key: cord-0005474-zffjloio authors: Groothuis, Jessie R.; Hoopes, J. Michael; Jessie, Val G. Hemming title: Prevention of serious respiratory syncytial virus-related illness. I: Disease pathogenesis and early attempts at prevention date: 2011-02-04 journal: Adv Ther DOI: 10.1007/s12325-010-0100-z sha: 9a918b6082992793ef6751bddf2f3db7f7051c0d doc_id: 5474 cord_uid: zffjloio Respiratory syncytial virus (RSV) was first described 160 years ago but was not officially recognized as a cause of serious illness in children until the late 1950s. It has been estimated that virtually all children have had at least one RSV infection by their second birthday. RSV is responsible for annual disease outbreaks, usually during a defined winter seasonal period that can vary by community and year. RSV is recognized as the leading cause of hospitalization among young children worldwide. Infants of young chronologic age and children with predisposing factors, such as premature birth, pulmonary disease, or congenital heart disease, are most susceptible to serious illness. Unlike other viruses, immunity to RSV infection is incomplete and short lived, and reinfection is common throughout life. Initial attempts to develop a vaccine in the 1960s met with unexpected and tragic results; many children vaccinated with a formalin-inactivated wild-type virus developed serious pulmonary disease upon subsequent natural infection. Numerous other vaccine technologies have since been studied, including vectored approaches, virus-like particles, DNA vaccines, and live attenuated virus vaccine. As of early 2010, only two companies or institutions had RSV vaccine candidates in early clinical trials, and no vaccine is likely to be licensed for marketing in the immediate future. Respiratory syncytial virus (RSV) is the leading cause of serious lower respiratory tract disease requiring hospitalization of infants and children in the United States 1-6 where it accounts for up to 120,000 hospitalizations annually in infants <12 months of age. 4, 7, 8 On a broader scale, RSV is the most common cause of childhood acute lower respiratory tract infection. 9 Costs associated with RSV-related hospitalization and outpatient visits for bronchiolitis are on the rise. 10, 11 The unique ability of RSV to evade maternal antibodies and infect infants very early in life increases the clinical impact of disease, due in part to narrow airways in infants that are susceptible to obstruction and an immature immune system in these children. In some cases, the clinical consequences of RSV-related illness do not end in childhood. Long-term studies of children hospitalized with RSV-related lower respiratory tract illness before age 24 months who were prospectively followed up for periods ranging from 18 to 25 years indicate that severe illness in early life is an independent risk factor for wheezing throughout childhood. [12] [13] [14] Despite the seriousness of RSV illness and its complications, there were few accounts of its existence as a major viral pathogen before the 1950s. The initial description of infants with cough, wheezing, and respiratory difficulty resembling asthma 160 years ago is believed to be the first report of disease resembling RSV in young children (Table 1) . Almost 100 years later, a series of winter epidemics was described in which a severe viral infection associated with cough, dyspnea, fever, bronchiolitis, and pneumonia occurred in newborn infants. 16 (2) epidemics appear annually each winter for a period of 3-5 months but those months vary from year to year; (3) most children become infected by age 4 years; and, (4) reinfection can Alphavirus vector Alphavirus vaccines have shown excellent protection in numerous models for infectious disease and cancer, including influenza, CMV, breast cancer, melanoma, SARS, HPV, HSV, RSV, PIV, Marburg and Ebola viruses, viral encephalitis viruses, and botulinum toxin. Safe and highly immunogenic in humans. Induces broad and robust humoral and cellular immune responses. Capable of expressing a wide array of bacterial, viral, parasitic, and tumor antigens. Naturally targets dendritic cells, the most efficient antigen-presenting cell in the body. Allows combination products to be produced through multigene or particle mixtures. DNA vaccine Antigen can be expressed without alterations to its original structure, and the vaccine can be made optimally attenuated and highly immunogenic. May be well suited for maternal immunization; protective immunity has been demonstrated in mice when maternal antibodies were present. Initial studies have suggested that DNA vaccines are immunogenic but offer only mildly protective effects in RSV challenge studies. Large amounts of DNA are required, although methods to overcome this include novel formulations such as nanoencapsulation and microparticles. Other proposed concerns include the risk of inducing autoimmune responses and tolerance to the administered antigen. Live attenuated virus Can be administered intranasally and induce a balanced local and systemic immune response. Potential efficacy in infants with maternal antibodies. Problems may arise concerning over/underattenuation. Must be frozen. Well tolerated in preclinical and phase 1 studies. SeV does not infect humans (naturally attenuated). SeV confers Jennerian protection against hPIV-1. SeV and rSeV induce rapid (by day 7) and long-lasting antibody responses versus hPIV-1 and passenger gene targets. rSeV-RSV-F produces RSV-specific antibody and T-cell responses and protects against RSV A and B subtypes. Can be formulated for intranasal administration. The virus is easy to grow and can be manufactured in large lots. VSV vector VSV has been shown to be an effective vaccine vector for use as immunoprophylaxis against numerous viral infections and to induce an immune response against cancer. The following diseases have been studied: hepatitis C, HIV, influenza, HPV, Ebola, RSV. VSV is not a human pathogen, and there is little pre-existing immunity that might impede its use in humans. It propagates efficiently in cell lines suitable for manufacturing immunogenic compositions. VSV infection is an efficient inducer of both cellular and humoral immunity. It can be administered intranasally or parenterally. 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