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OBJECTIVES: Evidence on the link between long-term ambient particulate matter (PM) exposures and childhood sleep disorders were scarce. We examined the associations between long-term exposures to PM2.5 and PM1 (PM with an aerodynamic equivalent diameter <2.5 µm and <1 µm, respectively) with sleep disorders in children. METHODS: We performed a population-based cross-sectional survey in 177,263 children aged 6 to 18 years in 14 Chinese cities during 2012-2018. A satellite-based spatiotemporal model was employed to estimate four-year annual average PM2.5 and PM1 exposures at residential and school addresses. Parents or guardians completed a checklist using the Sleep Disturbance Scale for Children. We estimated the associations using generalized linear mixed models with adjustment for characteristics of children, parents, and indoor environments. RESULTS: Long-term PM2.5 and PM1 exposures were positively associated with odds of sleep disorders for almost all domains. For example, increments in PM2.5 and PM1 per 10 µg/m3 were associated with odds ratios of global sleep disorder of 1.24 (95 % confidence interval [CI]: 1.14, 1.35) and 1.31 (95 %CI: 1.18, 1.46), respectively. Similar results were observed for subtypes of sleep disorder. These associations were heterogeneous regionally, with stronger associations among children residing in southeast region than in northeast and northwest regions. Moreover, larger estimates of PM1 were found than that of PM2.5 in southeast region. CONCLUSION: Long-term PM2.5 and PM1 exposures are independently associated with higher risks of childhood sleep disorders, and these associations vary by geographical region.
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Epidemiological evidence showed that serum high perfluorooctane sulfonate (PFOS) levels are associated with multiple eye related diseases, but the potential underlying molecular mechanisms remain poorly understood. Zebrafish and photoreceptor cell (661w) models were used to investigate the molecular mechanism of PFOS induced eye development defects. Our results showed a novel molecular mechanism of PFOS-induced inflammation response-mediated photoreceptor cell death associated with eye development defects. Inhibition of Caspase-8 activation significantly decreased photoreceptor cell death in PFOS exposure. Mechanistically, Toll-like receptor 4 (TLR4) mediates activation of Caspase-8 promote activation of NLR family pyrin domain-containing 3 (NLRP3) inflammasome to elicit maturation of interleukin-1 beta (IL-1ß) via Caspase-1 activation, facilitating photoreceptor cell inflammation damage in PFOS exposure. In addition, we also made a novel finding that Caspase-3 activation was increased via Caspase-8 activation and directly intensified cell death. Our results show the important role of Caspase-8 activation in PFOS induced eye development defects and highlight Caspase-8 mediated activation of the NLRP3 inflammation triggers activation of Caspase-1 and promote the maturation of IL-1ß in retinal inflammatory injury.
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Ácidos Alcanesulfónicos , Caspasa 8 , Fluorocarburos , Inflamasomas , Larva , Proteína con Dominio Pirina 3 de la Familia NLR , Pez Cebra , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamasomas/metabolismo , Caspasa 8/metabolismo , Caspasa 8/genética , Ácidos Alcanesulfónicos/toxicidad , Fluorocarburos/toxicidad , Larva/efectos de los fármacos , Interleucina-1beta/metabolismo , Ojo/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidadRESUMEN
Contaminants may induce immune response polarization, leading to immune diseases, such as allergic diseases. Evidence concerning the effects of chlorinated paraffins (CPs), an emerging persistent organic pollutant, on immune system is scarce, particularly for epidemiological evidence. This study explores the association between CPs exposure and allergic diseases (allergic rhinitis, atopic eczema, and allergic conjunctivitis) in children and adolescents in the Pearl River Delta (PRD) in China. Herein, 131,304 children and adolescents from primary and secondary schools in the PRD were included and completed the questionnaire survey. The particulate matter (PM) samples were collected in the PRD and the PM2.5-bound CP concentrations were analyzed. In the multivarious adjustment mixed effect model (MEM), an IQR increase in ∑CPs was significantly associated with allergic diseases (rhinitis, eczema, and conjunctivitis) with the estimated odds ratios (ORs) for 1.11 (95% CI: 1.10, 1.13), 1.17 (95% CI: 1.15, 1.19), and 1.82 (95% CI: 1.76, 1.88), respectively. Interaction analysis indicated that overweight and obese individuals might have greater risk. Similar effect estimates were observed in several sensitivity analyses. This study provided epidemiological evidence on the immunotoxicity of CPs. More studies to confirm our findings and investigate mechanisms are needed.
