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Clinical Trial
. 2008 Feb 20;26(8):1098-110.
doi: 10.1016/j.vaccine.2007.12.024. Epub 2008 Jan 10.

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime-protein boost HIV-1 vaccine in healthy human volunteers

Shixia Wang  1 , Jeffrey S Kennedy, Kim West, David C Montefiori, Scott Coley, John Lawrence, Siyuan Shen, Sharone Green, Alan L Rothman, Francis A Ennis, James Arthos, Ranajit Pal, Phillip Markham, Shan Lu
Affiliations
Clinical Trial

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime-protein boost HIV-1 vaccine in healthy human volunteers

Shixia Wang et al. Vaccine. .

Erratum in

  • Vaccine. 2008 Jul 23;26(31):3946

Corrected and republished in

Abstract

An optimally effective AIDS vaccine would likely require the induction of both neutralizing antibody and cell-mediated immune responses, which has proven difficult to obtain in previous clinical trials. Here we report on the induction of Human Immunodeficiency Virus Type-1 (HIV-1)-specific immune responses in healthy adult volunteers that received the multi-gene, polyvalent, DNA prime-protein boost HIV-1 vaccine formulation, DP6-001, in a Phase I clinical trial conducted in healthy adult volunteers of both genders. Robust cross-subtype HIV-1-specific T cell responses were detected in IFNgamma ELISPOT assays. Furthermore, we detected high titer serum antibody responses that recognized a wide range of primary HIV-1 Env antigens and also neutralized pseudotyped viruses that express the primary Env antigens from multiple HIV-1 subtypes. These findings demonstrate that the DNA prime-protein boost approach is an effective immunization method to elicit both humoral and cell-mediated immune responses in humans, and that a polyvalent Env formulation could generate broad immune responses against HIV-1 viruses with diverse genetic backgrounds.

