Biology subjects

Wilson, I. A.

Publications and source records attributed to Wilson, I. A..

At least 19 recordsLinked to original sources

bioRxiv2026

Affinity Maturation Enables Dual Targeting of Cancer-Associated MUC1-Tn/STn and Drives Potent Tumor Control

A major challenge in solid tumor immunotherapy is identifying tumor-restricted antigens while overcoming intratumoral antigen heterogeneity. The truncated O-glycans Tn (GalNAc-O-Ser/Thr) and STn (Neu5Ac2-6GalNAc-O-Ser/Thr) are aberrantly displayed on the transmembrane glycoprotein MUC1 across a broad spectrum of epithelial malignancies, making MUC1-Tn/STn an attractive shared tumor-associated antigen class. However, heterogeneous intratumoral Tn/STn expression renders single-glycoform-specific antibodies vulnerable to antigen-driven escape. To address this challenge, we used structure-guided directed evolution and yeast surface display to affinity-mature the anti-MUC1-Tn antibody 5E5, generating variants with high-affinity dual recognition of MUC1-Tn and MUC1-STn. Co-crystal structures revealed that heavy-chain CDR loops cooperatively engage the GalNAc moiety primarily through hydrogen-bonding networks, in which HCDR3 residue 98 fine-tunes glycoform preference: Tyr98 favors MUC1-Tn recognition, whereas His98 enhances MUC1-STn engagement, while both support high-affinity recognition of both glycoforms. When reformatted as bispecific T-cell engagers, the affinity-matured variants mediated potent and durable cytolytic activity against cancer cells with heterogeneous glycan profiles, suppressed mixed Tn/STn tumors in vivo where the parental antibody failed, and showed enhanced activity in patient-derived tumor-like clusters. Together, these findings establish functional glycoform coverage as a design principle for antibody engineering, whereby a single paratope is optimized to recognize a defined spectrum of tumor-associated glycoforms while preserving antigen specificity, providing a strategy to overcome glycan heterogeneity in solid tumor immunotherapy.

cancer biology↗

bioRxiv2026

Xenoglycosylation of the HIV-1 Glycan Shield Promotes Cross-Clade Neutralization and Diverse Human Antibody Lineages

Despite advances in HIV-1 envelope glycoprotein (Env)-based vaccine design, eliciting broadly neutralizing antibodies (bNAbs) remains a central challenge. Here, we identify core (1,3)-fucose as a key modulator of neutralizing antibody (NAb) induction and breadth. Uncleaved prefusion-optimized (UFO) trimers and self-assembling protein nanoparticles (SApNPs) produced in High Five (Hi5) insect cells incorporate core (1,3)-fucose into the Env glycan shield. Crystal structures of Hi5-produced BG505 UFO trimers in complex with bNAbs confirm native-like Env architecture and epitope presentation. In wild-type mice, these trimers and SApNPs elicit robust autologous and heterologous NAb responses. We then engineer Chinese hamster ovary (CHO) cells to co-express three insect- and plant-derived core (1,3)-fucosyltransferases. The resulting immunogens carry fucosylated mammalian glycans and elicit cross-clade NAb responses in mice, supporting an important role for core (1,3)-fucose in broadened neutralization. Env-specific IgE responses suggest engagement of associated immune pathways during vaccination. In ATX-Gx humanized mice, core (1,3)-fucosylated, glycan-trimmed Env elicits detectable cross-clade neutralization by week 11. Single-cell analysis identifies distinct human antibody lineages with cross-clade activity and noncanonical Env recognition. Repertoire and functional analyses uncover putatively related lineage members across two animals within the same group. Together, these findings support xenoglycosylation as a promising, germline-agnostic strategy for HIV-1 vaccine design.

immunology↗

bioRxiv2026

Protective near-germline antibodies to malaria elicited by RTS,S/AS01E vaccination in African infants

Malaria is a leading cause of childhood mortality, yet infant immune responses to vaccination remain poorly understood. Here, we characterize 88 monoclonal antibodies (mAbs) directed against the Plasmodium falciparum circumsporozoite protein cloned from African infants immunized with the RTS,S/AS01E malaria vaccine, identifying potent antiparasitic mAbs exhibiting molecular features resembling those observed in adults and minimal somatic hypermutation. Importantly, germline-reverted variants of four mAbs inducing sterile protection in vivo maintained high binding affinity and Fab-dependent parasite killing. Structural analyses revealed that a few amino acid replacements drive homotypic helical assemblies, fine-tuning parasite inhibition and protective efficacy. Thus, despite maturational constraints of early life, infants can generate potent antimalarial antibodies in a near-germline configuration, informing next-generation vaccine development for this vulnerable group.