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Parafina , Humanos , Adolescente , Niño , Masculino , Femenino , China/epidemiología , Parafina/toxicidad , Parafina/análisis , Hipersensibilidad/epidemiología , Exposición a Riesgos Ambientales/efectos adversos , Hidrocarburos Clorados/toxicidad , Hidrocarburos Clorados/análisis , Contaminantes Atmosféricos/toxicidad , Contaminantes Atmosféricos/análisis , Material Particulado/toxicidad , Material Particulado/análisis , Dermatitis Atópica/epidemiología , Dermatitis Atópica/inducido químicamente , Rinitis Alérgica/epidemiología , Rinitis Alérgica/inducido químicamenteRESUMEN
Alphaviruses are arboviruses transmitted by mosquitoes and are pathogenic to humans and livestock, causing a substantial public health burden. So far, several receptors have been identified for alphavirus entry; however, they cannot explain the broad host range and tissue tropism of certain alphaviruses, such as Getah virus (GETV), indicating the existence of additional receptors. Here we identify the evolutionarily conserved low-density lipoprotein receptor (LDLR) as a new cell entry factor for GETV, Semliki Forest virus (SFV), Ross River virus (RRV) and Bebaru virus (BEBV). Ectopic expression of LDLR facilitates cellular binding and internalization of GETV, which is mediated by the interaction between the E2-E1 spike of GETV and the ligand-binding domain (LBD) of LDLR. Antibodies against LBD block GETV infection in cultured cells. In addition, the GST-LBD fusion protein inhibits GETV infection both in vitro and in vivo. Notably, we identify the key amino acids in LDLR-LBD that played a crucial role in viral entry; specific mutations in the CR4 and CR5 domain of LDLR-LBD reduce viral entry to cells by more than 20-fold. These findings suggest that targeting the LDLR-LBD could be a potential strategy for the development of antivirals against multiple alphaviruses.
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Infecciones por Alphavirus , Alphavirus , Culicidae , Animales , Humanos , Alphavirus/genética , Internalización del Virus , Virus de los Bosques Semliki/genética , Virus de los Bosques Semliki/metabolismo , Infecciones por Alphavirus/genéticaRESUMEN
The retransmissions of SARS-CoV-2 from several mammals - primarily mink and white-tailed deer - to humans have raised concerns for the emergence of a new animal-derived SARS-CoV-2 variant to worsen the pandemic. Here, we discuss animal species that are susceptible to natural or experimental infection with SARS-CoV-2 and can transmit the virus to mates or humans. We describe cutting-edge techniques to assess the impact of a mutation in the viral spike (S) protein on its receptor and on antibody binding. Our review of spike sequences of animal-derived viruses identified nine unique amino acid exchanges in the receptor-binding domain (RBD) that are not present in any variant of concern (VOC). These mutations are present in SARS-CoV-2 found in companion animals such as dogs and cats, and they exhibit a higher frequency in SARS-CoV-2 found in mink and white-tailed deer, suggesting that sustained transmissions may contribute to maintaining novel mutations. Four of these exchanges, such as Leu452Met, could undermine acquired immune protection in humans while maintaining high affinity for the human angiotensin-converting enzyme 2 (ACE2) receptor. Finally, we discuss important avenues of future research into animal-derived viruses with public health risks.
