Most vaccines are delivered by the intramuscular or subcutaneous routes using a needle and syringe; the intradermal route is only widely used for the administration of Bacille Calmette-Guerin and rabies vaccines. However there is renewed interest in intradermal vaccine delivery, driven by the fact that the dermis and epidermis of human skin are rich in antigen-presenting cells, suggesting that delivery of vaccines to these layers, rather than to muscle or subcutaneous tissue, should be more efficient and induce protective immune responses with smaller amounts of vaccine antigen.
Clinicaltrials investigating intradermal delivery and its potential for dose-sparing have been conducted with several different vaccines, with variable results. These have been reviewed in a recent report from the Program for Appropriate Technology in Health (PATH) and the World Health Organization (WHO). (2) For some vaccines, there has been a clear demonstration of dose-sparing by intradermal delivery; however, there ate several gaps in knowledge as well as developmental and operational challenges to overcome if the benefits of using intradermal delivery are to be fully realized.
Dose-sparing arising from intradermal delivery of vaccines could be beneficial to immunization programmes, particularly in resource-poor settings, by potentially reducing the per-injection cost (including transport and storage) of vaccines because more doses might be obtained from the existing vaccine presentation.
Dose-sparing might also "stretch" the availability of vaccines in cases where supply is limited by manufacturing capacity. This is probably most relevant for pandemic influenza vaccines where global production capacity limits access to a vaccine at the start of a pandemic. (3) In 2009, H1N1 vaccine was not available in most low-income countries until 8 months after WHO's declaration of the influenza pandemic. (4)
Other vaccines with potential supply constraints include yellow fever and inactivated poliovirus vaccines. (5,6) The level of demand for inactivated poliovirus vaccine in the period following eradication of wild-type polioviruses and the end of the use of oral poliovirus vaccines is uncertain, but modelling suggests that there could be a "demand spike" and supply shortage of. inactivated poliovirus vaccine during this period. (6)
New delivery devices
New devices for easier, more reliable intradermal delivery as alternatives to the currently used Mantoux technique ate being developed. (2,7) Some of the devices such as disposable-syringe jet injectors ate needle-free and could therefore reduce of eliminate needlestick injuries and the costs associated with their treatment, estimated at USS 535 million per year worldwide. (8) Other intradermal delivery devices such as microneedle patches are likely to occupy less volume than vials of prefilled syringes, thereby reducing demands on cold-chain capacity.
Current clinical research
The recent PATH and WHO report reviewed more than 90 clinical trials of intradermal delivery with vaccines against 11 diseases. (2) For some vaccines, notably influenza and rabies vaccines, intradermal delivery of reduced doses resulted in equivalent immune responses to the standard dose delivered by the standard route. Data from trials with hepatitis B vaccine were more variable, but also regarded as encouraging. (9) Promising data demonstrating dose-sparing have also been obtained with other vaccines including inactivated poliovirus, yellow fever and hepatitis A vaccines. (2)
Results from clinicaltrials publishcd since the completion of the report provide further evidence for dose-sparing using the intradermal route. One study compared equivalent doses of modified vaccinia Ankara delivered by subcutaneous, intramuscular and intradermal routes; equivalent immune responses and protection against vaccinia-virus challenge were induced with intradermal doses ten-fold lower than those delivered by intramuscular or subcutaneous injection. (10,11)
Two recently published trials of intradermal delivery of reduced (20%) doses of inactivated poliovirus vaccines have reported contrasting results: one trial found that reduced intradermal doses administered to infants aged 2, 4 and 6 months induced similar rates of seroconversion but lower mean antibody titres, compared with intramuscular injection; (12) however a similar study administered the vaccine at 6, 10 and 14 weeks of age and observed inferior seroconversion rates with reduced intradermal doses. (13)
Trials of intradermal immunization with seasonal and pandemic influenza vaccines have also been reported in the past year. Dose-sparing was not observed with a nonadjuvanted, subvirion H5N1 vaccine, (14) whereas a 60% intradermal dose of a trivalent seasonal flu vaccine resulted in similar immunogenicity as a standard dose delivered intramuscularly. (15)
Some rabies vaccines are already delivered using intradermal regimens using needle and syringe. (16,17) Recently, a new intradermal injection device (Soluvia [TM], Becton Dickinson, Franklin Lakes, NJ, United States of America) was evaluated for intradermal delivery of rabies vaccine; intradermal administration of a 25% dose of rabies vaccine resulted in equivalent antibody titres and seroconversion rates to the full dose delivered intramuscularly. The same study also evaluated an epidermal vaccination device (Onvax[TM], Becton Dickinson) that did not in&ce an immune response in the recipients. (18)