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Figures

Figure 1
Figure 1
DP6−001 formulation induced HIV-1 specific cell-mediated immune responses in volunteers' PBMC. (a) Group averages of Env- and Gag-specific IFNγ ELISPOT responses at different time points following DNA or protein immunizations (see Table 2 for standard error and percentage of responders). The solid arrows indicate DNA immunizations and the open arrows indicate protein immunizations. Pools of overlapping peptides from either gp120 antigens of subtype A isolate 92UG037.8 (Env-A) and subtype B isolate 92US715.6 (Env-B) or Gag antigen of subtype C isolate 96ZM651 (Gag) were used for the assay. (b) HIV-1-specific IFNγ ELISPOT responses were detected at 2 weeks after either the 3rd DNA immunization (DNA-3), the 1st or 2nd protein boosts (Prot-1 and Prot-2), or at Week 52 (Closeout) against pools overlapping peptides from gp120 antigens of subtype C isolate 96ZM651 (Env-C) and subtype E isolate 93TH976.17 (Env-E). Results are shown as responses from each of six randomly selected volunteers in each group as well as the group average (short horizontal bars).
Figure 2
Figure 2
DP6−001 formulation induced HIV-1 gp120-specific antibody responses in volunteers' sera. (a) Titers of serum gp120-specific IgG were measured by ELISA in individual volunteers of different study groups. Each curve represents one volunteer. The solid arrows indicate DNA immunizations and the open arrows indicate protein immunizations. The dotted line denotes the average titer of gp120-specific IgG in sera of three patients chronically infected with HIV-1 (titer range: 1:102,400 to 1:204,800). (b) Reactivity of two DP6−001 immune sera (#022 of Group A and #023 of Group B at 1:100 dilution) at different time points of immunization against five autologous primary HIV-1 gp120 glycoproteins as measured by Western blot analysis. Normal human sera and HIV-1 positive patient sera, both at 1:100 dilution, or HIV-1 positive immunoglobulin (HIV-IG) (at 0.5 mg/ml total human IgG) were included as controls. (c) Cross reactivity of sera from one representative DP6−001 immune serum #003 (Group B) against a panel of heterologous primary HIV-1 gp120 glycoproteins by Western blot analysis. Two individual HIV+ patient sera (91BU003 and 93BR029) were included as the controls. Serum dilution of 1:100 was used for both DP6−001 and HIV+ patient sera.
Figure 2
Figure 2
DP6−001 formulation induced HIV-1 gp120-specific antibody responses in volunteers' sera. (a) Titers of serum gp120-specific IgG were measured by ELISA in individual volunteers of different study groups. Each curve represents one volunteer. The solid arrows indicate DNA immunizations and the open arrows indicate protein immunizations. The dotted line denotes the average titer of gp120-specific IgG in sera of three patients chronically infected with HIV-1 (titer range: 1:102,400 to 1:204,800). (b) Reactivity of two DP6−001 immune sera (#022 of Group A and #023 of Group B at 1:100 dilution) at different time points of immunization against five autologous primary HIV-1 gp120 glycoproteins as measured by Western blot analysis. Normal human sera and HIV-1 positive patient sera, both at 1:100 dilution, or HIV-1 positive immunoglobulin (HIV-IG) (at 0.5 mg/ml total human IgG) were included as controls. (c) Cross reactivity of sera from one representative DP6−001 immune serum #003 (Group B) against a panel of heterologous primary HIV-1 gp120 glycoproteins by Western blot analysis. Two individual HIV+ patient sera (91BU003 and 93BR029) were included as the controls. Serum dilution of 1:100 was used for both DP6−001 and HIV+ patient sera.
Figure 3
Figure 3
Neutralizing antibody (NAb) responses against different panels of pseudotyped viruses. (a) NAb titers against Tier 1/autologous viruses including a T-cell line adapted (TCLA) HIV-1 virus (MN) and five pseudotyped viruses each expressing one of the five autologous primary Env antigens included in the DP6−001 formulation. The neutralization assays were done in TZM-bl cells and the NAb titers were measured using individual volunteer sera from Groups A and B (N = 21) at 2 weeks after the 2nd protein boost. (b)-(c) NAb titers determined by PhenoSense™ assay in U87 cells with sera from Groups A and B at two weeks after the 2nd protein boost against pseudotyped viruses expressing either (b) three relatively sensitive to neutralization Env antigens of subtype B (MN, NL4−3 and SF162) or (c) eleven additional primary Env antigens of subtypes A, B, C, D and E. A serum dilution of 1:20 was used as the cut-off to score the positive NAb (shown as the broken line in each graph). (d) NAb responses against Tier 2 pseudotyped viruses expressing primary Env from subtypes A, B and C (4 viruses for each subtype). Individual subject sera from Groups A and B were collected at two weeks post the 2nd protein boost. The percent neutralization was measured at 1:10 serum dilution. The neutralization assays were done in TZM-bl cells.
Figure 3
Figure 3
Neutralizing antibody (NAb) responses against different panels of pseudotyped viruses. (a) NAb titers against Tier 1/autologous viruses including a T-cell line adapted (TCLA) HIV-1 virus (MN) and five pseudotyped viruses each expressing one of the five autologous primary Env antigens included in the DP6−001 formulation. The neutralization assays were done in TZM-bl cells and the NAb titers were measured using individual volunteer sera from Groups A and B (N = 21) at 2 weeks after the 2nd protein boost. (b)-(c) NAb titers determined by PhenoSense™ assay in U87 cells with sera from Groups A and B at two weeks after the 2nd protein boost against pseudotyped viruses expressing either (b) three relatively sensitive to neutralization Env antigens of subtype B (MN, NL4−3 and SF162) or (c) eleven additional primary Env antigens of subtypes A, B, C, D and E. A serum dilution of 1:20 was used as the cut-off to score the positive NAb (shown as the broken line in each graph). (d) NAb responses against Tier 2 pseudotyped viruses expressing primary Env from subtypes A, B and C (4 viruses for each subtype). Individual subject sera from Groups A and B were collected at two weeks post the 2nd protein boost. The percent neutralization was measured at 1:10 serum dilution. The neutralization assays were done in TZM-bl cells.
Figure 3
Figure 3
Neutralizing antibody (NAb) responses against different panels of pseudotyped viruses. (a) NAb titers against Tier 1/autologous viruses including a T-cell line adapted (TCLA) HIV-1 virus (MN) and five pseudotyped viruses each expressing one of the five autologous primary Env antigens included in the DP6−001 formulation. The neutralization assays were done in TZM-bl cells and the NAb titers were measured using individual volunteer sera from Groups A and B (N = 21) at 2 weeks after the 2nd protein boost. (b)-(c) NAb titers determined by PhenoSense™ assay in U87 cells with sera from Groups A and B at two weeks after the 2nd protein boost against pseudotyped viruses expressing either (b) three relatively sensitive to neutralization Env antigens of subtype B (MN, NL4−3 and SF162) or (c) eleven additional primary Env antigens of subtypes A, B, C, D and E. A serum dilution of 1:20 was used as the cut-off to score the positive NAb (shown as the broken line in each graph). (d) NAb responses against Tier 2 pseudotyped viruses expressing primary Env from subtypes A, B and C (4 viruses for each subtype). Individual subject sera from Groups A and B were collected at two weeks post the 2nd protein boost. The percent neutralization was measured at 1:10 serum dilution. The neutralization assays were done in TZM-bl cells.
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