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COVID-19 , Enfermedades de los Gatos , Ciervos , Enfermedades de los Perros , Animales , Perros , Gatos , Humanos , SARS-CoV-2/genética , Ciervos/metabolismo , Visón/metabolismo , Medición de Riesgo , Glicoproteína de la Espiga del Coronavirus/genética , Mutación , Unión ProteicaRESUMEN
Swine pathogens have a long history of zoonotic transmission to humans, occasionally leading to sustained outbreaks or pandemics. Through a retrospective epidemiological study of swine populations in China, we describe novel lineages of porcine hemagglutinating encephalomyelitis virus (PHEV) complex coronaviruses (CoVs) that cause exclusively respiratory symptoms with no signs of the neurological symptoms typically associated with classical PHEV infection. Through large-scale epidemiological surveillance, we show that these novel lineages have circulated in at least eight provinces in southeastern China. Phylogenetic and recombination analyses of twenty-four genomes identified two major viral lineages causing respiratory symptoms with extensive recombination within them, between them, and between classical PHEV and the novel respiratory variant PHEV (rvPHEV) lineages. Divergence times among the sampled lineages in the PHEV virus complex date back to 1886-1958 (mean estimate 1928), with the two major rvPHEV lineages separating approximately 20 years later. Many rvPHEV viruses show amino acid substitutions at the carbohydrate-binding site of hemagglutinin esterase (HE) and/or have lost the cysteine required for HE dimerization. This resembles the early adaptation of human CoVs, where HE lost its hemagglutination ability to adapt to growth in the human respiratory tract. Our study represents the first report of the evolutionary history of rvPHEV circulating in swine and highlights the importance of characterizing CoV diversity and recombination in swine to identify pathogens with outbreak potential that could threaten swine farming.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is a heavily mutated virus and designated as a variant of concern. To investigate the codon usage pattern of this new variant, we performed mutation and codon bias analysis for Omicron as well as for its sub-lineages BA.1 and BA.2 and compared them with the original SARS-CoV-2 and the Delta variant sequences obtained in this study. Our results indicate that the sub-lineage BA.1 and BA.2 have up to 23 sites of difference on the spike protein, which have minimal impact on function. The Omicron variant and its sub-lineages have similar codon usage patterns and A/U ending codons appear to be preferred over G/C ending codons. The Omicron has a lower degree of codon usage bias in spite of evidence that natural selection, mutation pressure and dinucleotide abundance shape the codon usage bias of Omicron, with natural selection being more significant on BA.2 than the other sub-lineages of Omicron. The codon usage pattern of Omicron variant that we explored provides valid information for a clearer understanding of Omicron and its sub-lineages, which could find application in vaccine development and optimization.
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COVID-19 , Uso de Codones , Humanos , Uso de Codones/genética , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/genética , COVID-19/genética , MutaciónRESUMEN
Developing broad coronavirus vaccines requires identifying and understanding the molecular basis of broadly neutralizing antibody (bnAb) spike sites. In our previous work, we identified sarbecovirus spike RBD group 1 and 2 bnAbs. We have now shown that many of these bnAbs can still neutralize highly mutated SARS-CoV-2 variants, including the XBB.1.5. Structural studies revealed that group 1 bnAbs use recurrent germline-encoded CDRH3 features to interact with a conserved RBD region that overlaps with class 4 bnAb site. Group 2 bnAbs recognize a less well-characterized "site V" on the RBD and destabilize spike trimer. The site V has remained largely unchanged in SARS-CoV-2 variants and is highly conserved across diverse sarbecoviruses, making it a promising target for broad coronavirus vaccine development. Our findings suggest that targeted vaccine strategies may be needed to induce effective B cell responses to escape resistant subdominant spike RBD bnAb sites.
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The COVID-19 pandemic has taught us many things, among the most important of which is that vaccines are one of the cornerstones of public health that help make modern longevity possible. While several different vaccines have been successful at stemming the morbidity and mortality associated with various infectious diseases, many pathogens/diseases remain recalcitrant to the development of effective vaccination. Recent advances in vaccine technology, immunology, structural biology, and other fields may yet yield insight that will address these diseases; they may also help improve societies' preparedness for future pandemics. On June 1-4, 2022, experts in vaccinology from academia, industry, and government convened for the Keystone symposium "Progress in Vaccine Development for Infectious Diseases" to discuss state-of-the-art technologies, recent advancements in understanding vaccine-mediated immunity, and new aspects of antigen design to aid vaccine effectiveness.
