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Infection

, Volume 22, Issue 2, pp 86–91 | Cite as

Phase I/II vaccination study of recombinant peptide F46 corresponding to the HIV-1 transmembrane protein coupled with 2.4 dinitrophenyl (DNP) Ficoll

  • S. Schwander
  • M. Dietrich
  • M. Opravil
  • R. Lüthy
  • D. G. Hanson
  • J. Schindler
  • A. Dawson
  • B. Letwin
Originalia

Summary

In order to evaluate tolerance, toxicity, andin vivo antigenicity, 29 HIV-1-infected patients (eight with ARC and 21 with AIDS) were vaccinated with a synthetic peptide derived from the gp41 transmembrane protein of the HIV-1. This peptide had been coupled with 2.4 dinitrophenyl-Ficoll (F46), a T-cell independent adjuvant. The patients received a single intradeltoid injection of either 0.1 or 0.3 mg of F46. Five of the individuals with AIDS were boostered, four of them twice. Anti-F46 antibody titers were measured before vaccination, and on days 7, 14, 21, 28, 90, 180 and 270 after vaccination. Anti-F46 titers rose at least twofold over prestudy values in 10/21 individuals with AIDS and in 1/8 individuals with ARC at least once during the observation period. The overall response, however, consisted of only weak antibody production that was independent of the dose or patient characteristics. No signs of toxicity or of clinical progression related to the vaccination were observed in this phase I/II trial of a T-cell independent therapeutic vaccine.

Keywords

Peptide Antibody Titer Transmembrane Protein Synthetic Peptide Clinical Progression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Phase I/II/Impfstudie mit einem an 2,4 Dinitrophenyl (DNP)-Ficoll gekoppelten rekombinanten Peptid F46 aus dem Transmembran Protein GP41 des HIV-1

Zusammenfassung

29 HIV-1 infizierte Patienten (8 mit ARC, 21 mit AIDS) wurden zur Evalüierung von Toleranz, Toxizität undin Vivo-Antigenität mit einem rekombinanten Peptid aus dem Transmembran-Protein des HIV-1 geimpft. Dieses Peptid ist an 2,4 Dinitrophenyl (DNP) Ficoll (F46), cin T-Zell unabhängiges Adjuvans, gekoppelt. Den Patienten wurden entweder 0,1 mg oder 0,3 mg F46 intradeltoidal verabreicht. Fünf der Patienten mit AIDS erhielten eine Boosterinjektion, vier davon zweimalig. Anti F46-Antikörper wurden vor der Impfung und an den Tagen 7, 14, 21, 28, 90, 180 und 270 nach der Impfung bestimmt. Bei 10/21 der Patienten mit AIDS und 1/8 der Patienten mit ARC überstiegen die Antikörpertiter zumindest einmal im Verlaufe der Beobachtungsperiode das Zweifache der Ausgangskonzentration. Insgesamt war die Antikörperantwort allerdings nur schwach und unabhängig von sowohl der F46-Dosis als auch den Patientencharakteristika. In dieser Phase I/II-Studie wurden keine Zeichen von Unverträglichkeit oder einer beschleunigten Krankheitsprogression nach der Impfung mit der therapeutischen Vakzine F46 beobachtet.

