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Production of atypical measles in rhesus macaques: Evidence for disease mediated by immune complex formation and eosinophils in the presence of fusion-inhibiting antibody

Abstract

The severe disease atypical measles occurred when individuals immunized with a poorly protective inactivated vaccine contracted measles, and was postulated to be due to a lack of fusion-inhibiting antibodies. Here, rhesus macaques immunized with formalin-inactivated measles vaccine developed transient neutralizing and fusion-inhibiting antibodies, but no cytotoxic T-cell response. Subsequent infection with measles virus caused an atypical rash and pneumonitis, accompanied by immune complex deposition and an increase in eosinophils. Fusion-inhibiting antibody appeared earlier in these monkeys than in non-immunized monkeys. These data indicate that atypical measles results from previous priming for a nonprotective type 2 CD4 T-cell response rather than from lack of functional antibody against the fusion protein.

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Figure 1: Immune responses of individual monkeys to inactivated and live measles virus vaccines.
Figure 2: Skin responses to measles virus infection.
Figure 3: Pulmonary responses to measles virus infection in monkeys preimmunized with the live or inactivated measles virus vaccine.
Figure 4: Systemic responses to measles virus challenge in naive monkeys and monkeys preimmunized with live and inactivated vaccine.

References

  1. 1

    Albrecht, P., Ennis, F.A., Saltzman, E.J. & Krugman, S. Persistence of maternal antibody in infants beyond 12 months: Mechanism of measles vaccine failure J.Pediatr. 91, 715 –178 (1977).

    CAS  Article  Google Scholar 

  2. 2

    Gans, H.A. et al. Deficiency of the humoral immune response to measles vaccine in infants immunized at age 6 months. J. Am. Med. Assoc. 280, 527–532 (1998).

    CAS  Article  Google Scholar 

  3. 3

    Holt, E.A., Moulton, L.H., Siberry, G.K. & Halsey, N.A. Differential mortality by measles vaccine titer and sex. J. Infect. Dis. 168, 1087–1096 ( 1993).

    CAS  Article  Google Scholar 

  4. 4

    Berry, S. et al. Comparison of high titer Edmonston-Zagreb, Biken-CAM and Schwarz measles vaccines in Peruvian infants. Pediatr. Infect. Dis. J. 11, 822–827 ( 1992).

    CAS  Article  Google Scholar 

  5. 5

    Garenne, M., Leroy, O., Beau, J.-P. & Sene, I. Child mortality after high-titre measles vaccines: prospective study in Senegal. Lancet 338, 903–907 ( 1991).

    CAS  Article  Google Scholar 

  6. 6

    Carter, C.H. et al. Serologic response of children to inactivated measles vaccine. J. Am. Med. Assoc. 179, 848– 853 (1962).

    CAS  Article  Google Scholar 

  7. 7

    Guinee, V.F., Henderson, D.A., Casey, H.L., et al. Cooperative measles vaccine field trial I. Clinical efficacy. Pediatrics 37, 649 –657 (1966).

    CAS  PubMed  Google Scholar 

  8. 8

    Fulginiti, V.A., Eller, J.J., Downie, A.W. & Kempe, C.H. Altered reactivity to measles virus: Atypical measles in children previously immunized with inactivated measles virus vaccines. J. Am. Med. Assoc. 202, 1075 (1967).

    CAS  Article  Google Scholar 

  9. 9

    Martin, D.B., Weiner, L.B., Nieburg, P.I. & Blair, D.C. Atypical measles in adolescents and young adults. Ann. Int. Med. 90, 877–881 ( 1979).

    CAS  Article  Google Scholar 

  10. 10

    Young, L.W., Smith, D.I. & Glasgow, L.A. Pneumonia of atypical measles. Residual nodular lesions. Am. J. Roentgenol. 110, 439– 448 (1970).

    CAS  Article  Google Scholar 

  11. 11

    Rauh, L.W. & Schmidt, R. Measles immunization with killed virus vaccine. Am. J. Dis. Child. 109, 232 –237 (1965).

