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Journal of Clinical Microbiology logoLink to Journal of Clinical Microbiology
. 1992 Jun;30(6):1392–1397. doi: 10.1128/jcm.30.6.1392-1397.1992

Humoral immune responses to VP4 and its cleavage products VP5* and VP8* in infants vaccinated with rhesus rotavirus.

L Padilla-Noriega 1, L Fiore 1, M B Rennels 1, G A Losonsky 1, E R Mackow 1, H B Greenberg 1
PMCID: PMC265298  PMID: 1320626

Abstract

The humoral immune response to rhesus rotavirus (RRV) VP4 and its cleavage products VP5* and VP8* was determined in paired serum samples from 44 infants vaccinated with RRV or human rotavirus-RRV reassortants and 5 placebo recipients. Our aim was to try to measure the response to those regions of VP4 most closely related to protection. An enzyme-linked immunosorbent assay (ELISA) was used to measure the immunoglobulin G immune response to baculovirus-expressed full-length RRV VP4, full-length VP8*, and the amino-terminal polypeptide of VP5* called VP5*(1) (amino acids 248 to 474). The two antigenic regions of VP4 selected for study, VP5*(1) and VP8*, have previously been shown to contain most of the cross-reactive and strain-specific neutralization epitopes, respectively, while the remaining carboxy-terminal half of VP5* (amino acids 475 to 776) has not been clearly associated with neutralization. All three recombinant proteins were antigenically conserved, since they reacted with a library of neutralizing monoclonal antibodies directed at VP4. There was a high percentage of seroresponders to VP4 (61%) or to VP8* (52%), but fewer infants seroresponded to VP5*(1) (11%). In addition, infants responding to VP5*(1) had considerably lower titers than to VP4 or VP8*. Immune response to VP4 correlated strongly with the responses detected by the plaque reduction neutralization assay but did not correlate with the responses detected by the ELISA to whole RRV. These data imply that the VP5*(1) region is less immunogenic than the VP8* region of VP4 in infants immunized with RRV or RRV reassortants. The low immunogenicity of VP5* might adversely affect the efficacy of RRV vaccine candidates.

