Sarbecoviruses are a subgenus of betacoronaviruses that includes SARS-CoV-1, SARS-CoV-2 and a large diversity of viruses carried predominantly by horseshoe bats. The surface spike protein of these viruses mediates entry into host cells by binding the ACE2 receptor through its receptor-binding domain, or RBD. This domain is the principal target of neutralising antibodies, but it is also the most variable region of the spike, which allows viruses to escape immune recognition through mutation. Antibody responses against sarbecoviruses are conventionally grouped into classes depending on which part of the RBD they engage, and antibodies that target the receptor-binding motif tend to be potent but narrow, whereas those that recognise more conserved surfaces often neutralise a wider spectrum of viruses at the cost of lower potency. Understanding which epitopes remain conserved across this viral family is therefore central to designing countermeasures with durable breadth.

The three antibodies examined in the study, designated V1WT_06, V1WT_41 and VA14_26, were isolated in earlier work and shown to neutralise a panel of sarbecoviruses that spans both the SARS-CoV-1 and SARS-CoV-2 clades. In the new research, the team used the spike protein of WIV-1 as the antigenic scaffold to define the epitopes of these antibodies in molecular detail. WIV-1 is a useful reference point because it uses the same ACE2 receptor family as SARS-CoV-2 yet is distinct enough from human viruses that epitopes conserved on its spike are likely to be conserved across a wide evolutionary range. The authors combined functional assays, competition experiments and structural analysis to establish exactly where each antibody binds and how that binding translates into neutralisation of diverse viruses.

The first antibody, V1WT_06, was found to target what the researchers describe as a highly conserved site V epitope on the RBD. A striking feature of this interaction is that it is mediated entirely by the heavy chain of the antibody, without contributions from the light chain. Heavy-chain-only engagement of an epitope has practical implications for antibody engineering, because it simplifies the construction of smaller binding formats and suggests that the paratope is geometrically constrained in a way that tolerates variation in the underlying viral surface. The contact residues that V1WT_06 recognises are highly conserved among sarbecoviruses currently circulating in nature, which the authors interpret as evidence that this region of the RBD is evolutionarily and functionally constrained. In other words, the virus cannot easily alter these positions without compromising some essential aspect of its biology, most plausibly the structural integrity of the spike or its receptor interactions.

This conservation has two important consequences. First, it makes V1WT_06 an attractive candidate for therapeutic development, since an antibody directed against a site the virus struggles to mutate is less likely to be defeated by escape variants, whether those variants arise in animal reservoirs or during prolonged infection in human patients. Second, it identifies site V as a rational target for vaccine design. If immunogens can be engineered to focus the immune response onto this constrained epitope, the resulting vaccines might elicit broadly neutralising responses that protect against sarbecoviruses not yet known to science, rather than only against the strain from which the vaccine was derived.

The other two antibodies, V1WT_41 and VA14_26, bind overlapping epitopes within RBD class 4, a category of antibody targets located away from the receptor-binding motif itself. Although the two antibodies recognise substantially the same region of the spike, the study shows that they approach it at different angles, and that this difference in angle of approach has a measurable effect on the degree to which each antibody competes with ACE2 for binding to the RBD. Antibodies whose angle of approach brings them into direct steric conflict with the receptor are expected to neutralise by physically blocking attachment, whereas antibodies approaching from less obstructed angles may neutralise at other steps of the entry process, such as by preventing the conformational changes the spike undergoes after receptor binding. The finding that two antibodies to a shared epitope can differ in this mechanistically important way illustrates how the geometry of antibody binding, and not merely the location of the epitope, determines antiviral function.

Because class 4 epitopes lie outside the receptor-binding motif, antibodies targeting them are typically less sensitive to mutations that alter receptor engagement, which helps explain the breadth these antibodies display across sarbecoviruses and SARS-CoV-2 variants of concern. The demonstration that V1WT_41 and VA14_26 bind overlapping but non-identical footprints with distinct functional consequences refines the map of conserved neutralising determinants on the sarbecovirus RBD and suggests that cocktails of antibodies recognising this region from complementary angles could be particularly difficult for viruses to escape.

A central question for any broadly neutralising antibody is whether its activity extends beyond cultured pseudoviruses to entry mechanisms that operate in natural reservoir hosts. The researchers addressed this by testing whether neutralisation by the three antibodies is maintained when viral entry is mediated by the ACE2 receptors of the Japanese horseshoe bat and the Halcyon horseshoe bat, two species that host sarbecoviruses in the wild. The antibodies retained their neutralising capacity under these conditions, indicating that the epitopes they recognise remain functionally exposed and accessible across spikes adapted to different host receptors. This result strengthens the case that these antibodies would be effective against viruses circulating in bat populations, not merely against laboratory-adapted or human-adapted strains, and it supports the idea that conserved RBD epitopes can serve as anchors for pan-sarbecovirus immunity.

