Development of Parainfluenza Virus and Respiratory Syncytial Virus Subunit Vaccines

  • M. Ewasyshyn
  • G. Cates
  • G. Jackson
  • A. Symington
  • N. Scollard
  • R. P. Du
  • M. Klein
Part of the NATO ASI Series book series (NSSA, volume 293)


Human respiratory syncytial virus (RSV) (McIntosh and Chanock, 1990) and parainfluenza virus (PIV) types 1,2,3 (Chanock and Mclntosh, 1990) have been identified as the major viral pathogens responsible for severe respiratory tract infections in infants and young children. In the United States alone, approximately 4,500 infants and young children are expected to die each year as a result of severe respiratory tract infections caused by RSV (Katz, 1985). The global annual infection and mortality figures for RSV are estimated to be 65 million and 160,000, respectively (Robbins and Freeman, 1988). Recent epidemiological data has indicated that RSV also causes significant morbidity and mortality in the elderly (Falsey et al, 1995), the immunocompromised (Englund et al., 1988) as well as in hospitalized adults with lower respiratory tract infections (Dowell et al., 1996). With respect to the parainfluenza viruses, PIV-3 is second only to RSV as the causative agent of bronchiolitis and pneumonia in infants less than 6 months of age. Annually, approximately 1,000 infants may die in the United States from severe respiratory tract infections caused by PIV-3. Furthermore, it is estimated that 600,000 children under the age of 6 develop laryngotracheobronchitis (croup) each year as a result of infection with PIV-1 and 2 (Katz, 1985). It has also been recently reported that the parainfluenza viruses can cause life threatening pneumonia in adult bone marrow transplant recipients (Lewis et al., 1996).


Respiratory Syncytial Virus Respiratory Syncytial Virus Infection Subunit Vaccine Pulmonary Pathology Human Respiratory Syncytial Virus 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ambrose, M.W., Wyde, P., Ewasyshyn, M., Bonneau, A.-M., Caplan, B., Meyer, H.L. and Klein, M., 1991, Evaluation of the immunogenicity and protective efficacy of a candidate parainfluenza virus type 3 subunit vaccine in cotton rats, Vaccine. 9: 505.PubMedCrossRefGoogle Scholar
  2. Belshe, R.B., Anderson, E.L. and Walsh, E.E., 1993, Immunogenicity of purified Flycoprotein of respiratory syncytial virus: clinical and immune responses to subsequent natural infection in children, J. Infect. Dis., 168: 1024.PubMedCrossRefGoogle Scholar
  3. Brideau, R.J., Walters, R.R., Stier, M.A. and Wathen, M.W., 1989, Protection of cotton rats against human respiratory virus by vaccination with a novel chimeric FG glycoprotein, J.Gen.Virol., 70: 2637.PubMedCrossRefGoogle Scholar
  4. Chanock, R.M. and McIntosh, K., 1990, Parainfluenza viruses, in: “Virology”, B.N. Fields, and D.M. Knipe, eds., Raven Press, New York.Google Scholar
  5. Chin, J., Magoffin, R.L., Shearer, L.A., Schieble, J.H. and Lennette, E.H., 1969, Field valuation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population, Am. J. Epidemiol. 89: 449.PubMedGoogle Scholar
  6. Connors, M., Collins, P.L., Firestone, C.-Y., Sotnikov, A.V., Waitze, A., Davis, A.R., Hung, P.P., Chanock, R.M. and Murphy, B., 1992, Cotton rats previously immunized with a chimeric RSV FG glycoprotein develop enhanced pulmonary pathology when infected with RSV, a phenomenon not encountered following immunization with vaccinia-RSV recombinants or RSV, Vaccine. 10: 475.PubMedCrossRefGoogle Scholar
