Biology subjects

Ferguson, M.

Publications and source records attributed to Ferguson, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Comparative transcriptomic analysis of cassava genotypes under extended photoperiodism across flowering stages

Cassava (Manihot esculenta Crantz) is a major staple crop across tropical and subtropical regions. Despite advances in genomic selection, delayed, non-flowering, and asynchronous flowering remain key bottlenecks in breeding programs. To better understand the molecular basis of flowering-time variation, we performed RNA sequencing across three genotypes with contrasting flowering phenotypes (early, late, and non-flowering) sampled at three developmental stages under contrasting light regimes in field conditions (natural light and three-hour night-break with white light). Comparative transcriptomic analysis revealed distinct gene expression patterns associated with flowering responses. Genotype comparisons with no light supplementation revealed stage-specific enrichment of biological processes. Light supplementation was associated with changes in the expression of key components of photoperiodic and circadian regulation, as well as pathways involved in flowering-time integration and hormone and sugar-related signaling. These findings suggest that coordinated changes across multiple biological pathways regulate flowering behavior in cassava. The candidate genes and expression patterns reported provide a foundation for functional studies and advance our understanding of molecular mechanisms governing flowering-time regulation in cassava.

plant biology↗

bioRxiv2026

Protective pan-betacoronavirus neutralizing antibodies by vaccination

The continued emergence of betacoronaviruses underscores the urgent need for vaccines that provide broadly protective immunity. Here, we present an epitope-focused vaccine strategy targeting the conserved S2 stem-helix region of the spike fusion machinery, a broadly neutralizing antibody-(bnAb) epitope shared across betacoronaviruses yet partially occluded on the native spike. Immunization of non-human primates with engineered S2 stem-helix nanoparticle immunogens, alone or followed by a SARS-CoV-2 BA.1 spike mRNA boost, elicited broadly cross-reactive antibody responses against sarbecoviruses, merbecoviruses, and embecoviruses and neutralized SARS-CoV-2, multiple variants, other sarbecoviruses, and MERS-CoV. Vaccine-elicited monoclonal antibodies displayed broad in-vitro neutralizing activity and protected against both SARS-CoV-2 and MERS-CoV in-vivo. Structural analyses revealed conserved features between rhesus and human stem-helix bnAbs, supporting the translational potential. Overall, our findings provide proof-of-concept that epitope-focused nanoparticle immunogens can target partially occluded, immunoquiescent bnAb epitopes, laying the groundwork for pan-betacoronavirus vaccines that provide broad protection and strengthen pandemic preparedness. ONE SENTENCE SUMMARYEpitope-focused S2 stem-helix nanoparticle immunogens elicit protective broadly neutralizing antibodies (bnAbs) against diverse betacoronaviruses in non-human primates, establishing a framework for development of pan-betacoronavirus vaccines.

immunology↗

bioRxiv2026

G4 DNA structures induced by UV radiation: a multi-omic approach

DNA G quadruplexes (G4s) are secondary structures with critical roles in regulating genome function. G4s in regulatory regions like promoters and enhancers are important for controlling gene expression, while aberrant formation of G4s has been linked to genomic instability and human disease. Despite G4s importance and inherent danger, their dynamic formation remains incompletely understood. Here, we show that ultraviolet (UV) radiation uniquely induces widespread and persistent G4 formation in human cells, distinguishing it from other genotoxins. Through integrated genomic, transcriptomic, and proteomic analyses, we uncovered key features and functions of UV-induced G4s. Proteomic profiling identified RCOR3 as a factor associated with specific UV-induced G4s at late time points. Functional studies revealed that RCOR3 is essential for the formation and persistence of these structures. Furthermore, genes associated with UV G4s that are differentially expressed are enriched in pathways related to response to UV radiation, highlighting their biological relevance. These findings define the multi-omic landscape of UV-induced G4s and reveal new mechanistic insights into the interplay between genotoxic stress responses and the regulation of non-canonical DNA structures. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/738736v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@8c2e32org.highwire.dtl.DTLVardef@12d1379org.highwire.dtl.DTLVardef@5971a3org.highwire.dtl.DTLVardef@33bcee_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2026

Strong effects of soil microbes on early-life defense alter phenotypic correlations in plant leaves

