Biology subjects

Haynes, B. F.

Publications and source records attributed to Haynes, B. F..

At least 19 recordsLinked to original sources

bioRxiv2026

Impact of RNA modification and IL-12 boosts on mRNA-LNP vaccine-elicited CD8+ T cell responses

Development of effective HIV-1 vaccines requires strategies for inducing both CD8+ T cell and neutralizing antibody responses. Nucleoside-modified mRNA-lipid-nanoparticles (LNP) induce more potent antibody responses than unmodified mRNA-LNP vaccines, while unmodified mRNA is typically employed for CD8+ T cell-inducing vaccines. Here, we compared the abilities of differing ratios of unmodified versus modified mRNA expressing a SIV conserved-region CD8+ T cell immunogen co-administered with IL-12-encoding mRNA-LNP during boosting to induce CD8+ T cell and humoral responses in non-human primates, assessing responses in ChAdOx1-primed controls in parallel. Serial priming and boosting with fully-unmodified mRNA elicited higher-magnitude, more CD8-biased T cell responses than fully-modified mRNA, that were durably maintained after the IL-12-encoding mRNA boosts. Inclusion of 30% nucleoside-modified mRNA enhanced antibody titers, suggesting potential benefits to a mixed-composition vaccine.

immunology↗

bioRxiv2026

Asymmetric Boost Responses to an HIV-1 Vaccine: Boost-site Controls Secondary B-cell Fates

Induction of broadly neutralizing antibody (bnAb) responses remains a central challenge to designing efficacious HIV vaccines. Lineage design strategies, in which bnAb precursors are guided via iterative immunizations to their mature forms, depend on high levels of somatic mutation and the recall of antigen-specific B cells. Recent studies have identified spatial context as an important determinant of boosting efficacy, but the application of this to HIV vaccines and the underlying mechanisms are incompletely understood. Here, using mice harboring a V3-glycan bnAb lineage precursor knock-in combined with lineage-tracing and single-cell analyses, we show that persistent germinal centers (GCs) support continued affinity maturation of founder clones and ipsilateral boosting preferentially engages these lineages in secondary GCs. In contrast, contralateral boosting predominantly recruits naive B cells and memory B cells not directed towards the immunizing antigen. The few memory cells recruited at this site were biased towards a plasma cell fate. Finally, we identify disfavored mutational trajectories within the V3-glycan bnAb lineage, revealing intrinsic constraints on bnAb lineage evolution.

immunology↗

bioRxiv2026

B Cell Receptor Signaling Sets Boundaries for Selection of Broadly Neutralizing Antibody Functional Mutations

B cell signaling is required for germinal center (GC) selection and synergizes with T cell-help leading to differentiation into effector cells and a protective antibody response. Here, we studied the relationship between B cell signaling and the selection of functional mutations in a humanized mouse model of a CD4 binding-site specific HIV-1 broadly neutralizing antibody precursor. While BCR signaling increased with antigen affinity, immunization-induced frequency of a functional mutation was inversely related to affinity and favored a gain in association rate. Antigen-specific GC B cells and key mutation frequency were higher in the mid-affinity (0.5 - 5M) than in either the higher or lower affinity group, and were consistent with the significantly higher serum neutralization titers in the mid-range group. Our studies show that BCR signaling imposes boundaries (upper/lower) for selection of antibody functional mutations and support a "Goldilocks Zone" model that defines the favored BCR signaling strength for GC selection.

immunology↗

bioRxiv2026

Elicitation of stem-directed antibodies in rhesus macaques by a conventional hemagglutinin immunogen

