurred in tandem with pre-existing common {beta}-coronavirus OC43 humoral immunity in survivors, which was selectively also expanded in individuals that develop paucisymptomatic infection. These data point to the importance of cross-coronavirus immunity as a correlate of protection against COVID-19.

immunology↗

bioRxiv2019

Glycan-dependent two-step cell adhesion mechanism of Tc toxins

Toxin complex (Tc) toxins are virulence factors widespread in insect and human bacterial pathogens. Tcs are composed of three subunits: TcA, TcB and TcC. TcA facilitates receptor-toxin interaction and membrane permeation, TcB and TcC form a toxin-encapsulating cocoon. While the mechanisms of holotoxin assembly and prepore-to-pore transition have been well-described, little is known about receptor binding and cellular uptake of Tcs. Here, we identify two classes of glycans, heparins/heparan sulfates and Lewis antigens, that act as receptors for different TcAs from insect- and human pathogenic bacteria. Glycan array screening and electron cryo microscopy (cryo-EM) structures reveal that all tested TcAs bind unexpectedly with their -helical part of the shell domain to negatively charged heparins. In addition, TcdA1 from the insect-pathogen Photorhabdus luminescens binds to Lewis antigens with micromolar affinity. A cryo-EM structure of the TcdA1-Lewis X complex reveals that the glycan interacts with the receptor-binding domain D of the toxin. Our results suggest a two-step association mechanism of Tc toxins involving glycans on the surface of host cells.

molecular biology↗