Recent vaccine approvals
A new presentation of a split, trivalent seasonal influenza vaccine, Intanza[R] (sanofi pasteur, Lyon, France) has been developed for intradermal immunization. The vaccine is delivered using the Soluvia[TM] device, a prefilled syringe with a single needle that is 1.5 mm in length. (19,20) Immune responses equivalent to those induced by the standard regimen can be achieved using this device and 60% of the standard dose of influenza vaccine. (21,22) A reduced-dose formulation (9-[micro]g haemag-glutinin rather than the standard 15-[micro]g haemagglutinin) for use in healthy adults and a 15-[micro]g haemagglutinin formulation for intradermal delivery in adults aged [greater than or equal to] 60 years have been approved in Australia, Europe and New Zealand. (23-25)
Despite the number of clinical trials conducted, there is still a lack of certainty whether intradermal delivery offers significant immunological advantages compared with intramuscular or subcutaneous delivery. Very few trials have compared equivalent doses (amounts of antigen) delivered by the different routes and, as such, do not permit direct comparison of relative immunological efficacy of the different methods; the recent studies with modified vaccinia Ankara are notable exceptions. (10,11) Most trials have aimed only to determine whether reduced intradermal doses were able to induce a sufficient or non-inferior immune response compared with the standard regimen. In these cases it is possible that a reduced dose delivered by the standard route would also have resulted in an equivalent immune response, as has been reported with some influenza vaccines. (26,27) Furthermore, the majority of dose-sparing trials have for reasons of practical simplicity delivered 10% or 20% of the standard dose intradermally. Finer dose-titrations such as those performed with influenza vaccines have shown that less-dramatic reductions in dose, such as a 40% reduction, might be more realistic. (22) To address these concerns, future studies should compare equivalent antigen doses given by the intradermal and standard route and, if possible, establish a dose-response relationship to determine whether any dose-sparing effect observed is simply due to using doses of antigen from the plateau-portion of the dose-response curve.
For any vaccine, the drivers for changing to the intradermal route, such as the need for dose-sparing to reduce costs and"stretch" the available manufacturing capacity, have to be assessed, but the suitability of the vaccine type and formulation for administration by this route also need to be considered.
Live-attenuated vaccines have been successfully delivered intradermally and should be good candidates for intradermal delivery providing that appropriate formulations can be developed. (2) Reduced doses of inactivated whole-virion vaccines, such as rabies and inactivated poliovirus vaccines, have also shown satisfactory immunogenicity when delivered intradermally. Inactivated whole-virion influenza vaccines might also be suitable because they have intrinsic immune-stimulating sequences, which might avoid the need for additional adjuvants. (28) There are no published clinical data regarding intradermal delivery of polysaccharide conjugate vaccines, which include meningococcal and pneumococcal conjugate vaccines, yet evaluation would be worthwhile particularly because high cost has limited the introduction of pneumococcal conjugate vaccines in some low-resource countries. (29)
Vaccines that contain aluminium-based or oil-in-water adjuvants are likely to have unacceptable local reactogenicity following intradermal administration. Clinicaltrials of intradermal delivery of vaccines formulated with these or novel adjuvants are needed.
Realistic estimates of the cost savings that might be achieved by ID dose-sparing have not been established for most vaccines, especially those that might be relevant to routine immunization in low- and middle-resource countries.
Cell-culture-produced rabies vaccines are expensive and are used in complex, multi-dose schedules for postexposure prophylaxis. A limited number of cell-culture-derived rabies vaccines and two intradermal immunization regimens are already recommended by WHO. (16,17) The overall costs involved in administering post-exposure prophylaxis using intramuscular or intradermal regimens in different clinic settings in India have been compared. (30) Although significant savings were achieved with intradermal regimens, reducing the dose to 20% of the intramuscular dose did not reduce the overall costs by 80%, instead savings of 15-38% were obtained, depending on the setting. Intradermal regimens that used 10% rather than 20% of the standard dose resulted in a further reduction in costs of only 9-15%. Furthermore, the estimates did not include costs resulting from vaccine wastage, which were expected to be higher in intradermal regimens.