immunology↗

bioRxiv2026

Pan-Coronavirus Protease Engagement and Differentiated Pharmacology of Antiviral Candidate CMX990

COVID-19 highlighted the need for antivirals that can be rapidly deployed against both current and future coronavirus threats. CMX990 is a clinical stage coronavirus main protease (Mpro) inhibitor bearing a unique trifluoromethoxymethyl ketone warhead. Here, we broadly evaluate its pan-coronavirus target engagement, antiviral breadth, and pharmacologic differentiation. Across a reporter panel of 24 Mpro enzymes spanning alpha-, beta-, delta-, and gamma-coronaviruses, CMX990 retained robust potent activity, including against nirmatrelvir-resistant SARS-CoV-2 variants. In direct comparison, nirmatrelvir and ensitrelvir showed diminished potency against non-SARS-CoV-2 coronaviruses. Live-virus assays corroborated this breadth, with potent, selective activity against SARS-CoV-2, SARS-CoV-1, MERS-CoV, and additional human coronaviruses. Structural studies revealed a conserved covalent binding mode centered on the catalytic Cys of coronavirus Mpro. In serial-passage studies, resistance emerged only after approximately twice as many serial passages under CMX990 selection as under nirmatrelvir selection, without selecting for the canonical nirmatrelvir-resistance substitution E166V. Extracellular washout experiments revealed superior persistence of antiviral activity relative to nirmatrelvir, consistent with durable target engagement. In a murine SARS-CoV-2 infection model, once-daily CMX990 protected against weight loss and reduced lung viral titers to near baseline levels. Collectively, these findings identify CMX990 as a structurally and functionally validated pan-coronavirus protease inhibitor supporting its potential as a pandemic-ready antiviral candidate.

pharmacology and toxicology↗

bioRxiv2026

De novo minibinders targeting RH5 achieve nanomolar inhibition of blood-stage malaria replication

Malaria kills {approx}600,000 people annually despite recently deployed vaccines. The parasite's blood-stage invasion of erythrocytes, driven by the essential, non-redundant interaction between Plasmodium falciparum RH5 and erythrocyte basigin, remains a leading therapeutic target. Here, we designed de novo mini-proteins (minibinders) to occlude this interface. From {approx}1,500 computationally generated designs, we synthesized 18 candidates ranging from 9.3 to 16.9 kDa which were easily expressed in E. coli as soluble, well-folded proteins. Of these, 7 minibinders blocked blood-stage replication of P. falciparum asexual stage parasites with greater potency than {approx}300nM IC50. Three potent candidate minibinders, mb-5, mb-7, and mb-21, were confirmed to bind RH5 via SPR and BLI and block the merozoite-to-ring transition in stage-synchronized parasite progression assays, with CryoEM of minibinder-RH5 complex confirming the predicted binding at RH5-basigin interface. Although pharmacological challenges remain, our data demonstrate that potent inhibitors of parasite growth, rivaling existing antimalarials, can be designed rather than discovered via extensive screening. Our data highlight the potential for artificial intelligence to change the development landscape of new antimalarial therapies.

microbiology↗

bioRxiv2026

Structure and functional diversity of antibodies targeting the P. falciparum circumsporozoite protein C-terminal domain

The Plasmodium falciparum circumsporozoite protein (PfCSP) is the major surface antigen on Pf sporozoites. WHO-recommended vaccines RTS,S/AS01E and R21/Matrix-M target the PfCSP major repeat region and C-terminal domain (ctCSP). Although multiple studies associated protection with antibody responses to ctCSP, only a few ctCSP-specific monoclonal antibodies (mAbs) have been characterized. Here, crystal structures of 11 Fab-ctCSP complexes reveal how mAbs against the conserved {beta}-epitope region achieve diverse modes of strain-transcending recognition, in contrast to mAbs to the hypervariable -epitope. Consistent with previous studies, ctCSP on sporozoites could be unmasked by mAbs that bind CSP repeats, with unmasking dependent on the mAb fine-specificity and binding mode. In vitro, ctCSP mAbs promoted stronger Fc-receptor signaling, cellular cytotoxicity, and phagocytosis than repeat region mAbs, while mAb combinations targeting distinct PfCSP epitopes modulated Fc-signaling and cellular cytotoxicity. This study provides a rationale for optimization of PfCSP-based immunogens to enhance Fc-mediated contributions to malaria vaccine efficacy.