Microbes have wide-ranging effects on host phenotype. However, whether these effects extend to the relationships among host traits remains unknown. We tested whether microbes affect phenotypic correlations among early life traits in the weedy legume Medicago lupulina. In a field common garden, we inoculated plants with two types of microbes: nitrogen-fixing bacteria and rhizosphere microbial communities. We found that microbes modify phenotypic integration (phenotypic correlations) in leaves, primarily due to effects on independent effects on leaflet area and trichome density, a defense trait. While microbial effects on leaflet size were associated with overall plant growth, variation in trichome density was decoupled from growth and not predicted by investment in mutualism. Our results highlight the unique insights that can come from a multivariate approach to organismal plasticity, and raise the intriguing possibility that microbes may have an outsized impact on defense traits and their integration with organismal function.

Plant Biology↗

bioRxiv2026

LVV SMRTcap reveals extensive proviral variation in lentiviral vector-transduced CAR T cells

Lentiviral vectors are commonly used to introduce chimeric antigen receptor transgenes into T cells, but routine assays quantify vector copy number or integration sites without sequencing full-length integrated vectors. HIV-1 proviruses often acquire large deletions and cytidine deaminase-driven hypermutation; whether similar variation occurs in therapeutic lentiviral vectors is unclear. We adapted a novel long-read capture approach to enrich long fragments spanning vector DNA and adjacent human sequence, enabling simultaneous integration-site mapping and proviral integrity analysis with single-molecule resolution. In research-grade CAR T cells produced with an experimental, transient-transfection lentiviral vector workflow, 40% of integrated vectors carried recurrent deletions that removed the internal promoter or parts of the chimeric antigen receptor cassette. The dominant promoter deletion was present in the viral stock. In clinical chimeric antigen receptor T cell products, promoter deletions were less frequent, but detectable pre-infusion and post-infusion. Across datasets we observed widespread G-to-A substitutions consistent with restriction factor editing, including changes predicted to introduce premature stop codons within the transgene open reading frame. Our method reveals proviral variants invisible to standard quality-control assays and provides a framework to improve vector production and monitor transgene integrity in clinical products.

cancer biology↗

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

Origin and Correlates of Viral Rebound in SIV-Infected Rhesus Macaques Following ART Discontinuation

The vast majority of persons living with HIV-1 who discontinue antiretroviral therapy (ART) demonstrate viral rebound, but the tissue-level events that lead to rebound viremia are poorly understood. Here we report the origin, dynamics, and correlates of viral rebound in 16 rhesus macaques (RMs) infected with molecularly barcoded SIVmac239M, treated with ART for 70 weeks, and necropsied on day 12 after ART discontinuation. Barcode analysis of plasma following ART discontinuation identified 1 to 38 rebounding barcode-defined viral lineages per animal, with 1 to 4 rebounding lineages contributing to first measurable rebound viremia. Analysis of barcode viral RNA (vRNA) expression in necropsy tissues revealed presumptive anatomic origin sites for 56 of 175 total rebounding viral lineages, with significant enrichment in the gastrointestinal (GI) tract and GI-associated lymph nodes. Daily transcriptomic and proteomic profiling in peripheral blood following ART discontinuation showed upregulation of pathways related to T cell signaling, cytokine responses, and cellular metabolism prior to detectable rebound viremia. These data suggest that viral rebound following ART discontinuation is initiated by local tissue replication of a limited number of clonal lineages, followed by systemic expansion of the initial rebounding lineages and serial initiation of replication of multiple additional clonal lineages. These findings provide mechanistic insights into the processes that result in viral rebound following ART discontinuation and will contribute to next generation HIV-1 cure strategies.

microbiology↗

bioRxiv2025

Composition of Carotid Plaques Differs Between Chinese and United States Patients: A Histology Study