Because they can bind many strains of influenza, antibodies targeting the hemagglutinin (HA) stem have been attractive targets for vaccine development. Many monoclonal antibodies (mAbs) directed at the HA stem have been isolated from humans, and these mAbs have mediated broad protection in animal models. We describe here HA stem-directed mAbs isolated from rhesus macaques immunized with an "ordinary" H1 HA trimer. All immunized rhesus macaques developed high serum titers with broad reactivity to diverse H1N1 and H5N1 viruses, and 7 isolated mAbs strongly blocked canonical stem antibody CR6261 binding to H1. MAb DH726.1 robustly protected mice from lethal challenge with H1N1 and H5N1 viruses, and cryo-EM showed the binding footprint overlapped that of some human mAbs. These findings suggest that vaccination with the standard, trimeric HA immunogens may be sufficient to elicit stem antibodies at titers adequate to protect against zoonotic H5N1 influenza. In BriefEfforts to achieve broad influenza protection have largely emphasized increasingly sophisticated immunogen designs to redirect antibody responses toward conserved epitopes. Here, we show that a single, conventional HA immunogen readily elicits antibodies targeting the conserved HA stem, suggesting that routine influenza vaccination may provide broader protection than previously appreciated. HighlightsO_LIMonovalent HA immunization induces strong, stem-directed immune responses in rhesus macaques C_LIO_LIEpitope on the HA stem confirmed by Cryo-EM C_LIO_LIFc-mediated activation of immune effector cell by rhesus-derived stem mAb C_LIO_LIHA stem-directed antibody protects mice against H1N1 and H5N1 viruses C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/738984v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1535b59org.highwire.dtl.DTLVardef@192422dorg.highwire.dtl.DTLVardef@136b3d5org.highwire.dtl.DTLVardef@586fd4_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Rapid vaccine induction of macaque HIV-1 V2 Apex broadly neutralizing antibodies with immunogenetic signatures that are potentially translatable to humans

Due to the complex biology of HIV-1 broadly neutralizing antibodies (bnAbs), HIV-1 vaccines must target unmutated germline precursor antibodies with B cell receptors that have the appropriate specificity and genetic features to develop neutralization breadth. Previous work has shown that immunization or infection in macaques primes unmutated precursor antibodies that target the broadly neutralizing epitope composed of the second variable region and proximal glycans (termed V2-apex site) of HIV-1 envelope (Env). Macaque V2-apex bnAb precursors elicited thus far have homogeneous usage of the second reading frame of a diversity (D) gene found only in macaques, calling into question whether HIV-1 Env immunogens can elicit only this canonical, macaque-specific V2-apex antibody response, limiting human vaccination success. Here, we show that vaccination of rhesus macaques with Env conjugated to a ferritin nanoparticle (OPT4-scNP) rapidly elicited V2-apex bnAbs with distinct D gene segment usage and motifs that are not restricted only to macaques. After two priming immunizations, V2-apex antibodies with non-canonical HCDR3s exhibited greater neutralization potency and breadth than V2-apex antibodies with previously observed HCDR3 motifs. Following sequential boosting immunizations, a V2-apex bnAb lineage with a novel HCDR3-encoded EDGED motif increased its neutralization breadth, including neutralization of viral isolates bearing the N130 glycan, which shields the V2-apex from recognition. High-resolution structures of two members of this V2-apex bnAb lineage, called DH2050, defined a novel binding mode in which it used its EDGED motif to contact the C-strand peptide and the N160 glycan within the V2-apex site. Altogether, we define a novel bnAb binding mode to the V2 Apex and demonstrate that HIV-1 Env sequential vaccination elicits V2-apex bnAbs with immunogenetic signatures that are potentially translatable to the human immune system.

immunology↗

bioRxiv2026

Shared Maturation Pathways of HIV-1 Envelope-reactive V3-glycan bnAb Lineages in Human and Rhesus Macaque

ABSTRACTUnderstanding broadly neutralizing antibody (bnAb) lineage development in rhesus macaques (RMs) infected with Simian-HIV (SHIV) may inform HIV-1 vaccine designs. We analyzed HIV-1 envelope-antibody coevolution in 18 RMs infected by SHIV.BG505 (subtype A) and found highly conserved patterns of antibody recognition and Env escape, including in three animals that developed V3-glycan bnAbs. From one RM with V3-glycan targeted plasma breadth, we isolated 203 members of a single clonal Ab lineage designated DH1030. DH1030 Abs demonstrated striking genetic, functional and structural similarities with the human V3-glycan bnAb lineage DH270, which was isolated from an individual with subtype C HIV-1 CH848 infection. Notably, human-DH270 and macaque-DH1030 bnAbs shared early improbable mutations in HCDR2 that were critical for bnAb development. Thus, key improbable mutations and convergent patterns of antibody evolution and epitope recognition were shared across primate species and distinct HIV-1 subtypes, findings that may be leveraged in new HIV-1 vaccine designs. ONE SENTENCE SUMMARYBroadly neutralizing antibodies targeting HIV-1 envelope surface protein develop via a common maturation pathway across primate phylogeny.