microbiology↗

bioRxiv2026

Substrate and target selectivity of 4'-fluoroadenosine against viral and host polymerases

Developing safe and effective treatments against emerging RNA viruses is an important goal in pandemic preparedness efforts. 4'-fluorouridine (4'-FlU) is a broad-spectrum antiviral that was shown to inhibit viral RNA-dependent RNA polymerases (RdRps). Given its notable range of antiviral activity, this class of nucleoside analogs warrants further investigation. Here, we studied the antiviral activity and underlying mechanism of inhibition of 4'-fluoroadenosine (4'-FlA). Like 4'-FlU, 4'-FlA demonstrates a broad-spectrum of antiviral activity against eight prototypic viruses representing diverse families. Enzyme kinetics show that the triphosphate (4'-FlA-TP) is efficiently incorporated by viral RdRps. A cryo-EM structure of RdRp of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in complex with double-stranded RNA and the incorporated monophosphate (4'-FlA-MP) characterizes interactions at the active site. The incorporated analog elicits heterogeneous inhibition patterns in primer extension reactions. In contrast, templates with embedded 4'-FlA-MP inhibit incorporation of complementary UTP across the viral RdRps. However, incorporation of 4'-FIA-TP is not limited to viral polymerases and likewise includes human mitochondrial RNA polymerase. These results demonstrate the general potential for 4'-fluorinated nucleotides as antiviral drugs and guide the development of more selective derivatives for medical use in appropriate settings.

microbiology↗

bioRxiv2026

Somatic evolution of a cross-reactive germline antibody that expands its breadth to neutralize new SARS-CoV-2 variants

Rapid antigenic drift of the SARS-CoV-2 receptor-binding domain (RBD) underlies immune escape and continues to challenge the durability of antibody-mediated protection. Among the major classes of RBD-directed antibodies, germline-encoded IGHV3-53 responses are highly potent against early SARS-CoV-2 variants but are generally compromised by Omicron-associated mutations. Here, we identify an intrinsically cross-reactive IGHV3-53 germline antibody that recognizes multiple pre-Omicron variants, including SARS-CoV-2 wild-type, Alpha, and Delta. Notably, we demonstrate that targeted somatic evolution can further expand this breadth to overcome the immune escape of different Omicron variants. Guided by integrated structural and sequence analyses, we introduce four somatic mutations (G26E, T28I, S53P, and Y58F) into the germline antibody, resulting in markedly enhanced binding and neutralization of Omicron BA.1, BA.2, and BA.4/5. High-resolution crystal structures reveal that these mutations re-establish critical interactions disrupted by substitutions on Omicron RBD and optimize affinity at a remodeled epitope interface. Collectively, our findings delineate a structural and mechanistic pathway through which an inherently cross-reactive germline antibody lineage can be adaptively refined to counter highly divergent SARS-CoV-2 variants. This work highlights the underappreciated breadth encoded within the naive B-cell repertoire and provides a conceptual framework for engineering and eliciting antibody responses resilient to future antigenic drift.

immunology↗

bioRxiv2026

The buried S2 apex of SARS-CoV-2 spike elicits an immunodominant germline-restricted public antibody response

The continued mutational pressure on the SARS-CoV-2 S1 subunit underscores the need to target the conserved S2 region for pan-coronavirus vaccine development. A detailed molecular understanding of S2-directed immune responses is therefore essential. In this study, we identified the S2 apex as the most immunodominant epitope within the S2 subunit, eliciting robust antibody responses despite occlusion by S1, using electron-microscopy-based polyclonal epitope mapping (EMPEM) of plasma from infected and vaccinated individuals. Structure-guided sequence analysis with antibody databases revealed that antibodies targeting a poorly characterized S2 Apex-B site form a convergent public clonotype, which is predominantly derived from the IGHV3-30 germline with a 14-residue CDRH3 containing a G/S-G-S/N-Y motif. This clonotype is extensively expanded, accounting for up to 40% of total spike-reactive antibody sequence counts in individual vaccinated donors. This study elucidates the molecular basis the high-frequency elicitation of this non-neutralizing clonotype emphasizing that its immunodominance acts as a primary hurdle for universal coronavirus vaccines and underscore the need for precision antigen design to redirect immunity toward more potent neutralizing targets.