BackgroundThe clinical manifestations of cerebrovascular disease are known to differ between the Chinese and United States (U.S.) populations as do the plaque features on imaging. ObjectivesThe aim of this study was to investigate and compare the histological features of excised carotid plaques from Chinese and U.S. patients. MethodsCarotid endarterectomy specimens collected from two prospective studies were included. The entire plaque was serially sectioned (10 {micro}m thickness) at 0.5-1 mm intervals. Hematoxylin and eosin staining and Mallorys trichrome staining were performed. The morphology and components of the plaques were measured and compared between the two groups. ResultsA total of 1,152 histological sections from 75 Chinese patients and 1,843 sections from 111 U.S. patients were analyzed. The Chinese group had significantly smaller minimum lumen diameters (median: 1.1 vs. 1.3 mm, p=0.046) and a larger percent wall volume (median: 74% vs. 70%, p=0.018) than the U.S. group. After adjusting for confounding factors, carotid plaques in the Chinese population were more likely to have more lipid pools ({beta}=10.0%, 95%CI: 4.9 to 15.9%), more recent intraplaque hemorrhage (IPH; {beta}=8.4%, 95%CI: 4.5 to 12.7%), and less late IPH ({beta}=-8.2%, 95%CI: -11.3 to -5.4), and fewer fibrous cap disruptions (45% vs. 67%, p=0.061). Chinese plaques were more homogeneous and had a higher percentage of plaques with features of xanthomas than did U.S. plaques (20% vs 2.7%, p<0.001). ConclusionsThe histology of Chinese plaques differs significantly from that of U.S. plaques, suggesting substantial differences in the pathophysiology of atherosclerotic cerebrovascular disease between Chinese and North American populations, which could enhance the gap in racial pathology comparison, indicating a need for a different management approach. Central illustration O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/658993v1_ufig1.gif" ALT="Figure 1"> View larger version (83K): org.highwire.dtl.DTLVardef@14f16corg.highwire.dtl.DTLVardef@f60d66org.highwire.dtl.DTLVardef@1e9a822org.highwire.dtl.DTLVardef@11d7a31_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2025

Stem cell-specific NF-kB is required for stem cell survival and epithelial regeneration upon intestinal damage.

Immune signals coordinate the repair of damaged epithelia by intestinal stem cells. However, it is unclear if immune pathways act autonomously within the stem cell to direct the damage response pathway. We consider this an important question, as stem cell dynamics are essential for formation and maintenance of the entire epithelium. We used Drosophila to determine the impact of stem cell-specific loss of NF-{kappa}B on tissue regeneration upon chemical injury. We found that loss of NF-{kappa}B enhanced cell death, impaired enterocyte renewal and increased mortality. Mechanistically, we showed that inhibition of stem cell apoptosis is essential for NF-{kappa}B-dependent maintenance of cell viability and tissue repair. Combined, our data demonstrate that stem cell-intrinsic NF-{kappa}B activity is essential for an orderly repair of damaged intestinal epithelia.

immunology↗

bioRxiv2025

Symbiont-specific uptake is mediated by integrins in cnidarian larvae

The symbiotic relationship between dinoflagellate algae and their cnidarian hosts is fundamental to the health of coral reefs. The selection of appropriate symbionts is paramount for the host to gain valuable nutrients and could be tailored to increase stress tolerance against anthropogenic induced changes in ocean environments, such as coral bleaching in response to ocean warming. Previous research suggests glycan-lectin interactions play a role in symbiont uptake; however, blockage of such interactions does not fully inhibit symbiosis establishment, suggesting other receptors are at play. Potential candidates include RGD peptide binding integrins, which are known to mediate phagocytosis of microbes in other systems. Here, we used a combination of cnidarian model systems and human cell lines to determine if integrins facilitate symbiont recognition and uptake. Integrins are highly expressed in the endodermal tissue of the host, where symbiosis takes place, and upon uptake into endodermal cells, symbionts altered the expression of integrins and downstream signaling molecules. Blockage of integrin binding sites with RGD competitor peptides reduced symbiont uptake, but had no effect on the general uptake of non-symbiotic algae, or uptake in a non-symbiotic cnidarian. In addition, inert beads coated with integrin RGD peptide ligands were phagocytosed more readily than beads coated with scrambled peptide. Finally, overexpression of RGD-binding integrins in human cells increased symbiont uptake and mutation of the active binding site abolished uptake. Our findings reveal RGD-binding integrins as key players in symbiosis establishment and shed light on the evolutionary functions of integrins as phagocytic receptors. Significance statementCorals engage in a symbiotic partnership with photosynthetic algae to survive in challenging environments. To date it is largely unclear how the two partners recognize each other. Using a comparative model systems approach, we have identified evolutionary conserved integrins as molecular receptors for specifically engulfing symbionts, but not other algae. This suggests that integrins allow the host to distinguish between symbiotic and non-symbiotic algae and preferentially take up symbionts. Our findings establish a new paradigm for symbiosis establishment in corals and shed light on the ancient function of integrins as environmental sensors.

