AIDSVAX protein boost improves breadth and magnitude of vaccine-induced HIV-1 envelope-specific responses after a 7-year rest period

Abstract

Background: Eliciting durable humoral immunity with sufficient breadth and magnitude is important for HIV-1 vaccine design. The HVTN 114 vaccine trial evaluated different boost regimens administered after a 7-year rest period in participants previously enrolled in HVTN 205, who received either three MVA/HIV62B (MMM) or two DNA and two MVA/HIV62B (DDMM) injections; both vaccines expressed multiple HIV-1 antigens in non-infectious virus-like-particles. The primary objective of HVTN 114 was to assess the impact of a heterologous gp120 protein AIDSVAX B/E boost on the magnitude, breadth and durability of vaccine-induced immune responses.

Methods: We enrolled 27 participants from HVTN 205 into five groups. Eight participants who previously received MMM were randomized and boosted with either MVA/HIV62B alone (T1; n = 4) or MVA/HIV62B and AIDSVAX B/E (T2; n = 4). Nineteen participants who received DDMM were randomized and boosted with MVA/HIV62B alone (T3; n = 6), MVA/HIV62B and AIDSVAX B/E (T4; n = 6), or AIDSVAX B/E alone (T5; n = 7). Boosts were at months 0 and 4. Participants were followed for safety and immunogenicity for 10 months and were pooled for analysis based on the regimen: MVA-only (T1 + T3), MVA + AIDSVAX (T2 + T4), and AIDSVAX-only (T5).

Results: All regimens were safe and well-tolerated. Prior to the boost vaccination, binding antibody and CD4+T-cell responses were observed 7 years after HVTN 205 vaccinations. Late boosting with AIDSVAX, with or without MVA, resulted in high binding antibody responses to gp120 and V1V2 epitopes, with increased magnitude and breadth compared to those observed in HVTN 205. Late boosting with MVA, with or without AIDSVAX, resulted in increased gp140 and gp41 antibody responses and higher CD4+T-cell responses to Env and Gag.

Conclusions: Late boosting with AIDSVAX, alone or in combination with MVA, can broaden binding antibody responses and increase T-cell responses even years following the original MVA/HIV62B with or without DNA-priming vaccine.

Keywords: AIDSVAX; DNA Vaccine; HIV vaccine; Late boost; MVA vaccine; V1V2 antibody.

Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [The authors of this manuscript have read the journal's policy and have the following competing interests: YH, CY, MDM, CP, SCD, KC, MJM, PG, JM, MK, MS, LRB, DM are recipients of funding from The National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health, and this publication is a result of activities funded by the NIAID. HLR was a co-founder of GeoVax, Inc. and is an inventor on patents that GeoVax licensed from Emory University and the NIAID for commercial development of the MVA/HIV62B and JS7 DNA vaccines. CFK receives research grants to her institution from NIH, CDC, Gilead Sciences, ViiV, Moderna, and Novavax. GDT received research grants to her institution from NIAID, BMGF, GSK and Macrogenics, has patent applications for HIV vaccine design and incidence testing, and has consulted for Axon Advisors. KES has a patent application for HIV incidence testing. SB receives research grants to her institution from NIH, Gilead Sciences, Merck, and Viiv. The rest of the authors have no conflicts.

Published by Elsevier Ltd.

Figures

Figure 1.. CONSORT diagram.

Allocation, follow-up, and analysis for HVTN 114 study. Abbreviations: MMM, a prime-boost vaccine regimen comprising 3 sequential administrations of MVA/HIV62B; DDMM, a vaccine regimen comprising 2 sequential priming administrations of JS7 DNA plasmid followed by 2 sequential boost administrations of MVA/HIV62B. *Intracellular cytokine staining data only available for month 0 (pre-boost) and month 4.5 (post 2nd boost).

Figure 2.. IgG binding antibody response rates and response magnitudes in HVTN 205 and HVTN 114 for T1+T3 (MVA-only), T2+T4 (MVA+ AIDSVAX), and T5 (AIDSVAX-only).

Panels A-D show the proportion of positive responders (number of responders out of total) and response magnitudes to HIV-1 Env gp120 (Con 6 gp120), the V1V2 loop (V1V2.B), HIV-1 Env gp140 (Con S gp140) and gp41.B, respectively, at baseline, 2 weeks and 6 months post the last vaccination in HVTN 205, and at baseline, 2 weeks post each boost and 6 months post the last vaccination in HVTN 114. Statistically significant differences in response magnitudes between the two peak time-points in HVTN 205 and HVTN 114 are indicated by the associated P-value and multiplicity-adjusted q-value. The q-value for response rate to V1V2.B for T2+T4 is 0.07.

Figure 3.. IgA binding antibody response rates and response magnitudes in HVTN 205 and HVTN 114 for T1+T3 (MVA-only), T2+T4 (MVA + AIDSVAX), and T5 (AIDSVAX-only).

Panels A-D show the proportion of positive responders (number of responders out of total) and response magnitudes to Con 6 gp120, gp41.B, Con S gp140 and gp140.A1 con, respectively, at baseline, 2 weeks and 6 months post the last vaccination in HVTN 205, and at baseline, and 2 weeks post each boost in HVTN 114. Statistically significant differences, if any, in response magnitudes between the two peak time-points in HVTN 114 and HVTN 205 are indicated by the associated P-value and multiplicity-adjusted q-value.

Figure 4.. IgG3 binding antibody response rates and response magnitudes in HVTN 205 and HVTN 114 for T1+T3 (MVA-only), T2+T4 (MVA + AIDSVAX), and T5 (AIDSVAX-only).

Panels A-C show the proportion of positive responders (number of responders out of total) and response magnitudes to Con 6 gp120, Con S gp140 and gp41.B, respectively, at baseline, 2 weeks and 6 months post the last vaccination in HVTN 205, and at baseline, and 2 weeks post each boost in HVTN 114. Statistically significant differences, if any, in response magnitudes between the two peak time-points in HVTN 114 and HVTN 205 are indicated by the associated P-value and multiplicity-adjusted q-value.

Figure 5.. IgG binding antibody response magnitude and breadth (MB) in HVTN 205 and HVTN 114.

Panels A-C show participant-specific (dotted) and group-averaged (solid) MB curves to panels of gp120 (n=8), gp140 (n=8) and V1V2 (n=16) antigens, respectively, for responses in HVTN 205 at 2 weeks post the last vaccination (blue), and for responses in HVTN 114 at 2 weeks post the second boost for MVA-only (purple), MVA+ AIDSVAX (green), and AIDSVAX-only (pink) treatment groups.

Figure 6.. CD4+ T-cell responses in HVTN 114 for T1+T3 (MVA-only), T2+T4 (MVA + AIDSVAX), and T5 (AIDSVAX-only).

Panel A shows Env-specific response rates and response magnitudes of T cells expressing IFN-γ and/or IL-2 at 2 weeks post the last vaccination in HVTN 205, and at baseline, and 2 weeks post the last boost in HVTN 114. Panel B shows the posterior probability averaged across individuals within each group at baseline and 2 weeks post the last boost in HVTN 114, in the range of 0 (white) to 1 (dark purple) that the corresponding combination of cytokines (column) is expressed. The same information is also shown for Gag-specific data in Panels C&D. Statistically significant differences between baseline and peak time-points are indicated by the associated P-value and multiplicity-adjusted q-value.