  7. Connors, M., Giese, N.A., Kulkarni, A.B., Firestone, C.Y., Morse, H.C., Sotnikov, A.V. and Murphy, B.R., 1992, Pulmonary histopathology induced by respiratory syncytial virus (RSV) challenge of formalin-inactivated RSV-immunized BALB/c mice is abrogated by depletion of CD4+ cells, J. Virol. 66: 7444.PubMedGoogle Scholar
  8. Connors, M., Giese, A.B., Firestone, C.Y., Morse, H.C. and Murphy, B.R., 1994, Enhanced pulmonary histopathology induced by respiratory syncytial virus (RSV) challenge of formalin-inactivated RSV-immunized BALB/c mice is abrogated by depletion of interleukin-4 (1L-4) and IL-10. J. Virol. 68: 5321.PubMedGoogle Scholar
  9. Dowell, S.F., Anderson, L.J., Gary, H.E., Erdman, D.D., Plouffe, J.E., File, T.M., Marston, B.J. and Breiman, R.F., 1996, Respiratory syncytial virus is an important cause of community-acquired lower respiratory infection among hospitalized adults, J. Infect. Dis., 174: 456.PubMedCrossRefGoogle Scholar
  10. Du, R-P., Jackson, E.D., Wyde, P.R., Yan, W.-Y., Wang, Q., Gissoni, L., Sanhueza, S.E., Klein, M.H. and Ewasyshyn, M.E., 1994, A prototype recombinant vaccine against respiratory syncytial virus and parainfluenza virus type 3, Biotechnology. 12: 813.PubMedCrossRefGoogle Scholar
  11. Englund, J.A., Sullivan, C.J., Jordan, M.C., Dehner, L.P., Vercellotti, G.M. and Balfour, H.H., 1988, Respiratory syncytial virus infection in immunocompromised adults, Ann. Intern. Med., 109: 203.PubMedCrossRefGoogle Scholar
  12. Ewasyshyn, M., Caplan, B., Bonneau, A.-M., Scollard, N., Graham, S., Usman, S. and Klein, M., 1992, Comparative analysis of the immunostimulatory properties of different adjuvants on the immunogenicity of a prototype parainfluenza virus type 3 subunit vaccine, Vaccine. 10: 412.PubMedCrossRefGoogle Scholar
  13. Ewasyshyn, M.E., Bonneau, A.-M., Usman, S., Scollard, N. and Klein, M., 1993, Comparative analysis of the immunoprotective abilities of glycosylated and deglycosylated parainfluenza virus type 3 surface glycoproteins. J. Gen. Virol., 74: 2781.PubMedCrossRefGoogle Scholar
  14. Ewasyshyn, M.E. and Klein, M., 1994, “Development of Paramyxoviridae vaccines”, in: Modern Vaccinology, E. Kurstak, ed., Plenum Publishing Corporation, New York.Google Scholar
  15. Falsey, A.R., Cunningham, C.K. and Barker, W.H., 1995, Respiratory syncytial virus and influenza A infections in the hospitalized elderly. J. Infect. Dis., 172: 389.PubMedCrossRefGoogle Scholar
  16. Fulginiti, V.A., Eller, J.J., Siever, O.F., Joyner, J.W., Minamitani, M. and Meiklejohn, G., 1969, respiratory virus immunization. A field trial of two inactivated virus vaccines: an aqueous trivalent parainfluenza virus vaccine and an alum-precipitated respiratory syncytial virus vaccine. Am. J. Epidemiol., 89: 435.PubMedGoogle Scholar
  17. Graham, B. S., Henderson, Y.-W., Tang, S., Lu, Neuzil, K.M. and Colley, D.G., 1993, Priming immunization determines T helper cytokine mRNA expression patterns in lungs of mice challenged with respiratory syncytial virus, J. Immunol., 151: 2032.PubMedGoogle Scholar
  18. Hancock, G. E., Speelman, D.J., Frenchick, P.J., Mineo-Kuhn, M.M., Baggs, R.B. and Hahn, D., 1995, Formulation of the purified fusion protein of respiratory syncytial virus with the saponin QS-21 induces protective immune responses in BALB/c mice that are similar to those generated by experimental infection, Vaccine. 13: 391.PubMedCrossRefGoogle Scholar