The authors conclude that V1WT_06, V1WT_41 and VA14_26 are ideal candidates for therapeutic antibody development. Monoclonal antibodies of this kind could be deployed prophylactically in people at high risk of exposure, such as laboratory workers, wildlife handlers and healthcare personnel during an outbreak, or therapeutically in infected patients, including immunocompromised individuals who mount weak responses to vaccination. Because the antibodies neutralise current SARS-CoV-2 variants of concern such as XEC, JN.1 and XFG alongside diverse bat viruses, a single product could in principle address both the continuing evolution of the pandemic virus and the threat of novel spillovers. Combination therapy using antibodies with non-overlapping or differently angled epitopes, as this study helps define, would further reduce the likelihood of viral escape.

Beyond therapeutics, the study contributes to the rational design of pan-betacoronavirus vaccines. Identifying conserved neutralising epitopes such as the site V region recognised by V1WT_06 tells immunogen designers exactly which molecular features a broadly protective vaccine must present to the immune system. Structure-guided vaccine strategies that display these constrained surfaces prominently, while masking or omitting more variable and immunodominant regions, could steer B cell responses toward the epitopes that matter most for cross-protection. As surveillance continues to uncover new sarbecoviruses in bats and other wildlife, and as SARS-CoV-2 itself keeps evolving, the ability to target the parts of the spike that the virus cannot easily change represents a strategic advantage. This work maps those targets with precision and demonstrates, through functional testing across host receptors from multiple bat species, that antibodies aimed at them can achieve the breadth that future coronavirus countermeasures will require.

Subject of Research: Broadly neutralising monoclonal antibodies targeting conserved sarbecovirus spike epitopes

Article Title: Targeting of conserved spike epitopes enables broad antibody neutralisation of diverse bat sarbecoviruses

Article References: Upadhyay, A., Seow, J., Alguel, Y., Newman, J., Thakur, N., Hay, A. L., Tam, J. C. H., Nans, A., Orton, R. J., Bailey, D., Cherepanov, P., & Doores, K. J. (2026). Targeting of conserved spike epitopes enables broad antibody neutralisation of diverse bat sarbecoviruses. PLOS Biology, 24(10), e3003882. https://doi.org/10.1371/journal.pbio.3003882

Image Credits: AI Generated

DOI: 10.1371/journal.pbio.3003882

Keywords: sarbecoviruses, monoclonal antibodies, spike protein, receptor-binding domain, WIV-1, SARS-CoV-2 variants, ACE2 receptor, horseshoe bats, epitope mapping, vaccine design, neutralisation, PLOS Biology

The team’s approach rests on a protein side chain-based network method, a technique in which each amino acid residue is represented as a node, and edges are drawn between residues whose side chains come into close non-covalent contact. Such contacts include the hydrogen bonds, hydrophobic interactions, and electrostatic attractions that hold proteins together without forming chemical bonds. Rather than analyzing a single static structure, the researchers averaged their network construction over many snapshots drawn from molecular dynamics simulations produced by D. E. Shaw Research, an unusually long and detailed set of simulations that capture the complex in motion at atomic resolution. Averaging across these frames filters out fleeting, transient contacts and reveals the persistent connectivity patterns that define the complex’s functional architecture.

Once the network is built, the analysis proceeds at multiple hierarchical levels. At the most local scale, the researchers examined cliques—fully connected subgroups of residues in which every member interacts with every other member. Cliques at the viral–human interface act as tightly knit hubs of interaction, and their abundance and composition reveal how densely the two proteins interlock. At the global scale, the team analyzed clusters of connected residues and performed percolation analysis, a concept borrowed from statistical physics that asks how a network holds together as connections are progressively removed. In a percolation framework, the strongest substructures are identified by stripping away weaker links and observing which clusters survive.

The central finding of the study is unambiguous: the SARS-CoV-2 spike protein forms a more dominant and robust connection with the human ACE2 receptor than SARS-CoV-1 does. At the global level, this superiority shows up clearly in the percolation results. When the researchers restricted the networks to only the strongest interfacial bonds, the interface cluster of the SARS-CoV-2–ACE2 complex persisted, remaining a single connected unit, whereas the corresponding cluster in the SARS-CoV-1–ACE2 complex fragmented. In other words, the stronger non-covalent interactions between the newer virus and its receptor form a self-reinforcing web that cannot be dismantled by discarding weak contacts—a hallmark of structural robustness.