immunology↗

bioRxiv2026

Structural basis for conserved and distinct antigen recognition by a lineage of malaria-protective antibodies

Monoclonal antibodies (mAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) have demonstrated substantial promise in preventing malaria infection and disease. PfCSP is characterized by a central region composed of repetitive NANP motifs, which serve as major targets for protective antibodies. Several potent mAbs targeting this region exhibit homotypic Fab-Fab interactions, which enhance antigen binding and contribute to their neutralization potency. Among these, mAb 399, encoded by the IGHV3-49/IGKV2D-29 (VH3-49/VK2D-29) germline lineages, forms head-to-head inter-Fab contacts mediated primarily by germline-encoded residues. In this study, we determined high-resolution X-ray crystal and cryo-EM structures of two additional Fabs, derived from the same germline lineages, 7160 and 7118, in complex with PfCSP-derived peptides. Both Fabs bound the NANP6 repeats with high affinity (KD 5-10 nM). Fab 7160 formed similar inter-Fab homotypic interactions to Fab 399 upon binding to an extended repeat peptide (NANP), indicating a conserved mode of recognition. In contrast, Fab 7118, which features a longer CDRH3, does not form homotypic contacts. Instead, Fab 7118 induced a bend in the peptide and adopted a distinct binding mode, which prevents inter-Fab interactions. A cryo-EM structure of Fab 7118 in complex with a recombinant shortened PfCSP construct (rsCSP) further revealed potential disruptions at inter-Fab contact sites. These findings highlight the structural versatility of VH3-49/VK2D-29-derived antibodies and demonstrate that CDR loop variations within a shared antibody lineage can modulate antibody conformation, homotypic Fab-Fab interactions, and epitope engagement. Our study provides mechanistic insights into the diverse strategies by which CSP-specific antibodies can achieve high-avidity binding and protective immunity.

microbiology↗

bioRxiv2026

Heterologous betacoronavirus spike immunization in nonhuman primates elicits cross-reactive antibodies that neutralize both sarbeco- and merbecoviruses

In anticipation of future coronavirus (CoV) pandemics, developing vaccines that elicit broadly neutralizing antibodies (bnAbs) against diverse CoVs is critical. Here, we vaccinated rhesus macaques with SARS-CoV-2 spike (S)-protein, then boosted with heterologous {beta}-CoV S-proteins to focus responses to common conserved S2 bnAb epitopes. Initial SARS-CoV-2 priming elicited receptor-binding domain (RBD)-focused responses, while MERS-CoV boosting redirected responses toward the S2 region, including the stem-helix bnAb site. Although S2-directed serum cross-neutralization was undetectable and most isolated cross-reactive monoclonal antibodies (mAbs) targeted non-neutralizing epitopes, two S2 stem-helix mAbs were identified from memory B cells. These bnAbs neutralized diverse sarbeco- and merbecoviruses, including MERS-CoV, and conferred robust in vivo protection against SARS-CoV-2 challenge. Structural studies revealed that these macaque bnAbs closely mimic human S2-stem bnAbs induced by infection. These findings provide proof-of-principle for vaccination strategies that elicit broadly protective {beta}-coronavirus responses and highlight non-human primates as a translational model for evaluating S2-targeted immunogens.

immunology↗

bioRxiv2025

Human coronavirus HKU1 neutralization by glycan receptor mimicry

Entry of seasonal human coronavirus HKU1 (HCoV-HKU1) into host cells is facilitated by sequential binding to sialoglycans and transmembrane serine protease 2 (TMPRSS2) receptors. However, the neutralizing capacity of antibodies disrupting these receptor interactions have not been examined. Here, we describe the isolation and characterization of a human monoclonal antibody (mAb) HKU1-2 that recognizes the HCoV-HKU1 spike protein and exhibits dose-dependent neutralization of the virus. Epitope mapping and structural analysis revealed that HKU1-2 mAb targets the sialoglycan binding site in the N-terminal domain of the spike protein. A cryo-electron microscopy (cryo-EM) structure of the spike-Fab complex further demonstrated the ability of HKU1-2 to mimic sialic acid binding thereby effectively blocking sialoglycan receptor engagement. HKU1-2 binding is primarily mediated by CDRH3 recognition of NTD residues K80 and W89 that are known to be critical for sialic acid engagement. Overall, our results demonstrate antibody recognition and neutralization of HCoV-HKU1 by receptor mimicry.