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COVID-19 , Enfermedades Transmisibles , Vacunas , Humanos , Pandemias/prevención & control , COVID-19/prevención & control , Vacunas/uso terapéutico , Vacunación , Desarrollo de VacunasRESUMEN
Farmed mammals may act as hosts for zoonotic viruses that can cause disease outbreaks in humans. This SnapShot shows which farmed mammals, and to what extent, are of particular risk of harboring and spreading viruses from viral families that are commonly associated with zoonotic disease. It also discusses genome surveillance methods and biosafety measures. To view this SnapShot, open or download the PDF.
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Virus , Zoonosis , Animales , Humanos , Mamíferos , Brotes de Enfermedades , Medición de RiesgoRESUMEN
Pan-betacoronavirus neutralizing antibodies may hold the key to developing broadly protective vaccines against novel pandemic coronaviruses and to more effectively respond to SARS-CoV-2 variants. The emergence of Omicron and subvariants of SARS-CoV-2 illustrates the limitations of solely targeting the receptor-binding domain (RBD) of the spike (S) protein. Here, we isolated a large panel of broadly neutralizing antibodies (bnAbs) from SARS-CoV-2 recovered-vaccinated donors, which targets a conserved S2 region in the betacoronavirus spike fusion machinery. Select bnAbs showed broad in vivo protection against all three deadly betacoronaviruses, SARS-CoV-1, SARS-CoV-2, and MERS-CoV, which have spilled over into humans in the past two decades. Structural studies of these bnAbs delineated the molecular basis for their broad reactivity and revealed common antibody features targetable by broad vaccination strategies. These bnAbs provide new insights and opportunities for antibody-based interventions and for developing pan-betacoronavirus vaccines.
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COVID-19 , SARS-CoV-2 , Humanos , Anticuerpos ampliamente neutralizantes , Anticuerpos Neutralizantes , Anticuerpos AntiviralesRESUMEN
Animal reservoirs of sarbecoviruses represent a significant risk of emergent pandemics, as evidenced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Vaccines remain successful at limiting severe disease and death, but the potential for further coronavirus zoonosis motivates the search for pan-coronavirus vaccines. This necessitates a better understanding of the glycan shields of coronaviruses, which can occlude potential antibody epitopes on spike glycoproteins. Here, we compare the structure of 12 sarbecovirus glycan shields. Of the 22 N-linked glycan attachment sites present on SARS-CoV-2, 15 are shared by all 12 sarbecoviruses. However, there are significant differences in the processing state at glycan sites in the N-terminal domain, such as N165. Conversely, glycosylation sites in the S2 domain are highly conserved and contain a low abundance of oligomannose-type glycans, suggesting a low glycan shield density. The S2 domain may therefore provide a more attractive target for immunogen design efforts aiming to generate a pan-coronavirus antibody response.
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COVID-19 , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , Animales , SARS-CoV-2 , Glicosilación , Polisacáridos/químicaRESUMEN
Getah virus (GETV) mainly causes disease in livestock and may pose an epidemic risk due to its expanding host range and the potential of long-distance dispersal through animal trade. Here, we used metagenomic next-generation sequencing (mNGS) to identify GETV as the pathogen responsible for reemerging swine disease in China and subsequently estimated key epidemiological parameters using phylodynamic and spatially-explicit phylogeographic approaches. The GETV isolates were able to replicate in a variety of cell lines, including human cells, and showed high pathogenicity in a mouse model, suggesting the potential for more mammal hosts. We obtained 16 complete genomes and 79 E2 gene sequences from viral strains collected in China from 2016 to 2021 through large-scale surveillance among livestock, pets, and mosquitoes. Our phylogenetic analysis revealed that three major GETV lineages are responsible for the current epidemic in livestock in China. We identified three potential positively selected sites and mutations of interest in E2, which may impact the transmissibility and pathogenicity of the virus. Phylodynamic inference of the GETV demographic dynamics identified an association between livestock meat consumption and the evolution of viral genetic diversity. Finally, phylogeographic reconstruction of GETV dispersal indicated that the sampled lineages have preferentially circulated within areas associated with relatively higher mean annual temperature and pig population density. Our results highlight the importance of continuous surveillance of GETV among livestock in southern Chinese regions associated with relatively high temperatures. IMPORTANCE Although livestock is known to be the primary reservoir of Getah virus (GETV) in Asian countries, where identification is largely based on serology, the evolutionary history and spatial epidemiology of GETV in these regions remain largely unknown. Through our sequencing efforts, we provided robust support for lineage delineation of GETV and identified three major lineages that are responsible for the current epidemic in livestock in China. We further analyzed genomic and epidemiological data to reconstruct the recent demographic and dispersal history of GETV in domestic animals in China and to explore the impact of environmental factors on its genetic diversity and its diffusion. Notably, except for livestock meat consumption, other pig-related factors such as the evolution of live pig transport and pork production do not show a significant association with the evolution of viral genetic diversity, pointing out that further studies should investigate the potential contribution of other host species to the GETV outbreak. Our analysis of GETV demonstrates the need for wider animal species surveillance and provides a baseline for future studies of the molecular epidemiology and early warning of emerging arboviruses in China.