cell biology↗

bioRxiv2024

Spatiotemporal variation in size-dependent growth rates in small isolated populations of Arctic charr (Salvelinus alpinus)

As a key life-history trait, growth rates are often used to measure individual performance and to inform parameters in demographic models. Furthermore, intra-specific trait variation generates diversity in nature. Therefore, partitioning out and understanding drivers of spatiotemporal variation in growth rate is of fundamental interest in ecology and evolution. However, this has rarely been attempted due to the amount of individual-level data required through both time and space, and issues with missing data in important covariates. Here we implemented a Bayesian state-space model using individual-level data from 20 populations of Arctic charr (Salvelinus alpinus) across 15 capture occasions, which allowed us to: (1) integrate over the uncertainty of missing recapture records; (2) robustly estimate size-dependence; and (3) include a covariate (water temperature) that contained missing data. Interestingly, although there was substantial spatial, temporal, and spatiotemporal variation in growth rate, this was only weakly associated with variation in water temperature and almost entirely independent of size, suggesting that spatiotemporal variation in other environmental conditions affected individuals across sizes similarly. This fine-scale spatiotemporal variation emphasises the importance of local conditions and highlights the potential for spatiotemporal variation in a size-dependent life-history trait, even when environmental conditions are apparently very similar.

ecology↗

bioRxiv2024

A Multi-Omics Approach to Defining Target Organ Injury in Youth with Primary Hypertension

BACKGROUNDPrimary hypertension in childhood tracks into adulthood and may be associated with increased cardiovascular risk. Studies conducted in children and adolescents provide an opportunity to explore the early cardiovascular target organ injury (CV-TOI) in a population free from many of the co-morbid cardiovascular disease risk factors that confound studies in adults. METHODSYouths (n=132, mean age 15.8 years) were stratified by blood pressure (BP) as low, elevated, and high-BP and by left ventricular mass index (LVMI) as low- and high-LVMI. Systemic circulating RNA, miRNA, and methylation profiles in peripheral blood mononuclear cells and deep proteome profiles in serum were determined using high-throughput sequencing techniques. RESULTSVASH1 gene expression was elevated in youths with high-BP with and without high-LVMI. VASH1 expression levels positively correlated with systolic BP (r=0.3143, p=0.0034). The expression of hsa-miR-335-5p, one of the VASH1-predicted miRNAs, was downregulated in high-BP with high-LVMI youths and was inversely correlated with systolic BP (r=-0.1891, p=0.0489). GSE1 hypermethylation, circulating PROZ upregulation (log2FC=0.61, p=0.0049 and log2FC=0.62, p=0.0064), and SOD3 downregulation (log2FC=-0.70, p=0.0042 and log2FC=-0.64, p=0.010) were observed in youths with elevated BP and high-BP with high-LVMI. Comparing the transcriptomic and proteomic profiles revealed elevated HYAL1 levels in youths displaying high-BP and high-LVMI. CONCLUSIONSThe findings are compatible with a novel blood pressure-associated mechanism that may occur through impaired angiogenesis and extracellular matrix degradation through dysregulation of Vasohibin-1 and Hyaluronidase1 was identified as a possible mediator of CV-TOI in youth with high-BP and suggests strategies for ameliorating TOI in adult-onset primary hypertension.

