Explore the vast range of titles available.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease in young children and elderly people. Although the virus was isolated in 1955, an effective RSV vaccine has not been developed, and the only licensed intervention is passive immunoprophylaxis of high-risk infants with a humanized monoclonal antibody. During the past 5 years, however, there has been substantial progress in our understanding of the structure and function of the RSV glycoproteins and their interactions with host cell factors that mediate entry. This period has coincided with renewed interest in developing effective interventions, including the isolation of potent monoclonal antibodies and small molecules and the design of novel vaccine candidates. In this Review, we summarize the recent findings that have begun to elucidate RSV entry mechanisms, describe progress on the development of new interventions and conclude with a perspective on gaps in our knowledge that require further investigation.Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease in young children and elderly people. In this Review, Battles and McLellan summarize our current understanding of RSV entry, describe progress on the development of new interventions and conclude with a perspective on gaps in our knowledge that require further investigation.

Nirsevimab, a long-acting monoclonal antibody, has been approved for the prevention of respiratory syncytial virus (RSV) infection in infants. In France, more than 210 000 single doses were administered in infants younger than 1 year during the 2023–24 season. In this context, the selection and spread of escape variants might be a concern. Here, we aimed to characterise RSV associated with breakthrough infection. We did a multicentre, national, observational study in France during the 2023–24 RSV season in RSV-infected infants (aged <1 year) who either received or did not receive a dose of nirsevimab before their first RSV season. We excluded infants with insufficient information about nirsevimab treatment or without parental consent. We used respiratory samples collected in each laboratory for full-length RSV RNA sequencing to analyse changes in the nirsevimab binding site Ø. We tested clinical RSV isolates for neutralisation by nirsevimab. We analysed F candidate substitutions by fusion-inhibition assay. Of the 695 RSV infected infants, we analysed 545 (78%) full-length RSV genome sequences: 260 (48%) from nirsevimab-treated breakthrough infections (236 [91%] RSV-A and 24 [9%] RSV-B) and 285 (52%) from untreated RSV-infected infants (236 [83%] RSV-A and 49 [17%] RSV-B). Analysis of RSV-A did not reveal any substitution in site Ø known to be associated with resistance to nirsevimab. Two (8%) of 24 RSV-B breakthrough infections had resistance-associated substitutions: F:N208D (dominant resistance-associated substitution) and a newly described F:I64M plus F:K65R combination (minority resistance-associated substitution), both of which induced high levels of resistance in the fusion-inhibition assay. This study is, to the best of our knowledge, the largest genotypic and phenotypic surveillance study of nirsevimab breakthrough infections to date. Nirsevimab breakthrough variants remain very rare despite the drug's widespread use. The detection of resistance-associated substitutions in the RSV-B F protein highlights the importance of active molecular surveillance. ANRS Maladies Infectieuses Emergentes and the French Ministry of Health and Prevention.

There is a need for effective treatment for RSV. EDP-938 is a nonfusion replication inhibitor of RSV that interferes with the viral nucleoprotein. In this human RSV-A challenge model, EDP-938 was shown to reduce RSV viral load, symptoms, and mucus production.

Biomolecular condensates have emerged as an important subcellular organizing principle. Replication of many viruses, including human respiratory syncytial virus (RSV), occurs in virus-induced compartments called inclusion bodies (IBs) or viroplasm. IBs of negative-strand RNA viruses were recently shown to be biomolecular condensates that form through phase separation. Here we report that the steroidal alkaloid cyclopamine and its chemical analogue A3E inhibit RSV replication by disorganizing and hardening IB condensates. The actions of cyclopamine and A3E were blocked by a point mutation in the RSV transcription factor M2-1. IB disorganization occurred within minutes, which suggests that these molecules directly act on the liquid properties of the IBs. A3E and cyclopamine inhibit RSV in the lungs of infected mice and are condensate-targeting drug-like small molecules that have in vivo activity. Our data show that condensate-hardening drugs may enable the pharmacological modulation of not only many previously undruggable targets in viral replication but also transcription factors at cancer-driving super-enhancers.

