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Respiratory Syncytial Virus (RSV) Pathogensis and Vaccines

Research Team and Collaborators

  • Project leader:  Sylvia van den Hurk
  • Scientists:  Andy Potter, Volker Gerdts
  • Technicians:  Zoe Lawman, Laura Latimer,  Shirley Hauta
  • Post-doctoral fellows:  Sheryl Maher, Bita Moazed, Srinivas Garlapati
  • Graduate students: Ellen Watkiss

Background

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. Human and bovine respiratory syncytial virus (HRSV and BRSV) are closely related members of the genus Pneumovirus within the family Paramyxoviridae. 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. 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. 

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. There currently is no vaccine against RSV. Disease caused by RSV is specifically severe in children between 1 and 3 months of age, even though maternal antibodies are usually present. RSV can also cause significant disease in the elderly and like influenza, is associated with high mortality.


Objectives

  1. Identify age-dependent differences in clinical disease, lung pathology, and immune responses using BRSV-infected newborn and older calves as a model for HRSV.
  2. Identify biomarkers of RSV infection, using BRSV as a model.
  3. 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.
  4. Develop the RSV vaccine formulations for mucosal delivery.
  5. Characterize mechanism of action of adjuvant components in RSV vaccine formulations.

Progress

Recovery from RSV is usually correlated to the development of a Th1-type immune response, whereas a Th2-type immune response may lead to more serious disease. This suggests that an effective RSV vaccine for infants should induce a Th1-biased or balanced immune response. However, newborns have difficulty mounting a robust immune response, specifically a cell-mediated response.

In order to develop a vaccine formulation that induces balanced or Th1-biased immune responses, we have developed a novel vaccine formulation consisting of CpG ODN, which signals through TLR9, host defense peptide, which is likely not dependent on TLR for its action, and polyphosphazene, which complexes with the vaccine antigen and can form microparticles. This triple adjuvant combination worked synergistically, and significantly enhanced immune responses in mice and cattle to two academic antigens, OVA and HEL, as well as RSV F protein both in vitro and in vivo.  This formulation also has potential as mucosal vaccine, which will avoid potential inactivation by maternal antibodies.

Future Direction

In the future we intend to initiate a phase I clinical trial using RSV F protein with a unique and specially developed adjuvant combination. We also plan to test RSV vaccine formulations as an approach to vaccinate pregnant mothers and thus enhance maternal antibody levels early in life, as well as to vaccinate elderly, who are also very susceptible to severe RSV disease.

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, in particular human parainfluenzavirus and human metapneumovirus antigens. 

Funding Partners


Publications

  • Kovacs-Nolan, J., Mapletoft, J.W., Lawman, Z., Babiuk L.A. and van Drunen Littel-van den Hurk, S. 2009. Formulation of bovine respiratory syncytial virus fusion protein with CpG oligodeoxynucleotide, cationic host defense peptide and polyphosphazene enhances humoral and cellular responses and induces a protective type 1 immune response in mice. J. Gen. Virol. Aug;90(Pt 8):1892-905 (Epub April 2009).
  • Kovacs-Nolan, J.,  Latimer, L., Landi, A., Jenssen, H., Hancock, R.E.W., Babiuk, L.A. and van Drunen Littel-van den Hurk , S. 2009. The novel adjuvant combination of CpG ODN, indolicidin and polyphosphazene induces potent antibody and cell-mediated immune responses in mice. Vaccine 27: 2055-2064.