Respiratory Syncytial Virus

RSV infection has an estimated global incidence of 33 million cases in children <5 years of age, with 10% requiring hospital admission and up to 199 000 dying of the disease. There is growing evidence that severe infantile RSV bronchiolitis, a condition characterised by an inflammatory reaction to the virus, is associated with later childhood wheeze in some vulnerable children; however, a direct causal relationship with asthma has not yet been established. RSV infection is also increasingly recognised as a cause of morbidity and mortality in those with underlying airway disease, the immunocompromised and frail elderly persons. Novel molecular-based diagnostic tools are becoming established, but treatment remains largely supportive, with palivizumab the only licensed agent currently available for passive prophylaxis of selected pre-term infants. While effective treatments remain elusive, there is optimism about the testing of novel antiviral drugs and the development of vaccines that may induce long-lasting immunity without the risk of disease augmentation

Prevention and Potential Treatment Strategies for Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) is a significant viral pathogen that causes respiratory infections in infants, the elderly, and immunocompromised individuals. RSV-related illnesses impose a substantial economic burden worldwide annually. The molecular structure, function, and in vivo interaction mechanisms of RSV have received more comprehensive attention in recent times, and significant progress has been made in developing inhibitors targeting various stages of the RSV replication cycle. These include fusion inhibitors, RSV polymerase inhibitors, and nucleoprotein inhibitors, as well as FDA-approved RSV prophylactic drugs palivizumab and nirsevimab. The research community is hopeful that these developments might provide easier access to knowledge and might spark new ideas for research programs

Macaque models of human infectious disease.

Macaques have served as models for more than 70 human infectious diseases of diverse etiologies, including a multitude of agents-bacteria, viruses, fungi, parasites, prions. The remarkable diversity of human infectious diseases that have been modeled in the macaque includes global, childhood, and tropical diseases as well as newly emergent, sexually transmitted, oncogenic, degenerative neurologic, potential bioterrorism, and miscellaneous other diseases. Historically, macaques played a major role in establishing the etiology of yellow fever, polio, and prion diseases. With rare exceptions (Chagas disease, bartonellosis), all of the infectious diseases in this review are of Old World origin. Perhaps most surprising is the large number of tropical (16), newly emergent (7), and bioterrorism diseases (9) that have been modeled in macaques. Many of these human diseases (e.g., AIDS, hepatitis E, bartonellosis) are a consequence of zoonotic infection. However, infectious agents of certain diseases, including measles and tuberculosis, can sometimes go both ways, and thus several human pathogens are threats to nonhuman primates including macaques. Through experimental studies in macaques, researchers have gained insight into pathogenic mechanisms and novel treatment and vaccine approaches for many human infectious diseases, most notably acquired immunodeficiency syndrome (AIDS), which is caused by infection with human immunodeficiency virus (HIV). Other infectious agents for which macaques have been a uniquely valuable resource for biomedical research, and particularly vaccinology, include influenza virus, paramyxoviruses, flaviviruses, arenaviruses, hepatitis E virus, papillomavirus, smallpox virus, Mycobacteria, Bacillus anthracis, Helicobacter pylori, Yersinia pestis, and Plasmodium species. This review summarizes the extensive past and present research on macaque models of human infectious disease

Chapter 5 Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) infection has an estimated global incidence of 33 million cases in children younger than 5 years, with 10% requiring hospital admission and up to 199,000 dying of the disease. There is growing evidence that severe infantile RSV bronchiolitis, a condition characterised by an inflammatory reaction to the virus, is associated with later childhood wheeze in some vulnerable children; however, a direct causal relationship with asthma has not yet been established. It is also increasingly recognised as a cause of morbidity and mortality in those with underlying airway disease, immunocompromise and frail elderly persons. Novel molecular based diagnostic tools are becoming established but treatment largely remains supportive, with palivizumab being the only licensed agent currently available for passive prophylaxis of selected pre-term infants. Whilst effective treatments remain elusive, there is optimism about the testing of novel antiviral drugs and the development of vaccines that may induce long-lasting immunity without the risk of disease augmentation

Delivery of RNAi Therapeutics to the Airways—From Bench to Bedside

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Engineered DNA-Mediated Antibody Gene Transfer for Prophylaxis Against Infectious Diseases

Monoclonal antibodies (mAbs) have become important therapeutic and prophylactic agents for a number of indications, including infectious diseases. However, due to many issues, particularly the high cost of antibody production, mAb therapies are limited to the world’s richest populations. Furthermore, lengthy product development programs mean only a small number of mAb products can be produced at any one time. Engineering novel, low-cost, and simple methods of developing and delivering mAbs would be highly advantageous, potentially expanding the utility of antibody approaches into a wider array of applications. Here, we describe an approach to deliver human IgG neutralizing mAbs in vivo using DNA plasmid-mediated antibody gene transfer. This approach, which we term DNA mAb (DMAb) delivery, generates biologically relevant levels of mAbs after a single intramuscular injection of antibody-encoding DNA followed by in vivo electroporation (EP). First, we developed antibody-encoding DNA plasmids that could reproducibly deliver human mAbs to mouse serum. We show that these plasmid-encoded antibodies have similar binding capacity and functionality to in vitro-produced purified antibodies. Then, we use a mouse model to show that intramuscular delivery of pDVSF-3 LALA, which encodes a human anti-Dengue virus (DENV) IgG1 neutralizing antibody modified with a mutation that abrogates Fcγ receptor binding, produces anti-DENV antisera capable of binding to and neutralizing DENV1-3. Importantly, mice receiving pDVSF-3 LALA, but not the unmodified pDVSF-3 WT, were protected from both virus-only disease and antibody-enhanced lethal disease. To build upon these initial findings, we evaluated targeted genetic approaches and alternative delivery regimens in order to increase DMAb expression in vivo. Using DMAbs encoding human IgG1 antibodies against Borrelia burgdorferi (the causative agent of Lyme disease) as a model, we show that specific amino acid modifications to the framework regions of antibody variable domains confer increased in vitro and in vivo DMAb expression levels compared to the original DMAb sequences. Of note, these modifications were found to have no detrimental effect on the antibody’s borreliacidal activity. Lastly, we observed that pre-treatment of the DMAb injection site with hyaluronidase resulted in a 2.4 to 6.4-fold increase in human IgG concentration levels in vivo compared to mice receiving EP-mediated DMAb delivery only. Taken together, these data establish DNA plasmid-based antibody gene transfer as a safe, effective means of delivering tailored, protective monoclonal antibodies to hosts