•A single dose of 3×105 CFUs of rBCG-N-hRSV cGMP elicits T-cell memory against hRSV.•rBCG-N-hRSV cGMP elicits a strong antiviral TH1/TH17 T-cell repertoire.•Vaccination prevents viral pneumonia and CNS-alterations associated with hRSV.•rBCG-N-hRSV cGMP elicits a strong anti-mycobacterial TH1/TH17 T-cell repertoire.•Immunity to hRSV and Mtb antigens develops without observable adverse effects. Human respiratory syncytial virus (hRSV) is a major health burden worldwide, causing the majority of hospitalizations in children under two years old due to bronchiolitis and pneumonia. HRSV causes year-to-year outbreaks of disease, which also affects the elderly and immunocompromised adults. Furthermore, both hRSV morbidity and epidemics are explained by a consistently high rate of re-infections that take place throughout the patient life. Although significant efforts have been invested worldwide, currently there are no licensed vaccines to prevent hRSV infection. Here, we describe that a recombinant Bacillus Calmette-Guerin (BCG) vaccine expressing the nucleoprotein (N) of hRSV formulated under current good manufacture practices (cGMP rBCG-N-hRSV) confers protective immunity to the virus in mice. Our results show that a single dose of the GMP rBCG-N-hRSV vaccine retains its capacity to protect mice against a challenge with a disease-causing infection of 1×107 plaque-forming units (PFUs) of the hRSV A2 clinical strain 13018-8. Compared to unimmunized infected controls, vaccinated mice displayed reduced weight loss and less infiltration of neutrophils within the airways, as well as reduced viral loads in bronchoalveolar lavages, parameters that are characteristic of hRSV infection in mice. Also, ex vivo re-stimulation of splenic T cells at 28days post-immunization activated a repertoire of T cells secreting IFN-γ and IL-17, which further suggest that the rBCG-N-hRSV vaccine induced a mixed, CD8+ and CD4+ T cell response capable of both restraining viral spread and preventing damage of the lungs. All these features support the notion that rBCG-N-hRSV is a promising candidate vaccine to be used in humans to prevent the disease caused by hRSV in the susceptible population.

Respiratory syncytial virus (RSV) is one of the most important viral pathogens causing respiratory tract infection in infants, the elderly and people with poor immune function, which causes a huge disease burden worldwide every year. It has been more than 60 years since RSV was discovered, and the palivizumab monoclonal antibody, the only approved specific treatment, is limited to use for passive immunoprophylaxis in high-risk infants; no other intervention has been approved to date. However, in the past decade, substantial progress has been made in characterizing the structure and function of RSV components, their interactions with host surface molecules, and the host innate and adaptive immune response to infection. In addition, basic and important findings have also piqued widespread interest among researchers and pharmaceutical companies searching for effective interventions for RSV infection. A large number of promising monoclonal antibodies and inhibitors have been screened, and new vaccine candidates have been designed for clinical evaluation. In this review, we first briefly introduce the structural composition, host cell surface receptors and life cycle of RSV virions. Then, we discuss the latest findings related to the pathogenesis of RSV. We also focus on the latest clinical progress in the prevention and treatment of RSV infection through the development of monoclonal antibodies, vaccines and small-molecule inhibitors. Finally, we look forward to the prospects and challenges of future RSV research and clinical intervention.

Remdesivir (GS-5734) is a 1′-cyano-substituted adenosine nucleotide analogue prodrug that shows broad-spectrum antiviral activity against several RNA viruses. This compound is currently under clinical development for the treatment of Ebola virus disease (EVD). While antiviral effects have been demonstrated in cell culture and in non-human primates, the mechanism of action of Ebola virus (EBOV) inhibition for remdesivir remains to be fully elucidated. The EBOV RNA-dependent RNA polymerase (RdRp) complex was recently expressed and purified, enabling biochemical studies with the relevant triphosphate (TP) form of remdesivir and its presumptive target. In this study, we confirmed that remdesivir-TP is able to compete for incorporation with adenosine triphosphate (ATP). Enzyme kinetics revealed that EBOV RdRp and respiratory syncytial virus (RSV) RdRp incorporate ATP and remdesivir-TP with similar efficiencies. The selectivity of ATP against remdesivir-TP is ~4 for EBOV RdRp and ~3 for RSV RdRp. In contrast, purified human mitochondrial RNA polymerase (h-mtRNAP) effectively discriminates against remdesivir-TP with a selectivity value of ~500-fold. For EBOV RdRp, the incorporated inhibitor at position i does not affect the ensuing nucleotide incorporation event at position i+1. For RSV RdRp, we measured a ~6-fold inhibition at position i+1 although RNA synthesis was not terminated. Chain termination was in both cases delayed and was seen predominantly at position i+5. This pattern is specific to remdesivir-TP and its 1′-cyano modification. Compounds with modifications at the 2′-position show different patterns of inhibition. While 2′-C-methyl-ATP is not incorporated, ara-ATP acts as a non-obligate chain terminator and prevents nucleotide incorporation at position i+1. Taken together, our biochemical data indicate that the major contribution to EBOV RNA synthesis inhibition by remdesivir can be ascribed to delayed chain termination. The long distance of five residues between the incorporated nucleotide analogue and its inhibitory effect warrant further investigation.

