Status: marketed in U.S. (approved by sBLA) and EU

Organizations involved:

Sanofi Pasteur S.A. – Manuf.; R&D; Tech.

Sanofi Pasteur Inc. – U.S. mark.

Sanofi Pasteur MSD - Europe mark.

Sanofi-Aventis S.A. – Parent

Cross ref.: See the Influenza Vaccine Products entry.

Description: Intanza or IDflu is a conventional formaldehyde-inactivated trivalent split (using octoxynol-9) virion seasonal influenza virus vaccine formulated for intradermal microinjection (using the Mantoux method). Intanza/IDflu is the first intradermal influenza vaccine. The antigen composition of the influenza strains, like other seasonal vaccines, is that officially recommended for the upcoming flu season purified by zonal centrifugation.and suspended in phosphate buffered saline (PBS) solution. Fluzone Intradermal vaccine contains 9 mcg of hemagglutinin per strain of influenza in a 0.1 mL dose (vs. Fluzone vaccine containing 15 mcg of hemagglutinin per strain of influenza in a 0.5 mL dose). The vaccine is stored refrigerated at 2° to 8°C (35° to 46°F).

Influenza virus for the vaccine is largely conventionally propagated in fertilized hens’ eggs. The manufacturing process includes an additional concentration step to obtain a concentrated monovalent bulk in order to formulate a lower volume vaccine for intradermal use. Two vaccine dosages are formulated from the concentrated monovalent bulk.

The vaccine is a suspension for injection in pre-filled syringe with a Micro-Injection System (from Becton Dickinson) which should allow easy fast and reproducible injection by the intradermal route. The Micro-Injection System features an integral micro-needle which protrudes only 1.5 mm from the proximal end of the glass syringe, a needle penetration depth limiter to ensure correct needle placement and a needle shielding system that protects the needle after injection, reducing the risk of inadvertent needle-stick injury. The key targets of the development of the Micro-Injection System were to facilitate the correct intradermal injection of the vaccine without any user training and to provide protection against unintentional puncturing post-injection. An intermediate version of the Micro-Injection System was used in Phase I clinical studies. However, the final Micro-Injection System was used in the Phase II and Phase III clinical studies.

Fluzone Intradermal vaccine incorporates a new, easy-to-use, prefilled microinjection system designed to consistently deposit vaccine antigens into the dermal layer of the skin of adults. The dermal layer contains a high concentration of specialized cells known as dendritic cells, which play a key role in generating an immune response. In clinical trials, Fluzone Intradermal vaccine produced an immune response at rates similar to Fluzone vaccine administered intramuscularly.

Fluzone Intradermal vaccine is the first influenza vaccine licensed in the U.S. that uses a novel microinjection system for intradermal delivery. Fluzone Intradermal vaccine has an ultra-fine needle that is 90% shorter than the typical needle used for intramuscular injection of influenza vaccine. Sanofi Pasteur has previously licensed microinjection intradermal influenza vaccines, marketed as Intanza or IDflu vaccines, in more than 40 countries including Australia, Canada and countries in Europe.

Nomenclature: Influenza vaccine, intradermal [BIO]; Fluzone Intradermal [TR US]; Intanza [TR Europe]; IDflu [TR Europe]; Influenza vaccine (split virion, inactivated) [EU generic name]; NDC 49281-705-55 [NDC]

Biological.: Vaccination via the ID route involves the administration of the antigen into the dermal layer of the skin A Micro-Injection System is used for delivery of the vaccine via the intradermal route. The aim of the intradermal (ID) vaccination is to allow for the presentation of the vaccine antigens to a large number of dermal or interstitial dendritic cells to induce an efficient immune response. In addition, the intradermal route of administration likely presents a lower risk of local neurovascular injury due to the short size of the needle.

The vaccine is packaged in 9 and 15 µg hemagglutinin single-use disposable syringes, with the lower dose used in adults up to age 59 and the higher dose used in those 60 years and older. The nominal dose of product is 0.1 ml. Intanza/IDflu is stored refrigerated and has a shelf life of 12 months.

Companies.: Intanza/IDflu was developed and is manufactured by Sanofi Pasteur S.A., and marketed in Europe by Sanofi Pasteur MSD, a joint venture of Sanofi Pasteur and Merck & Co., Inc. U.S. supplies are manufactured at company facilities in Swiftwater, PA.

In Dec. 2009, Sanofi Pasteur launched a new production units in Le Trait, France, specializing in producing high-tech sterile injectable products for export, expected to include Intanza.

