Basic Science: Original Papers
Recombinant gp160 as a therapeutic vaccine for HIV-infection: results of a large randomized, controlled trial
Goebel, Frank-D.; Mannhalter, Josef W.a; Belshe, Robert B.b; Eibl, Martha M.c; Grob, Peter J.d; de Gruttola, Victore; Griffiths, Paul D.f; Erfle, Volkerg; Kunschak, Mariannea; Engl, Wernera; the European Multinational IMMUNO AIDS Vaccine Study Group
From the Medizinische Poliklinik, University of Munich, Germany, aIMMUNO AG, Vienna, Austria, bSaint Louis University, St. Louis, Missouri, USA, the cInstitute of Immunology, Vienna, Austria, dUniversity of Zürich, Zürich, Switzerland, eHarvard University, Boston, USA, the fRoyal Free Hospital, School of Medicine, London, UK and the gInstitute of Molecular Virology, GSF, Munich, Germany. †See Appendix.
Sponsorship: Supported by IMMUNO AG, Vienna, Austria.
Requests for reprints to: F.-D. Goebel, Department of Infectious Diseases, Medizinische Poliklinik, Klinikum Innenstadt, University of Munich, Pettenkoferstr. 8a, 80336 Munich, Germany.
Received: 16 July 1998; revised: 5 May 1999; accepted: 11 May 1999.
Objectives: The primary objective of this study was to expand the safety and immunogenicity database of recombinant gp160 as a therapeutic vaccine in the treatment of HIV-infection. Preliminary efficacy data was also sought.
Design: This trial was a randomized, double-blind, placebo-controlled study. Two-hundred and eight volunteers, 96 therapy-naive with CD4 cell count >500×106/l (group A) and 112 with CD4 cell count of 200-500¥106/l (group B, 51 out of 112 on treatment with one or two nucleoside analogues), received monthly injections of rgp160 IIIB vaccine or placebo for the first 6 months of the study; booster immunizations with rgp160 MN or placebo were given at times 15, 18, and 21 months.
Methods: Safety and immunogenicity data were obtained and measurements of CD4 cell count, plasma viral RNA, and proviral DNA were performed. Clinical outcome was recorded for the 24 months of study.
Results: The vaccine was safe and well tolerated. Despite the induction of new rgp160-specific lymphoproliferative responses and the presence of positive delayed type hypersensitivity skin tests to rgp160 at the end of the 24 month study, no effect on the natural history of HIV infection was detected. Within 24 months, AIDS-defining illnesses had occurred in 19 of the vaccinated volunteers and in 18 of the placebo recipients. Persons with higher plasma viral RNA levels and higher proviral DNA had a more rapid decline in CD4 cell count when compared to persons with lower values. Vaccine did not alter viral RNA or proviral DNA levels.
Conclusion: There was no clinical benefit to therapeutic immunizations with rgp160, despite the induction of new lymphoproliferative responses.
Therapeutic vaccination to reduce the consequences of HIV-infection or slow disease progression would be a valuable addition to antiviral chemotherapy which potentially could help to reduce the need for antiretroviral compounds. One group of vaccine candidates to be considered in this context are glycoproteins derived from the viral envelope. These compounds have been shown to induce protective immune responses that prevent or decrease the severity of infection in animal retroviral infections [1-7], and the HIV-1 envelope glycoproteins gp160 or gp120 have been tested as potential preventive vaccines in several phase I prospective vaccine studies (reviewed in [8,9]).
The recombinant glycoprotein (rgp160) vaccine used in the present study has been evaluated previously in phase I safety trials conducted in both HIV-1-seronegative and HIV-1-infected persons [10-14] and new immune responses, including lymphoproliferation, were induced.
Therefore, we undertook a phase II study to expand the safety and immunogenicity database and possibly obtain preliminary data on efficacy in two groups of infected persons, subjects with relatively intact immune systems (CD4 cell count >500¥106 cells/l) and persons with moderate CD4 decline (200-500¥106 cells/l).