Health Canada recently authorized the RSVpreF pregnancy vaccine and nirsevimab to protect infants against respiratory syncytial virus (RSV) disease. Assess the cost-effectiveness of RSVpreF and nirsevimab programs in preventing RSV disease in infants, compared to a palivizumab program. We used a static cohort model of a Canadian birth cohort during their first RSV season to estimate sequential incremental cost-effectiveness ratios (ICERs) in 2023 Canadian dollars per quality-adjusted life year (QALY) for nine strategies implemented over a one-year time period, from the health system and societal perspectives. Sensitivity and scenario analyses were conducted to explore the impact of uncertainties on the results. All-infants nirsevimab programs averted more RSV-related outcomes than year-round RSVpreF programs, with the most RSV cases averted in a seasonal nirsevimab program with catch-up. Assuming list prices for these immunizing agents, all-infants nirsevimab and year-round RSVpreF programs were never cost-effective, with ICERs far exceeding commonly used cost-effectiveness thresholds. Seasonal nirsevimab with catch-up for infants born outside the RSV season was a cost-effective program if prioritized for infants at moderate/high-risk (ICER <$28,000 per QALY) or those living in settings with higher RSV burden and healthcare costs, such as remote communities where transport would be complex (ICER of $5700 per QALY). Using a $50,000 per QALY threshold, an all-infants nirsevimab program could be optimal if nirsevimab is priced at <$110–190 per dose. A year-round RSVpreF for all pregnant women and pregnant people plus nirsevimab for infants at high-risk was optimal if nirsevimab is priced at >$110–190 per dose and RSVpreF priced at <$60–125 per dose. Prophylactic interventions can substantially reduce RSV disease in infants, and more focused nirsevimab programs are the most cost-effective option at current product prices.

Respiratory syncytial virus (RSV) poses a significant public health challenge, especially among children. Although palivizumab and nirsevimab, neutralizing antibodies (nAbs) targeting the RSV F protein, have been used for prophylaxis, their limitations underscore the need for more effective alternatives. Herein, we present a potent and broad nAb, named 5B11, which exhibits nanogram level of unbiased neutralizing activities against both RSV-A and -B subgroups. Notably, 5B11 shows a ~20-fold increase in neutralizing efficacy compared to 1129 (the murine precursor of palivizumab) and approximately a 3-fold increase in neutralizing efficacy against B18537 in comparison to nirsevimab. Cryo-electron microscopy analysis reveals 5B11’s mechanism of action by targeting a highly conserved epitope within site V, offering a promising strategy with potentially lower risk of escape mutants. Antiviral testing in a female cotton rat model demonstrated that low-dose (1.5 mg/kg) administration of 5B11 achieved comparable prophylactic efficacy to that achieved by high-dose (15 mg/kg) of 1129. Furthermore, the humanized 5B11 showed a superior in vivo antiviral activity against B18537 infection compared to nirsevimab and palivizumab. Therefore, 5B11 is a promising RSV prophylactic candidate applicable to broad prevention of RSV infection. In this study, the authors report a potent neutralizing antibody targeting a conserved epitope within RSV pre-F that shows higher antiviral activity against both RSV-A and -B subgroups in vitro and in small animal models than FDA-approved prophylactic agents.

We examined the effect of probenecid in regulating the ERK and JNK downstream MAPK pathways affecting respiratory syncytial virus replication. Background: We have previously shown that probenecid inhibits RSV, influenza virus, and SARS-CoV-2 replication in vitro in preclinical animal models and in humans. In a Phase two randomized, placebo-controlled, single-blind, dose range-finding study using probenecid to treat non-hospitalized patients with symptomatic, mild-to-moderate COVID-19, we previously showed that a 1000 mg twice daily treatment for 5 days reduced the median time to viral clearance from 11 to 7 days, and a 500 mg twice daily treatment for 5 days reduced the time to viral clearance from 11 to 9 days more than the placebo. Methods: In this study, we sought to determine the mechanism of action of the probenecid inhibition of RSV replication in human respiratory epithelial (A549) cells. Results: We show that probenecid inhibits the RSV-induced phosphorylation of JNKs and ERKs and the downstream phosphorylation of c-jun, a component of the AP-1 transcription complex needed for virus replication. The inhibition of JNKs by probenecid reversed the repression of transcription factor HNF-4. Conclusion: The probenecid inhibition of JNK and ERK phosphorylation involves the MAPK pathway that precludes virus replication.