Manufacture: The overall manufacturing process involves culturing virus in embryonated hen eggs from healthy flocks, with SPF eggs used in the production of seed lots. The allantoic fluid is harvested, clarified by centrifugation and filtration, and then concentrated by ultrafiltration. The concentrated monovalent harvest is then purified by zonal centrifugation. A filtration is performed. Octoxynol-9 solution (Triton X-100; the splitting agent) is added, the split viral suspension is clarified by centrifugation and the octoxynol-9 content is reduced by diafiltration. A formaldehyde solution is added to the viral suspension for the inactivation. The inactivated and split viral suspension is filtered and diluted in phosphate buffered saline (PBS) resulting in the unconcentrated monovalent bulk. One or several batches of unconcentrated monovalent bulk are concentrated by ultrafiltration and sterile filtered, resulting in the concentrated monovalent bulk (drug substance). The concentrated monovalent bulk is filled into containers and stored at 5°C. The three monovalant bulk vaccines are mixed, sterile filtered, the final bulk product is formulated, sterile filtered and filled in syringes. Stainless steel vessels are used for the storage of the Unconcentrated and Concentrated Monovalent Bulks. Neomycin, an antibiotic, is used in virus culture. The inactivation method has been demonstrated to inactivate avian leucosis virus and mycoplasma.

The tests performed on seed lots comply with Ph. Eur. monograph 0158 “Influenza vaccine (split virion, inactivated)” except for the determination of the infectious titer, which is an additional test. The applicable requirements of Ph. Eur. monograph 0153 “Vaccines for Human use” are also covered.

Appprovals: Date = 20110510, supplemental BLA relative to Fluzone

Full text of the "INDICATIONS AND USAGE" section of product insert/labeling:
Fluzone Intradermal is indicated for active immunization against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine.
Fluzone Intradermal is approved for use in persons 18 through 64 years of age.

Status: Intanza/IDflu received European Union (EU) approval on Feb. 25, 2009. A 9 microgram strength was approved for "Prophylaxis of influenza in adults up to 59 years of age, especially in those who run an increased risk of associated complications;" and a 15 microgram strength was approved for "Prophylaxis of influenza in individuals 60 years of age and over, especially in those who run an increased risk of associated complications." This was the first major market license for Intanza/IDflu. Despited approval early in the year, Intanza/IDflu was not launched for the 2009/2010 flu season, primarily

Medical: Typically, adult influenza vaccines are administered into the muscle utilizing a needle 1 inch to 1.5 inches (25 mm to 38 mm) in length. Fluzone Intradermal vaccine features an ultra-fine needle that is 0.06 inches (1.5 mm) in length. The preferred site of injection is the skin in the region of the deltoid.NDC 49281-705-55.

When using the Mantoux intradermal (ID) injection technique, appearance of a wheal immediately after injection is considered indicative of successful ID vaccination. Other criteria for successful ID injection are appearance of an orange peel aspect and absence of leakage at the injection site.

Trials: The submission to the EMEA in Feb. 2008 was supported by the results of clinical trials involving more than 7,000 adult or elderly participants.

Antibody responses and non-inferiority of ID vs. IM vaccine were the primary end points of clinical trials. Overall, the antibody response was in the range of the response obtained with the IM Influenza Vaccine. In terms of EU CPMP criteria, the highest response was also observed with the ID 6µg and ID 9µg dose levels. The effectiveness of the ID injection was also demonstrated using three criteria for successful ID injection (presence of a wheal, presence of orange peel aspect, and absence of leakage on the skin). Immunogenicity results were not different in the subset of subjects with injection meeting at least two of these criteria for ID injection, and in the subjects with injection with no leakage on the skin after ID injection.

The ID route of immunization was at least as immunogenic as the IM route. The immune responses as determined by HI after ID vaccination with 9 µg in the adult population (18-59 years) were non-inferior to the responses to the company's licensed IM influenza vaccine (15 µg/dose) (Vaxigrip). Likewise, the immune responses after ID vaccination with 15 µg/dose in an elderly population (>60 years) were shown to be non-inferior. In addition the immune response in elderly was also shown to be statistically superior to that after IM vaccination with 15 µg/dose. Although the difference between the ID and IM administration routes in elderly was statistically significant, the clinical relevance of the difference was considered questionable. Although injection site reactions were as expected higher in subjects vaccinated by the ID route than by the IM route, no other data indicate that the safety of this vaccine is different from other authorised

IM influenza vaccines.