  19. Hildreth, S.W., Baggs, R.R., Brownstein, D.G., Castleman, W.L. and Paradiso, P.R., 1993, Lack of detectable enhanced pulmonary histopathology in cotton rats immunized with purified F glycoprotein of respiratory syncytial virus (RSV) when challenged at 3–6 months after immunization, Vaccine, 11: 615.PubMedCrossRefGoogle Scholar
  20. Homa, F.L., Brideau, R. J., Lehman, D.J., Thomsen, D. R., Olmsted, R.A. and Wathen, M.W., 1993, Development of a novel subunit vaccine that protects cotton rats against both human respiratory syncytial virus and human parainfluenza virus type 3. J. Gen. Virol., 74: 1995.PubMedCrossRefGoogle Scholar
  21. Johnson, P.R., Olmsted, R.a., Prince, G.A., Murphy, B.R., Ailing, D.W., Walsh, E.E. and Collins, P.L., 1987, Antigenic relatedness between glycoproteins of human respiratory syncytial virus subgroups A and B: evaluation of the contributions of the F and G glycoproteins to immunity. J. Virol., 61: 3163.PubMedGoogle Scholar
  22. Kakuk, T. J., Soike K., Brideau, R. J., Zaya, R. M., Cole, S.L., Zhang, J.-Y., Roberts, E.D., Wells, P.A. and Wathen, M.W., 1993, A human respiratory syncytial virus (RSV) primate model of enhanced pulmonary pathology induced with a formal in-inactivated RSV vaccine but not a recombinant FG subunit vaccine. J. Infect. Dis., 167: 553.PubMedCrossRefGoogle Scholar
  23. Katz, S.L. 1985, Prospects for immunizing against parainfluenza and respiratory synyctial viruses, in: “New Vaccine Development Establishing Priorities”, National Academic Press, Washington.Google Scholar
  24. Lewis, V.A., Champlin, R., Englund, J., Couch, R., Goodrich, J.M., Rolston, K., Przepiorka, D., Mirza, N.Q., Yousuf, H.A., Luna, M., Bodey, G.P. and Whimbey, E., 1996, Respiratory diseases due to parainfluenza virus in adult bone marrow transplant recipients. Clinical Infect. Dis., 23: 1033.CrossRefGoogle Scholar
  25. McIntosh, K. and Chanock, R.M., 1990, Respiratory syncytial virus, in: “Virology”, B. N. Fields, and D.M. Knipe, eds., Raven Press, New York.Google Scholar
  26. Murphy, B.R., Sotnikov, A., Paradiso, P.R., Hildreth, S.W., Jenson, A.B., Baggs, R.B., Lawrence, L., Zubak, J.J. Chanock, R.M., Beeler, J.A. and Prince, G.A., 1989, Immunization of cotton rats with the fusion (F) and large (G) glycoproteins of respiratory syncytial virus (RSV) protects against RSV challenge without potentiating RSV disease, Vaccine. 7: 533.PubMedCrossRefGoogle Scholar
  27. Murphy, B.R., Sotnikov, A., Lawrence, L., Banks, S. and Prince, G., 1990, Enhanced histopathology is observed in cotton rats immunized with formalin-inactivated respiratory syncytial virus (RSV) or purified F glycoprotein and challenged with RSV 3–6 months after immunization, Vaccine, 8: 497.PubMedCrossRefGoogle Scholar
  28. Pemberton, R.M., Cannon, M.J., Openshaw, L.A., Ball, G.W., Wertz, G.W. and Askonas, A., 1987. Cytotoxic T cell specificity for respiratory syncytial virus proteins: fusion protein is an important target antigen, J. Gen. Virol., 68: 2177.PubMedCrossRefGoogle Scholar
  29. Piedra, P.A., Camussi, F. and Ogra, P.L., 1989. Immune response to experimentally induced infections with respiratory syncytial virus: possible role in the development of pulmonary disease, J.Gen.Virol., 70: 325.PubMedCrossRefGoogle Scholar
  30. Piedra, P.A., Grace, S., Jewell, Al., Spinelli, S., Bunting, D., Hogerman, D.A., Malinoski, F. and Hiatt, P.W., 1996, Purified fusion protein vaccine protects against lower respiratory tract illness during respiratory syncytial virus season in children with cystic fibrosis, Pediatr. Infect. Dis.J., 15: 23.PubMedCrossRefGoogle Scholar
