Elsevier

Vaccine

Volume 25, Issue 24, 11 June 2007, Pages 4641-4650
Vaccine

IMP321 (sLAG-3) safety and T cell response potentiation using an influenza vaccine as a model antigen: A single-blind phase I study

https://doi.org/10.1016/j.vaccine.2007.04.019Get rights and content

Abstract

sLAG-3 (IMP321), a natural high affinity ligand for MHC class II, was tested for safety, tolerability and its ability to increase Th-1-type T cell responses to a commercial trivalent split influenza vaccine (Agrippal®) in a phase I single-blinded, randomized, controlled clinical trial. Twenty healthy volunteers were first injected with increasing doses of IMP321 alone (safety for first-in-man use). Then 40 volunteers were recruited into 4 consecutive cohorts of 10 subjects, who were randomly assigned to receive the flu vaccine plus 3, 10, 30 or 100 μg IMP321 or the flu vaccine plus saline control. All vaccine formulations were found to be generally well tolerated with similar frequency and intensity of adverse reaction in groups receiving IMP321 as in controls. Post-vaccination humoral immune responses, as determined 29 and 57 days later by assay of hemagglutinin inhibition activity were similar for both IMP321 and control groups. In contrast, the addition of 10, 30 or 100 μg IMP321 to the flu vaccine resulted in higher levels of Th1-type (IFN-γ, TNF-α or IL-2) flu-specific CD4 T cells in PBMC recovered at D29 and D57 and tested in a short-term ex vivo restimulation assay (6-colour FACS analysis after intra-cellular staining of cytokines). In summary, IMP321 as an adjuvant to a model antigen (Agrippal®) was well-tolerated and may enhance T cell response vaccine immunogenicity.

Introduction

Soluble LAG-3 (sLAG-3) binds to MHC class II molecules and induces dendritic cells (DC) to mature and migrate to secondary lymphoid organs where they can prime naive CD4-helper and CD8-cytotoxic T cells [1], [2], [3], leading to tumour rejection [4], [5], [6]. This maturation effect is dependent upon the specific binding of sLAG-3 to MHC class II molecules located in membrane lipid raft microdomains [7]. The immunostimulatory activity of sLAG-3 in inducing tumour-associated human antigen-specific CD8+ T cell responses [8], supports the use of this recombinant protein as a promising candidate adjuvant for therapeutic vaccination.

In the present study, we report on the clinical and biological effects, and safety evaluation of IMP321, a GMP-grade sLAG-3 (hLAG-3Ig) protein, used alone or mixed with a commercial influenza vaccine (Agrippal®). The results of this first proof-of-concept clinical study in healthy volunteers using influenza hemagglutinin (HA) as a model antigen with known strong skin reactivity has allowed the completion of a safety and immunogenicity package for this first-in-class product.

Section snippets

Study design and subject selection

This single-blind controlled phase I study was conducted at the Aster-Cephac S.A. facility in Paris (France). Ethical Review Board approval was obtained and each patient provided voluntary informed consent. Eligible subjects were healthy adult male volunteers, aged 18–40, not vaccinated against flu in the last 2 years. Other exclusion criteria included liver enzyme levels outside the normal range, chronic HIV, HBV or HCV infection, or evidence of any other clinically significant acute or

Population characteristics

The clinical part of this study was conducted between April 2005 and August 2005. A total of 93 subjects were screened, of which 60 were enrolled and received one dose of vaccine. Baseline characteristics and demographics were evenly distributed among the ten cohorts (see Table 1, Table 2), with the exception of race in the control Agrippal® group (Table 2). All subjects but one completed the study.

Safety and tolerability

Overall, IMP321 injected alone or in combination with Agrippal® was characterised by a good

Discussion

Half of the subjects injected with the flu vaccine experienced some AEs but the frequency and intensity for these AEs were not increased in the groups co-injected with 3, 10, 30 or 100 μg IMP321, establishing a first relevant safety package for IMP321 tested together with an “inflammatory-type” vaccine. Also, an s.c. injection of IMP321 did not induce specific antibodies in healthy individuals and this is another important finding in terms of safety, since anti-IMP321 antibodies could possibly

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