Biology subjects

Eckerle, I.

Publications and source records attributed to Eckerle, I..

6 recordsLinked to original sources

bioRxiv2026

A human monoclonal antibody from hybrid immunity exhibits exceptional neutralization breadth against antigenically divergent contemporary Omicron JN.1 lineage variants

Hybrid immunity offers stronger and more durable antibody-mediated protection against symptomatic SARS-CoV-2 infection. In the present study, we report the development of a durable antibody response in an individual with hybrid immunity who also received three doses of the prototype COVID-19 vaccine. Polyclonal plasma antibody obtained from this donor also showed extraordinary neutralization breadth against contemporary Omicron variants. One of the functional monoclonal antibodies (ATHS-C30) isolated from this individual, representing the IGHV4-30 lineage-specific B cell with strong binding affinity to JN.1 spike protein, showed extraordinary neutralization breadth, including variants of Omicron lineages that emerged beyond JN.1, such as KP.2, KP.3.1.1, KP.3.2, KP.3.3, LB.1 and XEC. ATHS-C30 was found to bind RBD with high affinity and showed distinct epitope specificity to the other neutralizing mAbs isolated from the same donor through the epitope binning assay. Molecular modelling of the CDHR3 sequence using existing structures indicated that ATHSC-30 belongs to the class 4 antibody, a feature that contributes to breadth, while epitope conservation analysis indicated that the majority of RBD-interacting residues of ATHSC-30 are evolutionarily conserved. Taken together, our study indicate that ATHS-C30 forms the basis of development of a robust and broadly neutralizing antibody response in this individual with hybrid immunity, which overcomes the antigenic variation by targeting highly conserved and cryptic epitopes in destabilizing the spike structure. ImportanceSARS-CoV-2 continues to pose a significant public health threat, particularly to immunocompromised individuals and older adults with underlying comorbidities. Hybrid immunity to SARS-CoV-2 in vaccinated individuals leads to the development of B cells that are qualitatively superior to those that are expected to develop in only vaccinated individuals. In the present study, we found that among individuals with hybrid immunity who developed robust, durable antigen-specific antibody responses, one developed antibody response capable of broadly cross-neutralising contemporary Omicron variants. This was correlated with development of antigen-specific B cell lineage, such as IGHV4-30, that produced antibodies with potent and extraordinary neutralisation breadth against contemporary Omicron lineages, such as KP.2, KP.3.1.1, KP.3.2, KP.3.3, LB.1 and XEC. This is believed to be due to heterologous antigen exposures driving the development of an antigen-specific B cell repertoire that, in turn, facilitates immune imprinting capable of overcoming the ineffectiveness of antibodies to effectively neutralize newly emerging Omicron variants.

immunology↗

bioRxiv2025

Age- and Virus-Specific Signatures of In Vitro Reconstituted Human Airway Epithelia in the Presence and Absence of Respiratory Viral Infections

While Influenza Virus and Respiratory Syncytial Virus (RSV) are considered as a significant health burden in children, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causes milder diseases in this age group compared to adults. To investigate the involvement of the upper respiratory tract human airway epithelium (HAE) in this pattern, we established an in-house model of reconstituted HAE cultured in air-liquid interface from nasal swabs of children and adults and characterised it before and after ex vivo respiratory viral infections using focused and unbiased approaches. Fully differentiated paediatric HAE exhibited an increasing induction level of genes related to mucociliary clearance, while higher expression of innate immune pathways was found in the ones from adults. While similar viral replication kinetics in both age groups were shown for SARS-CoV-2, Influenza A Virus (IAV), RSV and Rhinovirus (RV) infection, transcriptomic analysis showed stronger and earlier induction of IFN-related pathways in SARS-CoV-2-infected HAE from children compared to IAV, RSV and RV. IAV and RSV had the weakest innate immune response increase in HAE from children versus adults. RV infection showed an intermediate pattern, resembling SARS-CoV-2 more than RSV or IAV. Our work demonstrates a distinct sensing of SARS-CoV-2 compared to other respiratory viruses ex vivo, which may contribute to the milder course of disease in SARS-CoV-2 infected children and argues for a role of early virus-HAE interaction in shaping viral pathogenesis. Furthermore, we show that innate immune responses towards respiratory viruses are virus-specific and differ between age groups. Hence, findings on SARS-CoV-2 cannot be extrapolated to other respiratory viruses.

microbiology↗

bioRxiv2024

Immune escape of Omicron lineages BA.1, BA.2, BA.5.1, BQ.1, XBB.1.5, EG.5.1 and JN.1.1 after vaccination, infection and hybrid immunity

