Comparing Influenza and Rsv Viral and Disease Dynamics in Experimentally Infected Adults Predicts Clinical Effectiveness of Rsv Antivirals

Bagga, Bindiya; Woods, Christopher W.; Veldman, Timothy; Gilbert, Anthony; Mann, Alex; Balaratnam, Ganesh; Lambkin‐Williams, Robert; Oxford, John; McClain, Micah T.; Wilkinson, Tom; Nicholson, Brad; Ginsburg, Geoffrey S.; DeVincenzo, John P.

doi:10.3851/imp2629

Cited by 60 publications

(69 citation statements)

References 49 publications

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“…Moreover, at 4 d.p.i. rHRSV B05 EGFP(5) titers were similar to those obtained from patients or volunteers infected with HRSV (15,16,42). This illustrates the strength of the cotton rat model and shows the power of targeted pathology using EGFP-expressing recombinant viruses, which is only feasible due to the possibility of identifying infected tissues for blocking and processing immediately after necropsy.…”

Section: Discussionmentioning

confidence: 74%

“…Cotton rats represent a highly susceptible small-animal model for HRSV pathogenesis studies (14). Recently, adult human volunteers were infected with wild-type A strains to assess the effectiveness of HRSV antivirals (15)(16)(17). Irrespective of the approach used, it is critical to use naturally circulating viruses to ensure that study outcomes can be correlated with clinical outcomes.…”

mentioning

confidence: 99%

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Recombinant Subgroup B Human Respiratory Syncytial Virus Expressing Enhanced Green Fluorescent Protein Efficiently Replicates in Primary Human Cells and Is Virulent in Cotton Rats

Lemon

Nguyen

Ludlow

et al. 2015

J Virol

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Human respiratory syncytial virus (HRSV) is IMPORTANCEVirology as a discipline has depended on monitoring cytopathic effects following virus culture in vitro. However, wild-type viruses isolated from patients often do not cause significant changes to infected cells, necessitating blind passage. This can lead to genetic and phenotypic changes and the generation of high-titer, laboratory-adapted viruses with diminished virulence in animal models of disease. To address this, we determined the genome sequence of an unpassaged human respiratory syncytial virus from a sample obtained directly from an infected infant, assembled a molecular clone, and recovered a wild-type recombinant virus. Addition of a gene encoding enhanced green fluorescent protein allowed this wild-type virus to be tracked in primary human cells and living animals in the absence of significant cytopathic effects. Imaging of fluorescent cells proved to be a highly valuable tool for monitoring the spread of virus and may help improve assays for evaluating novel intervention strategies. H uman respiratory syncytial virus (HRSV) is the most important viral cause of respiratory tract disease in infants (1). HRSV infections are observed during seasonal outbreaks in winter or during the rainy season in the tropics (2). The virus usually causes a self-limiting upper respiratory tract (URT) infection, resulting in rhinorrhea and other common cold-like clinical signs (3). However, in a minority of cases the infection can also spread to the lower respiratory tract (LRT), resulting in severe pneumonia or bronchiolitis. Risk factors for developing severe LRT infections include prematurity, pulmonary or cardiac disease, compromised immunity, and old age (4). Current treatment options are limited, although a monoclonal antibody directed against the fusion (F) glycoprotein has been developed for prophylactic use (5). Despite significant efforts in vaccine development over the past 50 years, no HRSV vaccines are currently licensed (6). Limited availability of natural animal models of disease adds to the challenge of developing vaccines and antivirals.HRSV is a member of the family Paramyxoviridae, subfamily Pneumovirinae, genus Pneumovirus (1). It is an enveloped virus with a negative-sense, single-stranded RNA genome containing 10 transcription units. The glyco-(G) proteins facilitate virus attachment and entry (1, 7), and the F glycoprotein is an important target of virus neutralizing antibodies (8). Molecular epidemiological studies have identified two HRSV subgroups (A and B),

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Section: Discussionmentioning

confidence: 74%

mentioning

confidence: 99%

Recombinant Subgroup B Human Respiratory Syncytial Virus Expressing Enhanced Green Fluorescent Protein Efficiently Replicates in Primary Human Cells and Is Virulent in Cotton Rats

Lemon

Nguyen

Ludlow

et al. 2015

J Virol

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“…In adults, RSV replication continues in the airway for about 8 days (6 days longer than influenza virus) (139,(160)(161)(162). In a study that looked at RSV infection in a hamster model, 3 days after infection, there was significant rounding of RSV-infected columnar ciliated cells in the airway (162).…”

Section: Sloughing Of Ciliated Epithelial Cells Caused By Rsv Infectionmentioning

confidence: 99%

“…Tamiflu is a neuraminidase inhibitor that has been marketed for the treatment of influenza (345), but the efficacy of Tamiflu has been questioned (346). This is due, primarily, to a brief therapeutic window of opportunity whereby Tamiflu must be administered prior to the peak of influenza viral load which is within 48 h of influenza virus infection (160,223). Such a short window makes influenza difficult to treat because the onset of symptoms follows initial replication, leaving a mere few hours between transmission and therapeutic efficacy.…”

