ETIDIOH - NEW

Abstract Influenza virus neuraminidase (NA) is receiving increasing attention as a target for universal flu vaccines . Several broad NA inhibition monoclonal antibodies (BImAbs) targeting the highly conserved enzymatic pocket have been previously described. However, the molecular characteristics, clonal evolutionary trajectory, and B cell sources of BImAbs remain poorly understood. Here, using NA-mutant probes, we comprehensively profiled the immune signatures of NA-specific memory B cells (MBCs) from a healthy individual with NA cross-inhibition activity . From the NA-specific MBC repertoires, we identified a series of NA BImAbs with molecular features characterized by long HCDR3 regions with an xxxDRxxx motif, which exhibited broad inhibition against diverse influenza NAs. Clonal lineage tracing revealed that these BImAbs followed a clonal evolutionary trajectory encompassing classical MBC (cMBC) and atypical MBC (aMBC). Both cMBC- and aMBC-derived NA BImAbs displayed similar inhibit...

Summary Background Sipavibart is an anti-spike monoclonal antibody that neutralises SARS-CoV-2 with exceptions, including Phe456Leu-containing variants (eg, KP.2* and KP.3*). This trial assessed sipavibart efficacy and safety for prevention of symptomatic COVID-19 in participants who are immunocompromised. Methods In this ongoing, double-blind, international, phase 3 trial , we enrolled participants who were immunocompromised and aged 12 years or older at 197 hospitals, university health centres, and clinical trial units in 18 countries. Participants were randomly allocated 1:1 to a sipavibart group (intramuscular sipavibart 300 mg on days 1 and 181) or a comparator group (tixagevimab 300 mg–cilgavimab 300 mg on day 1 and placebo on day 181 or placebo on days 1 and 181), stratified by previous COVID-19 vaccination and infection status and use of tixagevimab–cilgavimab. The primary efficacy outcomes were symptomatic COVID-19 caused by any variant or symptomatic COVID-19 caused by non-Ph...

Abstract The highly pathogenic avian influenza H5N1 virus clade 2.3.4.4b has been spreading globally since 2022, causing mortality and morbidity in domestic and wild birds and mammals , including infection in humans , raising concerns about its pandemic potential . We aimed to generate a panel of anti-hemagglutinin (HA) human monoclonal antibodies (mAbs) against the H5 protein of clade 2.3.4.4b. H2L2 Harbour Mice, which express human immunoglobulin germline genes, were immunized with H5 and N1 recombinant proteins from A/mallard/New York/22-008760-007-original/2022 H5N1 virus, enabling the generation of human chimeric antibodies . Through hybridoma technology, sixteen full human mAbs were generated, most of which showed cross-reactivity against H5 proteins from different virus variants . The functionality of the sixteen mAbs was assessed in vitro using hemagglutination inhibition and microneutralization assays with viruses containing a clade 2.3.4.4b HA. Fourteen out of the sixteen mAb...

Abstract Influenza virus pandemics and seasonal epidemics have claimed countless lives. Recurrent zoonotic spillovers of influenza viruses with pandemic potential underscore the need for effective countermeasures . In this study, we show that pre-exposure prophylaxis with broadly neutralizing antibody (bnAb) MEDI8852 is highly effective in protecting cynomolgus macaques from severe disease caused by aerosolized highly pathogenic avian influenza H5N1 virus infection. Protection was antibody dose–dependent yet independent of Fc-mediated effector functions at the dose tested. Macaques receiving MEDI8852 at 10 milligrams per kilogram or higher had negligible impairment of respiratory function after infection, whereas control animals were not protected from severe disease and fatality. Given the breadth of MEDI8852 and other bnAbs, we anticipate that protection from unforeseen pandemic influenza A viruses is achievable. Source: Science,  https://www.science.org/doi/10.1126/science.ado64...

Abstract The repeated spill-over of Influenza A virus H5N1 clade 2.3.4.4b from cattle to humans highlights the risk of a human H5N1 pandemic . Given the impact of pre-existing immunity on the course and severity of viral infections , we assessed in detail the humoral immunity against the H5N1 A/Texas/37/2024 isolate in H5N1-naive individuals . To this end, we performed complementary binding and neutralization assays on 66 subjects and ranked activities among a panel of 76 influenza A virus isolates . We detected low but distinct cross-neutralizing titers against A/Texas/37/2024 with a 3.9 to 15.6-fold reduction compared to selected H1N1 or H3N2 strains. Moreover, by cloning and evaluating 136 monoclonal antibodies from single memory B cells , we identified potent A/Texas/37/2024-neutralizing monoclonal antibodies in five out of six investigated individuals. These antibodies predominantly utilize VH1-69 gene segments, cross-neutralize H1, and compete with antibodies targeting the HA ste...

Highlights -- Both NA-specific antibodies and memory B cells are detected in healthy adults -- NA broad-inhibition monoclonal antibodies are derived from classical memory B cells -- Broad inhibition monoclonal antibodies target the NA conserved enzymatic epitopes -- NA broad-inhibition antibodies protect mice against H1N1 and H5N1- clade 2.3.4.4b Summary Identifying broadly reactive B precursor cells and conserved epitopes is crucial for developing a universal flu vaccine . In this study, using influenza neuraminidase (NA) mutant probes , we find that human pre-existing NA-specific memory B cells (MBCs) account for ∼0.25% of total MBCs, which are heterogeneous and dominated by class-unswitched MBCs. In addition, we identify three NA broad-inhibition monoclonal antibodies (mAbs) (BImAbs) that block the activity of NA derived from different influenza strains, including the recent cow H5N1. The cryoelectron microscopy (cryo-EM) structure shows that the BImAb targets the conserved NA enzym...

ABSTRACT Neutralizing antibodies (nAbs) are important for the treatment of emerging viral diseases and for effective vaccine development. In this study, we generated and evaluated three nAbs (1H9, 2D7, and C4H4) against H7N9 influenza viruses and found that they differ in their ability to inhibit viral attachment, membrane fusion, and egress . We resolved the cryo-electron microscopy (cryo-EM) structures of H7N9 hemagglutinin (HA) alone and in complex with the nAb antigen-binding fragments (Fabs) and identified the HA head-located epitope for each nAb, thereby revealing the molecular basis and key residues that determine the differences in these nAbs in neutralizing H7N9 viruses. Moreover, we found that the humanized nAb CC4H4 provided complete protection in mice against death caused by a lethal H7N9 virus infection, even when nAb was given 3 days after the mice were infected. These findings provide new insights into the neutralizing mechanism and structural basis for the rational desi...