In the 5th year after the emergence of SARS-CoV-2, Omicron lineages continue to evolve and cause infections. Here, we used eight authentic SARS-CoV-2 isolates to assess their capacity to escape immunity of different exposure histories and their replicative capacity in polarized human airway epithelial cells (HAE) derived from the nasal and bronchial epithelium. Using live-virus neutralization assays of 108 human sera or plasma of different immunological backgrounds, progressive immune escape was observed from B.1 (ancestral virus) to EG.5.1, but no significant difference between EG.5.1 and JN.1.1. Vaccinated individuals without natural infection and individuals with a single infection, but no vaccination showed markedly reduced or completely lost neutralization against the latest variants, while in those with hybrid immunity almost all sera showed some neutralization capacity. Furthermore, although absolute titers differed between groups, the pattern of immune escape between the variants remains comparable with strongest loss of neutralization observed for the latest variants. In vitro studies with HAE at 33{degrees}C and 37{degrees}C showed some, but minor differences in virus replication and innate immune responses upon infection. Notably, infection with XBB.1.5, EG.5.1 and JN.1.1 showed slightly increased viral growth in nasal HAE at 33{degrees}C. Altogether, these data underscore increasing immune escape across heterogeneous immunological backgrounds with gradually increasing antibody escape of evolving Omicron lineages until variant EG.5.1, but not any further for the latest dominant lineage JN.1.1. They also suggest that viral dynamics within Omicron lineages are driven by a combination of immune evasion and increase in viral replication.

microbiology↗

bioRxiv2023

Comparative Analysis of SARS-CoV-2 Antigenicity across Assays and in Human and Animal Model Sera

The antigenic evolution of SARS-CoV-2 requires ongoing monitoring to judge the immune escape of newly arising variants. A surveillance system necessitates an understanding of differences in neutralization titers measured in different assays and using human and animal sera. We compared 18 datasets generated using human, hamster, and mouse sera, and six different neutralization assays. Titer magnitude was lowest in human, intermediate in hamster, and highest in mouse sera. Fold change, immunodominance patterns and antigenic maps were similar among sera. Most assays yielded similar results, except for differences in fold change in cytopathic effect assays. Not enough data was available for conclusively judging mouse sera, but hamster sera were a consistent surrogate for human first-infection sera.

bioinformatics↗

bioRxiv2022

Distinct phenotype of SARS-CoV-2 Omicron BA.1 in human primary cells but no increased host range in cell lines of putative mammalian reservoir species

SARS-CoV-2s genetic plasticity has led to several variants of concern (VOCs). Here we studied replicative capacity for seven SARS-CoV-2 isolates (B.1, Alpha, Beta, Gamma, Delta, Zeta, and Omicron BA.1) in primary reconstituted airway epithelia (HAE) and lung-derived cell lines. Furthermore, to investigate the host range of Delta and Omicron compared to ancestral SARS-CoV-2, we assessed replication in 17 cell lines from 11 non-primate mammalian species, including bats, rodents, insectivores and carnivores. Only Omicrons phenotype differed in vitro, with rapid but short replication and efficient production of infectious virus in nasal HAEs, in contrast to other VOCs, but not in lung cell lines. No increased infection efficiency for other species was observed, but Delta and Omicron infection efficiency was increased in A549 cells. Notably replication in A549 and Calu3 cells was lower than in nasal HAE. Our results suggest better adaptation of VOCs towards humans, without an extended host range.

microbiology↗

bioRxiv2019

A novel experimental system reveals immunoregulatory responses as mediators of persistent orthohantavirus infections in a rodent reservoir host

Orthohantaviruses are globally emerging zoonotic pathogens. Human infections are characterized by an overt immune response that is efficient at counteracting virus replication but can also cause severe tissue damage. In contrast, orthohantavirus infections in rodent reservoir hosts are persistent and asymptomatic. The mechanisms facilitating asymptomatic virus persistence in reservoir hosts are not well understood but could help to guide therapeutic strategies for human infections. Here we report on a study using in vivo and in vitro experiments to investigate immune responses associated with persistent Puumala orthohantavirus (PUUV) infections in the bank vole (Myodes glareolus), its reservoir host. We examined adaptive cellular and humoral responses by quantifying changes in T-cell related gene expression in the spleen and immunoglobulin (Ig) responses in blood, respectively. Since existing Vero E6-cell adapted hantavirus isolates have been demonstrated to have lost their wild-type infection characteristics, infections were conducted with a novel PUUV strain isolated on a bank vole cell line. Whole virus genome sequencing revealed that only minor sequence changes occurred during the isolation process, and critically, experimental infections of bank voles with the new isolate resembled natural infections. In vitro infection of bank vole splenocytes with the novel isolate demonstrated that PUUV promotes immunoregulatory responses by inducing interleukin-10, a cytokine strongly associated with chronic viral infections. A delayed virus-specific humoral response occurred in experimentally infected bank voles, which is likely to allow for initial virus replication and the establishment of persistent infections. These results suggest that host immunoregulation facilitates persistent orthohantavirus infections in reservoir hosts.\n\nImportanceOrthohantaviruses are a group of global pathogens that regularly spillover from rodent reservoirs into humans and can cause severe disease. Conversely, infections in reservoir hosts do not cause obvious adverse effects. The mechanisms responsible for persistent asymptomatic reservoir infections are unknown, and progress has been hindered by the absence of an adequate experimental system. Knowledge on these mechanisms could help provide strategies to treat human infections. We developed and validated an experimental system based on an orthohantavirus isolated in cells of its vole reservoir host. Using animal and cell culture experiments in the reservoir host system, we demonstrated that infection suppresses immunity in the vole reservoir via specific mechanisms, likely allowing the virus to take hold and preventing immune responses that can cause self-damage.

microbiology↗