Search

Respiratory syncytial virus (RSV) commonly causes severe respiratory tract infections in infants, peaking between 2 and 6 months of age; an age at which direct vaccination is unlikely to be effective. Maternal immunization can deliver high levels of antibodies to newborns, providing immediate protection. Following natural infection, antibodies targeting the prefusion conformation of RSV F protein (PreF) have the greatest neutralizing capacity and thus, may provide infants with a high degree of RSV protection when acquired through maternal vaccination. However, the influence of anti-PreF maternal antibodies on infant immunity following RSV exposure has not been elucidated. To address this knowledge gap, offspring born to dams immunized with a RSV PreF vaccine formulation were challenged with RSV and their immune responses were analyzed over time. These studies demonstrated safety and efficacy for RSV-challenged, maternally-immunized offspring but high and waning maternal antibody levels were associated with differential innate and T cell immunity.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in children worldwide, with the most severe disease occurring in very young infants. Despite half a century of research there still are no licensed RSV vaccines. Difficulties in RSV vaccine development stem from a number of factors, including: (a) a very short time frame between birth and first RSV exposure; (b) interfering effects of maternal antibodies; and (c) differentially regulated immune responses in infants causing a marked T helper 2 (Th2) immune bias. This review seeks to provide an age-specific understanding of RSV immunity critical to the development of a successful pediatric RSV vaccine. Historical and future approaches to the prevention of infant RSV are reviewed, including passive protection using monoclonal antibodies or maternal immunization strategies versus active infant immunization using pre-fusion forms of RSV F protein antigens formulated with novel adjuvants such as Advax that avoid excess Th2 immune polarization.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections among infants with most infections occurring in the first year of life. Multiple RSV exposures are required for children to mount adult-like immune responses. Although adult RSV immunity is associated with less severe disease, the protection induced through natural infection is short-lived. Therefore, vaccination of RSV-experienced young children may accelerate immunity and provide long-term protection from RSV reinfection. However, the extent to which different Th-biased vaccine regimens influence pre-existing humoral and cellular immunity in RSV-experienced young children is unknown. To address this question, infant BALB/c mice were RSV-infected and subsequently immunized with the prefusion RSV F (PreF) antigen formulated with either a Th2-skewing (Alum) or Th1/Th2-balanced (Advax-SM) adjuvant. These studies show that both adjuvants boosted neutralizing antibody and protected from RSV reinfection, but Advax-SM adjuvant prevented the Th2-skewed immunity observed in RSV-experienced young mice immunized with PreF/Alum.

Respiratory syncytial virus (RSV) remains the most common cause of lower respiratory tract infections in children worldwide. Development of a vaccine has been hindered by the risk of developing enhanced respiratory disease (ERD) upon natural exposure to the virus. Generation of higher quality neutralizing antibodies with stabilized pre-fusion F protein antigens has been proposed as a strategy to prevent ERD. We sought to test whether there was evidence of ERD in naïve BALB/c mice immunized with an unadjuvanted, stabilized pre-fusion F protein, and challenged with RSV line 19. We further sought to determine the extent to which formulation with a Th2-biased (alum) or a more Th1/Th2-balanced (Advax-SM) adjuvant influenced cellular responses and lung pathology. When exposed to RSV, mice immunized with pre-fusion F protein alone (PreF) exhibited increased airway eosinophilia and mucus accumulation. This was further exacerbated by formulation of PreF with Alum (aluminum hydroxide). Conversely, formulation of PreF with a Th1/Th2-balanced adjuvant, Advax-SM, not only suppressed RSV viral replication, but also inhibited airway eosinophilia and mucus accumulation. This was associated with lower numbers of lung innate lymphocyte cells (ILC2s) and CD4+ T cells producing IL-5+ or IL-13+ and increased IFNγ+ CD4+ and CD8+ T cells, in addition to RSV F-specific CD8+ T cells. These data suggest that in the absence of preimmunity, stabilized PreF antigens may still be associated with aberrant Th2 responses that induce lung pathology in response to RSV infection, and can be prevented by formulation with more Th1/Th2-balanced adjuvants that enhance CD4+ and CD8+ IFNγ+ T cell responses. This may support the use of stabilized PreF antigens with Th1/Th2-balanced adjuvants like, Advax-SM, as safer alternatives to alum in RSV vaccine candidates.

OBJECTIVES Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections worldwide, causing disproportionate morbidity and mortality in infants and children. Infants with stronger Th1 responses have less severe disease, yet little is known about the infant T-cell response within the air space. Thus, we tested the hypothesis that RSV infected infant mice would have quantitative and qualitative deficiencies in CD4+ and CD8+ T-cell populations isolated from the bronchoalveolar lavage when compared to adults and that local delivery of IFN-γ would increase airway CD4+ Tbet+ and CD8+ Tbet+ T-cell responses. METHODS We compared the localization of T-cell responses in RSV-infected infant and adult mice and investigated the effects of local IFN-γ administration on infant cellular immunity. RESULTS Adult CD8+ CD44HI and CD4+ CD44HI Tbet+ T-cells accumulated in the alveolar space whereas CD4+ CD44HI Tbet+ T-cells were evenly distributed between the infant lung tissue and airway and infant lungs contained higher frequencies of CD8+ T-cells. Delivery of IFN-γ to the infant airway failed to increase the accumulation of T-cells in the airspace and unexpectedly reduced CD4+ CD44HI Tbet+ T-cells. However, intranasal IFN-γ increased RSV F protein-specific CD8+ T-cells in the alveolar space. CONCLUSION Together, these data suggest that quantitative and qualitative defects exist in the infant T-cell response to RSV but early, local IFN-γ exposure can increase the CD8+ RSV-specific T-cell response.