The atomic-scale analysis tells a complementary story. In the SARS-CoV-2 complex, network cliques at the interface form in a manner that reflects denser and better-organized inter-protein communication. Cliques are demanding structures: because every residue in a clique must contact every other, their emergence signals a level of mutual reinforcement that looser collections of contacts lack. The fact that these clique structures at the SARS-CoV-2 interface consistently encode stronger connectivity provides a mechanistic, residue-level explanation for the virus’s enhanced receptor engagement, one that emerges naturally from the geometry of interactions rather than from any single pinned atom or bond.

Beyond confirming what virologists had suspected from binding-affinity measurements, the network framework delivers something more practical: an objective method to map how atomic-level non-covalent interactions give rise to global connectivity between any two amino acids in the complex. Bridging these scales has long been a challenge in molecular biophysics. A single hydrogen bond at an interface may seem inconsequential in isolation, yet through the network it can contribute to pathways of communication that span the entire protein assembly. The side chain-network approach makes this propagation explicit, allowing researchers to trace exactly which local interactions feed into which large-scale structural couplings, and to rank residues by their contribution to overall interface integrity.

Using this ranking ability, the team pinpointed key functional residues in SARS-CoV-2 that play important roles in establishing the higher connectivity with ACE2. These residues, identified through their network centrality and their participation in robust interfacial clusters and cliques, constitute the structural backbone of the viral grip on human cells. The authors also examined specific individual snapshots from the molecular dynamics trajectories rather than only time-averaged networks, and this analysis highlighted prominent variations in network topology across different conformations. The spike–ACE2 complex does not sit in a single rigid state; it explores a diverse conformational landscape, and the connectivity architecture shifts meaningfully from one moment to another. Capturing these fluctuations matters because a receptor-binding interface is a dynamic entity, and transient configurations may expose vulnerabilities or reveal alternative interaction modes.

Perhaps the most striking connection to real-world virology emerges when the network map is overlaid with the evolutionary record of the pandemic. The researchers found that most mutations occurring in the SARS-CoV-2 spike protein in variants of concern and variants of interest—including the currently active JN.1 variant and its subvariants—have been observed at the interface with the ACE2 receptor. This is precisely the region that the network analysis identifies as the seat of the virus’s enhanced connectivity. The convergence is telling: as the virus evolves to evade immunity generated by prior infection or vaccination, natural selection keeps returning to the same interfacial neighborhood that network science flags as functionally dominant. Mutations there can simultaneously alter antibody recognition and tune receptor binding, which explains why this region is both the engine of immune escape and the object of intense surveillance by public health laboratories worldwide.

This convergence between evolutionary observation and network topology gives the study practical significance for therapeutic design. If a defined set of residues sustains the robust connectivity between the viral spike and ACE2, then molecules that mimic the relevant receptor surface could, in principle, compete with ACE2 for spike binding and neutralize the virus. The authors note that their analyses highlight the importance of interface interactions and provide a rationale for designing receptor-like peptides and proteins to combat immunity-escaping variants. Because such decoys target the physical grip on ACE2 rather than the antibody-recognized epitopes that mutate most rapidly under immune pressure, they may retain effectiveness even as the virus drifts genetically—a property that conventional antibody drugs increasingly struggle to maintain against JN.1-descended lineages.

More broadly, the work demonstrates the value of complex-systems thinking in molecular biology. A virus–receptor complex is not merely a collection of atoms or a static ribbon diagram; it is a network whose resilience, communication pathways, and failure points determine biological function. By providing an objective, quantitative bridge from atomic non-covalent interactions to global connectivity between any two amino acids, the framework developed by Subramanyan and colleagues can in principle be applied to any protein complex, well beyond coronaviruses. For SARS-CoV-2 specifically, it delivers a durable conceptual map of why this virus binds human cells so effectively, why evolution keeps redrawing the same interfacial territory, and where next-generation antiviral designs might most productively aim as the virus continues to diversify.

Subject of Research: Network analysis of the SARS-CoV-2 spike–human ACE2 receptor complex connectivity

Article Title: From atomic to global connectivity in the structure of the SARS-CoV2-human ACE2 receptor complex

Article References: Subramanyan, V., Anto, A., Bhattacharyya, M., Vishveshwara, S., & Vishveshwara, S. (2026). From atomic to global connectivity in the structure of the SARS-CoV2-human ACE2 receptor complex. PLOS Complex Systems, 3(4), e0000096. https://doi.org/10.1371/journal.pcsy.0000096

Image Credits: AI Generated

DOI: 10.1371/journal.pcsy.0000096

Keywords: SARS-CoV-2, ACE2 receptor, spike protein, SARS-CoV-1, molecular dynamics, protein structure networks, percolation analysis, network cliques, variants of concern, JN.1 variant, immune escape, peptide design

The study focused on sarbecoviruses, the specific sub-group of coronaviruses that includes both SARS-CoV-1 and SARS-CoV-2. Researchers examined how these viruses interact with angiotensin-converting enzyme 2, or ACE2, the cellular receptor that many coronaviruses utilize to enter host cells. By investigating the ability of various bat coronaviruses to use ACE2 proteins from a broad spectrum of species, the team aimed to understand the host range of these viruses. This host range is a key determinant of spillover risk, as viruses capable of infecting a wide variety of animals are generally considered more likely to jump to humans.

