#SARS-CoV-2 #vaccination and #infection elicit cross-neutralizing responses against clade 3 and 4 #sarbecoviruses

 

Abstract

Two sarbecoviruses, SARS-CoV-1 and SARS-CoV-2 that engage ACE2 through their receptor-binding domains, have caused major human outbreaks. The pandemic potential of sarbecoviruses has prompted the discovery and classification of bat and other zoonotic sarbecoviruses that are also able to use human ACE2 or ACE2 ortholog receptors for infection. However, the current human immunological landscape reactive to these SARS-CoV-2-related viruses is not well profiled. Using a panel of pseudotyped lentiviruses expressing only spike proteins, we assess serum neutralization activity against clade 3 and 4 (also designated as clade 1c) receptor binding domain classified sarbecoviruses in a cohort who received a primary series of COVID-19 mRNA vaccines as well as individuals before and after infection with BA.5 or XBB.1.5 variants. Detectable neutralizing responses against clade 3 and 4 sarbecoviruses are observed in both vaccinees and convalescents and are comparable in magnitude to titers against SARS-CoV-2 variants. Infection with XBB.1.5 increases neutralization titers against SARS-CoV-2 variants as well as against clade 3 and 4 sarbecoviruses. Collectively, our findings suggest that the current immunologic landscape of vaccination and infection may confer some level of immunity against a variety of clade 3 and 4 sarbecoviruses, which should inform future pandemic response and pan-sarbecovirus countermeasure efforts.

Source: 

Link: https://www.nature.com/articles/s41467-026-71662-y

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Next-generation #inhibitors of #SARS-CoV-2 #Mpro overcome the deficiencies of #Paxlovid

 

Abstract

It remains elusive to design peptidomimetic inhibitors of SARS-CoV-2 main protease (Mpro) refractory to multiple deficiencies of Paxlovid (ritonavir-boosted nirmatrelvir), pertaining mainly to E166X mutations-conferred drug resistance and inherent pharmacokinetic limitations to nirmatrelvir. We identify via virtual screening an iso-quinoline P1 moiety in place of the traditional γ-lactam and design iso-quinoline-containing inhibitors with high affinity for Mpro and its nirmatrelvir-resistant E166X mutants. Further optimization at P4 cultivates distinctive peptidomimetic inhibitors with drastically improved pharmacokinetic properties and significantly enhanced antiviral efficacy independent of ritonavir. Two such inhibitors, FD3-32 and FD3-36, also potent against SARS-CoV-1 and MERS-CoV Mpro, are more effective as a monotherapy regimen than Paxlovid in reducing viral loads in vivo and protecting infected male mice from acute lung injury. Here, we report the discovery of next-generation SARS-CoV-2 Mpro inhibitors that overcome the deficiencies of Paxlovid, promising efficacious antivirals critical for mitigating the current and future pandemics of coronaviruses.

Source: 

Link: https://www.nature.com/articles/s41467-026-71436-6

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Strategic #plan for #coronavirus disease #threat #management - Advancing integration, sustainability, and equity, 2025–2030 (#WHO, summary)

{Summary}

Context 

Over five years since the detection of the first COVID-19 cases, SARS-CoV-2 continues to circulate globally, causing acute illness, hospitalization, and death, alongside prolonged negative impacts on individuals, health systems, and economies, including post-COVID-19 condition (PCC or Long COVID). 

While global population-level immunity has increased significantly through both infection and vaccination, the virus continues to evolve, challenging control efforts and underscoring the need for long-term, sustainable disease management. 

Confirming earlier warnings from MERS-CoV and SARS-CoV-1, SARS-CoV-2 has demonstrated the pandemic potential of coronaviruses, which remain one of the most consequential infectious disease threats of our time. 

Purpose of the strategic plan 

This plan sets out WHO’s strategic framework to support Member States in the sustained, integrated, evidence-based management of coronavirus disease threats, including COVID-19, MERS, and novel coronavirus diseases of public health importance. 

It emphasizes the long-term, routine management of coronavirus diseases, embedded within national healthcare and health emergency systems and aligned with broader respiratory and other infectious disease management strategies and the WHO Health Emergency Preparedness, Response and Resilience (HEPR) Framework.  

The plan builds on and supersedes previous WHO strategic preparedness and response plans for COVID-19 and MERS. 