Materials and methods
Design and study groups
This study was conducted between 1993 and 1996 as a double-blind, placebo-controlled, and randomized study to evaluate the safety, immunogenicity and effects of a recombinant gp160 HIV-1 vaccine in infected persons and to obtain preliminary efficacy data after rgp160 vaccination, if possible. Sixteen clinical centres in eight European countries recruited persons aged >18 years with HIV-1 infection. Volunteers were enrolled into two groups: group A consisted of male and female volunteers who were asymptomatic and had >500¥106 CD4 T cells/l at entry, and who were not taking antiretroviral agents; group B consisted of male and female volunteers with CD4 cell counts of 200-500¥106 cells/l and this group was allowed to take reverse transcriptase inhibitors. Antiretroviral therapy followed the accepted indications of 1993 and was based on the primary physician‚s decision. Prophylaxis for opportunistic infections was encouraged if patients developed AIDS-defining diseases or if the CD4 cell count decreased to <200¥106 cells/l. Approval from the respective institutional review board was obtained by each participating centre. All volunteers gave written informed consent.
At study entry volunteers were randomized per clinic to vaccine or placebo in a 1:1 ratio. Computer generated random numbers determined the content of the identical syringes coded for each volunteer. Clinics had no access to codes except for emergencies. The study was monitored by an independent monitoring board, which reviewed quarterly data summaries prepared by the study statistician, who was the only trial team member with access to non-blinded data.
Patients received monthly injections of vaccine or placebo for the first 6 months. Follow-up visits were at months 7, 9 and 12 for clinical and laboratory assessment. A subsequent trial amendment provided for booster immunizations with vaccine or placebo at months 15, 18 and 21 with follow-up evaluations at months 16, 19, 22 and 24 (Fig. 1).
Descriptive statistics included medians and interquartile ranges for demographics and base line characteristics and means and SEM for virological and proliferative response data. Two-sided confidence intervals (CI) and t tests were used with significance defined as P£0.05. CD4 cell count decline was analysed by medians and median differences of slopes of least square regression lines. The c2 test and Cohen‚s k was used for dichotomous data. Time-to-event data were analysed by the Kaplan-Meier technique, log-rank and by Cox‚s proportional hazards model. Volunteers were analysed as randomized (intent-to-treat) except for two subjects (one in each arm) who were consistently switched by mistake.
Preparation and use of candidate vaccines, placebo and skin test reagent
Vaccine preparations, skin test reagents and placebo were provided by IMMUNO AG, Vienna, Austria. Production and purification of rgp160 IIIB and rgp160 MN were as described . The vaccine was formulated at 50μg/ml rgp160 with 0.25% deoxycholate, 0.20% aluminium hydroxide, 0.1% thiomersal in phosphate-buffered saline at pH 7.4. The placebo consisted of adjuvant and thiomersal at identical concentrations. The vaccine was divided into two portions and given by intramuscular injection of 1ml into each arm (total dose 2ml containing 100μg antigen for vaccine recipients) with the exception of haemophiliacs who received subcutaneous injections. The rgp160 IIIB antigen was used for the first six vaccinations and the rgp160 MN antigen was given as the booster at 15, 18 and 21 months. Skin test reagent consisted of 10μg or 100μg rgp160 MN without adjuvant.
Clinical and laboratory evaluation
The protocol provided for two baseline CD4 cell count assessments of volunteers within 1 month before the first vaccination. Each volunteer had a physical examination, complete blood count, blood chemistry and urine analysis (and pregnancy test for women) at screening and prior to each vaccination and at each follow-up visit. CD3, CD4 and CD8 lymphocyte subset analyses (by two-colour flow cytometry, whole blood procedure) were performed at baseline and at months 4, 7, 12, 15, 18, 21 and 24 at each participating centre. After each immunization, volunteers were observed for at least 30 min with body temperature and any reactions recorded at the end of the period. In addition, patients were requested to record any events during the vaccination and follow-up periods of the study to include the following information: temperature twice daily for 7 days after each vaccination, any medication taken, days off work due to illness and hospitalization (in/out patient) with reason for it and duration.
A subset of volunteers had quantitative determination of HIV-1 RNA plasma level at baseline and at months 4, 7, 12 and 24, and proviral HIV-1 DNA quantified at baseline and at months 4, 7, 12 and 15 (Fig. 1). For quantification of HIV-1 RNA and DNA, quantitative competitive reverse transcription PCR or quantitative competitive PCR was used as described previously [16,17].