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Arbovirus , Genoma Viral , Filogenia , Animales , Humanos , Ratones , Arbovirus/genética , China/epidemiología , Genómica , Ganado/virologíaRESUMEN
Immunocompromised cancer patients are at significant risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A method to identify those patients at highest risk is needed so that prophylactic measures may be employed. Serum antibodies to SARS-CoV-2 spike protein are important markers of protection against COVID-19 disease. We evaluated total and neutralizing antibody levels pre and post third booster vaccine and compared responses among different cancer-bearing and healthy veterans. This as a prospective, single site, comparative cohort observational trial. The setting was the West Palm Beach VA Medical Center cancer center. All veterans received a third SARS-CoV-2 mRNA booster. The main outcomes were anti-SARS-CoV-2 spike IgG and neutralizing antibodies to wild-type, and B.1.617, BA1, BA2, and BA4/5 variants were measured. Disease type and therapy, COVID-19 infection, and anti-CD20 antibody treatments were documented. The third mRNA vaccine booster increased the mean blood anti-spike IgG five-fold. The second anti-spike level was equal or greater than the first in 129/140 veterans. All the groups except the myeloma group, had post-booster antibody levels significantly higher than pre-booster with 4-fold, 12-fold, 4-fold, 6-fold and 3.5-fold increases for the control, solid tumor, CLL, B cell lymphoma and all B cell malignancy cohorts. The myeloma set showed only a non-significant 1.7-fold increase. Recently anti-CD20 antibody-treated patients were shown to have approximately 200-fold less anti-S IgG production after vaccine booster than other patients. There was a 2.5-fold enhancement of wild-type virus mean neutralizing antibodies after a third mRNA booster and mean neutralization of Delta and Omicron variants increased 2.2, 6.5, 7.7, and 6.2-fold versus pre-boost levels. B cell malignancies failed to show increased post-booster neutralization. The third SARS CoV-2 booster increased total anti-spike IgG and neutralizing antibodies for most subjects. Veterans with B cell malignancies particularly myeloma and those receiving anti-CD20 monoclonal antibodies had the weakest humoral responses. Neutralizing antibody responses to Omicron variants were less than for wild-type virus. A subset of patients without humoral immunity post-booster should be considered for prophylactic antibody or close monitoring.
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The animal reservoirs of sarbecoviruses represent a significant risk of emergent pandemics, as evidenced by the impact of SARS-CoV-2. Vaccines remain successful at limiting severe disease and death, however the continued emergence of SARS-CoV-2 variants, together with the potential for further coronavirus zoonosis, motivates the search for pan-coronavirus vaccines that induce broadly neutralizing antibodies. This necessitates a better understanding of the glycan shields of coronaviruses, which can occlude potential antibody epitopes on spike glycoproteins. Here, we compare the structure of several sarbecovirus glycan shields. Many N-linked glycan attachment sites are shared by all sarbecoviruses, and the processing state of certain sites is highly conserved. However, there are significant differences in the processing state at several glycan sites that surround the receptor binding domain. Our studies reveal similarities and differences in the glycosylation of sarbecoviruses and show how subtle changes in the protein sequence can have pronounced impacts on the glycan shield.