immunology↗

bioRxiv2026

Functional Convergence of Genetically Diverse B-Cell Receptors in Simian-HIV Infected Rhesus Macaques

Germline-targeting or lineage-design vaccine strategies are being used to induce HIV broadly neutralizing antibody (bnAb) responses. These strategies assume that genetically diverse individuals respond similarly to the same immunogen by mobilizing comparable germline precursors, although outcomes vary across bnAb epitopes. Here we explored this premise using a simian-HIV infection model in rhesus macaques. Antigen-unbiased Env- reactive B-cell populations were profiled, followed by systematic analysis of antibody function and B-cell receptor (BCR) genetics. We find that while global Env-reactive B-cell response profiles and antibody functional properties are similar across individuals, underlying BCR genetics are diverse, particularly among non-bnAbs. These results indicate that functional convergence of Env-reactive antibody responses does not necessarily require genetic convergence and suggest that specific germline-targeting may not be an absolute prerequisite for successful vaccine design. These findings support an epitope-focused framework in which bnAb epitopes are engineered to enhance population-level immunogenicity, with potential applicability to other challenging pathogens.

immunology↗

bioRxiv2025

An integrated workflow for structural virology with a 100 keV electron microscope

Cryo-EM has revolutionized structural biology, especially for flexible and heterogeneous samples, although access to high end microscopes that enable these studies remains a bottleneck. While 300 keV microscopes have been the go-to for high-resolution structural determination, they are expensive and restricted to institutional and national facilities needing specialized expertise, with access falling far short of the demand. Here, we present the user-managed operation of a cheaper 100 keV electron microscope within a structural biology laboratory enabling close integration with protein production, biochemical and biophysical studies. We provide details and considerations for the installation of the microscope, its day-to-day maintenance, and operations. Using virus surface glycoproteins as case studies, we illustrate the workflow from grid screening, data collection, and data processing, and provide examples of data quality. This user-administered setup provides a training platform for researchers at all levels, with beginners in cryo-EM achieving proficiency to independently operate the microscope within a month of regular use and training. We have demonstrated routine high-quality low-resolution reconstructions using a Ceta CMOS camera and high-resolution reconstructions enabling building of atomic models using a Falcon C direct detector. While there are several examples of facilities that manage cryo-EM and individual laboratories leveraging cryo-EM, we provide here the first demonstration of a modern group independently doing both successfully, something that has been talked about frequently but rarely seen.

biochemistry↗

bioRxiv2025

A neutralizing human antibody induces movement of the HCoV-229E receptor binding domain

HCoV-229E is an endemic Alphacoronavirus that typically causes common cold-like disease in most healthy adults, but can also cause severe respiratory disease in the very young and the elderly. Although the virus was discovered over sixty years ago and undergoes continuous antigenic drift, remarkably little is known about the humoral immune response to HCoV-229E infection. Here we report the isolation of two receptor binding domain-targeting neutralizing human antibodies raised in response to natural HCoV-229E infection. One of these, DH1533, potently neutralizes HCoV-229E, binds to spike with sub-nanomolar affinity and prevents the association between the RBD and the host cell receptor aminopeptidase N. Structural characterization of this antibody bound to HCoV-229E spike delineated a neutralization-sensitive epitope on the RBD and revealed that DH1533 induces conformational flexibility in neighboring RBDs, reminiscent of the "up-and-down" kinetics observed in the related Betacoronavirus spikes. These findings provide insight into the humoral immune response to HCoV-229E infection and will serve as a guide for the design of future therapeutic interventions.

immunology↗

bioRxiv2025

Env-antibody coevolution identifies B cell priming as the principal bottleneck to HIV-1 V2 apex broadly neutralizing antibody development