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References

  1. 1.
    Fauci, A. S. AIDS: immunopathogenic mechanisms and research strategies. Clin. Res. 35 (1987) 503–510.Google Scholar
  2. 2.
    Fisher, A. G., Ratner, L., Mitsuya, H., Marselle, L. M., Harper, M. E., Broder, S., Gallo, R. C., Wong-Staal, F. Infectious mutants of HTLV-III with changes in the 3'region and markedly reduced cytopathic effects. Science 233 (1986) 655–659.Google Scholar
  3. 3.
    Kowalski, M., Potz, J., Basiripour, L., Dorfman, T., Goh, W. C., Terwilliger, E., Dayton, A., Rosen, C., Haseltine, W., Sodroski, J. Functional regions of the envelope glycoprotein of human immunodeficiency virus type 1. Science 237 (1987) 1351–1355.Google Scholar
  4. 4.
    Sodroski, J., Goh, W. C., Rosen, C., Campbell, K., Haseltine, W. A. Role of the HTLV-III/LAV envelope in syncytium formation and cytopathicity. Nature 322 (1986) 470–474.Google Scholar
  5. 5.
    Lifson, J., Feinberg, M. B., Reyes, G. R., Rabin, L., Banapour, B., Chakrabarti, S., Moss, B., Wong-Staal, F., Steimer, K. S., Engleman, E. G. Induction of CD4-dependent cell fusion by the HTLV-III/LAV envelope glycoprotein. Nature 323 (1986) 725–728.Google Scholar
  6. 6.
    Bowen, D. L., Lane, H. C., Fauci, A. S. Immunopathogenesis of the acquired immunodeficiency syndrome. Ann. Intern. Med. 103 (1985) 704–709.Google Scholar
  7. 7.
    Burny, A., Bex, F., Brasseur, R., Khim, M. C. L., Delchambre, M., Horth, M., Verdin, E. Human immunodeficiency virus cell entry: new insights into the fusion mechanism. J. AIDS 1 (1988) 579–582.Google Scholar
  8. 8.
    Slepushkin, V. A., Andreev, S. M., Sidorova, M. V., Melikyam, G. B., Grigoriev, V. B., Chumakov, V. M., Grinfeldt, A. E., Manukyan, R. A., Karamov, E. V. Investigation of human immunodeficiency virus fusion peptides, analysis of interrelations between their structure and function. AIDS Res. Hum. Retroviruses 8 (1992) 9–18.Google Scholar
  9. 9.
    Stein, B. S., Engleman, E. G. Mechanism of HIV-1 entry into CD4+ T-cells. Adv. Exp. Med. Biol. 300 (1991) 71–86.Google Scholar
  10. 10.
    Koenig, S. Immunopathogenic mechanisms in human immunodeficiency virus (HIV) infection. Ann. Intern. Med. 114 (1991) 678–693.Google Scholar
  11. 11.
    Lake, D. F., Kawamura, T., Tomiyama, T., Robinson, W. E., Matsumoto, Y., Masuho, Y., Hersh, E. M. Generation and characterization of a human monoclonal antibody that neutralizes diverse HIV-1 isolatesin vitro. AIDS 6 (1992) 17–24.Google Scholar
  12. 12.
    Tilley, S. A., Honnen, W. J., Racho, M. E., Hilgartner, M., Pinter, A. A human monoclonal antibody against the CD4-binding site of HIV-1 gp 120 exhibits potent, broadly neutralizing activity. Res. Virol. 142 (1991) 247–259.Google Scholar
  13. 13.
    Chanh, T. C., Dreesman, G. R., Kanda, P., Linette, G. P., Sparrow, J. T., Ho, D. D., Kennedy, R. C. Induction of anti-HIV neutralizing antibodies by synthetic peptides. EMBO J. 5 (1986) 3065–3071.Google Scholar
  14. 14.
    Lasky, L. A., Groopman, J. E., Fennie, C. W., Benz, P. M., Capon, D. J., Dowbenko, D. J., Nakamura, G. R., Nunes, W. M., Renz, M. E., Berman, P. W. Neutralization of the AIDS retrovirus by antibodies to a recombinant envelope glycoprotein. Science 233 (1986) 209–212.Google Scholar
  15. 15.
    Weiss, R. A., Claham, P. R., Cheinsong-Popov, R., Dalgleish, A. G., Carne, C. A., Weller, I. V. D., Tedder, R. S. Neutralization of human T-lymphotropic virus type III by sera of AIDS and AIDS-risk patients. Nature 316 (1985) 69–72.Google Scholar
  16. 16.
