Syncytial Virus Respiratory Syncytial Virus Immunopathology and Vaccine Development Bessey Geevarghese, DO1 and Adriana Weinberg, MD2


1. Fellow, Pediatric Infectious Diseases, University of Colorado Denver School of Medicine, The Children's Hospital, Denver; 2. Professor, Departments of Pediatrics, Medicine and Pathology, Director, Molecular and Virology Clinical Laboratories, University of Colorado Denver


Abstract


Respiratory syncytial virus (RSV) infection causes respiratory tract illness in all age groups, and is the leading cause of hospitalization of infants and children around the world. Morbidity remains highest in infants less than six months old, children with underlying immunodeficiencies, congenital heart disease, or who were born prematurely, and the elderly. In general, humoral immune responses appear to protect against infection of the upper and lower respiratory tracts, whereas cell-mediated responses are needed to terminate the infection. During the 1960s, attempts to vaccinate children with a formalin-inactivated RSV (FI-RSV) vaccine resulted in more severe disease on subsequent exposure to wild-type virus in vaccinated compared with unvaccinated children. These results negatively affected the field. Other difficulties in RSV vaccine development include the need to immunize immunologically immature infants who might still harbor maternal anti-RSV antibodies and the impact of RSV antigenic and genetic variability on the host immune response. New and promising approaches to the development of a vaccine for RSV include live attenuated, subunit, vectored, and DNA vaccine preparations.


Keywords Respiratory syncytial virus (RSV), cellular and humoral immune response, vaccine development


Disclosure: The authors have no conflicts of interest to declare Received: November 1, 2010 Accepted: December 15, 2010 Citation: US Respiratory Disease, 2010;6:60–4 Correspondence: Bessey Geevarghese, DO, Fellow, Pediatric Infectious Diseases, University of Colorado Denver School of Medicine, The Children's Hospital, Denver, 13123 E 16th Ave., B055, Aurora, CO 80045. E: Geevarghese.Bessey@tchden.org


Human respiratory syncytial virus (RSV) is the major cause of lower respiratory tract illness in children.1


Most infants become infected with


RSV during the first two years of life, and infants younger than six months old are at the highest risk of severe illness. In a recent meta-analysis looking at the global incidence and mortality from episodes of acute lower respiratory infections (ALRI), it was estimated that, in 2005, at least 33.8 million episodes of RSV-associated ARLI occurred worldwide in children younger than five years of age.2 Although mainly a pediatric pathogen, RSV has also been shown to cause life-threatening disease in elderly patients, immunocompromised patients and adults with cardiopulmonary disease.3


Several studies


also suggest that severe RSV infection during childhood is associated with an increased risk for the development of asthma and allergies in adulthood.4


Since it was first isolated in 1956 from chimpanzees suffering from common colds, scientists have worked to understand the pathogenesis and immunity of this infectious virus. Despite over four decades of research, there are currently no licensed vaccines for the prevention of RSV disease. Significant obstacles exist in the development of a safe and effective RSV vaccine.5


Given that infection


can, and does, occur in the presence of circulating antibodies, reinfection is common in all age groups.6


An ideal vaccine would provide 60


protection in infants who are immunologically immature and might still have maternal antibodies, provide better defense compared with that resulting from natural disease, and be suitable for the elderly and other immunocompromised hosts.


Classification and Structure


Although both F and G proteins are important targets for antibody response, the F protein is considered to be the major stimulus for virus-neutralizing antibodies. Epidemiological studies have shown that strains of both groups circulate simultaneously in the population, but that the proportions of A and B vary, as do those of the subtypes.


RSV is a member of the Paramyxoviridae family and, more specifically, the Pneumovirinae subfamily, which also includes the recently discovered pediatric respiratory pathogen human metapneumovirus. RSV is an enveloped RNA virus with a non-segmented single-stranded negative-sense genome. The RNA is associated with viral proteins, comprising a nucleocapsid core that is packaged within a lipid envelope. The two glycosylated surface proteins, the fusion (F) and G proteins, are the major antigenic determinants of the virus. The F protein mediates viral penetration and initiates viral spread to adjacent uninfected cells, thus resulting in syncytia formation. The G protein mediates attachment of the virus to the host cells. There are two major groups of RSV strains, A and B, which are differentiated primarily by variations within the G protein.7,8


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