Intranasal administration of a therapeutic HIV vaccine (Vacc-4x) induces dose-dependent systemic and mucosal immune responses in a randomized controlled trial

Kristin Brekke, Andreas Lind, Carol Holm-Hansen, Inger Lise Haugen, Birger Sørensen, Maja Sommerfelt, Dag Kvale, Kristin Brekke, Andreas Lind, Carol Holm-Hansen, Inger Lise Haugen, Birger Sørensen, Maja Sommerfelt, Dag Kvale

Abstract

Background: Vacc-4x, a Gag p24-based therapeutic HIV vaccine, has been shown to reduce viral load set-points after intradermal administration. In this randomized controlled pilot study we investigate intranasal administration of Vacc-4x with Endocine as adjuvant.

Methods: Safety and immunogenicity were tested in patients on effective ART. They were randomized to low, medium or high dose Vacc-4x or adjuvant alone, administered four times at weekly intervals with no booster. Vacc-4x-specific T cell responses were measured in vitro by proliferation and in vivo by a single DTH skin test at the end of study. Nasal and rectal mucosal secretions were analyzed for Vacc-4x-specific antibodies by ELISA. Immune regulation induced by Vacc-4x was assessed by functional blockade of the regulatory cytokines IL-10 and TGF-β.

Results: Vacc-4x proliferative T cell responses increased only among the vaccinated (p ≤ 0.031). The low dose group showed the greatest increase in Vacc-4x CD8+T cell responses (p = 0.037) and developed larger DTH (p = 0.005) than the adjuvant group. Rectal (distal) Vacc-4x IgA and IgG antibodies also increased (p = 0.043) in this group. In contrast, the high dose generated higher nasal (local) Vacc-4x IgA (p = 0.028) and serum IgG (p = 0.030) antibodies than the adjuvant. Irrespective of dose, increased Vacc-4x CD4+T cell responses were associated with low proliferation (r = -0.82, p < 0.001) and high regulation (r = 0.61, p = 0.010) at baseline.

Conclusion: Intranasal administration of Vacc-4x with Endocine was safe and induced dose-dependent vaccine-specific T cell responses and both mucosal and systemic humoral responses. The clinical significance of dose, immune regulation and mucosal immunity warrants further investigation.

Trial registration: ClinicalTrials.gov NCT01473810.

Conflict of interest statement

Competing Interests: This was an investigator-driven study, funded by the Research Council of Norway, where Vacc-4x was provided by Bionor Pharma. Maja Sommerfelt is currently employed as Chief Scientific Officer at Bionor Pharma and has shares in the company. Birger Sørensen is founder and former employee of Bionor and owns shares in the company. Maja Sommerfelt and Birger Sørensen confirm that this does not alter their adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1. The study CONSORT diagram.
Figure 1. The study CONSORT diagram.
Patients were randomized to either Vacc-4x with Endocine as adjuvant (right) or adjuvant alone (left).
Figure 2. Vacc-4x DTH skin tests at…
Figure 2. Vacc-4x DTH skin tests at week 8.
Induration areas in the adjuvant and the vaccinated group (left panel) and the four dose groups (right panel). Adj  =  adjuvant, LD  =  low, MD  =  median and HD  =  high dose. Data are given as medians, interquartile and overall ranges. Differences between dose groups and the adjuvant group with p-values less than 0.10 are indicated (Mann-Whitney U test).
Figure 3. Vacc-4x proliferative T cell responses.
Figure 3. Vacc-4x proliferative T cell responses.
A. Individual responses at baseline (week1) and end of study (week 8) for CD4+ (upper panels) and CD8+ (lower panels) T cell subsets in the adjuvant (left) and the vaccinated (right) group. Doses are indicated as solid (low), dashed (median) or dotted (high dose) lines, respectively. B. Responses in both T cell subsets at baseline (week 1) and end of study (week 8) in the adjuvant (Adj) and the vaccinated group (Vacc), respectively. Changes within each group are indicated (Wilcoxon matched pairs test). C. Changes (Δ) in responses from baseline to end of study in the four dose groups. Adj  =  adjuvant, LD  =  low, MD  =  median and HD  =  high dose. Data are given as medians, interquartile and overall ranges. Significant differences between dose groups and the adjuvant group are indicated (Mann-Whitney U test).
Figure 4. Relation between regulation and in…
Figure 4. Relation between regulation and in vitro and in vivo T cell responses.
A. Relation between Vacc-4x-induced regulation at baseline and change (Δ) in Vacc-4x proliferative T cell responses from baseline to end of study in the CD4+T cell subset (vaccinated group). Spearman rank correlation and p-value are indicated. B. Relation between Vacc-4x-induced regulation in the CD4+T cell subset and Vacc-4x DTH induration at week 8 (vaccinated group). Spearman rank correlation and p-value are indicated.
Figure 5. Vacc-4x Ig antibody levels.
Figure 5. Vacc-4x Ig antibody levels.
Changes (Δ) from baseline to end of study in rectal IgA, nasal IgA and serum IgG antibody levels in the four dose groups. Adj  =  adjuvant, LD  =  low, MD  =  median and HD  =  high dose. IgA antibody levels are adjusted to total IgA in rectal and nasal samples (please note different scales). Data are given as medians, interquartile and overall ranges. Differences between dose groups and the adjuvant group with p-values less than 0.10 are indicated (Mann-Whitney U test). Kruskal-Wallis ANOVA analysis for all four groups yielded p = 0.044 (rectal IgA), p = 0.093 (nasal IgA) and p = 0.067 (serum IgG).

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