Non-HIV Vaccine-Induced Immune Responses as Potential Baseline Immunogenicity Predictors of ALVAC-HIV and AIDSVAX B/E-Induced Immune Responses

Abstract

Identifying correlations between immune responses elicited via HIV and non-HIV vaccines could aid the search for correlates of HIV protection and increase statistical power in HIV vaccine-efficacy trial designs. An exploratory objective of the HVTN 097 phase 1b trial was to assess whether immune responses [focusing on those supported as correlates of risk (CoR) of HIV acquisition] induced via the RV144 pox-prime HIV vaccine regimen correlated with those induced via tetanus toxoid (TT) and/or hepatitis B virus (HBV) vaccines. We measured TT-specific and HBV-specific IgG-binding antibody responses and TT-specific and HBV-specific CD4+ T-cell responses at multiple time points in HVTN 097 participants, and we assessed their correlations at peak time points with HIV vaccine (ALVAC-HIV and AIDSVAX B/E)-induced responses. Four correlations were significant [false discovery rate-adjusted p-value (FDR) ≤ 0.2]. Three of these four were with IgG-binding antibody responses to TT measured one month after TT receipt, with the strongest and most significant correlation [rho = 0.368 (95% CI: 0.096, 0.588; p = 0.008; FDR = 0.137)] being with IgG-binding antibody responses to MN gp120 gDneg (B protein boost) measured two weeks after the second ALVAC-HIV and AIDSVAX B/E boost. The fourth significant correlation [(rho = 0.361; 95% CI: 0.049, 0.609; p = 0.021; FDR = 0.137)] was between CD4+ T-cell responses to a hepatitis B surface antigen peptide pool, measured 2 weeks after the third HBV vaccination, and IgG-binding antibody responses to gp70BCaseAV1V2 (B V1V2 immune correlate), measured two weeks after the second ALVAC-HIV and AIDSVAX B/E boost. These moderate correlations imply that either vaccine, TT or HBV, could potentially provide a moderately useful immunogenicity predictor for the ALVAC-HIV and AIDSVAX B/E HIV vaccine regimen.

Keywords: HIV vaccine; T-cell responses; binding antibodies; biomarkers; immune correlates.

Figure 1

Schema of the HVTN 097 trial, along with sampling time points.

Figure 2

CD4+ T-cell responses (% CD4+ T cells expressing IFNγ and/or IL-2) to tetanus toxoid (TT) at Month 0 and at Month 1 [1 month after TT vaccination; T1_TT-HIV-HBV and T3_TT-HBV] in HVTN 097 participants, stratified by treatment assignment arm. At Month 0, T1_TT-HIV-HBV and T3_TT-HBV received TT; T2_HIV received a placebo. Response rates and numbers of participants are shown at the top of the plot. Responders: red dot; non-responders: open blue triangle.

Figure 3

Net IgG-binding antibody responses (MFI-blank) to tetanus toxoid (TT) (1:2000 dilution) at Month 1 [1 month after TT vaccination; T1_TT-HIV-HBV and T3_TT-HBV] and at Month 7.5 [2 weeks after the last ALVAC and AIDSVAX B/E vaccination; T1_TT-HIV-HBV and T2_HIV] in the HVTN 097 participants, stratified by treatment assignment arm. At Month 0, T1_TT-HIV-HBV and T3_TT-HBV received TT; T2_HIV received a placebo. At Month 7, T1_TT-HIV-HBV and T2_HIV received the last dose of ALVAC and AIDSVAX B/E; T3_TT-HBV received a placebo. Response rates and numbers of participants are shown at the top of the plot. Responders: red dot; non-responders: open blue triangle.

Figure 4

CD4+ T-cell responses (% CD4+ T cells expressing IFNγ and/or IL-2) to an HBsAg peptide pool at Month 7.5 and Month 9 [2 weeks after the second hepatitis B virus (HBV) vaccination; T1_TT-HIV-HBV and T3_TT-HBV], and Month 13.5 [2 weeks after the third HBV vaccination; T1_TT-HIV-HBV and T3_TT-HBV] in the HVTN 097 participants, stratified by treatment assignment arm. At Months 7.5, 8.5, and 13, T1_TT-HIV-HBV and T3_TT-HBV received HBV; T2_HIV received a placebo. Response rates and numbers of participants are shown at the top of the plot. Responders: red dot; non-responders: open blue triangle.

Figure 5

Net IgG-binding antibody responses [mean fourescence intensity (MFI)-blank] to HBsAg (1:50 dilution) at Month 1 [1 month after TT vaccination; T1_TT-HIV-HBV and T3_TT-HBV], Month 7.5 [two weeks after the last ALVAC and AIDSVAX B/E vaccination; T1_TT-HIV-HBV and T2_HIV], Month 9 [2 weeks after the second HBV vaccination; T1_TT-HIV-HBV and T3_TT-HBV], and Month 13.5 [2 weeks after the third HBV vaccination; T1_TT-HIV-HBV and T3_TT-HBV] in the HVTN 097 participants, stratified by treatment assignment arm. At Month 0, T1_TT-HIV-HBV and T3_TT-HBV received TT; T2_HIV received a placebo. At Months 7.5, 8.5, and 13, T1_TT-HIV-HBV and T3_TT-HBV received HBV; T2_HIV received a placebo. Response rates and numbers of participants are shown at the top of the plot. Responders: red dot; non-responders: open blue triangle.