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Selected References

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  1. Arias C. F., López S., Espejo R. T. Gene protein products of SA11 simian rotavirus genome. J Virol. 1982 Jan;41(1):42–50. doi: 10.1128/jvi.41.1.42-50.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brüssow H., Offit P. A., Gerna G., Bruttin A., Sidoti J. Polypeptide specificity of antiviral serum antibodies in children naturally infected with human rotavirus. J Virol. 1990 Sep;64(9):4130–4136. doi: 10.1128/jvi.64.9.4130-4136.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Coulson B. S., Fowler K. J., Bishop R. F., Cotton R. G. Neutralizing monoclonal antibodies to human rotavirus and indications of antigenic drift among strains from neonates. J Virol. 1985 Apr;54(1):14–20. doi: 10.1128/jvi.54.1.14-20.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Coulson B. S., Tursi J. M., McAdam W. J., Bishop R. F. Derivation of neutralizing monoclonal antibodies to human rotaviruses and evidence that an immunodominant neutralization site is shared between serotypes 1 and 3. Virology. 1986 Oct 30;154(2):302–312. doi: 10.1016/0042-6822(86)90456-3. [DOI] [PubMed] [Google Scholar]
  5. Estes M. K., Graham D. Y., Mason B. B. Proteolytic enhancement of rotavirus infectivity: molecular mechanisms. J Virol. 1981 Sep;39(3):879–888. doi: 10.1128/jvi.39.3.879-888.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fiore L., Greenberg H. B., Mackow E. R. The VP8 fragment of VP4 is the rhesus rotavirus hemagglutinin. Virology. 1991 Apr;181(2):553–563. doi: 10.1016/0042-6822(91)90888-i. [DOI] [PubMed] [Google Scholar]
  7. Gorziglia M., Larralde G., Ward R. L. Neutralization epitopes on rotavirus SA11 4fM outer capsid proteins. J Virol. 1990 Sep;64(9):4534–4539. doi: 10.1128/jvi.64.9.4534-4539.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Green K. Y., Taniguchi K., Mackow E. R., Kapikian A. Z. Homotypic and heterotypic epitope-specific antibody responses in adult and infant rotavirus vaccinees: implications for vaccine development. J Infect Dis. 1990 Apr;161(4):667–679. doi: 10.1093/infdis/161.4.667. [DOI] [PubMed] [Google Scholar]
  9. Greenberg H. B., Flores J., Kalica A. R., Wyatt R. G., Jones R. Gene coding assignments for growth restriction, neutralization and subgroup specificities of the W and DS-1 strains of human rotavirus. J Gen Virol. 1983 Feb;64(Pt 2):313–320. doi: 10.1099/0022-1317-64-2-313. [DOI] [PubMed] [Google Scholar]
  10. Greenberg H. B., Kalica A. R., Wyatt R. G., Jones R. W., Kapikian A. Z., Chanock R. M. Rescue of noncultivatable human rotavirus by gene reassortment during mixed infection with ts mutants of a cultivatable bovine rotavirus. Proc Natl Acad Sci U S A. 1981 Jan;78(1):420–424. doi: 10.1073/pnas.78.1.420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Greenberg H. B., Valdesuso J., van Wyke K., Midthun K., Walsh M., McAuliffe V., Wyatt R. G., Kalica A. R., Flores J., Hoshino Y. Production and preliminary characterization of monoclonal antibodies directed at two surface proteins of rhesus rotavirus. J Virol. 1983 Aug;47(2):267–275. doi: 10.1128/jvi.47.2.267-275.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Greenberg H., McAuliffe V., Valdesuso J., Wyatt R., Flores J., Kalica A., Hoshino Y., Singh N. Serological analysis of the subgroup protein of rotavirus, using monoclonal antibodies. Infect Immun. 1983 Jan;39(1):91–99. doi: 10.1128/iai.39.1.91-99.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hoshino Y., Saif L. J., Sereno M. M., Chanock R. M., Kapikian A. Z. Infection immunity of piglets to either VP3 or VP7 outer capsid protein confers resistance to challenge with a virulent rotavirus bearing the corresponding antigen. J Virol. 1988 Mar;62(3):744–748. doi: 10.1128/jvi.62.3.744-748.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hoshino Y., Sereno M. M., Midthun K., Flores J., Kapikian A. Z., Chanock R. M. Independent segregation of two antigenic specificities (VP3 and VP7) involved in neutralization of rotavirus infectivity. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8701–8704. doi: 10.1073/pnas.82.24.8701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hoshino Y., Wyatt R. G., Greenberg H. B., Flores J., Kapikian A. Z. Serotypic similarity and diversity of rotaviruses of mammalian and avian origin as studied by plaque-reduction neutralization. J Infect Dis. 1984 May;149(5):694–702. doi: 10.1093/infdis/149.5.694. [DOI] [PubMed] [Google Scholar]
