Intranasal Administration of a Therapeutic HIV Vaccine (Vacc-4x) Induces Dose-Dependent Systemic and Mucosal Immune Responses in a Randomized Controlled Trial

Abstract

BackgroundVacc-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.MethodsSafety 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.ResultsVacc-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.ConclusionIntranasal 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 RegistrationClinicalTrials.gov NCT01473810

The therapeutic HIV Env C5/gp41 vaccine candidate Vacc-C5 induces specific T cell regulation in a phase I/II clinical study

“…In previous studies, this parameter has been associated with rapid disease progression [25] and inconsistent boosting effects of the HIV p24-based Vacc-4× [22]. In a recent study, where Vacc-4× was administered intranasally, immune regulation could explain most cases of T cell anergy towards HIV p24 as well as the variable final responses [23]. In the present study, increased immune regulation might partially explain the coinciding declining T cell responses after the second booster period (Figs.…”

“…In previous papers [22, 23, 25], we have defined antigen-induced cytokine-mediated regulation as a parameter which also included control cultures with and without mAbs to IL-10 and TGF-β. Net regulation is a more simplified assessment, as reported by others [27] and illustrated in Fig.…”

“…T cell responses to HIV antigens, such as C5, may be strongly regulated in chronic HIV infection [17–19], and immune regulatory mechanisms to HIV vaccine antigens may therefore be important to consider before and during therapeutic HIV vaccination [20, 21]. We have previously assessed an exploratory parameter for vaccine antigen-induced T cell regulation, based on simultaneous blockade of the two potent, soluble cytokines downregulating HIV-specific T cell proliferation, a key feature of effector T cells [22, 23]. Our approach does not intend to differentiate the mechanistic pathways of immune regulation, but rather measure the net impact on proliferative capacity of effector T cells to simplify implementation in a clinical trial setting.…”

Nasal vaccination using novel mucosal adjuvants : with main focus on influenza A virus

“…All these are used parenterally and at the moment there are no mucosal adjuvants licensed for human use. There are many mucosal adjuvants under development, for example: Endocine™ [165][166][167][168], CAF01 [169,170], nanoemulsion W805EC [171,172], GPI-0100 [173], CCS [174,175], cholera toxin (CT) and Escherichia coli heat-label toxin (LT) mutants [176][177][178][179][180].…”

“…The adjuvant has been shown to be safe and well tolerated in both clinical and pre-clinical studies [165][166][167][168]200]. Endocine™-adjuvanted vaccine induces both serum antibodies and IgA in nasal wash [165,166].…”