Lymphocyte proliferation and skin testing
Induction of T-cell memory was assessed in a subset of 77 volunteers (39 vaccine and 38 placebo). Tested were all volunteers from selected centres which could guarantee timely transport of blood to the core laboratories participating in the lymphocyte proliferation studies. There were no significant differences between volunteers with lymphocyte proliferation assay data and the parent group in terms of both baseline CD4 cell counts and baseline RNA levels.
Peripheral blood mononuclear cells (PBMC) were isolated from venous blood according to standard procedures [18,19], washed and suspended in RPMI 1640 medium supplemented with 10% pooled, heat-inactivated (56∞C, 30 min.) HIV-1 antibody-negative AB serum, antibiotics (100U/ml penicillin, 100μg/ml streptomycin) and L-glutamine (2mM) (complete medium). Quadruplicate cultures were then set up in flat-bottomed microtiter plates (1¥105 PBMC/well in 0.2ml complete medium) and the cells were incubated (37°C, CO2 incubator) for 7 days in the presence or absence of rgp160 at a concentration of 1μg/ml or an equivalent amount of mock antigen. Mock antigen contains the small amounts of vaccinia, cellular and medium proteins still present in rgp160 after purification and was used to control for possible proliferative responses to these contaminants. For the last 4 h of the incubation period 3H-thymidine (1μCi/well) was added to the cultures and the cells were then harvested onto glass fibre filters and incorporated radioactivity was measured in a b-counter.
A skin test for delayed type hypersensitivity was not available at the start of the study. After it became available it was performed according to a protocol amendment as an optional test at the end of the 24-month study in all patients who gave written informed consent. Based on previous information , two doses of rgp160 antigen, 10μg and 100μg, were used for skin testing. The vaccine antigen, rgp160 MN was dissolved in saline to give the appropriate concentration and 0.1ml of each dose was adminstered simultaneously in each forearm. The skin test was considered positive if an induration of ≥5¥5mm was observed after 48 h.
Enrolment and vaccination
Two-hundred and eight volunteers participated in this study; 96 volunteers had >500¥106 CD4 cells/l at entry (group A) and 112 volunteers had 200-500¥106 CD4 T cells/l at entry (group B). There were 25 women and 183 men in the study, and there was no significant difference in their distribution into vaccine or placebo group (Table 1). Similarly, there was no difference in the vaccine or placebo groups in baseline CD4 cell counts, baseline viral RNA copies/ml of plasma or baseline proviral DNA copies/105 cells. Fig. 1 summarizes the randomization, follow-up and compliance. Of the 208 participants, 183 completed the 24 months of study; seven patients had died during this time. Compliance with immunizations was high; 94% received all six injections of rgp160 IIIB or placebo during the initial phase of the study and 76% of participants received the three booster injections of rgp160 MN at months 15, 18, and 21. Only 3.7% of scheduled injections were missed by the subjects.
Safety and adverse events
Pain at the injection site was common in both the vaccine and placebo recipients. Systemic complaints including fever, malaise, myalgia, arthralgia and headache were observed with equal frequency in the vaccine and placebo group. These symptoms were usually mild and of short duration. Among the seven patients who died during the study five had received placebo and two had received vaccine. The causes of death were one each of suicide, heart failure, trauma, liver failure with hepatitis B and C, intestinal infection and wasting, central nervous system toxoplasmosis, and unknown. No significant differences between vaccine or placebo groups were observed in the safety laboratory tests (data not shown).
Lymphocyte proliferation and skin tests
Fig. 2 shows lymphoproliferation in response to stimulation with the rgp160 IIIB, rgp160MN and the mock antigens. All but one of the vaccinated group A (14 out of 15) and 14 out of 24 vaccinated group B volunteers showed a positive lymphoproliferative response after rgp160 immunization (a positive response is defined as three or more rgp160-induced proliferative responses which are greater than three times the medium background but at least greater than 2000cpm). The positive proliferative response was not limited to the homologous rgp160 IIIB (Fig. 2, upper panels), as rgp160 MN-specific lymphocyte proliferation was already present prior to boosting with MN subtype vaccine (Fig. 2, centre panels). The mock antigen preparation (Fig. 2, lower panels) gave a much lower lymphoproliferative response.
HIV-1 Env-induced lymphoproliferation data were confirmed by development of positive delayed type hypersensitivity skin reactions in both groups of vaccine recipients following subcutaneous application of a rgp160 MN preparation at month 24. The results of these skin tests are shown in Table 2. They indicate a significantly higher proportion of positive skin tests in the vaccination group. There also was a high degree of concordance (k, 0.64; c2, 13.6, P=0.0004) between a positive lymphoproliferative response and a positive skin test result (Table 3).
