Routes of Immunization and Flu Immune Responses

Phase 1

Completed

• Conditions: Influenza
• Interventions: Biological: INTANZA® 15 T; Biological: INTANZA® 15; Biological: Vaxigrip®

• Registration Number: NCT01707602
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

Brief Summary

The project aims to evaluate the impact of skin routes of immunization (transcutaneous and intradermal vs intramuscular) on cellular and humoral responses to seasonal influenza vaccination in adults (18-45 years old).

Detailed Description

New approaches addressing intradermal (ID) and transcutaneous (TC) routes of immunization have been developed over the past few years and have brought novel insight in quality and efficacy of the immune response. Indeed, compared to the muscular tissue widely used for vaccination, the skin is particularly rich in antigen presenting cells. Our recent works show that penetration of vaccine compounds into the hair follicular ducts surrounded by Langerhans cells induces potent cellular immunity in contrast to the intra-muscular immunization. Our results also suggest that differential targeting of epidermal Langerhans cells (by TC route) or dermal dendritic cells (by ID route) could modulate the intensity and quality of the immune response to vaccine.

The aim of this study is to evaluate the immune response to a seasonal influenza vaccine when administrated byTC (hair follicular targeting needle-free method), ID (micro-needle injection) and IM (conventional intramuscular injection) routes of immunization. Along with our previous pre-clinical and clinical studies, here we hypothesize that differential targeting of epidermis or dermis antigen-presenting cells will have a differential impact on the cellular and humoral immune responses to Influenza vaccine.

Objectives:

We will conduct a phase I/II clinical trials on 60 healthy volunteers to compare TC and ID routes of immunization to the conventional intramuscular (IM) vaccination. The impact of these routes on cellular and humoral immune responses to seasonal influenza vaccine will be assessed at baseline, day 21 (effector phase) and month 5 (memory phase) after vaccination.

Outcomes:

Using the seasonal Influenza vaccine as an example of conventional vaccine, this study will evaluate and compare the efficacy ofTC, ID and IMroutes of immunization to induce cellular responses at day 21 and memory responses at month 5 phases. The generation and maintenance of Flu specific and neutralizing antibodies will be measured by Haemagglutination Inhibition and microneutralization assays.Moreover, safety and tolerance to each vaccination methods will be evaluated as well as inflammation and innate immune response induced at day 1 after vaccination.

Addressing innovative skin routes of immunization, this study represents an essential step to move forward in the development of new vaccination strategies. These results will have an important impact on the amelioration of vaccine efficacy and less invasive method of immunization.

Study Timeline

• Study Start: 2012-10
• Study First Submitted: 2012-10-12
• Study First Submitted QC: 2012-10-15
• Study First Posted: 2012-10-16
• Primary Completion: 2012-12
• Study Completion: 2013-04
• Status Verified: 2013-07
• Last Update Submitted: 2013-08-02
• Last Update Posted: 2013-08-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• Healthy volunteers, age between 18 and 45 years,
• BMI between 21 - 26,
• Phototype I to IV,
• Subjects able to receive vaccine administration by any of the three administration routes,
• Signature of the written informed consent,
• Affiliated to a health social security system,

Exclusion Criteria

• Known pregnancy or positive urine pregnancy test for women of child-bearing age,
• Known infection with HIV or/and HCV or/and HBV (AgHBs+),
• Known or suspected immune dysfunction that is caused by a medical condition, or any other Cause,
• Use, within the past 3 months, of any topical and systemic treatment that would interfere with assessment and/or investigational treatment (anti-inflammatory drugs, immunosuppressors or any immune modulator agent),
• Use of any topical treatment on the injection site within the last four weeks,
• Excessive terminal hair growth on the two investigational skin areas used for the transcutaneous mode of vaccination,
• Phototype V-VI,
• Any allergy or hypersensibility to one of the components of the Investigational Product,
• Medical history of allergy or hypersensitization to any ingredient of colorant used in the transcutaneous mode of administration,
• Administration of a live vaccine(≤ 28 days) or inactivated (≤ 14 days) or planned vaccination within 3months of inclusion (D0),
• Medical history of skin cancer,
• Any acute skin affection which may interfere with the trial assessment on the injection site,
• Any acute or chronic infectious which may interfere with the trial assessment four weeks prior to enrolment,
• Prevision of UV sessions or sun exposure 6 weeks prior to the study or during the study period,
• Febrile illness(at least 37.5°Cmeasuredorally), any acute infectious event within one week prior to enrolment,
• Flu confirmed by the presence of fever≥38.5°Cassociated with respiratory symptoms
• History of GuillainBarre syndrome or brachial neuritis following a previous vaccination.
• Participation in an other biomedical research during the study period or period of exclusion when inclusion
• Subject being in the exclusion period of a previous clinical trial,

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A	INTANZA® 15 T	Type Vaccine Name: INTANZA® 15 T Description : transcutaneous vaccination
Arm B	INTANZA® 15	Type: Vaccine Name: INTANZA® 15ug Description : intradermal vaccination
Arm C	Vaxigrip®	Type : Vaccine Name: Vaxigrip® Description :Intramuscular vaccination

Primary Outcome Measures

Name	Time	Method
CD8 T cell responses	21 days	CD8 T cell responses against the specific vaccine strain will be measured at baseline and day 21 after vaccination by flow cytometry. Secretion of cytokines measured by intracellular staining will be compared between TC, ID and IM routes of vaccination.

Secondary Outcome Measures

Name	Time	Method
CD4 T cell responses	21 days	CD4 T cell responses against the specific vaccine strain will be measured at baseline and day 21 by intracellular staining and flow cytometry. Effector CD4 T cell responses will be compared between TC, ID and IM vaccination groups.
Memory CD8 and CD4 T cell responses	5 months	Memory CD8 and CD4 T cell responses against the specific vaccine strain will be assessed by flow cytometry 5 month after vaccination by TC, ID and IM routes.
Inflammation	1 day	Inflammation and systemic innate immune response will be assessed on day 1 after vaccination (compared with the basal inflammatory status) by studying the transcriptional profile of blood cells (microarrays) and inflammatory cytokines dosage in the serum.
Safety	5 months	Safety will be assessed at each visit by recording clinical local and systemic tolerance including reporting of adverse events. Frequency and severity of local and systemic adverse events following vaccination will be compared between TC, ID and IM vaccination groups.
Haemagglutination Inhibition	5 months	Haemagglutination Inhibition and microneutralization assays will be performed at day0, day 21 and month 5 after vaccination to define the humoral response against a vaccine-homologous virus that meets or exceeds the EMEA (CHMP) guidance targets for influenza vaccine seroconversion rate (SCR), seroprotection rate (SPR), and geometric mean fold rise (GMFR).

Trial Locations

Locations (1)

GH Cochin - Broca - Hôtel-Dieu CIC BT505; 🇫🇷 PARIS Cedex 14, France