  16. Kalica A. R., Flores J., Greenberg H. B. Identification of the rotaviral gene that codes for hemagglutination and protease-enhanced plaque formation. Virology. 1983 Feb;125(1):194–205. doi: 10.1016/0042-6822(83)90073-9. [DOI] [PubMed] [Google Scholar]
  17. Kalica A. R., Greenberg H. B., Wyatt R. G., Flores J., Sereno M. M., Kapikian A. Z., Chanock R. M. Genes of human (strain Wa) and bovine (strain UK) rotaviruses that code for neutralization and subgroup antigens. Virology. 1981 Jul 30;112(2):385–390. doi: 10.1016/0042-6822(81)90285-3. [DOI] [PubMed] [Google Scholar]
  18. Kitaoka S., Fukuhara N., Tazawa F., Suzuki H., Sato T., Konno T., Ebina T., Ishida N. Characterization of monoclonal antibodies against human rotavirus hemagglutinin. J Med Virol. 1986 Aug;19(4):313–323. doi: 10.1002/jmv.1890190404. [DOI] [PubMed] [Google Scholar]
  19. Kobayashi N., Taniguchi K., Urasawa S. Identification of operationally overlapping and independent cross-reactive neutralization regions on human rotavirus VP4. J Gen Virol. 1990 Nov;71(Pt 11):2615–2623. doi: 10.1099/0022-1317-71-11-2615. [DOI] [PubMed] [Google Scholar]
  20. Lambert J. P., Marbehant P., Marissens D., Zissis G. Monoclonal antibodies directed against different antigenic determinants of rotavirus. J Virol. 1984 Jul;51(1):47–51. doi: 10.1128/jvi.51.1.47-51.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Liu M., Offit P. A., Estes M. K. Identification of the simian rotavirus SA11 genome segment 3 product. Virology. 1988 Mar;163(1):26–32. doi: 10.1016/0042-6822(88)90230-9. [DOI] [PubMed] [Google Scholar]
  22. Losonsky G. A., Rennels M. B., Lim Y., Krall G., Kapikian A. Z., Levine M. M. Systemic and mucosal immune responses to rhesus rotavirus vaccine MMU 18006. Pediatr Infect Dis J. 1988 Jun;7(6):388–393. doi: 10.1097/00006454-198806000-00004. [DOI] [PubMed] [Google Scholar]
  23. Mackow E. R., Barnett J. W., Chan H., Greenberg H. B. The rhesus rotavirus outer capsid protein VP4 functions as a hemagglutinin and is antigenically conserved when expressed by a baculovirus recombinant. J Virol. 1989 Apr;63(4):1661–1668. doi: 10.1128/jvi.63.4.1661-1668.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mackow E. R., Shaw R. D., Matsui S. M., Vo P. T., Benfield D. A., Greenberg H. B. Characterization of homotypic and heterotypic VP7 neutralization sites of rhesus rotavirus. Virology. 1988 Aug;165(2):511–517. doi: 10.1016/0042-6822(88)90595-8. [DOI] [PubMed] [Google Scholar]
  25. Mackow E. R., Shaw R. D., Matsui S. M., Vo P. T., Dang M. N., Greenberg H. B. The rhesus rotavirus gene encoding protein VP3: location of amino acids involved in homologous and heterologous rotavirus neutralization and identification of a putative fusion region. Proc Natl Acad Sci U S A. 1988 Feb;85(3):645–649. doi: 10.1073/pnas.85.3.645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Matsui S. M., Offit P. A., Vo P. T., Mackow E. R., Benfield D. A., Shaw R. D., Padilla-Noriega L., Greenberg H. B. Passive protection against rotavirus-induced diarrhea by monoclonal antibodies to the heterotypic neutralization domain of VP7 and the VP8 fragment of VP4. J Clin Microbiol. 1989 Apr;27(4):780–782. doi: 10.1128/jcm.27.4.780-782.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Midthun K., Greenberg H. B., Hoshino Y., Kapikian A. Z., Wyatt R. G., Chanock R. M. Reassortant rotaviruses as potential live rotavirus vaccine candidates. J Virol. 1985 Mar;53(3):949–954. doi: 10.1128/jvi.53.3.949-954.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Morita Y., Taniguchi K., Urasawa T., Urasawa S. Analysis of serotype-specific neutralization epitopes on VP7 of human rotavirus by the use of neutralizing monoclonal antibodies and antigenic variants. J Gen Virol. 1988 Feb;69(Pt 2):451–458. doi: 10.1099/0022-1317-69-2-451. [DOI] [PubMed] [Google Scholar]