CD4 cell counts
Among all group A volunteers (with initial CD4 cell counts >500¥106 cells/l) the CD4 cell count decreased with a median of 62¥106 cells/l per year (95% CI, 47-91¥106). Among the vaccine recipients in this group, CD4 cells decreased by 96¥106 cells/l per year (95% CI, 57-107¥106) and in subjects receiving placebo CD4 cells fell by 49¥106cells/l per year (95% CI, 13-76¥106). In group B volunteers (with baseline CD4 cell counts of 200-500¥106 CD4 cells/l) the CD4 cell count decreased by a median of 41¥106 cells/l per year (95% CI, 25-56¥106); the vaccine group had a median decline of 35¥106 cells/l per year (95% CI, 20-63) and the placebo recipients had a median decline of 48¥106 cells/l per year (95% CI, 17-74¥106). In both groups of volunteers the difference between vaccine and placebo recipients was not statistically significant.
To assess the potential impact of vaccine on plasma viral RNA and proviral DNA, subjects were stratified at entry according to treatment with antiretroviral compounds (for number of subjects taking or not taking antiretrovirals see Table 1). As shown in Fig. 3, there was no significant change over time in either HIV RNA or proviral DNA copy numbers in volunteers taking or not taking antiretroviral compounds. Among the volunteers taking antiretroviral compounds, there was a trend towards increasing proviral DNA (and higher plasma RNA on one occasion) with the placebo group. However, this did not achieve statistical significance. Vaccination by itself did not increase viral RNA or DNA (assessed 4 weeks after administration).
Although this study was not designed as a phase III efficacy study, sufficient AIDS-defining events occurred in group B (CD4 cell count 200-500¥106 cells/l) relative to group A (CD4 cell count >500¥106 cells/l) to be significant after 24 months (data not shown). However, no impact of vaccine could be determined in this time, nor was there a trend. Among the 103 vaccinated volunteers, there were 19 with one or more AIDS-defining events and among the 105 placebo recipients, there were 18 with one or more AIDS-defining events (c2, 0.06, P=0.86). Results of time-to-event analyses were similar (data not shown).
Similarly, when stratified by baseline CD4 cell count, no effect of vaccine on CD4 cell count decline was observed. Within 24 months 132 of 208 subjects had experienced a decline in CD4 cell count of ≥33% from baseline or to <200¥106 cells/l. Among group A, 58 (32 vaccine versus 26 placebo), and in group B 74 (34 vaccine versus 40 placebo) developed this immunologic deterioration. There was no statistically significant difference between vaccine and placebo recipients in the probability of CD4 decline in either group A or group B (Fig. 4a). When these subjects were stratified according to viral RNA or proviral DNA at baseline, a significant difference in probability of CD4 decline was observed. However, no significant difference between vaccine and placebo recipients was found in these analyses (Fig. 4b and 4c).
Despite induction of new lymphoproliferative responses by vaccination with rgp160 IIIB and rgp160 MN, no clinical benefit was found in this trial. This was true for subjects with relatively intact immune systems as shown by baseline CD4 cell counts of >500¥106 CD4 cells/l, as well as subjects with moderate CD4 cell decline (200-500¥106 CD4 cells/l) at study entry. The results of the trial also imply, therefore, that CD4 cell count as the only marker for patient selection is not sufficient in future vaccination trials as evidenced by a comparatively high plasma viral RNA and by a considerable proportion of patients progressing to AIDS even in group A. Clinical outcome was predicted by either viral RNA or proviral DNA at baseline as has been shown by others [21-25]. When subjects were stratified into high or low plasma RNA or proviral DNA baseline levels, vaccine had no effect on CD4 cell count (see Fig. 4) or clinical events (data not shown). Although there was no benefit from vaccine, neither was there an adverse effect. The vaccine was safe and well tolerated, and use of vaccine was not associated with any change in CD4 cell decline, viral RNA in plasma or proviral DNA.