This example reinforces the point that the cost of manufacturing a vaccine is only a proportion of the overall cost of delivering each dose; furtherm0re, vaccine manufacturers will not necessarily pass on the full savings arising from a reduction in antigen content per dose. Novel devices for intradermal delivery are likely to be more expensive than needles and syringes, and immunization programmes using new devices will also incur the costs of retraining health workers.
A major benefit of changing to needle-free devices is a reduction in the direct health-care and societal costs resulting from needlestick injuries, although this is difficult to quantify in financial terms. (8,31) A reduction in the use of sharps and their associated costs could also be achieved, possibly more easily, by using needle-free delivery devices such as disposable-syringe jet injectors, without changing the route or dose of vaccine administered.
The incremental costs associated with changing some routine childhood vaccinations in Brazil, India and South Africa to intradermal delivery of reduced (20%) doses have been modelled. (32) For India and South Africa, the model indicated that intradermal delivery of reduced doses of hepatitis B vaccine using disposable-syringe jet injectors would increase the overall costs per fully-immunized child by USS 0.45 and by USS 0.76, respectively; hepatitis B vaccine is only one of five or six infant vaccines routinely administered in these two countries. In contrast, in Brazil, the model indicated that intradermal reduced doses of hepatitis B and yellow fever vaccines would reduce overall costs per fully-immunized child by USS 0.11. Although antigen content of the vaccines delivered intradermally was reduced by 80%, the model assumed that prices were only reduced by 20%. The model did not include costs associated with treatment of bloodborne infections transmitted by sharps.
PATH has modelled the potential incremental costs of routine immunization with inactivated poliovirus vaccines in India. This analysis assumed that the full cost savings resulting from reduced antigen content were passed on by manufacturers and included estimates for costs due to transmission of bloodborne infection. In this case, delivery of a 20% intradermal dose with either needle and syringe or disposable-syringe jet injectors could result in cost savings of 71-73% per immunized child. (33)
In applications where it is warranted, significant investment by vaccine manufacturers and other stakeholders will be required to change the route of vaccine delivery. It is important, therefore, to model accurately the costs involved to determine the potential benefits and to support the case for investment. Decisions should be based on cost modelling and economic analysis, with continual improvement of inputs and assumptions.
Changing the delivery route and dose for a vaccine is not a straightforward task, and several challenges and operational issues need to be addressed.
Demonstration of efficacy
The applicability and benefits of intradermal administration will vary among vaccines; it cannot be assumed that reduced intradermal doses will be efficacious in all cases. Even when there is dose-sparing, it might not be with a dose as low as 20% of 10% of the standard dose. The degree of dose-sparing that can be achieved will need to be determined for each vaccine in non-inferiority trials. It will also be important to maintain a "margin of safety" to ensure adequate immunogenicity across the whole target population and to ensure the potency of the reduced dose is sufficient to induce protection at the end of the vaccine's shelf life.
Intradermal doses of 20% of a standard 0.5 ml dose or 10% of a 1.0 ml dose might not require reformulation; 0.1 ml of the existing formulation could easily be administered, as is the usual practice in clinical trials of intradermal delivery. If more antigen per dose is required, then the vaccine will need to be concentrated so that it can be delivered in the smaller volume. In the development of Intanza[R], which contains 60% of the standard amount of antigen in 20% of the volume, there were challenges filling the device with a small volume as well as adjusting vaccine concentration and viscosity. (34) Even if there is no need to adjust the concentration of the vaccine, it might be necessary to incorporate a preservative into the formulation if dose-sparing means that more than one dose can be obtained per vial.
One consequence of delivering a smaller volume per dose is that a single-dose vial presentation would effectively become a multi-dose vial, yielding perhaps 5 or 10 intradermal doses. Liquid vaccines with multi-dose vial presentations can contain preservatives so that unused vaccine can be stored more safely beyond the end of an immunization session. (35) Single-dose vials do not typically contain thiomersal or other preservatives. If dose-sparing allows multiple doses to be drawn from preservative-free vaccines insingle-dose vials, unused vaccine would have to be discarded at the end of the immunization session. Computer modelling has shown that matching the number of doses per vial with the immunization session's size has a significant economic impact in terms of minimizing vaccine wastage as well as supply, storage and disposal costs. (36) For some vaccines and settings, fewer than five doses per vial would be the most cost-effective option. Therefore, alternative, smaller-volume presentations might be required, otherwise intradermal delivery might not yield the expected cost savings in settings where immunization session-sizes are small.