Figure 6

Correlations in HVTN 097 participants [T1_TT-HIV-HBV arm only] for (A) Month 1 TT-specific CD4+ T-cell responses versus Month 13.5 HBsAg-specific CD4+ T-cell responses; (B) Month 1 TT-specific CD4+ T-cell responses versus Month 13.5 HBV-specific BAMA IgG responses; (C) Month 1 TT-specific BAMA IgG responses versus Month 13.5 HBsAg-specific CD4+ T-cell responses; (D) Month 1 TT-specific BAMA IgG responses versus Month 13.5 HBV-specific BAMA IgG responses. ICS CD4: CD4+ T-cell responses (% CD4+ T cells expressing IFNγ and/or IL-2) to the designated peptide pool; BAMA IgG: Net IgG-binding antibody responses (MFI-blank) to the designated antigen. Each dot represents one participant. At Month 0, T1_TT-HIV-HBV participants received TT. At Months 7.5, 8.5, and 13), T1_TT-HIV-HBV participants received HBV. For the correlation with FDR ≤ 0.2, the p-value and false discovery rate (FDR) value are shown in red font (panel D). For all other panels, the correlation was not significant (FDR > 0.2).

Figure 7

Correlation plots for (A–E) Month 1 TT-specific CD4+ T-cell responses versus Month 7.5 IgG-binding antibody responses against the HIV antigen designated on each y-axis; (F–J) Month 1 TT-specific IgG-binding antibody responses versus Month 7.5 IgG-binding antibody responses against the HIV antigen designated on each y-axis. Data are shown for HVTN 097 participants [T1_TT-HIV-HBV arm only]. ICS CD4 TT: CD4+ T-cell responses (% CD4+ T cells expressing IFNγ and/or IL-2) to TT; BAMA IgG TT: Net IgG-binding antibody responses (MFI-blank) to TT. Each dot represents one participant. At Month 0, T1_TT-HIV-HBV participants received TT. At Month 7, T1_TT-HIV-HBV received the last dose of ALVAC and AIDSVAX B/E. For correlations with FDR ≤ 0.2, the p-values and FDR values are shown in red font (panels G, H). For all other panels, the correlation was not significant (FDR > 0.2).

Figure 8

Correlation plots for (A–E) Month 13.5 HBsAg-specific CD4+ T-cell responses versus Month 7.5 IgG-binding antibody responses against the HIV antigen designated on each y-axis; (F–J) Month 13.5 HBsAg-specific IgG-binding antibody responses versus Month 7.5 IgG-binding antibody responses against the HIV antigen designated on each y-axis. Data are shown for HVTN 097 participants [T1_TT-HIV-HBV arm only]. ICS CD4 HBsAg pool: CD4+ T-cell responses (% CD4+ T cells expressing IFNγ and/or IL-2) to HBsAg pool; BAMA IgG HBsAg: Net IgG-binding antibody responses (MFI-blank) to HBsAg. Each dot represents one participant. At Month 13, T1_TT-HIV-HBV participants received HBV. At Month 7, T1_TT-HIV-HBV received the last dose of ALVAC and AIDSVAX B/E. For the correlation with FDR ≤ 0.2, the p-value and FDR value are shown in red font (panel D). For all other panels, the correlation was not significant (FDR > 0.2).

Figure 9

Correlation plots for (A,B) Month 1 TT-specific CD4+ T-cell responses versus Month 7.5 mean ADCP scores against the HIV antigen designated on each y-axis; (C,D) Month 1 TT-specific IgG-binding antibody responses versus Month 7.5 mean ADCP scores against the HIV antigen designated on each y-axis; (E,F) Month 13.5 HBsAg-specific CD4+ T-cell responses versus Month 7.5 mean ADCP scores against the HIV antigen designated on each y-axis; (G,H) Month 13.5 HBsAg-specific IgG-binding antibody responses versus Month 7.5 mean ADCP scores against the HIV antigen designated on each y-axis. Data are shown for HVTN 097 participants [T1_TT-HIV-HBV arm only]. ICS CD4 HBsAg pool: CD4+ T-cell responses (% CD4+ T cells expressing IFNγ and/or IL-2) to HBsAg pool; BAMA IgG HBsAg: Net IgG-binding antibody responses (MFI-blank) to HBsAg. Each dot represents one participant. At Month 13, T1_TT-HIV-HBV participants received HBV. At Month 7, T1_TT-HIV-HBV received the last dose of ALVAC and AIDSVAX B/E. For the correlation with FDR ≤ 0.2, the p-value and FDR value are shown in red font (panel D). For all other panels, the correlation was not significant (FDR > 0.2).