Respiratory Syncytial Virus (RSV)
Research Team
- Project leader: Sylvia van den Hurk
- Scientists: Andrew Potter, Volker Gerdts
- Technicians: Zoe Lawman; Laura Latimer; Shirley Hauta
- Post-doctoral fellows: Sheryl Maher, Bita Moazed, Srinivas Garlapati.
- Graduate students: Ellen Watkiss
Overview
Respiratory syncytial virus (RSV) is the most common respiratory pathogen in infants and children under 2 years of age with at least 64 million infections per year. RSV also is the most common viral cause of death in infants and children less than 5 years of age. Human and bovine respiratory syncytial virus (HRSV and BRSV) are closely related members of the genus Pneumovirus within the family Paramyxoviridae. There currently is no vaccine against RSV.HRSV is the leading cause of bronchiolitis and viral pneumonia in infants and young children and BRSV is one of the major respiratory pathogens in calves. The pathologic lesions caused by HRSV and BRSV are very similar. Both viruses induce lymphocyte bronchitis, bronchiolar epithelial necrosis, bronchiolar occlusion, parenchyma inflammation and alveolar exudation. RSV is unique amongst viruses in its ability to create a Th2 cytokine microenvironment that supports an immunopathologic response; this has been observed for both HRSV and BRSV, in target and model species including mice, cotton rats, humans and cattle. Disease caused by RSV is specifically severe in children and calves between 1 and 3 months of age, even though maternal antibodies are usually present. In older children, RSV is thought to be an important contributor to otitis media. RSV can also cause significant disease in the elderly and is associated with higher mortality than influenza.
RSV infects the epithelial cells of the respiratory tract, which release pro-inflammatory cytokines and chemokines, leading to infiltration of various immune cells, including neutrophils, macrophages, dendritic cells, NK cells and sometimes eosinophils. This results in further production of cytokines and chemokines and ultimately an adaptive immune response involving B and T lymphocytes. There is evidence that depending on the genetic background, immune status and age at the time of infection, RSV infections may either progress to recovery or immune pathological responses. Many children experience a mild infection of the upper respiratory tract, such as rhinitis, pharyngitis, and/or bronchitis, which resolves within days or weeks. In other children RSV causes immunopathology which manifests itself as severe pneumonia and/or bronchiolitis. An increased incidence of asthma has been associated with these more severe lower respiratory tract infections.
The overall goal of our research is to identify age-dependent differences in clinical disease, lung pathology, and immune responses between BRSV- infected newborn and older calves, and to develop RSV vaccine formulations that are effective in newborns even in the presence of maternal antibodies. BRSV will be used for part of these studies as it is generally accepted as an appropriate model for RSV.
In addition, we plan to test RSV vaccine formulations as an approach to vaccinate pregnant mothers and thus enhance maternal antibody levels early in life, as well to vaccinate elderly, who are also very susceptible to severe RSV disease. Finally, we plan to combine and/or apply the RSV F protein vaccine formulation with additional vaccines for newborns, including existing vaccines, such as B. pertussis (whooping cough), and new vaccines, for example human parainfluenzavirus and human metapneumovirus antigens.
Objectives
- Examine in vitro effects of CpG oligonucleotides (CpG ODN), host defence peptides (HDP) and polyphosphazenes (PP) on bovine peripheral blood mononuclear cells, monocytes and DCs.
- Evaluate co-formulation of RSV F protein with CpG ODN, HDP and PP for intranasal vs subcutaneous delivery, in the presence and absence of maternal antibodies.
- Identification of age-dependent differences in clinical disease, lung pathology and immune responses between BRSV- infected newborn and older calves.
- Assess protection from BRSV after mucosal vs. systemic immunization with CpG/HDP/PP formulated F protein.
- Test safety and stability of F protein vaccine formulations and individual components.
- Initiate phase I clinical trial.
- Evaluate F protein vaccine formulations against RSV in elderly.
- Add and test additional viral and/or bacterial antigens in CpG/HDP/PP adjuvanted vaccine formulation.
Future Directions
In the immediate future, we will focus on characterizing the effects of the F protein formulated with the CpG/HDP/PP adjuvant combination, both in vitro and in vivo in a number of animal models. Secondly, age-dependent differences in clinical disease, lung pathology and immune responses between newborn and older calves will be studied using BRSV as a model. This will ultimately define the optimal dose, method and route of delivery for this subunit vaccine in newborns, and potentially identify biomarkers.
Vision
In the future we plan to test the RSV F protein vaccine formulation in phase I clinical trials. Prior to those trials stability and safety of the vaccine components will be determined. An alternative method to protect infants from RSV infection is increasing the level of maternal antibodies transferred from the mothers. Since we expect that the F protein vaccine formulation will be appropriate for vaccination of adults, this vaccine will also be tested as an approach to vaccinate pregnant mothers and thus enhance maternal antibody levels early in life. Furthermore, we will evaluate the F protein vaccine formulation in elderly, who are also very susceptible to severe RSV disease.
Finally, since the adjuvant formulation comprises a platform for formulation of subunit vaccines in general, we plan to combine the RSV F protein vaccine formulation with additional vaccines for newborns, including existing vaccines, such as B. pertussis and hepatitis B virus antigen, and new vaccines, for example human parainfluenzavirus and human metapneumovirus antigens.
