Daily Respiratory Research Analysis
Analyzed 187 papers and selected 3 impactful papers.
Summary
Real-world genomic surveillance in France identified diverse nirsevimab-resistant RSV-B variants in infant breakthrough infections, underscoring the need for ongoing resistance monitoring. Two high-impact mechanistic/translational studies mapped neutralizing antibody vulnerabilities on EV-D68 and revealed that intact mitochondrial oxidative phosphorylation restricts SARS-CoV-2 replication, informing vaccine and host-directed antiviral strategies.
Research Themes
- Monoclonal antibody resistance emergence in RSV-B
- Structure-guided vaccine/antibody design for respiratory enteroviruses
- Host metabolism (mitochondrial OXPHOS) as an antiviral barrier
Selected Articles
1. Real-world emergence of nirsevimab resistance in breakthrough infections with respiratory syncytial virus-B: a multicentre observational study in France.
Among 858 high-quality RSV genomes from infants (419 nirsevimab-exposed; 439 unexposed), resistance-associated substitutions were found in 12.5% of RSV-B breakthrough infections versus 1.0% in RSV-A. Novel F-protein substitutions clustered at residue N208 and other Φ-site positions conferred reduced nirsevimab neutralization; no resistant viruses were detected in nirsevimab-naive infants. Resistant RSV-B variants were detected up to ~1 year after prophylaxis.
Impact: This is the first large-scale real-world evidence of nirsevimab resistance in RSV-B, integrating full-genome sequencing with phenotypic neutralization, and has immediate implications for infant prophylaxis programs.
Clinical Implications: Sustained genomic surveillance should accompany nirsevimab rollout, with attention to RSV-B. Clinical algorithms may need contingency plans (e.g., alternative products, timing, or combined strategies) if resistant clusters emerge.
Key Findings
- Resistance-associated substitutions were detected in 23/184 (12.5%) RSV-B breakthrough cases but only 2/195 (1.0%) RSV-A.
- Novel F-protein mutations (e.g., N208D/I/K/S/Y; I64V+K65E; K68I; L204S; P205S) reduced nirsevimab susceptibility.
- No resistant RSV was identified among nirsevimab-naive infants.
- Resistant RSV-B variants were observed up to ~1 year post-prophylaxis, suggesting persistence/spread potential.
Methodological Strengths
- Multicentre national surveillance with paired clinical, genomic, and phenotypic data.
- Full-length RSV genome sequencing with stringent coverage and neutralization assays for functional validation.
Limitations
- Observational design limits causal inference on clinical outcomes of resistance.
- Country-specific season; generalizability to other regions and seasons requires confirmation.
Future Directions: Integrate routine sequencing with real-time phenotyping to guide public health responses; assess clinical impact of resistant variants on hospitalization, severity, and transmission; evaluate next-generation antibodies or combinations to mitigate escape.
BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in infants. Nirsevimab, a long-acting monoclonal antibody targeting a conserved epitope on the prefusion F protein (site Φ), has shown high efficacy in clinical trials and early real-world studies. Although widespread resistance has not been reported, concerns remain about the emergence of escape variants, particularly among RSV-B viruses. During the 2024-25 RSV season in France, RSV-B predominated, pro
2. Neutralizing antibodies elicited in nonhuman primates by an enterovirus D68 virus-like particle vaccine target receptor binding sites.
EV-D68 VLP immunization in NHPs elicited potent neutralizing mAbs that bound overlapping epitopes near the VP1 fivefold axis bridging the sialic-acid and MFS6 receptor-binding sites. Cryo-EM structures (e.g., 1E11, 5H03) showed receptor-site targeting, and mAbs disrupted multiple life-cycle steps, including premature uncoating. VLP-elicited NHP antibodies protected in a mouse challenge comparably to a best-in-class human mAb, though single amino acid substitutions enabled viral escape.
Impact: The study defines EV-D68 sites of vulnerability with atomic precision and demonstrates protective efficacy of VLP-elicited antibodies, directly informing vaccine and antibody cocktail design against respiratory EV-D68 and AFM risk.