IntradermaI delivery of fractional doses of an existing vaccine formulation intended for subcutaneous/intramuscular injection would have to be undertaken on an "off-label" basis. A licensing amendment between the relevant national regulatory authority and the vaccine producer would be needed to authorize official "on-label" use of fractional doses. (37) Alternatively, marketing approval for the new intradermal formulation and presentation of the vaccine would be needed.
For many existing vaccines, there might not be a sufficiently strong commercial incentive for manufacturers to undertake the expensive processes of reformulation, production of new presentations and application for marketing authorizations for a new delivery route. Novel vaccines might, therefore, be more likely candidates for intradermal delivery. This route should be evaluated early in research and development to avoid expensive retesting and redevelopment at a later stage. Unless there are strong drivers to use the intradermal route, vaccine manufacturers are likely to continue to use standard presentations and routes of delivery even for new vaccines, thereby reducing risk from the development process.
Novel devices for simple, reliable and reproducible intradermal delivery of vaccines will be needed if this route is to be widely used. There are several different types of intradermal delivery devices in development. (1,2,7) However they cannot be developed in isolation; the device inventors require access to vaccines and collaboration with vaccine manufacturers to enable development, testing and approval of device/vaccine combinations.
In the shorter term, delivery technologies could include simple adapters fitted to existing needles and syringes to control the depth and angle of delivery, syringe-mounted arrays of hollow microneedles and needle-free disposable-syringe jet injectors. (2) Each of these approaches is compatible with existing liquid and lyophilized formulations and presentations and so should be simpler to introduce into immunization programmes than some other technologies.
Devices that are in earlier stages of development include skin-patches covered in microneedles coated with, or composed of, vaccine. Encouraging preclinical data have been obtained with several formats of this type of device. (38-40) Challenges remain in producing solid formulations of different types of vaccine antigens, developing methods for coating sufficient antigen onto the microneedles and controlling the reproducibility of antigen delivery. If these can be overcome, microneedle patches could provide several benefits in addition to dose-sparing, including small-packaged volumes and simplicity of use.
Data from clinical trials indicate that intradermal delivery of reduced doses of some, although not all, vaccines results in equivalent immune responses to the standard regimen. An increasing number of trials are producing data that support dose-sparing. However, there are significant operational challenges, such as reformulation, changing from a single- to a multiple-dose presentation, development of intradermal delivery devices and training health workers. Economic studies and modelling exercises have shown that cost savings should be achievable with intradermal immunization with some vaccines. These analyses are needed to help guide and support development and implementation of intradermal vaccine delivery as well as provide an indication of potential savings.
Research and development in all of these disciplines is required if the promise of intradermal delivery is to be realized; this will require collaboration between academic and clinical researchers, vaccine manufacturers, device developers, regulatory authorities, national immunization programmes and nongovernmental global health organizations. A careful evaluation of all aspects of this route of delivery for vaccines should continue to be a priority for global public health.
Competing interests: None declared.
We thank Courtney Jarrahian and Kristina Lorensen for reviewing the manuscript and Emily Griswold for proofreading.
Funding: Work on this article by PATH staff members and consultants was supported by funding from the Bill & Melinda Gates Foundation. The authors had full control of all primary data.
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JK Hickling, (a) KR Jones, (a) M Friede, (b) D Zehrung, (c) D Chenc & D Kristensen (c)
(a) Working in Tandem Ltd, Carnbridge, England.
(b) Department of Immunization, Vaccines and Biologicals, World Health Organization, Geneva, Switzerland.
(c) Program for Appropriate Technology in Health (PATH), PO Box 900922, Seattle, WA, 98109, UnJted States of America.
Correspondence to Darin Zehrung (e-mail: email@example.com) (Submiited: 5 May 2010 - Revised version received: 1 November 2010 - Accepted: 2 November 2010 - Published online: 5 January 2011)…