Transdermal delivery of vaccines
Figure 1: Human epidermal Langerhans cells (stained red) are randomly distributed in the epidermis. Their long dendrites
ensure detection of foreign invaders. (FIGURE 1 IS REPRINTED BY PERMISSION FROM NICOLAS AND GUY (REF. 2))
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Within the epidermis and the dermis, the skin provides immunological protection to the body. The skin houses specialized cells
in both the epidermis (Langerhans Cells, LC) and the dermis (dermal dendritic cells, dDC) (8, 9); these cells are an important
component of the immune system and are not found anywhere else in the body. Collectively, these specialized cells act as sentinels,
probing their surroundings for signs of immunological threats. They are able to process microbial antigens and ultimately
migrate into lymphatic capillaries to lymph nodes initiating an immune response that may be both faster and stronger than
that generated in response to the same amount of antigen administered via intramuscular injection. Although LCs account for only 2% of cells in the epidermis, they are relatively large, and their
long dendrites stretch across the epidermis to form a tight network that effectively captures particulate- or macromolecule-challengers
(see Figure 1).
Dermal dendritic cells play a similar role in the dermis. Upon capture of antigen, both the LCs and the dDCs are directed
to the secondary lymph nodes via draining lymphatic capillaries to initiate an immune response (5). An excellent review on the mechanism of intradermal immunization
is reported by Nicolas and Guy (2).
The potential for leveraging this specialized system to achieve an enhanced immune response via intradermal vaccine delivery has been recognized for decades. In a 1932 publication, Tuft et al. described a human clinical
trial that demonstrated the potential of intradermal delivery to provide an enhanced antibody response to typhoid vaccine.
The trial showed that an antibody response, on par with those measured following intramuscular (IM) or subcutaneous (SC) delivery,
required only one-seventh as much antigen when delivered intradermally (10).
Since that time, many others have explored and developed the potential benefits associated with intradermal delivery of vaccines.
Of particular interest is a 2004 study where researchers studied the efficacy of influenza vaccine administered intradermally.
Results showed that an immune response equivalent with or superior to that observed for IM administration can be achieved
with intradermal delivery using just one-fifth the amount of vaccine (11). This dose-sparing potential is particularly appealing
to the World Health Organization (WHO) and vaccine manufacturers as governments contemplate how to handle perpetual vaccine
shortages and to provide adequate civilian protection against a pandemic flu (8).
A 2009 report published by WHO provides a summary of human intradermal vaccination trials that have been conducted (8). Results
are categorized by data that demonstrate intradermal delivery studies providing dose superiority, dose equivalence, or dose
inferiority when compared with conventional administration routes. A summary of key clinical trials is also provided elsewhere
(2).
Figure 2: Comparison of Anti-HBs Ag Titer following intramuscular or intradermal administration of comparable doses in hairless
guinea pigs. GMT is group mean titer.
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A graphical example of the dose-sparing potential associated with intradermal vaccine delivery is provided below. Figure 2
shows the results of a prime/boost immunogenicity study conducted in hairless guinea pigs (HGPs). Hepatitis B surface antigen
(HBsAg) was coated onto the tips of 1300 polymeric microneedles contained on a patch approximately 1 cm in diameter and inserted
approximately 150 µm into the skin so as to deliver the vaccine to the epidermis and upper dermis. The microneedle patches
were held in place with an adhesive ring for 15 min. before being removed. Anti-HBsAg titers were determined at 4 weeks (boost),
8 weeks (boost), and 12 weeks after primary immunization. An equal amount of antigen was delivered to a second group of HGPs
via IM injection, who were dosed following the same schedule (12).
Devices and components designed to help make ID delivery of vaccines a reality are an exciting continuation of the potential
posited by Tuft in the early 1930s.
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