Meeting Report: Harmonization of RSV therapeutics – from design to performance (original) (raw)
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Influenza and other respiratory viruses, 2015
As the most important viral cause of severe respiratory disease in infants and increasing recognition as important in the elderly and immunocompromised, respiratory syncytial virus (RSV) is responsible for a massive health burden worldwide. Prophylactic antibodies were successfully developed against RSV. However, their use is restricted to a small group of infants considered at high risk of severe RSV disease. There is still no specific therapeutics or vaccines to combat RSV. As such, it remains a major unmet medical need for most individuals. The World Health Organisations International Clinical Trials Registry Platform (WHO ICTRP) and PubMed were used to identify and review all RSV vaccine, prophylactic and therapeutic candidates currently in clinical trials. To perform an expert commentary on all RSV-specific prophylactic and therapeutic candidates that have entered clinical trials since 2008. This article is protected by copyright. All rights reserved.
Advances in RSV vaccine research and development – A global agenda
Vaccine, 2016
Highlights RSV is a significant annual cause of lower respiratory tract illness globally. Pediatric and elderly populations are most vulnerable, but no vaccine exists. The current state of RSV vaccine research and development is summarized. 60 RSV vaccine candidates in development, of which 16 are in Phase 1-3 trials.
Ongoing developments in RSV prophylaxis: a clinician’s analysis
Current Opinion in Virology, 2017
Respiratory syncytial virus (RSV) is the most common respiratory pathogen in infants and young children worldwide. Lower respiratory tract infection due to RSV is one of the most common causes of hospitalization for infants, especially those born premature or with chronic lung or heart disease. Furthermore, RSV infection is an important cause of morbidity in adults, particularly in the elderly and immunocompromised individuals. The acute phase of this infection is often followed by episodes of wheezing that recur for months or years and usually lead to a physician diagnosis of asthma. RSV was discovered more than 50 years ago, and despite extensive research to identify pharmacological therapies, the most effective management of this infection remains supportive care. The trial of a formalin-inactivated RSV vaccine in the 1960s resulted in priming the severe illness upon natural infection. Currently, Palivizumab is the only available option for RSV prophylaxis, and because of restricted clinical benefits and high costs, it has been limited to a group of high-risk infants. There are several ongoing trials in preclinical, Phase-I,-II, or-III clinical stages for RSV vaccine development based on various strategies. Here we review the existing available prophylactic options, the current stages of RSV vaccine clinical trials, different strategies, and major hurdles in the development of an effective RSV vaccine.
Targeting RSV with Vaccines and Small Molecule Drugs
Infectious Disorders - Drug Targets, 2012
Respiratory syncytial virus (RSV) is the most significant cause of pediatric respiratory infections. Palivizumab (Synagis ® ), a humanized monoclonal antibody, has been used successfully for a number of years to prevent severe RSV disease in at-risk infants. However, despite intense efforts, there is no approved vaccine or small molecule drug for RSV. As an enveloped virus, RSV must fuse its envelope with the host cell membrane, which is accomplished through the actions of the fusion (F) glycoprotein, with attachment help from the G glycoprotein. Because of their integral role in initiation of infection and their accessibility outside the lipid bilayer, these proteins have been popular targets in the discovery and development of antiviral compounds and vaccines against RSV. This review examines advances in the development of antiviral compounds and vaccine candidates.