Broadly neutralizing antibodies (bNAbs) are rarely elicited during HIV-1 infection. To identify obstacles to bNAb development, we longitudinally studied 122 rhesus macaques infected by one of 16 different simian-human immunodeficiency viruses (SHIVs). We identified V2 apex as the most common bNAb target and a subset of Envs that preferentially elicited these antibodies. In 10 macaques, we delineated Env-antibody coevolution from B cell priming to bNAb development. Antibody phylogenies revealed permissive developmental pathways guided by evolving Envs that contained few mutations in or near the V2 apex C-strand, which were a sensitive indicator of apex-targeted responses. The absence of such mutations reflected a failure in bNAb priming. These results indicate that efficiency of B cell priming, and not complexities in Env-guided affinity maturation, is the primary obstacle to V2 apex bNAb elicitation in SHIV-infected macaques and identify specific HIV-1 Envs to advance as novel vaccine platforms. One sentence summaryB cell priming is the primary bottleneck to HIV-1 V2 apex bNAb elicitation.

immunology↗

bioRxiv2025

Glycan-reactive antibodies isolated from human HIV-1 vaccine trial participants show broad pathogen cross-reactivity

HIV-1 continues to pose a significant global health challenge, requiring ongoing research into effective prevention and treatment strategies. Understanding the B cell repertoire that can be engaged upon vaccination in humans is crucial for the development of future preventive vaccines. In this study, PBMCs from HIV-negative participants in the multivalent HVTN124 human HIV-1 vaccine clinical trial were interrogated for HIV-reactive B cells using LIBRA-seq, a high-throughput B cell mapping technology. We report the discovery of glycan-reactive antibodies capable of neutralizing diverse heterologous HIV-1 virus strains. Further, isolated antibodies showed broad cross-reactivity against antigens from a variety of other pathogens, while remaining mostly negative on autoreactivity assays. The emerging class of glycan- reactive virus-neutralizing antibodies with exceptional breadth of pathogen cross- reactivity may present an effective target for vaccination at the population level.

immunology↗

bioRxiv2025

Design of SARS-CoV-2 RBD Immunogens to Focus Immune Responses Towards Conserved Coronavirus Epitopes

SARS-CoV-2 continues to evolve, with new variants emerging that evade pre-existing immunity and limit the efficacy of existing vaccines. One approach towards developing superior, variant-proof vaccines is to engineer immunogens that preferentially elicit antibodies with broad cross-reactivity against SARS-CoV-2 and its variants by targeting conserved epitopes on spike. The inner and outer faces of the Receptor Binding Domain (RBD) are two such conserved regions targeted by antibodies that recognize diverse human and animal coronaviruses. To promote the elicitation of such antibodies by vaccination, we engineered "resurfaced" RBD immunogens that contained mutations at exposed RBD residues outside the target epitopes. In the context of pre-existing immunity, these vaccine candidates aim to disfavor the elicitation of strain-specific antibodies against the immunodominant Receptor Binding Motif (RBM) while boosting the induction of inner and outer face antibodies. The engineered resurfaced RBD immunogens were stable, lacked binding to monoclonal antibodies with limited breadth, and maintained strong interactions with target broadly neutralizing antibodies. When used as vaccines, they limited humoral responses against the RBM as intended. Multimerization on nanoparticles further increased the immunogenicity of the resurfaced RBDs immunogens, thus supporting resurfacing as a promising immunogen design approach to rationally shift natural immune responses to develop more protective vaccines.

immunology↗

bioRxiv2024

Transient glycan-shield reduction induces CD4-binding site broadly neutralizing antibodies in SHIV-infected macaques

Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 CD4-binding site (CD4bs) occur infrequently in macaques and humans and have not been reproducibly elicited in any outbred animal model. To address this challenge, we first isolated RHA10, an infection-induced rhesus bNAb with 51% breadth. The cryo-EM structure of RHA10 with HIV-1 envelope (Env) resembled prototypic human CD4bs bNAbs with CDR-H3-dominated binding. Env-antibody co-evolution revealed transient elimination of two Env CD4bs-proximal glycans near the time of RHA10-lineage initiation, and these glycan-deficient Envs bound preferentially to early RHA10 intermediates, suggesting glycan deletions in infecting SHIVs could consistently induce CD4bs bNAbs. To test this, we constructed SHIV.CH505.D3 with CD4bs-proximal glycan deletions. Infection of 10 macaques resulted in accelerated CD4bs bNAb responses in 8, compared with 1 of 115 control macaques. Glycan hole-based immunofocusing coupled to Env-Ab co-evolution can consistently induce broad CD4bs responses in macaques and thus serve as a model for HIV vaccine design. HighlightsO_LIOut of 115 wildtype HIV-1 Env bearing SHIV infected macaques, only one macaque (T681) developed CD4bs bNAbs C_LIO_LICD4bs bNAbs in macaque T681 recognized Env similarly to previously described CDR-H3 dominated human CD4bs bNAbs and exhibited comparable breadth and potency C_LIO_LITransient CD4bs-proximal glycan deletions in macaque T681 preceded bNAb induction C_LIO_LIA novel SHIV with CD4bs-proximal glycan holes and enhanced CD4bs antigenicity immunofocused B cell responses to the CD4bs and elicited cross-clade neutralizing responses in 80% of macaques C_LI