It is aligned with and advances WHO’s 14th General Programme of Work (2025-28), the WHO Pandemic Agreement, and the IHR Standing Recommendations for COVID-19. 

It further interlinks with other relevant strategic frameworks, including the Quadripartite One Health Joint Plan of Action and the Immunization Agenda 2030, among others. 

Strategic objectives 

The plan aims to support and guide Member States and the broader global health community to: 

-- 1 Sustain essential, evidence-based COVID-19 and other coronavirus disease threat management activities across core public health capabilities to reduce morbidity, mortality, and socioeconomic disruption, right-sized to burden.

-- 2 Integrate coronavirus disease threat management into broader disease prevention and control programmes and systems, across all levels (local, national, regional, global), in particular with other respiratory diseases, like influenza and respiratory syncytial virus (RSV).

-- 3 Enhance core capabilities as outlined in the HEPR Framework to identify, prioritize, and address operational gaps in coronavirus disease threat management.

-- 4 Generate, share, and apply evidence to close knowledge gaps and translate research and lessons learned into improved programmes, policies, and evidence-based guidance and control tools. 

Operationalizing the strategic objectives across core public health capabilities 

The strategic objectives are operationalized across core public health capabilities, as organized under the five pillars of the WHO HEPR Framework: 

-- Collaborative surveillance: 

- Multi-source, multi-tiered surveillance systems for early detection, variant monitoring, and risk assessment of SARS-CoV-2, MERS-CoV, and novel coronaviruses, aligned with the One Health approach. 

-- Community protection: 

- Community-centred public health action empowering communities to make informed decisions that protect their health, including risk communication, community engagement, misinformation management, and context-driven population interventions.  

-- Safe and scalable care: 

- High-quality clinical management of patients with coronavirus diseases, including PCC, and other acute respiratory infections embedded within scalable clinical pathways and with infection prevention and control (IPC) standards at all levels of care. 

-- Access to and delivery of countermeasures: 

- Equitable, timely access to and uptake of safe and effective vaccines, diagnostics and therapeutics able to prevent, detect, characterize, and reduce the severity of coronavirus diseases. 

-- Coordination: 

- National, regional, and global coordination mechanisms, networks, and partnerships enabling agile, multi-sectoral responses and information sharing relating to (re-)emerging coronavirus disease threats. 

Implementation approach 

Implementation of the plan will follow a flexible, risk-based, and Member State-driven approach, recognizing national contexts vary greatly and that Member States are at different stages of coronavirus disease threat management capacity development.  

WHO will continue to convene and coordinate global and regional stakeholders, networks, and advisory groups, develop evidence-based guidance and policy recommendations, and provide tailored support to assist Member States in building and sustaining core capabilities, in collaboration with other partners. 

(...)

Source: 

Link: https://www.who.int/publications/i/item/9789240117662

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Broadly #Sarbecovirus-Neutralizing #Antibodies Induced by Ancestral #SARS-CoV-2 #Infection

 

Abstract

The COVID-19 pandemic, driven by SARS-CoV-2, continues to challenge global health due to emerging variants and the potential risk posed by related sarbecoviruses. Neutralizing antibodies targeting the spike (S) glycoprotein, particularly the receptor-binding domain (RBD), play a crucial role in viral neutralization and vaccine design. Although broadly neutralizing anti-RBD antibodies have been identified, the nature of cross-reactive humoral responses induced by natural infection with ancestral SARS-CoV-2 strains remains incompletely understood. Here, we isolated 105 S-specific monoclonal antibodies (mAbs) from individuals recovered from prototype SARS-CoV-2 infection. Of these, 30 mAbs cross-recognized SARS-CoV-1, including 25 RBD-directed mAbs, of which 12 displayed cross-neutralizing activity against both viruses. Among them, mAb 12C2 potently neutralized SARS-CoV-1 and multiple SARS-CoV-2 variants, likely through mechanisms that include inhibition of membrane fusion and potential destabilization of the S trimer. Cryo-electron microscopy revealed that 12C2 engages the outer face of the RBD, overlapping with the epitope recognized by the broadly neutralizing antibody S309 derived from SARS-CoV-1 convalescent. Collectively, these findings demonstrate that ancestral SARS-CoV-2 infection can elicit robust cross-neutralizing antibody responses and provide valuable insights for the design of broadly protective antibodies and vaccines.