    Robert-Guroff, M., Brown, M., Gallo, R. C. HTL V-III-neutralizing antibodies in patients with AIDS and AIDS-related complex. Nature 316 (1985) 72–74.Google Scholar
  17. 17.
    Zagury, D., Bernard, J., Cheynier, R., Desportes, I., Leonard, R., Fouchard, M., Reveil, B., Ittele, D., Lurhama, Z., Mbayo, K., Wane, J., Salaun, J.-J., Goussard, B., Dechazal, L., Burny, A., Nara, P., Gallo, R. C. A group specific anamnestic immune reaction against HIV-1 induced by a candidate vaccine against AIDS. Nature 332 (1988) 728–731.Google Scholar
  18. 18.
    Looney, D. J., Fisher, A., Putney, S. D., Rusche, J. R., Redfield, R. R., Burke, D. S., Gallo, R. C., Wong-Staal, F. Type-restricted neutralization of molecular clones of human immunodeficiency virus. Science 241 (1988) 357–359.Google Scholar
  19. 19.
    Thomas, E. K., Weber, J. N., McClure, J., Clapham, P. R., Singhal, M. C., Shriver, M. K., Weiss, R. A. Neutralizing monoclonal antibodies the AIDS virus. AIDS 2 (1988) 25–29.Google Scholar
  20. 20.
    Ljunggren, K., Moschese, V., Broliden, P.-A., Giaquinto, C., Quinti, I., Fenyö, E.-M., Wahren, B., Rossi, P., Jondal, M. Antibodies mediating cellular cytotoxicity and neutralization correlate with a better clinical stage in children born to human immunodeficiency virus-infected mothers. J. Infect. Dis. 161 (1990) 198–202.Google Scholar
  21. 21.
    Devash, Y., Calvelli, T. A., Wood, D. G., Reagan, K J., Rubinstein, A. Vertical transmission of human immunodeficiency virus is correlated with the absence of high affinity/avidity maternal antibodies to the gp 120 principal neutralizing domain. Proc. Natl. Acad. Sci. USA 87 (1990) 3445–3449.Google Scholar
  22. 22.
    Goedert, J. J., Mendez, H., Drummond, J. E., Robert-Guroff, M., Minkoff, H. L., Holman, S., Stevens, R., Rubinstein, A., Blattner, W. A., Willoughby, A., Landesman, S. H.: Mother to infant transmission of human immunodeficiency virus type 1: association with prematurity or low anti-gp 120. Lancet (1989) 1351–1354.Google Scholar
  23. 23.
    Rossi, P., Moschese, V., Broliden, P. A., Fundaro, C., Quinti, I., Plebani, A., Giaquinto, C., Tovo, P. A., Ljundgren, K., Rosen, J., Wigzell, H., Jondal, M., Wahren, B. Presence of maternal antibodies to human immunodeficiency virus 1 envelope glycoprotein gp 120 epitopes correlates with the uninfected status of children born to seropositive mothers. Proc. Natl. Acad. Sci. USA 86 (1989) 8055–8058.Google Scholar
  24. 24.
    Broliden, P. A., Moschese, V., Ljunggren, K., Rosen, J., Fundaro, C., Plebani, A., Jondal, M., Rossi, P., Wahren, B. Diagnostic implication of specific immunoglobulin G patterns of children born to HIV-infected mothers. AIDS 3 (1989) 577–582.Google Scholar
  25. 25.
    Portera, M., Vitale, F., LaLicata, R., Alesi, D. R., Lupo, G., Bonura, F., Romano, N., DiCuonzo, G. Free and antibody-complexed antigen and antibody profile in apparently healthy HIV seropositive individuals and in AIDS patients. J. Med. Virol. 30 (1990) 30–35.Google Scholar
  26. 26.
    Yunzhen, C., Friedman-Kien, A. E., Mirabile, M., Li, X. L., Alam, M., Dieterich, D., Ho, D. D. HIV-1 neutralizing antibodies in urine from seropositive individuals. J. Acquir. Immune Defic. Syndr. 3 (1990) 195–199.Google Scholar
  27. 27.
    Klasse, P. J., Pipkorn, R., Blomberg, J. Presence of antibodies to a putatively immunosuppressive part of human immunodeficiency virus (HIV) envelope glycoprotein gp 41 is strongly associated with health among HIV-positive subjects. Proc. Natl. Acad. Sci. USA 85 (1988) 5225–5229.Google Scholar
  28. 28.