microbiology↗

bioRxiv2024

Structural and antigenic characterization of novel and diverse Henipavirus glycoproteins

Henipaviruses, a genus within the Paramyxoviridae family, include the highly virulent Nipah and Hendra viruses that cause reoccurring outbreaks of deadly disease. Recent discoveries of several new Paramyxoviridae species, including the zoonotic Langya virus, have revealed much higher antigenic diversity than currently characterized and prompted the reorganization of these viruses into the Henipavirus and Parahenipavirus genera. Here, to explore the limits of structural and antigenic variation in both genera, collectively referred to here as HNVs, we constructed an expanded, antigenically diverse panel of HNV fusion and attachment glycoproteins from 56 unique HNV strains that better reflects global HNV diversity. We expressed and purified the fusion protein ectodomains and the attachment protein head domains and studied their biochemical, biophysical and structural properties. We performed immunization experiments in mice leading to the elicitation of antibodies reactive to multiple HNV fusion proteins. Cryo-electron microscopy structures of diverse fusion proteins elucidated molecular determinants of differential pre-fusion state metastability and higher order contacts. A crystal structure of the Gamak virus attachment head domain revealed an additional domain appended to the conserved 6-bladed, {beta}-propeller fold. Taken together, these studies expand the known structural and antigenic limits of the HNVs, reveal new cross-reactive epitopes within both genera and provide foundational data for the development of broadly reactive countermeasures.

biochemistry↗

bioRxiv2024

Anti-HIV-1 B cell antigen receptor signaling and structure

The B cell antigen receptor (BCR) complex, comprised of antigen recognition and signaling components, functions in initiating B cell activation. While structural studies have described BCR domain organization, gaps remain in our understanding of its antigen binding domain (Fab, fragment antigen-binding) disposition, and how antigen binding is sensed to initiate signaling. Here, we report antigen affinity and signaling of the immunoglobulin (Ig) class IgM and IgG BCRs and define conformational states of full-length BCRs of two human broadly neutralizing antibodies, the glycan-specific, heavy chain domain-swapped, I-shaped 2G12, and a canonical Y-shaped antibody, CH31, that recognizes the CD4-binding site on the HIV-1 Envelope protein (Env). The BCRs adopted the shapes (I or Y) of their respective soluble antibodies, and both Ig class of BCRs of the same specificity bound Env trimers with similar affinities. We observed antigen-valenc y dependent differential signaling by the 2G12 IgM and IgG BCRs with trimeric Envs. Cryo-electron microscopy of the 2G12 IgG and CH31 IgM BCRs revealed varied Fab orientations. Structural comparisons revealed hinge points and regions of flexibility in the BCRs suggesting a highly dynamic structure of the BCR complex. Taken together, our results provide an integrated understanding of BCR structure, conformation, antigen recognition and signaling, and provide the basis for understanding antigen induced BCR signal transmission. One Sentence SummaryCryo-electron microscopy structures of full-length B cell antigen receptor complex provide a novel dynamic BCR model and a basis for understanding antigen binding induced signal transmission.

immunology↗

bioRxiv2024

A high affinity monoclonal antibody against HLA-E-VL9 enhances natural killer cell anti-tumor killing