genomics↗

bioRxiv2024

Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer

Deciphering the structural variation across tumour genomes is crucial to determine the events driving tumour progression and better understand tumour adaptation and evolution. High grade serous ovarian cancer (HGSOC) is an exemplar tumour type showing extreme, but poorly characterised structural diversity. We comprehensively describe the mutational landscape driving HGSOC, exploiting a large (N=324), deeply whole genome sequenced dataset. We reveal two divergent evolutionary trajectories, affecting patient survival and involving differing genomic environments. One involves homologous recombination repair deficiency (HRD) while the other is dominated by whole genome duplication (WGD) with frequent chromothripsis, breakage-fusion-bridges and extra-chromosomal DNA. These trajectories contribute to structural variation hotspots, containing novel candidate driver genes with significantly altered expression. While structural variation predominantly drives tumorigenesis, we also find high mtDNA mutation loads associated with shorter patient survival, and acting in combination with alterations in the nuclear genome to impact prognosis and suggesting new strategies for patient stratification.

cancer biology↗

bioRxiv2023

Use of Epivolve phage display to generate a monoclonal antibody with opsonic activity directed against a subdominant epitope on extracellular loop 4 of Treponema pallidum BamA (TP0326)

Syphilis, a sexually transmitted infection caused by the spirochete Treponema pallidum (Tp), is resurging globally. Opsonic antibodies (Abs) targeting surface-exposed epitopes of the spirochetes outer membrane proteins (OMPs) are believed to promote macrophage-mediated clearance of the bacterium during infection and are presumed to be key to vaccine development. Tps repertoire of outer membrane proteins includes BamA ({beta}-barrel assembly machinery subunit A/TP0326), the central component of the molecular machine that inserts newly exported OMP precursors into the OM lipid bilayer. BamA is a bipartite protein consisting of an 18-stranded {beta}-barrel with nine extracellular loops (ECLs) and five periplasmic POTRA (polypeptide transport-associated) domains. Antisera directed against BamA ECL4 promote internalization of Tp by rabbit peritoneal macrophages. Herein, we employed a novel two-stage, phage display strategy, termed "Epivolve" (for epitope evolution), to generate five site-directed murine monoclonal Abs (mAbs) targeting a centrally located peptide (S2) of BamA ECL4. Each of the five mAbs demonstrated reactivity by immunoblotting and ELISA to nanogram amounts of BamA ECL4 displayed by a Pyrococcus furiosus thioredoxin (PfTrx) scaffold (PfTrxBamA/ECL4). One mAb containing a unique amino acid sequence in both light and heavy chains showed activity in an opsonophagocytosis assay employing murine bone marrow-derived macrophages. Mice and rabbits hyperimmunized with PfTrxBamA/ECL4 produced opsonic antisera that strongly recognized the ECL presented in a heterologous scaffold and overlapping ECL4 peptides including S2. In contrast, Abs generated during Tp infection of mice and rabbits poorly recognized the peptides, indicating that S2 contains a subdominant epitope. Epivolve, which circumvents the natural immune response, can be utilized for the generation of mAbs that target subdominant opsonic epitopes in ECLs of Tp OMPs.

immunology↗

bioRxiv2022

Development of a yeast whole-cell biocatalyst for MHET conversion into terephthalic acid and ethylene glycol

BackgroundOver the 70 years since the introduction of plastic into everyday items, plastic waste has become an increasing problem. With over 360 million tonnes of plastics produced every year, solutions for plastic recycling and plastic waste reduction are sorely needed. Recently, multiple enzymes capable of degrading PET (polyethylene teraphthalate) plastic have been identified and engineered. In particular, the enzymes PETase and MHETase from Ideonella sakaiensis depolymerize PET into the two building blocks used for its synthesis, ethylene glycol (EG) and terephthalic acid (TPA). Importantly, EG and TPA can be re-used for PET synthesis allowing complete and sustainable PET recycling. ResultsIn this study, we used Saccharomyces cerevisiae as a platform to develop a whole-cell catalyst expressing the MHETase enzyme, which converts MHET (monohydroxyethyl terephthalate) into TPA and EG. We assessed six expression architectures and identified those resulting in efficient MHETase expression on the yeast cell surface. We show that the MHETase whole-cell catalyst has activity comparable to recombinant MHETase purified from Escherichia coli. Finally, we demonstrate that surface displayed MHETase is stable to pH, temperature, and for at least 12 days at room temperature. ConclusionsWe demonstrate the feasibility of using S. cerevisiae as a platform for the expression and surface display of PET degrading enzymes and predict that the whole-cell catalyst will viable alternatives to protein purification-based approaches for plastic degradation.