Clinical Implications: Vaccine antigens should preserve epitopes spanning both sialic-acid and MFS6 binding sites; antibody combinations may be required to mitigate single-residue escape; findings prioritize VLP platforms for EV-D68 countermeasures.
Key Findings
- Five potently neutralizing mAbs from VLP-immunized NHPs targeted overlapping epitopes near the VP1 fivefold axis.
- Cryo-EM (mAbs 1E11, 5H03) revealed epitopes bridging sialic-acid and MFS6 receptor-binding sites.
- mAbs disrupted multiple life-cycle steps, including promoting premature uncoating.
- VLP-elicited NHP antibodies protected mice comparably to a best-in-class human mAb, but single-residue mutations enabled escape.
Methodological Strengths
- Integration of NHP immunization, monoclonal isolation, cryo-EM structural mapping, and in vivo challenge.
- Mechanistic dissection of neutralization across multiple viral life-cycle steps.
Limitations
- Preclinical (NHP and mouse) data; human immunogenicity and protection remain to be established.
- Demonstrated single-residue escape underscores need for polyclonal breadth or antibody cocktails.
Future Directions: Advance EV-D68 VLP vaccine candidates to clinical trials; design epitope-focused immunogens and mAb cocktails resilient to single-residue escape; evaluate cross-clade breadth and durability.
Enterovirus D68 (EV-D68) is a picornavirus that causes biennial outbreaks of respiratory disease in young children that can progress to rare but severe complications, including acute flaccid myelitis (AFM). EV-D68 virus-like particles (VLPs) elicit potent neutralizing antibodies that are protective in animal models. Here, we report the isolation and characterization of monoclonal antibodies elicited by EV-D68 VLPs in nonhuman primates (NHPs). We identified five potently neutralizing mAbs targeting o
3. Mitochondrial OXPHOS restricts SARS-CoV-2 replication.
In human ACE2-expressing A549 lung cells, inhibition of OXPHOS via mtDNA depletion (ρ0 state) resulted in approximately 5–100-fold higher SARS-CoV-2 production compared with cells with intact mitochondria. The work delineates a restrictive role of mitochondrial respiration on viral replication, indicating that host bioenergetics modulates coronavirus output beyond glycolysis.
Impact: Revealing OXPHOS as a host restriction pathway for SARS-CoV-2 reframes metabolic antiviral strategies and highlights mitochondrial integrity as a determinant of coronavirus replication.
Clinical Implications: Host-directed therapies that preserve or enhance mitochondrial respiration, or avoid unintended OXPHOS suppression, may complement direct-acting antivirals; metabolic status could inform risk stratification.
Key Findings
- MtDNA depletion inhibiting OXPHOS led to ~5–100-fold increase in SARS-CoV-2 production in ACE2-A549 lung cells.
- Mitochondrial respiration acts as a restriction factor for SARS-CoV-2 replication beyond glycolysis dependence.
- Findings implicate host bioenergetics as a modulator of coronavirus output.
Methodological Strengths
- Direct manipulation of mitochondrial genetics (mtDNA depletion) to interrogate OXPHOS function.
- Quantitative virology readouts in physiologically relevant lung cell models.
Limitations
- Cell-based findings; in vivo validation and mechanistic dissection (e.g., innate signaling interfaces) are needed.
- Abstracted data limit detail on pathway intermediates and generalizability across variants/cell types.
Future Directions: Define how OXPHOS interfaces with antiviral signaling and replication complexes; test metabolic modulators in animal models; evaluate patient metabolic/mitochondrial phenotypes versus viral load and outcomes.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rewires host metabolism to optimize virus production. Although glycolysis is necessary for virus production, the importance of mitochondrial oxidative phosphorylation (OXPHOS) is unknown. The mitochondrial DNA (mtDNA) codes for 13 critical OXPHOS polypeptides plus the 22 transfer RNAs (tRNAs) and 2 ribosomal RNAs (rRNAs) for mitochondrial protein synthesis. We found an ∼5- to 100-fold greater SARS-CoV-2 virus production in infected human