A major natural killer (NK) cell and CD8+ T cell checkpoint is mediated by the inhibitory receptor NKG2A/CD94 and its ligand, HLA-E complexed with 9 amino acid HLA-Ia leader sequence-derived peptides termed VL9 (HLA-E-VL9). Here, we used structure-based design and high throughput library screening to generate antibodies that block NKG2A/CD94 interactions, resulting in direct NK and CD8+ T cell cytotoxicity, and trigger NK cell antibody-dependent cellular cytotoxicity (ADCC). Anti-HLA-E-VL9 antibodies limited HLA-E-VL9+ tumor growth in mice, demonstrating checkpoint inhibition activity in vivo. HLA-E-VL9 was found to be expressed on HIV-infected cells, and its engagement by HLA-E-VL9 antibodies eliminated infected cells by NK-mediated ADCC. HLA-E-VL9 antibodies also enhanced the killing of HIV-infected cells by NKG2A/CD94+ CD8+ T cells targeting a novel HLA-E binding HIV Rev-derived epitope. Therefore, anti-HLA-E-VL9 antibodies represent a novel approach to eliminate pathogenic target cells by enhancing NK and CD8+ T cell function and promoting ADCC.

immunology↗

bioRxiv2024

HIV-1 neutralizing antibodies in SHIV-infected macaques recapitulate structurally divergent modes of human V2 apex recognition with a single D gene

Broadly neutralizing antibodies targeting the V2 apex of the HIV-1 envelope trimer are among the most common specificities elicited in HIV-1-infected humans and simian-human immunodeficiency virus (SHIV)-infected macaques. To gain insight into the prevalent induction of these antibodies, we isolated and characterized 11 V2 apex-directed neutralizing antibody lineages from SHIV-infected rhesus macaques. Remarkably, all SHIV-induced V2 apex lineages were derived from reading frame two of the rhesus DH3-15*01 gene. Cryo-EM structures of envelope trimers in complex with antibodies from nine rhesus lineages revealed modes of recognition that mimicked three canonical human V2 apex-recognition modes. Notably, amino acids encoded by DH3-15*01 played divergent structural roles, inserting into a hole at the trimer apex, H-bonding to an exposed strand, or forming part of a loop scaffold. Overall, we identify a DH3-15*01-signature for rhesus V2 apex broadly neutralizing antibodies and show that highly selected genetic elements can play multiple roles in antigen recognition. HighlightsO_LIIsolated 11 V2 apex-targeted HIV-neutralizing lineages from 10 SHIV-infected Indian-origin rhesus macaques C_LIO_LICryo-EM structures of Fab-Env complexes for nine rhesus lineages reveal modes of recognition that mimic three modes of human V2 apex antibody recognition C_LIO_LIAll SHIV-elicited V2 apex lineages, including two others previously published, derive from the same DH3-15*01 gene utilizing reading frame two C_LIO_LIThe DH3-15*01 gene in reading frame two provides a necessary, but not sufficient, signature for V2 apex-directed broadly neutralizing antibodies C_LIO_LIStructural roles played by DH3-15*01-encoded amino acids differed substantially in different lineages, even for those with the same recognition mode C_LIO_LIPropose that the anionic, aromatic, and extended character of DH3-15*01 in reading frame two provides a selective advantage for V2 apex recognition compared to B cells derived from other D genes in the naive rhesus repertoire C_LIO_LIDemonstrate that highly selected genetic elements can play multiple roles in antigen recognition, providing a structural means to enhance recognition diversity C_LI

immunology↗

bioRxiv2024

SARS-CoV-2 Omicron lineage XBB spike structures, conformations, antigenicity, and receptor recognition

A recombinant lineage of the SARS-CoV-2 Omicron variant, named XBB, appeared in late 2022 and evolved descendants that successively swept local and global populations. XBB lineage members were noted for their improved immune evasion and transmissibility. Here, we determine cryo-EM structures of XBB.1.5, XBB.1.16, EG.5 and EG.5.1 spike (S) ectodomains to reveal reinforced 3-RBD-down receptor inaccessible closed states mediated by interprotomer receptor binding domain (RBD) interactions previously observed in BA.1 and BA.2. Improved XBB.1.5 and XBB.1.16 RBD stability compensated for stability loss caused by early Omicron mutations, while the F456L substitution reduced EG.5 RBD stability. S1 subunit mutations had long-range impacts on conformation and epitope presentation in the S2 subunit. Our results reveal continued S protein evolution via simultaneous optimization of multiple parameters including stability, receptor binding and immune evasion, and the dramatic effects of relatively few residue substitutions in altering the S protein conformational landscape.

biochemistry↗