  31. Robbins, A. and Freeman, P., 1988, Obstacles for developing vaccines for the third world. Sci.Am. 259: 126.PubMedCrossRefGoogle Scholar
  32. Sanz, M. C., Kew, O.M. and Anderson, L.J., 1994, Genetic heterogeneity of the attachment glycoprotein G among group A respiratory syncytial viruses, Virus Research. 33: 203.PubMedCrossRefGoogle Scholar
  33. Spriggs, M.K., Murphy, B.R., Prince, G.A., Olmsted, R.A. and Collins, P.L., 1987, Expression of the F and HN glycoproteins of human parainfluenza virus type 3 by recombinant vaccinia viruses: contributions of the individual proteins to host immunity, J. Virol., 61: 3416.PubMedGoogle Scholar
  34. Tristam, D.A., Welliver, R.C., Mohar, C.K., Hogerman, D.A., Hildreth, S.W. and Paradiso, P., 1993, Immunogenicity and safety of respiratory synyctial virus subunit vaccine in seropositive children 18–36 months old. J. Infect. Dis., 167: 191.CrossRefGoogle Scholar
  35. Vaux-Peretz, F., Chapsal, J.-M. and Meignier, B., 1992, Comparison of the ability of formalin-inactivated respiratory syncytial virus, immunopurified F, G, and N proteins and cell lysates to enhance pulmonary changes in BALB/c mice, Vaccine. 10: 113.PubMedCrossRefGoogle Scholar
  36. Walsh, E.E. and Hruska, J., 1983. Monoclonal antibodies to respiratory syncytial virus proteins identification of the fusion protein, J. Virol., 47: 171.PubMedGoogle Scholar
  37. Walsh, E.E., Hall, C.B., Briselli, M., Brandriss, M.W. and Schlesinger, J.J., 1987, Immunization with glycoprotein subunits of respiratory syncytial virus to protect cotton rats against viral infection, J. Infect. Dis., 155: 1198.PubMedCrossRefGoogle Scholar
  38. Waris, M.E., Tsou, P., Erdman, P.P., Zaki, S. and Anderson, L.J., 1996, Respiratory syncytial virus infection in BALB/c mice previously immunized with formalin-inactivated virus induced enhanced pulmonary inflammatory response with a predominant Th2-like cytokine pattern, J. Virol., 70: 2852.PubMedGoogle Scholar
  39. Wathen, M.W., Brideau, R.J. and Thomsen, P.R., 1989a, Immunization of cotton rats with the human respiratory syncytial virus F glycoprotein produced using a baculovirus vector, J. Infect. Dis., 159: 255.PubMedCrossRefGoogle Scholar
  40. Wathen, M.W., Brideau, R.J. and Thomsen, D.R., 1989b, Characterization of a novel human respiratory syncytial virus chimeric FG glycoprotein expressed using a baculovirus vector, J. Gen. Virol., 70: 2625.PubMedCrossRefGoogle Scholar
  41. Wathen, M.W., Kakuk, T.J., Brideau, R. J., Hausknecht, E.D., Cole, S.L. and Zaya, R.M., 1991, Vaccination of cotton rats with a chimeric FG glycoprotein of human respiratory syncytial virus induces minimal pulmonary pathology on challenge, J. Infect. Dis., 163: 477.PubMedCrossRefGoogle Scholar
  42. Wertz, G.W. and Sullender, W.M., 1992, Approaches to immunization against respiratory syncytial virus, Biotechnology. 20: 151.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • M. Ewasyshyn
    • 1
  • G. Cates
    • 1
  • G. Jackson
    • 2
  • A. Symington
    • 2
  • N. Scollard
    • 1
  • R. P. Du
    • 1
  • M. Klein
    • 1
  1. 1.Connaught Centre for Biotechnology ResearchPasteur Mérieux Connaught CanadaNorth YorkCanada
  2. 2.Connaught Product Development CentrePasteur Mérieux Connaught CanadaNorth YorkCanada

Personalised recommendations