immunology↗

bioRxiv2025

The conserved bridging domain on HCV E1E2 glycoprotein complex is targeted by neutralizing antibodies from diverse lineages

The induction of potent and cross-reactive neutralizing antibody (nAb) responses remains a challenge in vaccine development against antigenically diverse viruses such as hepatitis C virus (HCV). The HCV E1E2 glycoprotein complex contains two major neutralizing sites: the neutralizing face (NF) and the less explored bridging domain (BD). Here, we characterized 25 BD-targeting nAbs isolated from infection or immunization. These antibodies arise from diverse B cell lineages but share convergent CDRH3 features. Epitope mapping by alanine scanning and negative-stain electron microscopy revealed overlapping epitopes on BD spanning antigenic regions AR4 and AR5, with variable back layer engagement. The crystal structure of a non-human primate BD nAb RM3-26 in complex with E2 uncovered a back layer-directed recognition mode analogous to that of the human nAb hcab40. Together, BD- and NF-directed nAbs exhibited additivity in their neutralization, highlighting BD as a conserved site of vulnerability on HCV and a valuable target for rational vaccine design.

immunology↗

bioRxiv2025

Single-component self-assembling protein nanoparticles displaying stabilized prefusion-closed hemagglutinin trimers for influenza vaccine development

Current influenza vaccines primarily target hemagglutinin (HA), the major surface glycoprotein and principal determinant of neutralizing antibody (NAb) responses. However, antigenic drift and shift, together with HAs intrinsic metastability and low-pH sensitivity, pose major challenges to the development of broadly protective influenza vaccines. Here, we stabilize HA in the prefusion-closed conformation through rationally selected amino acid substitutions. One approach targets a conserved residue across multiple influenza A subtypes (H1, H3, H5, and H7) and both influenza B lineages, providing a unified and broadly applicable framework for HA stabilization to support vaccine development. Using H1 and H3 as test cases, stabilized HA trimers were displayed on 24- and 60-mer single-component self-assembling protein nanoparticles (SApNPs) to enhance lymph node trafficking and immunogenicity. Compared with soluble trimers, HA-presenting SApNPs exhibited prolonged retention in lymph node follicles and elicited robust germinal center (GC) responses, key hallmarks of effective virus-like particle (VLP) vaccines. In mice, these SApNPs induced strong humoral immunity and conferred protection against homologous viral challenge. Furthermore, glycan engineering to enrich oligomannose content augments vaccine-induced NAb responses. Together, these findings provide mechanistic insights and establish design principles for next-generation HA-based influenza vaccines targeting both seasonal and pandemic strains. ONE-SENTENCE SUMMARYRational HA design and nanoparticle display guide next-generation strategies for influenza vaccine development

microbiology↗

bioRxiv2025

Structural and genetic signatures of two classes of HCV E2 neutralizing face antibodies from non-human primates immunized with a recombinant E1E2

Hepatitis C continues to be a significant public health problem despite advancements in antiviral therapeutics. To eliminate this disease, an effective vaccine against new infections and re-infections is needed. However, to date only one Hepatitis C virus (HCV) envelope protein (E1E2) immunogen, developed by Chiron Inc., has been tested in a Phase I clinical trial (ClinicalTrials.gov identifier NCT00500747). To establish a benchmark for elicitation of broadly neutralizing antibodies (bnAbs) by E1E2, we previously immunized non-human primates (NHPs) with this immunogen and isolated monoclonal nAbs that exhibit neutralization potency comparable to human nAbs. Here we show that NHP nAbs, encoded by germline genes IGHV1-138*01 and IGHV4-NL_5*01 (homologs of human IGHV1-69*10 and IGHV4-59*12, respectively), recognize a relatively E2 conserved region (neutralizing face) proximal to antigenic region 3 (AR3). These NHP AR3-targeting nAbs share highly similar binding modes to human AR3-targeting nAbs, suggesting a similarity in human and NHP immune responses to the same HCV immunogen.