    CAS  Article  Google Scholar 

  12. 12

    Nader, P.R., Horwitz, M.S. & Rousseau, J. Atypical exanthem following exposure to natural measles: Eleven cases in children previously inoculated with killed vaccine. J. Pediatr. 72, 22–28 ( 1968).

    Article  Google Scholar 

  13. 13

    McLean, D.M. et al. Atypical measles following immunization with killed measles vaccine Cand. Med. Assoc. J. 103, 743– 744 (1970).

    CAS  Google Scholar 

  14. 14

    Centers for Disease Control. Atypical measles - California, 1974-1975. Morb. Mort. Weekly. Rep. 25, 245–246 (1976).

  15. 15

    Buser, F. Side reaction to measles vaccination suggesting the Arthus phenomenon. N. Engl. J. Med. 277, 250–251 (1967).

    CAS  Article  Google Scholar 

  16. 16

    Lennon, R.G. et al. Skin test with measles and poliomyelitis vaccines in recipients of inactivated measles virus vaccine. J. Am. Med. Assoc. 200, 99–104 (1967).

    Google Scholar 

  17. 17

    Fulginiti, V.A., Arthur, J.H., Pearlman, D.S. & Kempe, C.H. Altered reactivity to measles virus:Local reactions following attenuated measles virus immunization in children who previously received a combination of inactivated and attenuated vaccines. Am. J. Dis. Child. 115, 67–72 (1968).

    Article  Google Scholar 

  18. 18

    Scott, T.F.M. & Bonanno, D.E. Reactions to live-measles-virus vaccine in children previously inoculated with killed-virus vaccine. N. Engl. J. Med. 277, 248–250 (1967).

    CAS  Article  Google Scholar 

  19. 19

    Krause, P.J., Cherry, J.D., Naiditch, M.J., Deseda-Tous, J. & Walbergh, E.J. Revaccination of previous recipients of killed measles vaccine: Clinical and immunologic studies. J. Pediatr. 93, 565–571 ( 1978).

    CAS  Article  Google Scholar 

  20. 20

    Fulginiti, V.A. & Arthur, J.H. Altered reactivity to measles virus. J. Pediatr. 75, 609– 616 (1969).

    CAS  Article  Google Scholar 

  21. 21

    Norrby, E., Enders-Ruckle, G. & ter Meulen, V. Difference in the appearance of antibodies to structural components of measles virus after immunization with inactivated and live virus. J. Infect. Dis. 132, 262– 269 (1975).

    CAS  Article  Google Scholar 

  22. 22

    Norrby, E. & Gollmar, Y. Identification of measles virus-specific hemolysis-inhibiting antibodies separate from hemagglutination-inhibiting antibodies. Infect. Immun. 11, 231– 239 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Merz, D.C., Scheid, A. & Choppin, P.W. Importance of antibodies to the fusion glycoprotein of paramyxoviruses in the prevention of spread of infection. J. Exp. Med. 151, 275–288 ( 1980).

    CAS  Article  Google Scholar 

  24. 24

    Kim, H.W. et al. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am. J. Epidemiol. 89, 422–434 ( 1968).

    Article  Google Scholar 

  25. 25

    Fulginiti, V.A. et al. Respiratory virus immunization I. A field trial of two inactivated respiratory virus vaccines; an aqueous trivalent parainfluenza virus vaccine and an alum-precipitated respiratory syncytial virus vaccine. Am. J. Epidemiol. 89, 435–447 (1968).

    Article  Google Scholar 

  26. 26

    Connors, M. et al. Pulmonary histopathology induced by respiratory syncytial virus (RSV) challenge of formalin-inactivated RSV-immunized BALB/c mice is abrogated by depletion of CD4+ T cells. J. Virol. 66 , 7444–7451 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Waris, M., Ziegler, T., Kivivirta, M. & Ruuskanen, O. Rapid detection of respiratory syncytial virus and influenza A virus in cell cultures by immunoperoxidase staining with monoclonal antibodies. J. Clin. Microbiol. 28, 1159–1162 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Auwaerter, P.G. et al. Measles virus infection in rhesus macaques: Altered immune responses and comparison of the virulence of six different virus strains. J. Infect. Dis. (in the press).