Antiviral efficacy of an RSV fusion inhibitor in a bovine model of RSV infection
Antimicrobial Agents and Chemotherapy, 2015
word count: 238 31 Text word count: 6248 32 ABSTRACT 33 34 Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants. 35 Effective treatment for RSV infection is a significant unmet medical need. While new RSV 36 therapeutics are now in development, there are very few animal models that mimic the 37 pathogenesis of human RSV, making it difficult to evaluate new disease interventions. 38 Experimental infection of Holstein calves with bovine RSV (bRSV) causes a severe respiratory 39 infection that is similar to human RSV infection, providing a relevant model for testing novel 40 therapeutic agents. In this model, viral load is readily detectable in nasal secretions by qRT-PCR 41 and cumulative symptom scoring together with histopathology evaluations of infected tissue 42 allow for the assessment of disease severity. The bovine RSV model was used to evaluate the 43 antiviral activity of a RSV fusion inhibitor, GS1, which blocks virus entry by inhibiting the 44 fusion of the viral envelope with the host cell membrane. The efficacy of GS1, a close structural 45 analog of GS-5806 that is being developed to treat RSV infection in humans was evaluated in 46 two randomized, blinded, placebo controlled studies in bRSV-infected calves. Intravenous 47 administration of GS1 at 4 mg/kg/day for 7 days starting at 24 h or 72 h post-inoculation 48 provided clear therapeutic benefit by reducing the viral load, disease symptom scores, respiration 49 rates and lung pathology associated with bRSV infection. These data support the use of the 50 bovine RSV model for evaluation of experimental therapeutics for treatment of RSV. 51 52 53 Respiratory syncytial virus (RSV) is a member of the Paramyxoviridae family. RSV is an 54 enveloped virus with a negative single-strand ribonucleic acid (RNA) genome that encodes for 55 11 proteins, including 3 surface glycoproteins (F, G, and SH) and 4 proteins that comprise the 56 viral RNA polymerase complex (N, P, L, and M2-1). The virus replicates in the ciliated 57 respiratory epithelial cells that line the respiratory tract. Replication of the virus can induce 58 syncytia (cell fusion) that can be readily observed in transformed cell lines and has also been 59 detected in infant lung tissue from fatal cases of RSV infection (1). However, replication of RSV 60 in primary human airway epithelial cells does not cause measurable cytopathic effects (2). While 61 direct virus-induced cytopathic effects may not be the primary cause of clinical disease, virus 62 replication activates the host immune responses which can lead to immune-mediated 63 pathogenesis (3). 64 65 RSV circulates in the population as a single serotype with two major antigenic subgroups, A and 66 B, that cause seasonal infections during fall and winter in the US and other temperate regions of 67 the world (4). Children younger than 2 years of age, immunocompromised individuals, and 68 adults with underlying respiratory dysfunction such as asthma or COPD are at greater risk for 69 developing complications due to RSV (5-10). While most infections resolve without medical 70 intervention, RSV infection can cause acute bronchiolitis and pneumonia in infants and in elderly 71 adults (5, 11). Infection of the lower respiratory tract can cause severe pneumonia requiring 72 hospitalization and resulting in mortality. 73 74 Despite extensive study of the clinical features and immunopathogenesis of RSV, there are no 75 effective therapeutics or vaccines to treat RSV infection. A prophylactic monoclonal antibody 76 Synagis ® (palivizumab) is recommended for preventing RSV infection among infants at high risk 77 for lower respiratory tract RSV infection (12). Vaccine strategies using formalin-fixed RSV as 78 the immunogen did not fully protect infants from RSV infection and in some cases enhanced 79 disease, underscoring the challenges of developing effective infant vaccines for RSV (13). The 80 only approved antiviral treatment for RSV is Virazole ® (ribavirin), which is delivered as an 81 inhaled agent. Virazole has shown equivocal efficacy in bone marrow transplant patients and is 82 4 not typically used to treat infants with RSV due to poor efficacy and tolerability, as well as the 83 complexity of the specialized aerosol drug delivery system (14-16). A number of small molecule 84 inhibitors of RSV have been evaluated as potential therapeutics for treating RSV infections that 85 target viral entry and replication (17-23). While several clinical candidates have been evaluated 86 in human studies, only ribavirin has been approved for the treatment of RSV infection. 87 88 Preclinical development of new therapeutics requires evaluation of efficacy in animal models of 89 RSV infection. The cotton rat model is commonly used to measure RSV replication and evaluate 90 RSV therapeutics (24, 25). While cotton rats are permissive to RSV infection, virus replication 91 does not produce quantifiable symptoms and the extent of virus infection is measured by 92 determining viral lung titers from infected animals following euthanasia. Thus, the cotton rat 93 model is not suitable for measuring changes in disease pathogenesis resulting from antiviral 94 therapy. Additional animal models have been developed using chimpanzees, African green 95 monkeys, infant Rhesus monkeys, and mice to study RSV infection (18, 26-29). As in the cotton 96 rat model, virus replication does not induce significant disease and symptoms tend to be mild or 97 absent. Infection of neonatal lambs with RSV produces mild symptoms that include fever, 98 tachypnea, and malaise as well as histologic lesions in lung tissue (27, 30). However, the natural 99 history of RSV infection in this model has not been fully characterized and there is limited data 100 on quantitative viral load measurements in tissues over the course of infection or on the 101 development of techniques to quantify symptoms to correlate virus replication with disease 102 progression. 