Biology subjects

Ysenbaert, T.

Publications and source records attributed to Ysenbaert, T..

5 recordsLinked to original sources

bioRxiv2026

The breadth of protection mediated by anti-N2 neuraminidase antibody responses relies on cross-reactive and not cross-inhibiting antibodies

Neuraminidase (NA) inhibition (NAI) titers have been identified as an independent correlation of protection against influenza. Few studies, however, have investigated the breadth of NA-based immune protection. Previously, we have reported that N2 NAs derived from human H3N2 viruses that circulated between 2009 and 2017 can be subdivided into four antigenic groups. Here, we immunized mice with recombinant soluble tetrameric NA from H3N2 strains representing those four antigenic groups or passively transferred N2 NA immune serum into naive mice to evaluate the breadth of protection against a heterologous HxN2 influenza virus challenge. We show that the breadth of protection goes beyond the breadth of NAI but still requires the presence of cross-reactive antibodies. Interestingly, in the absence of cross-reactive antibodies, the immunization of DBA/2J mice with heterologous NA was associated with an early onset of disease upon challenge with the reassortant HxNind11 or H2N2 A/Singapore/1/1957.

immunology↗

bioRxiv2025

Multi-segment mouse-adaptation of a recent B/Victoria-lineage virus independent from hemagglutinin and neuraminidase

Influenza B viruses (IBVs) contribute significantly to the annual influenza epidemics in human. Most IBV strains are non- or poorly pathogenic in mice, which are frequently used for vaccine studies. We describe the generation of a mouse-adapted IBV strain that retains pathogenicity in mice when carrying hemagglutinin (HA) and neuraminidase (NA) gene segments from a heterologous IBV strain. Serial passage of an influenza B reassortant virus, containing the HA and NA segments from B/Washington/02/2019 on a mouse-adapted B/Memphis/12/1997 backbone, resulted in the selection of an IBV that was highly pathogenic for mice. This mouse-adapted IBV strain had acquired non-synonymous mutations in 5 gene segments. Sequence analysis of the intermediate passages indicated that mutations in the matrix (M), polymerase acidic (PA), and polymerase basic 1 (PB1) gene segments appeared at passages 9 and 13, suggesting that these mutations contributed to the pathogenicity in mice. Mouse challenge studies with rescued reassortant viruses with one or multiple mutated gene segments, confirmed the importance of substitutions in the M and PA segments for pathogenicity. Using the novel mouse-adapted IBV backbone, we rescued reassortant viruses containing the HA and NA segments of B/Austria/1359417/2021 and demonstrated its increased pathogenicity in BALB/c mice compared to IBV rescued on the parental strain. This mouse-adapted IBV backbone provides a valuable tool for the study of IBV in mice.

immunology↗

bioRxiv2024

The antigenic landscape of N1 neuraminidase in human influenza A virus strains isolated between 2009 and 2020

The clinical burden caused by influenza can be mitigated by the prophylactic use of seasonal influenza vaccines. Their immunogen composition is revised biannually to optimally match the antigenic drift of the hemagglutinin of circulating influenza virus strains. Antibodies directed against the influenza neuraminidase also correlate with protection against influenza, yet the antigenic evolution of influenza neuraminidase remains underexplored. To evaluate the antigenic diversity of N1 neuraminidase, we generated a panel of immune sera directed against 17 N1 neuraminidases derived from human H1N1 strains that were isolated between 2009 and 2020 and determined its neuraminidase inhibition titers against a panel of 15 HxN1 viruses. The resulting neuraminidase inhibition pattern revealed two antigenic groups that circulated in this period. A machine learning method identified K432E and I321V as key determinants of N1 neuraminidase antigenicity.

immunology↗

bioRxiv2024

Mosaic display of stable hemagglutinin monomers induces broad immune responses

The nature of the interplay between immunity and viral variation is infinitely adaptive. Infection frequently induces immune responses against variation-prone epitopes, rather than against spatially hidden conserved epitopes. It thus remains a substantial challenge to elicit the immune responses to the conserved epitopes providing broad-spectrum immunity. We developed an approach of scaffold-mediated mosaic display to present monomeric influenza virus hemagglutinins (HAs), which exposes highly conserved stem and interface epitopes. Stable monomers were rationally engineered from H1 and H3 subtypes and B type HA trimers, with amino acid mutations at the monomer-monomer interface and for disulfide bond formation, and fused to a self-assembling scaffold, to generate a mosaic HA monomer-displaying nanoparticle, 3HA-np. Immunization with 3HA-np induced broadly neutralizing antibodies (bnAbs) in mice and ferrets and protected against challenges with H1N1 and H3N2 viruses. Competitive immunoassays revealed that 3HA-np induced high interface- and stem-binding Ab titers as compared to head Ab titers, indicating that the monomeric and mosaic nature of 3HA-np elicit cross-reactive Abs. Our results suggest that exposure of the hidden conserved epitope by monomer-displaying nanoparticles is a promising approach to generate a universal influenza vaccine.

bioengineering↗

bioRxiv2023

The antigenic landscape of human influenza N2 neuraminidases from 2009 until 2017

Human H3N2 influenza viruses are subject to rapid antigenic evolution which translates into frequent updates of the composition of seasonal influenza vaccines. Despite these updates, the effectiveness of influenza vaccines against H3N2-associated disease is suboptimal. Seasonal influenza vaccines primarily induce hemagglutinin-specific antibody responses. However, antibodies directed against influenza neuraminidase (NA) also contribute to protection. Here, we analyzed the antigenic diversity of a panel of N2 NAs derived from human H3N2 viruses that circulated between 2009 and 2017. The antigenic breadth of these NAs was determined based on the NA inhibition (NAI) of a broad panel of ferret and mouse immune sera that were raised by infection and recombinant N2 NA immunization. This assessment allowed us to distinguish at least 4 antigenic groups in the N2 NAs derived from human H3N2 viruses that circulated between 2009 and 2017. Computational analysis further revealed that the amino acid residues in N2 NA that have a major impact on susceptibility to NAI by immune sera are in proximity of the catalytic site. Finally, a machine learning method was developed that allowed to accurately predict the impact of mutations that are present in our N2 NA panel on NAI. These findings have important implications for the renewed interest to develop improved influenza vaccines based on the inclusion of a protective NA antigen formulation.

immunology↗