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In open quantum systems, the precision of metrology inevitably suffers from the noise. In Markovian open quantum dynamics, the precision can not be improved by using entangled probes although the measurement time is effectively shortened. However, it was predicted over one decade ago that in a non-Markovian one, the error can be significantly reduced by the quantum Zeno effect (QZE) [Chin, Huelga, and Plenio, Phys. Rev. Lett. 109, 233601 (2012)PRLTAO0031-900710.1103/PhysRevLett.109.233601]. In this work, we apply a recently developed quantum simulation approach to experimentally verify that entangled probes can improve the precision of metrology by the QZE. Up to n=7 qubits, we demonstrate that the precision has been improved by a factor of n^{1/4}, which is consistent with the theoretical prediction. Our quantum simulation approach may provide an intriguing platform for experimental verification of various quantum metrology schemes.
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To prepare for future coronavirus (CoV) pandemics, it is desirable to generate vaccines capable of eliciting broadly neutralizing antibody responses to CoVs. Here, we show that immunization of macaques with SARS-CoV-2 spike (S) protein with a two-shot protocol generated potent serum receptor binding domain cross-neutralizing antibody responses to both SARS-CoV-2 and SARS-CoV-1. Furthermore, responses were equally effective against most SARS-CoV-2 variants of concern (VOCs) and some were highly effective against Omicron. This result contrasts with human infection or many two-shot vaccination protocols where responses were typically more SARS-CoV-2 specific and where VOCs were less well neutralized. Structural studies showed that cloned macaque neutralizing antibodies, particularly using a given heavy chain germline gene, recognized a relatively conserved region proximal to the angiotensin converting enzyme 2 receptor binding site (RBS), whereas many frequently elicited human neutralizing antibodies targeted more variable epitopes overlapping the RBS. B cell repertoire differences between humans and macaques appeared to influence the vaccine response. The macaque neutralizing antibodies identified a pan-SARS-related virus epitope region less well targeted by human antibodies that could be exploited in rational vaccine design.
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COVID-19 , SARS-CoV-2 , Animales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Anticuerpos ampliamente neutralizantes , Epítopos , Humanos , Macaca mulatta , Glicoproteína de la Espiga del CoronavirusRESUMEN
Many neutralizing antibodies (nAbs) elicited to ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through natural infection and vaccination have reduced effectiveness to SARS-CoV-2 variants. Here, we show that therapeutic antibody ADG20 is able to neutralize SARS-CoV-2 variants of concern (VOCs) including Omicron (B.1.1.529) as well as other SARS-related coronaviruses. We delineate the structural basis of this relatively escape-resistant epitope that extends from one end of the receptor binding site (RBS) into the highly conserved CR3022 site. ADG20 can then benefit from high potency through direct competition with ACE2 in the more variable RBS and interaction with the more highly conserved CR3022 site. Importantly, antibodies that are able to target this site generally neutralize a broad range of VOCs, albeit with reduced potency against Omicron. Thus, this conserved and vulnerable site can be exploited for the design of universal vaccines and therapeutic antibodies.
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Anticuerpos Monoclonales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19 , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , COVID-19/virología , Epítopos/inmunología , Humanos , Pruebas de Neutralización , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunologíaRESUMEN
The emergence of current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) and potential future spillovers of SARS-like coronaviruses into humans pose a major threat to human health and the global economy. Development of broadly effective coronavirus vaccines that can mitigate these threats is needed. Here, we utilized a targeted donor selection strategy to isolate a large panel of human broadly neutralizing antibodies (bnAbs) to sarbecoviruses. Many of these bnAbs are remarkably effective in neutralizing a diversity of sarbecoviruses and against most SARS-CoV-2 VOCs, including the Omicron variant. Neutralization breadth is achieved by bnAb binding to epitopes on a relatively conserved face of the receptor-binding domain (RBD). Consistent with targeting of conserved sites, select RBD bnAbs exhibited protective efficacy against diverse SARS-like coronaviruses in a prophylaxis challenge model in vivo. These bnAbs provide new opportunities and choices for next-generation antibody prophylactic and therapeutic applications and provide a molecular basis for effective design of pan-sarbecovirus vaccines.