Previous studies of vaccines in infected persons have included phase I studies of this and other gp160 preparations [14,26-31], gp120 , HIV-1 core proteins [33-35], whole inactivated HIV-1 [36,37], live vector vaccine including canarypox  and polynucleotide vaccine . Larger studies to evaluate some of these vaccines for efficacy are currently ongoing, but to date the results on efficacy have not been reported. Although the present trial was not designed as a phase III efficacy trial, the long duration of follow-up (2 years) in both vaccine and placebo groups resulted in sufficient AIDS-defining events to suggest that this type of vaccine was not highly efficacious.
New immune responses to HIV antigens among infected persons who have received an HIV vaccine have included the induction of lymphocyte proliferative responses to HIV Env [27-31], as found in the present study. Although lymphocyte proliferation responses to Env would be an expected response to HIV-1-infection, this is not usually the case. Vaccination clearly is adding this type of immune response to the infecting agent. In previous studies, gp160 has been a much more powerful inducer of lymphoproliferation than has gp120  and the vaccine used in this study was shown to have significant immunogenicity in uninfected persons, particularly with regard to lymphocyte proliferation [10,11,13]. Recent observations suggest that HIV-1-specific lymphoproliferative responses develop after treatment of acutely infected persons with potent antiretroviral drugs . This has lead to speculation on the importance of HIV-1-specific T helper cell responses in controlling HIV infection. However, despite these immune responses that were induced in our study, the clinical outcome observed to date does not support this hypothesis.
Identification of immune parameters that correlate with slowing disease progression may refocus approaches on therapeutic vaccine in HIV. High levels of neutralizing antibodies, high frequency cytotoxic T-cell precursors, or other parameters may emerge as correlates of slow disease progression. Therapeutic vaccine to induce one or more of these parameters in conjunction with chemotherapy may provide significant immune control over the virus. Future trials should examine the effect of vaccine on persons who were vigorously treated with chemotherapy and responded with reduction in viral load.
1. Girard M, Kieny M-P, Pinter A, et al. Immunization of chimpanzees confers protection against challenge with human immunodeficiency virus. Proc Natl Acad Sci USA 1991, 88:542-546.
2. Berman PW, Murthy KK, Wrin T, et al. Protection of MN-rgp120-immunized chimpanzees from heterologous infection with a primary isolate of human immunodeficiency virus type 1. J Infect Dis 1996, 173:52-59.
3. Hu S-L, Abrams K, Barber GN, et al. Protection of macaques against SIV infection by subunit vaccines of SIV envelope glycoprotein gp160. Science 1992, 255:456-459.
4. Hu S-L, Polacino P, Stallard V, et al. Recombinant subunit vaccines as an approach to study correlates of protection against primate lentivirus infection. Immunol Lett 1996, 51:115-119.
5. Mossman SP, Bex F, Berglund P, et al. Protection against lethal simian immunodeficiency virus SIVsmmPBj14 disease by a recombinant Semliki Forest Virus gp160 vaccine and by a gp120 subunit vaccine. J Virol 1996, 70:1953-1960.
6. Lutz H, Hofmann-Lehmann R, Leutenegger C, et al. Vaccination of cats with recombinant envelope glycoprotein of feline immunodeficiency virus: decreased viral load after challenge infection. AIDS Res Hum Retroviruses 1996, 12:431-433.
7. Hosie MJ, Dunsford TH, de Ronde A, et al. Suppression of virus burden by immunization with feline immunodeficiency virus Env protein. Vaccine 1996, 14:405-411.
8. Mannhalter JW. Acquired immunodeficiency syndrome vaccines: current concepts and future prospects. In Symposium in Immunology VII. Vaccination. Edited by Eibl MM, Huber C, Peter HH, Wahn U. Berlin Heidelberg: Springer Verlag; 1998:137-153.
9. Dolin R. Human studies in the development of human immunodeficiency virus vaccines. J Infect Dis 1995, 172:1175-1183.
10. Belshe RB, Clements ML, Dolin R, et al. Safety and immunogenicity of a fully glycosylated recombinant gp160 human immunodeficiency virus type 1 vaccine in subjects at low risk of infection. J Infect Dis 1993, 168:1387-1395.
11. Gorse GJ, Schwartz DH, Graham BS, et al. HIV-1 recombinant gp160 vaccine given in accelerated dose schedules. Clin Exp Immunol 1994, 98:178-184.