  29. Offit P. A., Blavat G. Identification of the two rotavirus genes determining neutralization specificities. J Virol. 1986 Jan;57(1):376–378. doi: 10.1128/jvi.57.1.376-378.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Offit P. A., Shaw R. D., Greenberg H. B. Passive protection against rotavirus-induced diarrhea by monoclonal antibodies to surface proteins vp3 and vp7. J Virol. 1986 May;58(2):700–703. doi: 10.1128/jvi.58.2.700-703.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Perez-Schael I., Blanco M., Vilar M., Garcia D., White L., Gonzalez R., Kapikian A. Z., Flores J. Clinical studies of a quadrivalent rotavirus vaccine in Venezuelan infants. J Clin Microbiol. 1990 Mar;28(3):553–558. doi: 10.1128/jcm.28.3.553-558.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Prasad B. V., Burns J. W., Marietta E., Estes M. K., Chiu W. Localization of VP4 neutralization sites in rotavirus by three-dimensional cryo-electron microscopy. Nature. 1990 Feb 1;343(6257):476–479. doi: 10.1038/343476a0. [DOI] [PubMed] [Google Scholar]
  33. Prasad B. V., Wang G. J., Clerx J. P., Chiu W. Three-dimensional structure of rotavirus. J Mol Biol. 1988 Jan 20;199(2):269–275. doi: 10.1016/0022-2836(88)90313-0. [DOI] [PubMed] [Google Scholar]
  34. Richardson S. C., Bishop R. F. Homotypic serum antibody responses to rotavirus proteins following primary infection of young children with serotype 1 rotavirus. J Clin Microbiol. 1990 Sep;28(9):1891–1897. doi: 10.1128/jcm.28.9.1891-1897.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Shaw R. D., Fong K. J., Losonsky G. A., Levine M. M., Maldonado Y., Yolken R., Flores J., Kapikian A. Z., Vo P. T., Greenberg H. B. Epitope-specific immune responses to rotavirus vaccination. Gastroenterology. 1987 Nov;93(5):941–950. doi: 10.1016/0016-5085(87)90555-5. [DOI] [PubMed] [Google Scholar]
  36. Shaw R. D., Vo P. T., Offit P. A., Coulson B. S., Greenberg H. B. Antigenic mapping of the surface proteins of rhesus rotavirus. Virology. 1986 Dec;155(2):434–451. doi: 10.1016/0042-6822(86)90205-9. [DOI] [PubMed] [Google Scholar]
  37. Sonza S., Breschkin A. M., Holmes I. H. Derivation of neutralizing monoclonal antibodies against rotavirus. J Virol. 1983 Mar;45(3):1143–1146. doi: 10.1128/jvi.45.3.1143-1146.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Svensson L., Sheshberadaran H., Vene S., Norrby E., Grandien M., Wadell G. Serum antibody responses to individual viral polypeptides in human rotavirus infections. J Gen Virol. 1987 Mar;68(Pt 3):643–651. doi: 10.1099/0022-1317-68-3-643. [DOI] [PubMed] [Google Scholar]
  39. Taniguchi K., Hoshino Y., Nishikawa K., Green K. Y., Maloy W. L., Morita Y., Urasawa S., Kapikian A. Z., Chanock R. M., Gorziglia M. Cross-reactive and serotype-specific neutralization epitopes on VP7 of human rotavirus: nucleotide sequence analysis of antigenic mutants selected with monoclonal antibodies. J Virol. 1988 Jun;62(6):1870–1874. doi: 10.1128/jvi.62.6.1870-1874.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Taniguchi K., Maloy W. L., Nishikawa K., Green K. Y., Hoshino Y., Urasawa S., Kapikian A. Z., Chanock R. M., Gorziglia M. Identification of cross-reactive and serotype 2-specific neutralization epitopes on VP3 of human rotavirus. J Virol. 1988 Jul;62(7):2421–2426. doi: 10.1128/jvi.62.7.2421-2426.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Taniguchi K., Urasawa S., Urasawa T. Preparation and characterization of neutralizing monoclonal antibodies with different reactivity patterns to human rotaviruses. J Gen Virol. 1985 May;66(Pt 5):1045–1053. doi: 10.1099/0022-1317-66-5-1045. [DOI] [PubMed] [Google Scholar]
  42. Taniguchi K., Urasawa T., Kobayashi N., Ahmed M. U., Adachi N., Chiba S., Urasawa S. Antibody response to serotype-specific and cross-reactive neutralization epitopes on VP4 and VP7 after rotavirus infection or vaccination. J Clin Microbiol. 1991 Mar;29(3):483–487. doi: 10.1128/jcm.29.3.483-487.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Ward R. L., Knowlton D. R., Greenberg H. B., Schiff G. M., Bernstein D. I. Serum-neutralizing antibody to VP4 and VP7 proteins in infants following vaccination with WC3 bovine rotavirus. J Virol. 1990 Jun;64(6):2687–2691. doi: 10.1128/jvi.64.6.2687-2691.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Ward R. L., Knowlton D. R., Schiff G. M., Hoshino Y., Greenberg H. B. Relative concentrations of serum neutralizing antibody to VP3 and VP7 proteins in adults infected with a human rotavirus. J Virol. 1988 May;62(5):1543–1549. doi: 10.1128/jvi.62.5.1543-1549.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Yeager M., Dryden K. A., Olson N. H., Greenberg H. B., Baker T. S. Three-dimensional structure of rhesus rotavirus by cryoelectron microscopy and image reconstruction. J Cell Biol. 1990 Jun;110(6):2133–2144. doi: 10.1083/jcb.110.6.2133. [DOI] [PMC free article] [PubMed] [Google Scholar]

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