  29. 29

    Wild, T.F., Malvoisin, E. & Buckland, R. Measles virus: both the haemagglutinin and fusion glycoproteins are required for fusion. J. Gen. Virol. 72, 439–442 (1991).

    CAS  Article  Google Scholar 

  30. 30

    Cardoso, A.I., Beauverger, P., Gerlier, D., Wild, T.F. & Rabourdin-Combe, C. Formaldehyde inactivation of measles virus abolishes CD46-dependent presentation of nucleoprotein to murine class I-restricted CTLs but not to class II-restricted helper T cells. Virology 212, 255–258 (1995).

    CAS  Article  Google Scholar 

  31. 31

    Norrby, E., Lagercrantz, R. & Gard, S. Measles Vaccination VI. Serological and clincal follow-up analysis 18 months after a booster injection. Acta Paediatr. Scand. 55, 457–462 ( 1966).

    CAS  Article  Google Scholar 

  32. 32

    Hankins, R.W. & Black, F.L. Western blot analyses of measles virus antibody in normal persons and in patients with multiple sclerosis, subacute sclerosing panencephalitis, or atypical measles. J. Clin. Microbiol. 24, 324–329 ( 1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Warren, J., Kammer, H. & Gallian, M.J. Immunization of monkeys with an inactivated measles antigen and their response to a subsequent measles infection. Arch. ges Virusforsch 11, 748–753 (1962).

    CAS  Article  Google Scholar 

  34. 34

    Lentsch, A.B., Czermak, B.J., Bless, N.M. & Ward, P.A. NF-KappaB activation during IgG immune complex-induced lung injury: requirements for TNF-alpha and IL-1beta but not complement. Am. J. Pathol. 152, 1327–1331 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Warren, J.S., Yabroff, K.R., Remick, D.G., et al. Tumor necrosis factor participates in the pathogenesis of acute immune complex alveolitis in the rat. J. Clin. Invest. 84, 1873–1882 (1989).

    CAS  Article  Google Scholar 

  36. 36

    Warren, J.S., Barton, P.A. & Jones, M.L. Contrasting roles for tumor necrosis factor in the pathogenesis of IgA and IgG immune complex lung injury. Am. J. Pathol. 138, 581–590 ( 1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Hall, W.J. & Hall, C.B. Atypical measles in adolescents: Evaluation of clinical and pulmonary function. Ann. Intern. Med. 90, 882–886 ( 1979).

    CAS  Article  Google Scholar 

  38. 38

    Annunziato, D. et al. Atypical measles syndrome: Pathologic and serologic findings. Pediatrics 70, 203–209 (1982).

    CAS  PubMed  Google Scholar 

  39. 39

    Bellanti, J.A. Biologic significance of the secretory γA immunoglobulins. Pediatrics 48, 715–729 ( 1971).

    CAS  PubMed  Google Scholar 

  40. 40

    Bellanti, J.A., Sanga, R.L., Klutinis, B., Brandt, B. & Artenstein, M.S. Antibody responses in serum and nasal secretions of children immunized with inactivated and attenuated measles-virus vaccines. N. Engl. J. Med. 280, 628–633 (1969).

    CAS  Article  Google Scholar 

  41. 41

    Beauverger, P., Buckland, R. & Wild, F. Establishment and characterisation of murine cells constitutively expressing the fusion, nucleoprotein and matrix proteins of measles virus. J. Virol. Meth. 44, 199– 210 (1993).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank T. DeLozier and Y. Jeng for technical assistance, J. Rowell for help in establishing the CTL assay and A. Haase for suggestions. This work was supported by research grants AI 35149 (D.E.G.), AI 34577 (K.M.L.) and training grants NS07000 (P.G.A.) AI07417 (A.V.) and AI07541 (A.V.) from the National Institutes of Health and the Pasteur Mérieux Connaught Laboratories Fellowship in Pediatrics (F.P.P.).

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Correspondence to Diane E. Griffin.

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Polack, F., Auwaerter, P., Lee, SH. et al. Production of atypical measles in rhesus macaques: Evidence for disease mediated by immune complex formation and eosinophils in the presence of fusion-inhibiting antibody. Nat Med 5, 629–634 (1999). https://doi.org/10.1038/9473

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