103 104 Bovine RSV (bRSV) is a natural pathogen of cattle that causes a disease in young animals 105 similar to hRSV in humans (31, 32). The virus replicates in the upper and lower respiratory tract 106 to produce a spectrum of illness ranging from subclinical to severe bronchiolitis and pneumonia 107 (33). The similarity in pathogenesis between bRSV and hRSV is underscored by studies that 108 have demonstrated disease enhancement by a formalin-inactivated bRSV/alum vaccine made 109 using the protocol that created the disease enhancing RSV vaccine the sickened and killed 110 several children in the 1960's (13, 34). 111 112 5 The goal of this study was to develop a preclinical animal model to evaluate efficacy of 113 experimental therapeutics for treatment of human RSV infection. To validate the bRSV model 114 for testing antiviral therapeutic interventions, we tested the therapeutic efficacy of a novel RSV 115 fusion inhibitor GS1, a close structural analog of GS-5806 which has recently been shown to 116 reduce RSV viral load and clinical symptoms in a human model of experimental RSV infection 117 (Figure 1) (20). The effects of GS1 on bRSV replication and disease symptoms were assessed in 118 two randomized, placebo controlled, blinded efficacy studies in calves less than 8 weeks old to 119 assess GS1 efficacy. The results demonstrate that the bRSV infection of young calves is a 120 suitable model for quantifying the impact of antiviral intervention on the viral load and disease 121 symptoms and can be used to evaluate the in vivo efficacy of RSV antiviral compounds. 122 6 MATERIALS AND METHODS 123 124 Compounds 125 GS1 was synthesized by the Department of Medicinal Chemistry, Gilead Sciences (Foster City, 126 CA) (Figure 1). 127 128 Cells and Viruses 129 Primary bovine turbinate (BT) cells were grown in Dulbecco's modified Eagle's medium 130 (DMEM) supplemented with 10% fetal bovine serum (FBS), penicillin (10 U/mL), and 131 streptomycin (100 μg/mL) at 37°C with 5% CO 2 . Primary bovine alveolar type 2 (BAT2) cells 132 were isolated from newborn calf lung as described previously (35). Cells were grown in DMEM-133 keratinocyte medium at a ratio of 1:1 (Invitrogen, Carlsbad, CA), supplemented with 2% FBS, 5 134 mM l-glutamine, 0.02% lactalbumin dehydrogenase, and penicillin (100/mL)-streptomycin (100 135 μg/mL) (Invitrogen), at 37°C in a humidified incubator with 5% CO 2 . 136 137 Stocks of bRSV were prepared from a clinical isolate of a virulent bRSV strain (CA-1) as 138 previously described (36, 37). Virus stocks were prepared by infecting BT cell monolayer in a 139 T75 culture flask with 3 × 10 5 plaque forming units (pfu) of virus. The infected cells were 140 incubated until viral cytopathic effects (CPE) reached approximately 30 to 50% of the cell 141 monolayer, usually by day 5 post infection. The cultures were harvested and subjected to a single 142 freeze thaw cycle to release cell associated virus. Aliquots of virus suspensions were placed on 143 ice and administered to calves by aerosol within approximately one hour. Additional aliquots 144 were used to quantify viral titer by plaque assay and any remaining virus was frozen at -80°C. 145 146 In Vitro Antiviral Activity 147 The antiviral activity of GS1 against bRSV was measured on bovine turbinate (BT) and bovine 148 alveolar type 2 (BAT2) cells using a cell viability assay that measures cellular ATP levels. Serial 149 3-fold dilutions of GS1 prepared in DMSO and added to cell culture media at 2X the final 150 concentration. Cell monolayers were prepared in 96-well plates at 1 x 10 4 cells per well and the 151 next day infected with bRSV at 0.05 pfu/cell (MOI 0.05) in 100 μL final volume. A parallel set 152 of plates was prepared and mock-infected to measure compound cytotoxicity. The assay plates 153 Cell Immune Response during Respiratory Virus Infection. J Virol 86:5422-5436.
New insights for development of a safe and protective RSV vaccine
Human Vaccines, 2010
Respiratory Syncytial Virus (RSV) is the leading cause of pneumonia and bronchiolitis in infants and children <1 year old, resulting in significant morbidity and mortality worldwide. There is currently no RSV vaccine. In the 1960's, a formalin-inactivated RSV (FI-RSV) vaccine trial led to exacerbated disease upon natural infection of vaccinees, including two deaths. The causes involved in the disastrous results of these vaccine trials are still unclear but they remain the engine for searching new avenues to develop a safe vaccine that can provide long-term protection against this important pathogen. This article reviews some of the early history of RSV vaccine development, as well as more recent information on the interaction between RSV and the host innate and adaptive immune responses. A safe and efficacious vaccine for RSV will require "re-education" of the host immune response against RSV to prevent vaccine-enhanced or severe RSV disease.