The team analyzed fifteen representative bat coronavirus spike proteins using libraries of ACE2 receptors derived from thirty-four different species. These species included humans, livestock, rodents, and animals previously proposed as intermediate hosts in the transmission chain. The analysis revealed a distinct pattern in receptor usage among the different evolutionary groups of bat sarbecoviruses. Specifically, the researchers identified so-called generalist sarbecoviruses, which can utilize ACE2 receptors from many different species, and found that these were largely confined to the same evolutionary lineage as SARS-CoV-2.

Dr. Nazia Thakur, a postdoctoral scientist at Pirbright and the lead author of the study, explained that the bat coronaviruses currently considered most likely to spill over into humans are also the most likely to be recognized by existing COVID-19 immunity. She noted that while the risk of spillover can never be entirely eliminated, the global exposure to SARS-CoV-2 may have created a more robust immune defense against related viruses. This finding implies that the immune systems of many people are already primed to recognize and neutralize potential future pathogens that share structural similarities with the virus that caused the current pandemic.

The research also highlighted the dynamic nature of viral evolution during the pandemic. The team investigated how the host range of SARS-CoV-2 itself has changed over time. They found that variants, particularly those within the Omicron lineage, acquired specific mutations in the receptor binding domain. These mutations resulted in shifting patterns of ACE2 usage across different animal species, demonstrating that the relationship between viral evolution and host susceptibility is not static but continuously evolving in response to immune pressure and environmental factors.

To assess the practical implications for human health, the scientists examined blood samples from individuals who had recovered from COVID-19. The antibodies present in these samples were tested against a range of bat coronaviruses to measure their neutralizing capacity. The results showed that these antibodies successfully neutralized a variety of closely related bat coronaviruses. This cross-neutralization indicates that the immune response triggered by SARS-CoV-2 is not strictly specific to that single virus but extends to a broader family of related pathogens, providing a layer of protection against potential new infections.

Professor Katie Doores of King’s College London emphasized that the viruses showing the strongest antigenic similarity to SARS-CoV-2 were the most readily recognized and neutralized by the antibodies generated following infection. In contrast, more distantly related bat coronaviruses tended to be specialists, capable of using ACE2 receptors from only a limited range of hosts. However, the researchers also detected lower levels of neutralization against these more distant viruses, suggesting that there is some degree of broader protection even against pathogens that are not closely related to SARS-CoV-2.

Further experiments conducted at both institutions identified several monoclonal antibodies capable of recognizing a remarkably diverse range of sarbecoviruses. The second companion article in the study detailed where these monoclonal antibodies bind on the viral surface, highlighting conserved regions of the coronavirus spike protein. These conserved regions are less likely to mutate without compromising the virus’s ability to infect cells, making them ideal targets for the development of next-generation vaccines and therapeutics. This approach could lead to the creation of pan-sarbecovirus vaccines that offer protection against multiple strains simultaneously.

Dr. Dalan Bailey, head of the Viral Glycoproteins group at Pirbright, described the evidence of cross-neutralization of even some distantly related bat coronaviruses as an encouraging finding. He suggested that this capability points toward the feasibility of developing broadly protective vaccines or therapeutics that can cover a wide spectrum of sarbecoviruses. By targeting conserved epitopes, such interventions could provide a more durable and comprehensive defense against future zoonotic spillover events, reducing the likelihood of a new pandemic emerging from the bat reservoir.

The work underscores the importance of understanding virus host range, receptor usage, and immune recognition in an integrated manner rather than in isolation. By identifying the specific characteristics that distinguish higher-risk viruses from those less likely to spill over into humans, researchers hope to strengthen global pandemic preparedness efforts. This study provides a scientific basis for monitoring specific bat coronavirus lineages and developing targeted interventions that leverage existing immunity to protect against future viral threats, ultimately contributing to a more resilient global health system.

Subject of Research: Cross-immunity between SARS-CoV-2 and bat sarbecoviruses via ACE2 receptor usage

Article Title: COVID-19 immunity may help protect against other bat coronaviruses

Article References: COVID-19 immunity may help protect against other bat coronaviruses. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: SARS-CoV-2, bat coronaviruses, ACE2 receptor, cross-immunity, spillover risk, Pirbright Institute, King's College London, pandemic preparedness, monoclonal antibodies, zoonotic diseases, COVID-19, immunity