Section: Rsv Therapeutic Window Compared To That Of Influenza Virusmentioning

confidence: 99%

Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

2017

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SUMMARY Respiratory syncytial virus (RSV) infection is a significant cause of hospitalization of children in North America and one of the leading causes of death of infants less than 1 year of age worldwide, second only to malaria. Despite its global impact on human health, there are relatively few therapeutic options available to prevent or treat RSV infection. Paradoxically, there is a very large volume of information that is constantly being refined on RSV replication, the mechanisms of RSV-induced pathology, and community transmission. Compounding the burden of acute RSV infections is the exacerbation of preexisting chronic airway diseases and the chronic sequelae of RSV infection. A mechanistic link is even starting to emerge between asthma and those who suffer severe RSV infection early in childhood. In this article, we discuss developments in the understanding of RSV replication, pathogenesis, diagnostics, and therapeutics. We attempt to reconcile the large body of information on RSV and why after many clinical trials there is still no efficacious RSV vaccine and few therapeutics.

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“…A human challenge model has been developed for HRSV (17) but has not yet been developed for HPIVs, and early experiments have focused efforts on inoculating adults with low levels of serum antibodies in experimental drug trials. Small-animal models are attractive for basic studies of infection and immunity.…”

mentioning

confidence: 99%

Relationships among Dissemination of Primary Parainfluenza Virus Infection in the Respiratory Tract, Mucosal and Peripheral Immune Responses, and Protection from Reinfection: a Noninvasive Bioluminescence-Imaging Study

Burke

Hurwitz

et al. 2015

J Virol

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Respiratory paramyxoviruses such as respiratory syncytial virus (RSV) and human parainfluenza virus type 1 (HPIV1) to HPIV4 infect virtually all children by the age of 2 to 5 years, leading to partial but incomplete protection from reinfection. Here, we used luciferase-expressing reporter Sendai viruses (the murine counterpart of HPIV1) to noninvasively measure primary infection, immune responses, and protection from reinfection by either a lethal challenge or natural transmission in living mice. Both nonattenuated and attenuated reporter Sendai viruses were used, and three inoculation strategies were employed: intramuscular (i.m.), intranasal (i.n.) at a low dose and low volume, and i.n. at a high dose and high volume. High-dose, high-volume i.n. inoculation resulted in the highest levels of antibody responses and protection from reinfection. Low-dose, low-volume i.n. inoculation afforded complete protection from contact transmission and protection from morbidity, mortality, and viral growth during lethal challenge. i.m. inoculation was inferior to i.n. inoculation at inducing antibody responses and protection from challenge. For individual mice and across groups, the levels of serum binding and neutralizing antibody responses correlated with primary infection and protection from reinfection in the lungs. Contact transmission, the predominant mode of parainfluenza virus transmission, was modeled accurately by direct i.n. inoculation of Sendai virus at a low dose and low volume and was completely preventable by i.n. vaccination of an attenuated virus at a low dose and low volume. The data highlight differences in infection and protection from challenge in the upper versus lower respiratory tract and bear upon live attenuated vaccine development. IMPORTANCEThere are currently no licensed vaccines against HPIVs and human RSV (HRSV), important respiratory pathogens of infants and children. Natural infection leads to partial but incomplete protective immunity, resulting in subsequent reinfections even in the absence of antigenic drift. Here, we used noninvasive bioluminescence imaging in a mouse model to dissect relationships among (i) the mode of inoculation, (ii) the dynamics of primary infection, (iii) consequent immune responses, and (iv) protection from high-dose, high-volume lethal challenge and contact transmission, which we find here to be similar to that of a mild low-dose, low-volume upper respiratory tract (URT)-biased infection. Our studies demonstrate the superiority of i.n. versus i.m. vaccination in protection against both lethal challenge and contact transmission. In addition to providing correlates of protection that will assist respiratory virus vaccine development, these studies extend the development of an increasingly used technique for the study of viral infection and immunity, noninvasive bioluminescence imaging.H uman respiratory syncytial virus (HRSV), human metapneumovirus (HMPV), and human parainfluenza virus type 1 (HPIV1) to HPIV4 are leading viral causes of pediatric hospitaliza...

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Comparing Influenza and Rsv Viral and Disease Dynamics in Experimentally Infected Adults Predicts Clinical Effectiveness of Rsv Antivirals

Abstract: Viral and disease dynamics in experimental human infections suggest that reducing RSV load, if timed similarly to clinically-effective influenza antivirals, might be expected to have a similar or greater window of opportunity for reducing clinical RSV disease.

Cited by 60 publications

References 49 publications

Recombinant Subgroup B Human Respiratory Syncytial Virus Expressing Enhanced Green Fluorescent Protein Efficiently Replicates in Primary Human Cells and Is Virulent in Cotton Rats

Recombinant Subgroup B Human Respiratory Syncytial Virus Expressing Enhanced Green Fluorescent Protein Efficiently Replicates in Primary Human Cells and Is Virulent in Cotton Rats

Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

Relationships among Dissemination of Primary Parainfluenza Virus Infection in the Respiratory Tract, Mucosal and Peripheral Immune Responses, and Protection from Reinfection: a Noninvasive Bioluminescence-Imaging Study

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