synthetic biology↗

bioRxiv2022

Relish/NF-kB acts in intestinal stem cells to promote epithelial repair in Drosophila

Immune signals coordinate the repair of damaged epithelia by intestinal stem cells. However, it is unclear if immune pathways act autonomously within the stem cell to direct the damage response pathway. We consider this an important question, as stem cell dynamics are essential for formation and maintenance of the entire epithelium. We used Drosophila to determine the impact of stem cell-specific loss of NF-{kappa}B on tissue regeneration upon chemical injury. We found that loss of NF-{kappa}B enhanced cell death, impaired enterocyte renewal and increased mortality. Mechanistically, we showed that the Ras/ERK pathway is essential for NF-{kappa}B-dependent maintenance of cell viability and tissue repair. Combined, our data demonstrate that stem cell-intrinsic NF-{kappa}B activity is essential for an orderly repair of damaged intestinal epithelia.

immunology↗

bioRxiv2022

Aligning Model and Macaque Inferior Temporal Cortex Representations Improves Model-to-Human Behavioral Alignment and Adversarial Robustness

While some state-of-the-art artificial neural network systems in computer vision are strikingly accurate models of the corresponding primate visual processing, there are still many discrepancies between these models and the behavior of primates on object recognition tasks. Many current models suffer from extreme sensitivity to adversarial attacks and often do not align well with the image-by-image behavioral error patterns observed in humans. Previous research has provided strong evidence that primate object recognition behavior can be very accurately predicted by neural population activity in the inferior temporal (IT) cortex, a brain area in the late stages of the visual processing hierarchy. Therefore, here we directly test whether making the late stage representations of models more similar to that of macaque IT produces new models that exhibit more robust, primate-like behavior. We conducted chronic, large-scale multi-electrode recordings across the IT cortex in six non-human primates (rhesus macaques). We then use these data to fine-tune (end-to-end) the model "IT" representations such that they are more aligned with the biological IT representations, while preserving accuracy on object recognition tasks. We generate a cohort of models with a range of IT similarity scores validated on held-out animals across two image sets with distinct statistics. Across a battery of optimization conditions, we observed a strong correlation between the models IT-likeness and alignment with human behavior, as well as an increase in its adversarial robustness. We further assessed the limitations of this approach and find that the improvements in behavioral alignment and adversarial robustness generalize across different image statistics, but not to object categories outside of those covered in our IT training set. Taken together, our results demonstrate that building models that are more aligned with the primate brain leads to more robust and human-like behavior, and call for larger neural data-sets to further augment these gains.

neuroscience↗

bioRxiv2021

Broadly neutralizing antibodies to SARS-related viruses can be readily induced in rhesus macaques

To prepare for future coronavirus (CoV) pandemics, it is desirable to generate vaccines capable of eliciting neutralizing antibody responses against multiple CoVs. Because of the phylogenetic similarity to humans, rhesus macaques are an animal model of choice for many virus-challenge and vaccine-evaluation studies, including SARS-CoV-2. Here, we show that immunization of macaques with SARS-CoV-2 spike (S) protein generates potent receptor binding domain cross- neutralizing antibody (nAb) responses to both SARS-CoV-2 and SARS-CoV-1, in contrast to human infection or vaccination where responses are typically SARS-CoV-2-specific. Furthermore, the macaque nAbs are equally effective against SARS-CoV-2 variants of concern. Structural studies show that different immunodominant sites are targeted by the two primate species. Human antibodies generally target epitopes strongly overlapping the ACE2 receptor binding site (RBS), whereas the macaque antibodies recognize a relatively conserved region proximal to the RBS that represents another potential pan-SARS-related virus site rarely targeted by human antibodies. B cell repertoire differences between the two primates appear to significantly influence the vaccine response and suggest care in the use of rhesus macaques in evaluation of vaccines to SARS-related viruses intended for human use. ONE SENTENCE SUMMARYBroadly neutralizing antibodies to an unappreciated site of conservation in the RBD in SARS- related viruses can be readily induced in rhesus macaques because of distinct properties of the naive macaque B cell repertoire that suggest prudence in the use of the macaque model in SARS vaccine evaluation and design.

immunology↗