Intradermal delivery

Definition: for the purposes of this website and the accompanying consultation, intradermal includes delivery to the dermis and overlying epidermis.

Current usage of intradermal delivery of vaccines

The vast majority of vaccines for humans are delivered intra-muscularly (IM) or subcutaneously (SC) using a needle and syringe.

Intradermal (ID) delivery has been, and is being used as the route of choice for only a very limited number of vaccines, such as Bacille Calmette Guérin (BCG) against tuberculosis, smallpox (vaccinia) and in some countries for post-exposure rabies vaccination. It has also been investigated in recent decades as an alternative delivery route for several other vaccines, including hepatitis B, inactivated poliovirus vaccine, measles and influenza, and also for vaccines in development (see below).

Possible advantages of intradermal route for vaccines

The current renewed interest in intradermal delivery has been largely driven by the perception or realization that it might offer a number of clinical (including vaccinee acceptability), immunological, safety and/or logistical advantages compared with IM/SC delivery.

Despite this renewed interest, the issue of whether or not intradermal delivery offers real benefits over IM or SC administration is complex and remains somewhat controversial.

Why should the skin be immunologically superior for vaccine delivery?

The dermis and epidermis are extremely rich in various resident and recruited types of dendritic cells, a professional antigen-presenting cell capable of stimulating both innate and adaptive (i.e. antigen-specific) immune responses.

Consequently, it has been proposed that the skin in particular should be an anatomical site capable of stimulating potent immune responses. For these reasons:

Delivery of antigens to the skin (i.e. the dermis, epidermis, or both), as opposed to the muscle or subcutaneous tissue, could result in quantitatively or qualitatively superior immune responses;
An equivalent or non-inferior immune response to that seen following SC or IM injection might be induced by delivery of a smaller quantity of antigen to the dermis, i.e. be dose-sparing.

Skin anatomy

Skin thickness varies significantly between different parts of the body and this variation between sites is greater than the variation in thickness between the same site on different individuals.

The average thickness of skin also remains relatively unchanged between ages 18–70 years. In contrast, the amount of subcutaneous fat can vary greatly between individuals, in theory making ID and/or epidermal immunization a more consistent method than IM for vaccine delivery (reviewed in Lambert and Laurent 2008).

Skin thickness

Schematic diagram of relevant features of the anatomy of the skin, and layers targeted by different methods of vaccine delivery (derived from Lambert and Laurent 2008)

Clinical trials - existing vaccines

Over the past few decades, clinical trials have been conducted with vaccines against 11 different diseases to determine whether equivalent immune responses can be obtained by delivering reduced doses intradermally to those seen following standard IM or SC injection. A recent report (**link coming soon**) includes a review of these trials.

Clinical trials - vaccines in development

Clinical trials involving intradermal delivery have been completed for a number of novel vaccines or novel formulations of vaccines, including:

Enterotoxigenic E. coli (ETEC),
Hepatitis C virus,
HIV,
Influenza (seasonal and pandemic),
Malaria,
Rift valley fever and
Tuberculosis.

Intradermal delivery is also being actively explored as a route for delivering certain vaccine platform technologies, such as:

DNA vaccines,
Live-virus vectors and
Heterologous prime-boost strategies.

Delivery to the dermis (or possibly epidermis) might be the most appropriate route for some of these new vaccines and vaccine types due to their formulations. Also, there are major benefits in considering route of delivery early in the development of a vaccine.

Devices

Several novel devices for intradermal delivery of vaccines are being developed; these each offer a different set of possible benefits.

Role of adjuvants

Intradermal delivery of vaccines presents several challenges in terms of vaccine formulation, possibly the most significant being the role of adjuvants.

Many licensed vaccines are formulated with aluminium and/or oil-in-water adjuvants to improve immunogenicity (and/or vaccine stability). These adjuvants might be too reactogenic locally when delivered intradermally and might need to be removed or replaced with novel adjuvants more suitable or designed specifically for intradermal use. Well-designed studies to evaluate the reactogenicity of existing and novel adjuvants when delivered intradermally are needed.

It is also possible that if intradermal or epidermal delivery of vaccines results in improved immunogenicity, the amount of adjuvant required in vaccine formulations could be reduced.

Novel adjuvants, designed to activate specifically antigen presenting cells in the dermis or epidermis have the potential to further enhance any dose-sparing effects that might be obtained by targeting antigen delivery to these layers of the skin. Developing and obtaining regulatory approval for vaccines incorporating novel adjuvants can, however, be a lengthy process.

Also on this website:

On other websites:

NEW: For Project Optimize (PATH/WHO) and PATH's Jet injectors project: 'Intradermal delivery of vaccines' - a review of the literature and the potential for development for use in low and middle-income countries - 27 August 2009 - WHO Optimize webpage: direct link to report (large PDF)

Last updated: 16 April 2010

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