12. Gorse GJ, Rogers JH, Perry JE, et al. HIV-1 recombinant gp160 vaccine induced antibodies in serum and saliva. Vaccine 1995, 13:209-214.
13. Gorse GJ, McElrath MJ, Matthews TJ, et al. Modulation of immunologic responses to HIV-1MN recombinant gp160 vaccine by dose and schedule of administration. Vaccine 1998, 16:493-506.
14. Schwartz D, Clements ML, Belshe R, et al. Interim results of rgp160 vaccine trial in HIV + volunteers. IX International Conference on AIDS/IV STD World Congress. Berlin, June 1993 [abstract PO-A28-0668].
15. Barrett N, Mitterer A, Mundt W, et al. Large-scale production and purificaiton of a vaccinia recombinant-derived HIV-1 gp160 and analysis of its immunogenicity. AIDS Res Hum Retroviruses 1989, 5:159-171.
16. Piatak M, Luk K-C, Williams B, Lifson JD. Quantitative competitive polymerase chain reaction for accurate quantitation of HIV DNA and RNA species. BioTechniques 1993, 14:70-80.
17. Hämmerle T, Himmelspach M, Dorner F, Falkner FG. A sensitive PCR assay system for quantitation of viral genome equivalents: Human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV). Arch Virol 1997, 142:1297-1306.
18. Bøyum A. Isolation of mononuclear cells and granulocytes from human blood. Scand J Clin Lab Invest 1968, 21 (suppl 97):77-89.
19. Mannhalter JW, Pum M, Wolf HM, et al. Immunization of chimpanzees with the HIV-1 glycoprotein gp160 induces long-lasting T-cell memory. AIDS Res Hum Retroviruses 1991, 7:485-493.
20. AIDS Vaccine Evaluation Group: Protocol 13. 1995
21. Mellors JW, Rinaldo Jr CR, Gupta P, White RM, Todd JA, Kingsley LA. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 1996, 272:1167-1170.
22. O‚Brien TR, Blattner WA, Waters D, et al. Serum HIV-1 RNA levels and time to development of AIDS in the multicenter hemophilia cohort study. JAMA 1996, 276:105-110.
23. Phillips AN, Eron JJ, Bartlett JA, et al. HIV-1 RNA levels and the development of clinical disease. AIDS 1996, 10:859-865.
24. Mellors JW, Muños A, Giorgi JV, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997, 126:946-954.
25. Chevret S, Kirstetter M, Mariotti M, Lefrère F, Frottier J, Lefrère J-J. Provirus copy number to predict disease progression in asymptomatic human immunodeficiency virus type 1 infection. J Infect Dis 1994, 169:882-885.
26. Redfield RR, Birx DL, Ketter N, et al. A phase I evaluation of the safety and immunogenicity of vaccination with recombinant gp160 in patients with early human immunodeficiency virus infection. N Engl J Med 1991, 324:1677-1684.
27. Loomis LD, Deal CD, Kersey KS, Burke DS, Redfield RR, Birx DL. Humoral responses to linear epitopes on the HIV-1 envelope in seropositive volunteers after vaccine therapy with rgp160. J Acquir Immune Defic Syndr Hum Retrovirol 1995, 10:13-26.
28. Valentine FT, Kundu S, Haslett PAJ, et al. A randomized, placebo-controlled study of the immunogenicity of human immunodeficiency virus (HIV) rgp160 vaccine in HIV-infected subjects with ≥400/mm3 CD4 T lymphocytes (AIDS Clinical Trials Group Protocol 137). J Infect Dis 1996, 173:1336-1346.
29. Kundu SK, Katzenstein D, Valentine FT, Spino C, Efron B, Merigan TC. Effect of therapeutic immunization with recombinant gp160 HIV-1 vaccine on HIV-1 proviral DNA and plasma RNA: relationship to cellular immune responses. J Acquir Immune Defic Syndr Hum Retrovirol 1997, 15:269-274.
30. Leandersson A-C, Bratt G, Hinkula J, et al. Induction of specific T-cell responses in HIV infection. AIDS 1998, 12:157-166.
31. Pontesilli O, Guerra EC, Ammassari A, et al. Phase II controlled trial of post-exposure immunization with recombinant gp160 versus antiretroviral therapy in asymptomatic HIV-1-infected adults. AIDS 1998, 12:473-480.