immunology↗

bioRxiv2025

Directed evolution of a stem-helix targeting antibody enables MERS-CoV cross-neutralization through enhanced binding affinity

Broadly neutralizing antibodies (bnAbs) targeting conserved regions of the betacoronavirus spike are important for pan-betacoronavirus protection and pandemic preparedness. Here, we report on the isolation of a human monoclonal antibody, CC65.1, from a SARS-CoV-2 convalescent donor that targets the conserved S2 stem helix region. CC65.1 neutralizes various sarbecoviruses, including SARS-CoV-2, and binds the MERS-CoV spike but lacks MERS-CoV-neutralizing activity due to insufficient binding affinity. We utilized directed evolution to enhance the binding affinity of CC65.1 for the MERS-CoV S2 stem helix, yielding engineered antibody variants with newly acquired MERS-CoV-neutralizing activity. High-resolution structural analysis reveals key paratope mutations that optimize binding and stabilize epitope engagement. Our findings demonstrate the potential of rational antibody engineering to expand bnAb breadth across divergent betacoronaviruses. This work supports the development of engineered bnAbs and S2-targeted vaccines for broad betacoronavirus countermeasures and highlights strategies to achieve cross-lineage immunity for future pandemic threats. Author SummaryThe persistent emergence of new SARS-CoV-2 variants of concern that evade neutralizing antibody responses and other zoonotic betacoronaviruses with pandemic potential have provided strong motivation to develop broadly neutralizing antibodies (bnAbs) that target more conserved regions of the spike protein in sarbecoviruses and other betacoronaviruses. Here, we employed a directed evolution strategy to engineer the sarbecovirus-neutralizing antibody CC65.1, which targets the conserved S2 stem helix, to enhance its binding affinity with the MERS-CoV stem helix region, thereby conferring MERS-CoV neutralization. High-resolution structural studies of engineered CC65.1 revealed that key mutations reshape the paratope to better accommodate and stabilize the MERS-CoV S2 stem helix, resulting in increased binding affinity and neutralization potency. This study emphasizes the critical role of affinity maturation in expanding neutralization breadth and provides valuable insights for design of bnAbs to prevent and treat pandemic threats by betacoronaviruses.

immunology↗

bioRxiv2025

HIV Env trimers elicit NHP apex cross-neutralizing antibodies mimicking human bNAbs

As a chronically replicating virus, HIV has evolved extreme sequence variability and effective shielding of functionally constrained spike protein determinants by host-derived glycans. Broadly neutralizing antibodies (bNAbs), though rare, can be isolated from people living with HIV, revealing conserved Env sites as key targets for vaccine development. One such target is the apex of the envelope glycoprotein (Env) spike. Here, we identified a vaccination strategy using heterologous HIV Env trimers covalently coupled to liposomes for multivalent display that resulted in the elicitation of cross-neutralizing HIV serum antibody responses in all immunized non-human primates (NHPs). Critically, we isolated a set of monoclonal antibodies (mAbs) that cross-neutralized multiple divergent HIV clinical isolates. High-resolution cryoEM structural analysis of mAbs from three different NHPs demonstrated that they targeted the Env trimer apex in a manner remarkably similar to that of the human infection-elicited, apex-directed bNAb PG9, representing a substantial advance in HIV vaccine development.

immunology↗

bioRxiv2025

Structural Hijacking of FcRn by Human Astrovirus Spikes Reveals Conserved Epitopes for Broad-Spectrum Antivirals

Human astroviruses (HAstVs) are a leading cause of pediatric gastroenteritis and emerging systemic infections, yet no targeted therapies exist. A critical barrier to intervention has been the lack of molecular insights into viral entry, particularly the interaction between the HAstV capsid spike and its receptor, the neonatal Fc receptor (FcRn). Here, we report high-resolution crystal structures of the HAstV spike from classical serotypes 2 and 6 in complex with human FcRn, defining the conserved receptor-binding interface at atomic resolution. These structures reveal serotype-specific variations dictating receptor affinity and that reported neutralizing antibodies inhibit infection primarily by sterically blocking the receptor-binding site. Mapping conserved epitopes across classical HAstV serotypes provides a blueprint for design of broad-spectrum antivirals that disrupt viral entry. Notably, our structural data rationalize the potential repurposing of clinical FcRn inhibitors, such as Nipocalimab, to block HAstV infection, bridging critical gaps in astrovirus biology and antiviral development.

biophysics↗