Antiviral Research, 2008
Effective treatments for respiratory syncytial virus (RSV) infection are lacking. We report a human proof-of-concept study for RV521, a small-molecule antiviral inhibitor of the RSV-F protein. In this randomized, double-blind, placebo-controlled trial (NCT03258502), healthy adults were challenged with RSV-A Memphis-37b. After infection was confirmed (or 5 days after challenge virus inoculation), subjects received RV521 (350 mg or 200 mg) or placebo, orally every 12 hours for 5 days. Primary endpoint was area under the curve (AUC) for viral load, as assessed by reverse transcriptase quantitative PCR (RT-qPCR), in nasal wash samples. Primary efficacy analysis set included subjects successfully infected with RSV who received ≥1 dose of study drug. Sixty-six subjects were enrolled (n=22 per group); 53 were included in the primary analysis set (RV521 350 mg: n=16; 200 mg: n=18; placebo: n=19). Mean AUC of RT-qPCR-assessed RSV viral load (log 10 PFUe/mL x hours) was significantly lower with RV521 350 mg (185.26 [SE, 31.17], P=0.002) and 200 mg (224.35 [37.60], P=0.007) versus placebo (501.39 [86.57]). Disease severity improved with RV521 350 mg and 200 mg versus placebo (P=0.002 and P=0.009, respectively, for AUC total symptom score [score x hours]). Daily nasal mucus weight was significantly reduced (P=0.010 and P=0.038 for RV521 350 mg and 200 mg versus placebo). All treatment-emergent adverse events were grade 1-2. No subjects discontinued due to adverse events. There was no evidence of clinically significant viral resistance, with only three variants detected. RV521 effectively reduced RSV viral load and disease severity in humans and was well tolerated.
Global molecular diversity of RSV – the “INFORM RSV” study
BMC Infectious Diseases
Background: Respiratory syncytial virus (RSV) is a global cause of severe respiratory morbidity and mortality in infants. While preventive and therapeutic interventions are being developed, including antivirals, vaccines and monoclonal antibodies, little is known about the global molecular epidemiology of RSV. INFORM is a prospective, multicenter, global clinical study performed by ReSViNET to investigate the worldwide molecular diversity of RSV isolates collected from children less than 5 years of age. Methods: The INFORM study is performed in 17 countries spanning all inhabited continents and will provide insight into the molecular epidemiology of circulating RSV strains worldwide. Sequencing of > 4000 RSV-positive respiratory samples is planned to detect temporal and geographical molecular patterns on a molecular level over five consecutive years. Additionally, RSV will be cultured from a subset of samples to study the functional implications of specific mutations in the viral genome including viral fitness and susceptibility to different monoclonal antibodies. Discussion: The sequencing and functional results will be used to investigate susceptibility and resistance to novel RSV preventive or therapeutic interventions. Finally, a repository of globally collected RSV strains and a database of RSV sequences will be created.
Update on current views and advances on RSV infection (Review)
International Journal of Molecular Medicine, 2020
Respiratory syncytial virus (RSV) infection represents an excellent paradigm of precision medicine in modern paediatrics and several clinical trials are currently performed in the prevention and management of RSV infection. A new taxonomic terminology for RSV was recently adopted, while the diagnostic and omics techniques have revealed new modalities in the early identification of RSV infections and for better understanding of the disease pathogenesis. coordinated clinical and research efforts constitute an important step in limiting RSV global predominance, improving epidemiological surveillance, and advancing neonatal and paediatric care. This review article presents the key messages of the plenary lectures, oral presentations and posters of the '5th workshop on paediatric virology' (Sparta, Greece, 12th October 2019) organized by the Paediatric Virology Study Group, focusing on recent advances in the epidemiology, pathogenesis, diagnosis, prognosis, clinical management and prevention of RSV infection in childhood. Contents 1. Introduction 2. Epidemiology of RSV infection 3. Pathogenesis, diagnosis and prognosis of RSV infection 4. Imaging in children with RSV infection 5. Therapeutics of RSV infection 6. Prevention of RSV infection
Antimicrobial Agents and Chemotherapy
Effective treatments for respiratory syncytial virus (RSV) infection are lacking. We report a human proof-of-concept study for RV521, a small-molecule antiviral inhibitor of the RSV-F protein. In this randomized, double-blind, placebo-controlled trial (NCT03258502), healthy adults were challenged with RSV-A Memphis-37b. After infection was confirmed (or 5 days after challenge virus inoculation), subjects received RV521 (350 mg or 200 mg) or placebo, orally every 12 hours for 5 days. Primary endpoint was area under the curve (AUC) for viral load, as assessed by reverse transcriptase quantitative PCR (RT-qPCR), in nasal wash samples. Primary efficacy analysis set included subjects successfully infected with RSV who received ≥1 dose of study drug. Sixty-six subjects were enrolled (n=22 per group); 53 were included in the primary analysis set (RV521 350 mg: n=16; 200 mg: n=18; placebo: n=19). Mean AUC of RT-qPCR-assessed RSV viral load (log10 PFUe/mL x hours) was significantly lower wit...