    Lal, R. B., Heiba, I. M., Dhawan, R. R., Smith, E. S., Perine, P. L. IgG sublass responses to human immunodeficiency virus-1 antigens: lack of IgG2 response to gp 41 correlates with clinical manifestation of the disease. Clin. Immunol. Immunopathol. 58 (1991) 267–277.Google Scholar
  29. 29.
    Chiodi, F., Mathiesen, T., Albert, J., Parks, E., Norrby, E., Wahren, B. IgG subclass responses to a transmembrane protein (gp 41) peptide in HIV infection. J. Immunol. 142 (1989) 3809–3814.Google Scholar
  30. 30.
    Amlot, P. L., Hayes, A. E.: Impaired human antibody response to the thymus-independent antigen, DNP-Ficoll, after splenectomy. Lancet (1985) 1008–1011.Google Scholar
  31. 31.
    Amlot, P. L., Hayes, A. E., Gordon-Smith, E. C., Humphrey, J. H. Human immune responsesin vivo to protein (KLH) and polysaccharide (DNP-Ficoll) neoantigens: normal subjects compared with bone marrow transplant patients on cyclosporine. Clin. Exp. Immunol. 64 (1986) 125–135.Google Scholar
  32. 32.
    Centers for Disease Control Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR 36 (1987) 1S-15S.Google Scholar
  33. 33.
    Centers for Disease Control Classification system for human T-lymphotropic virus type III lymphadenopathy-associated virus infections. MMWR 35 (1986) 334–339.Google Scholar
  34. 34.
    Opravil, M., Fierz, W., Matter, L., Blaser, J., Lüthy, R. Poor antibody response after tetanus and pneumococcal vaccination in immunocompromised, HIV-infected patients. Clin. Exp. Immunol. 84 (1991) 185–189.Google Scholar
  35. 35.
    Manclark, C. R., Meade, B. D., Burstyn, D. G. Serological response toBordetella pertussis. In:Rose, N. R., Friedman, H., Fahey, J. L. (eds): Manual of clinical laboratory immunology (3rd ed.). The American Society for Microbiology, Washington D.C., 1986, pp. 388–394.Google Scholar
  36. 36.
    Berman, P. W., Gregory, T. J., Riddle, L., Nakamura, G. R., Champe, M. A., Porter, J. P., Wurm, F. M., Hershberg, R. D., Cobb, E. K., Eichberg, J. W. Protection of chimpanzees from infection by HIV-1 after vaccination with recombinant glycoprotein gp 120 but not gp160. Nature 345 (1990) 622–625.Google Scholar
  37. 37.
    Cooney, E. L., Collier, A. C., Greenberg, P. D., Coombs, R. W., Zarling, J., Arditi, D. E., Hoffman, M. C., Hu, S.-L., Corey, L. Safety of and immunological response to a recombinant vaccinia virus vaccine expressing HIV envelope glycoprotein. Lancet 337 (1991) 567–572.Google Scholar
  38. 38.
    Redfield, R., Birx, D. L., Ketter, N., Tramont, E., Polonis, V., Davis, C., Brundage, J. F., Smith, G., Johnson, S., Fowler, A., Wierzba, T., Shafferman, A., Volvovitz, F., Oster, C., Burke, D. S., andthe Military Medical Consortium for Applied Retroviral Research A phase I evaluation of the safety and immunogenicity of vaccination with recombinant gp 160 in patients with early human immunodeficiency virus infection. N. Engl. J. Med. 324 (1991) 1677–1684.Google Scholar
  39. 39.
    Letvin, N. L. Vaccines against human immunodeficiency virus-progress and prospects. N. Engl. J. Med. 329 (1993) 1400–1405.Google Scholar

Copyright information

© MMV Medizin Verlag GmbH München 1994

Authors and Affiliations

  • S. Schwander
    • 1
  • M. Dietrich
    • 2
  • M. Opravil
    • 3
  • R. Lüthy
    • 3
  • D. G. Hanson
    • 4
  • J. Schindler
    • 4
  • A. Dawson
    • 4
  • B. Letwin
    • 4
  1. 1.School of MedicineCase Western Reserve UniversityClevelandUSA
  2. 2.Bernhard-Nocht-Institut für TropenmedizinHamburgGermany
  3. 3.Medizinische PoliklinikUniversitätsspital, Departement für Innere MedizinZürichSwitzerland
  4. 4.Biogen Inc.Fourteen Cambridge CenterCambridgeUSA

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