Date Published: April 24, 2014
Publisher: Public Library of Science
Author(s): Jia Meng, Christopher C. Stobart, Anne L. Hotard, Martin L. Moore, Vincent Racaniello.
Respiratory Syncytial Virus (RSV), a member of the Paramyxoviridae family, is the leading cause of lower respiratory tract illness (LRI) in infants. From 1993 to 2008, the total RSV hospitalization rate in the United States across all age groups was 55 per 100,000 person-years, slightly lower than the rate of 64 per 100,000 person-years for influenza viruses . In infants, the hospitalization rate was 2,345 per 100,000 person-years for RSV compared to 151 for influenza, consistent with reports that RSV hospitalizes 1–2% of infants in the US each winter, a staggering statistic . RSV disease is not limited to infants. RSV resulted in more hospitalizations in 1–4-year-olds than influenza . One in 13 children under the age of five in the US required medical attention for RSV each year, and 60% of office visits were for 2–5-year-olds .
RSV apically infects ciliated epithelial cells of the airways. RSV bronchiolitis is characterized by mucus in the airways, sloughed epithelial cell debris, and abundant neutrophils. Airway mucus is a hallmark of RSV LRI, contributing to pulmonary obstruction, but mechanisms of RSV-induced mucus expression remain unclear. RSV-induced mucus is a particular problem in the small diameter airways of premature infants.
Immunity to natural RSV infection is partial but protective. Symptomatic RSV reinfection in early childhood is common. Homologous RSV strains can reinfect persons of all ages; thus, sterilizing immunity is not established. However, repeat infections are associated with decreased risk of LRI even if the secondary infection occurs in the first year of life . Thus, in contrast to the lack of solid immunity to RSV upper respiratory tract illness (URI), protective immunity to RSV LRI builds rapidly. This provides rationale for RSV vaccines in the target population aimed at preventing disease. In one study, 64% of infants younger than 9 months old developed neutralizing antibodies (nAb) after primary RSV infection .
The RSV nonstructural-1 and -2 (NS1 and NS2) proteins inhibit innate and adaptive immune responses to RSV. NS1 and NS2 have multiple functions. For example, NS1 antagonizes type I interferon, dendritic cell maturation, and T cell responses . NS2 binds RIG-I and potently degrades STAT-2 , . RSV G is immunomodulatory by at least two mechanisms. RSV produces a secreted G (sG) form in abundance that serves as an antigen decoy, similar to the Ebola virus secreted glycoprotein . Also, a chemokine motif conserved in G modulates immune responses .
The challenges to RSV vaccine development are substantial . In 1969, a formalin-inactivated RSV plus alum adjuvant (FI-RSV) vaccine resulted in severe disease exacerbation upon natural RSV exposure. FI-RSV has fettered RSV vaccine development in the past. The FI-RSV vaccination+RSV challenge-enhanced disease immunopathology phenotype is reproducible across laboratories, animal models, and related viruses in their natural host, such as bovine RSV and pneumonia virus of mice. However, mechanisms of FI-RSV-enhanced disease appear multifactorial and remain to be fully elucidated. F and G subunit vaccines studied early on have a history of disease enhancement, albeit to a lesser extent than FI-RSV. RSV subunit vaccines have never been tested in naïve infants. RSV live attenuated vaccines (LAV) have a good safety record in infants.