Source: Viruses, https://www.mdpi.com/1999-4915/17/10/1285

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#SARS-CoV-2 #infection induces pro-fibrotic and pro-thrombotic #foam cell #formation

 

Abstract

COVID-19 and long COVID are characterized by a dysregulated immune response. However, the role of macrophages during viral infection is poorly defined. Here we demonstrate that SARS-CoV-2 infection results in increased macrophage numbers and extensive formation of enlarged lipid-laden macrophages or foam cells using humanized mice, rhesus macaques and post-mortem human lung tissue. Notably, infection by other coronaviruses tested, SARS-CoV-1, MERS-CoV and two bat coronaviruses (SHC014-CoV or WIV1-CoV), did not result in macrophage proliferation or foam cell formation. Foam cells in SARS-CoV-2-infected human lung tissue display a pro-fibrotic and pro-thrombotic phenotype as they are enriched for genes associated with platelet activation and aggregation, as well as extracellular matrix organization and collagen synthesis. After viral clearance, macrophage numbers remain elevated, and lung fibrosis and thrombi persist. Importantly, we show that pre-exposure prophylaxis or early treatment with a SARS-CoV-2 antiviral, EIDD-2801, prevents increases in macrophage cell numbers and foam cell formation, and reduces fibrosis markers. These observations highlight the contribution of macrophages to lung inflammation and tissue injury leading to the pulmonary fibrosis observed in COVID-19 patients.

Source: Nature Microbiology, https://www.nature.com/articles/s41564-025-02090-9

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The Differences in the Evolutionary #Dynamics of #MERS and #SARS #Coronaviruses

 

Abstract

SARS-CoV and MERS-CoV are two coronaviruses that have received significant attention due to their high pathogenicity and mortality rates in human populations. In this study, we compared their evolutionary dynamics to provide a One Health perspective on their differences in terms of the results of disease control. The phylogenetic network of SARS-CoVs showed that human isolates gathered into a “super-spreader” cluster and were distinct from civet isolates. In contrast, dromedary camel- and human-isolated MERS-CoVs were clustered together. Thus, most clades of MERS-CoV can infect humans, and MERS-CoVs seem to more easily spill over the animal-to-human interface. Additionally, the civet can be easily controlled, while the intermediate host (dromedary camels) of MERS-CoV is an important livestock species, so it is impossible to eliminate all animals. This further leads to difficulties in disease control in MERS. Although MERS-CoVs are endemic to dromedary camels in both the Middle East and Africa, human infections are mainly linked to the Middle East. The nucleotide sequences of the MERS-CoV receptor gen (dipeptidyl peptidase 4 (DPP4)) from 30 Egyptians, 36 Sudanese, and 34 Saudi Arabians showed little difference. These findings suggest that the observed disparities in MERS prevalence between populations in the Middle East and Africa may be more strongly attributed to inadequate disease surveillance and the limited camel-to-human transmission of clade C MERS-CoV in Africa, rather than variations in DPP4 gene.

Source: Viruses, https://www.mdpi.com/1999-4915/17/8/1114

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Highly conserved #Betacoronavirus #sequences are broadly recognized by #human T cells

Highlights

• Conserved T cell epitope regions elicit strong CD4+ and CD8+ T cell responses in SARS2-exposed

• CTERs enhance cross-reactivity across multiple Betacoronaviruses

• Targeting non-spike proteins expands immune breadth and HLA coverage

• Removing low population coverage regions preserves cross-reactivity

Summary

The COVID-19 pandemic highlighted the critical need for vaccine strategies capable of addressing emerging viral threats. Betacoronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS), and SARS-CoV-2, present significant pandemic risks due to their zoonotic potential and genetic diversity. T cell-mediated immunity has demonstrated durable responses and strong cross-reactivity, offering a promising avenue for achieving broad immunity within a viral family. In this study, we combined comprehensive epitope mapping with sequence conservation analyses to identify conserved T cell epitope regions (CTERs), which constitute 12% of the complete SARS-CoV-2 proteome. We showed that SARS-CoV-2 CTER-specific T cells cross-reactively recognize sequences from multiple Betacoronavirus subgenera. Importantly, incorporating CTERs from non-spike proteins significantly enhanced T cell cross-reactivity potential and human leukocyte antigen (HLA) coverage compared with T cells targeting only spike proteins. Our findings lay the groundwork for a multi-antigen vaccine strategy that includes non-spike proteins to expand cross-reactive immunity across a broader spectrum of Betacoronaviruses.