32. Eron JJ, Ashby MA, Giordano MF, et al. Randomised trial of MNrgp120 HIV-1 vaccine in symptomless HIV-1 infection. Lancet 1996, 348:1547-1551.
33. Klein MR, Veenstra J, Holwerda AM. et al. Gag-specific immune responses after immunization with p17/p24:Ty virus-like particles in HIV type 1-seropositive individuals. AIDS Res Hum Retroviruses 1996, 13:393-399.
34. Peters BS, Cheingsong-Popov R, Callow D, et al. A pilot phase II study of the safety and immunogenicity of HIV p17/p24:VLP (p24-VLP) in asymptomatic HIV seropositive subjects. J Infection 1997, 35:231-235.
35. Kelleher AD, Roggensack M, Jaramillo AB, et al. Safety and immunogenicity of a candidate therapeutic vaccine, p24 virus-like particle, combined with zidovudine, in asymptomatic subjects. AIDS 1998, 12:175-182.
36. Trauger RJ, Ferre F, Daigle AE, et al. Effect of immunization with inactivated gp120-depleted human immunodeficiency virus type 1 (HIV-1) immunogen on HIV-1 immunity, viral DNA, and percentage of CD4 cells. J Infect Dis 1994, 169:1256-1264.
37. Moss RB, Giermakowska W, Lanza P, et al. Cross-clade immune responses after immunization with a whole-killed gp120-depleted human immunodeficiency virus type-1 immunogen in incomplete Freund‚s adjuvant (HIV-1 immunogen, REMUNE) in human immunodeficiency virus type-1 seropositive subjects. Virol Immunol 1997, 10:221-228.
38. Tubiana R, Gomard E, Fleury H, et al. Vaccine therapy in early HIV-1 infection using a recombinant canarypox virus expressing gp160MN (ALVAC-HIV): a double-blind controlled randomized study of safety and immunogenicity [letter]. AIDS 1997, 11:819-820.
39. Calarota S, Bratt G, Nordlund S, Hinkula J, Leandersson AC, Sandström E. Cellular cytotoxic response induced by DNA vaccination in HIV-1-infected patients. Lancet 1998, 351:1320-1325.
40. Rosenberg ES, Billingsley JM, Caliendo AM, et al. Vigorous HIV-1-specific CD4(+) T cell responses associated with control of viremia. Science 1997, 278:1447-1450.
E. Tschachler, Universiäts Hautklinik, Vienna, Austria; B. Colebunders, Institute of Tropical Medicine, Antwerpen, Belgium; F. Black, Marselisborg Hospital, Aarhus, Denmark; A. Ranki, Deptartment of Dermatology and Venereal Diseases, Helsinki, Finland; J. Rockstroh, Department of Medicine, University of Bonn, Germany; R. Zimmermann, Kurpfalzkrankenhaus Heidelberg, Germany; I. Scharrer, University Hospital, Frankfurt, Germany; J. R. Bogner, Medizinische Poliklinik, University of Munich, Germany; C. F. Mantel, Landesinstitut für Tropenmedizin, Berlin, Germany; H. Jablonowski, Medizinische Universitätsklinik, Düsseldorf, Germany; W. Schramm, F. Rommel, Medizinische Klinik, University of Munich, Germany; W. Brockhaus, Zentrum innere Medizin, Klinikum der Stadt Nürnberg, Germany; S. S. Fröland, Rikshospitalet, Oslo, Norway; E. Sandström, Södersjukhuset, Stockholm, Sweden; E. Berntorp, Malmö General Hospital, Malmö, Sweden; M. Flepp, Universitätsspital Zürich, Switzerland; L. Stigendal, Sahlgrenska Sjukhuset, Göteborg, Sweden.
K. Krohn, V. Blazevic, A. Lagerstedt, Institute of Medical Technology, University of Tampere, Finland; B. Wahren, G. Gilliam, A. C. Leanderson, Karolinska Institut, Stockholm, Sweden; J. D. Lifson, M. Piatak, Genelabs Technologies Inc. Redwood City, CA, USA; B. Husch, L. Trawnicek, N. Barrett, T. Hämmerle, F. Dorner, G. Eder, IMMUNO AG, Vienna, Austria.
HIV-infection; rgp160 vaccine; immune response; safety; clinical outcome
© 1999 Lippincott Williams & Wilkins, Inc.
Highlight selected keywords in the article text.