Source: Cell, https://www.cell.com/cell/fulltext/S0092-8674(25)00804-9?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867425008049%3Fshowall%3Dtrue

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Genomic #Surveillance Detection of #SARS-CoV-1–Like Viruses in Rhinolophidae #Bats, Bandarban Region, #Bangladesh

Abstract

We sequenced sarbecovirus from Rhinolophus spp. bats in Bandarban District, Bangladesh, in a genomic surveillance campaign during 2022–2023. Sequences shared identity with SARS-CoV-1 Tor2, which caused an outbreak of human illnesses in 2003. Describing the genetic diversity and zoonotic potential of reservoir pathogens can aid in identifying sources of future spillovers.

Source: US Centers for Disease Control and Prevention, https://wwwnc.cdc.gov/eid/article/31/8/25-0071_article

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A #coronavirus assembly #inhibitor that targets the viral #membrane protein

Abstract

The coronavirus membrane protein (M) is the main organizer of coronavirus assembly. Here, we report on an M-targeting molecule, CIM-834, that blocks the assembly of SARS-CoV-2. CIM-834 was obtained through high-throughput phenotypic antiviral screening followed by medicinal-chemistry efforts and target elucidation. CIM-834 inhibits the replication of SARS-CoV-2 (including a broad panel of variants) and SARS-CoV. In SCID mice and Syrian hamsters intranasally infected with SARS-CoV-2, oral treatment reduced lung viral titres to nearly undetectable levels, even (as shown in mice) when treatment was delayed until 24 h before the end point. Treatment of infected hamsters prevented transmission to untreated sentinels. Transmission electron microscopy studies show that virion assembly is completely absent in cells treated with CIM-834. Single-particle cryo-electron microscopy reveals that CIM-834 binds and stabilizes the M protein in its short form, thereby preventing the conformational switch to the long form, which is required for successful particle assembly. In conclusion, we have discovered a new druggable target in the replication cycle of coronaviruses and a small molecule that potently inhibits it.

Source: Nature, https://www.nature.com/articles/s41586-025-08773-x

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#XBB.1.5 monovalent #vaccine induces lasting cross-reactive responses to #SARS-CoV-2 #variants such as HV.1 and #JN1, as well as SARS-CoV-1, but elicits limited XBB.1.5 specific #antibodies

ABSTRACT

The evolution of the antibody response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is impacted by the nature and number of antigenic exposures. First-generation coronavirus disease 2019 (COVID-19) vaccines encoded an ancestral spike protein. Updated bivalent vaccines and breakthrough infections have shaped the intricate diversity of the polyclonal antibody response and specificity of individual antibody clones. We and others previously showed that bivalent vaccines containing the ancestral and Omicron (BA.5) spikes induce high levels of cross-reactive antibodies but undetectable BA.5-specific antibodies in serum. Here, we assessed sera collected before as well as 1 and 3 months following administration of an updated XBB.1.5 monovalent vaccine to individuals with diverse infection and vaccination histories. Vaccination increased neutralization against recent variants of concern, including HV.1, JN.1, and the vaccine-homologous XBB.1.5. Antibody binding and avidity against ancestral and XBB.1.5 antigens significantly increased after vaccination. However, antibody depletion experiments showed that most of the response was cross-reactive to the ancestral spike, and only low levels of XBB.1.5-specific antibodies to the spike or the receptor-binding domain were detected. Importantly, increased antibody levels were still detectable in circulation 3 months post-vaccination and cross-reacted with severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) as measured by pseudovirus neutralization and binding assays. Overall, our data suggest that the XBB.1.5 monovalent vaccine predominantly elicits a cross-reactive response imprinted by viral spike antigens encountered early during the pandemic.

IMPORTANCE

Updated COVID-19 vaccine formulations and SARS-CoV-2 exposure history affect the antibody response to SARS-CoV-2. High titers of antibodies are induced in serum by XBB.1.5 monovalent vaccination. Antibody depletion experiments reveal that the majority of the antibody response is cross-reactive to the ancestral spike, despite vaccination increasing neutralization against recently circulating Omicron variants. Vaccine-induced SARS-CoV-2 antibodies cross-react with SARS-CoV-1 and remain in the bloodstream for at least 3 months after immunization.

Source: mSphere, https://journals.asm.org/doi/10.1128/mbio.03607-24

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