Several Cutaneous Vaccination Routes Being Studied

CHICAGO – Of all the novel cutaneous delivery methods being studied for vaccine administration, noninvasive patchlike systems appear to offer the most advantages, according to Dr. Bruce G. Weniger.

"This is maybe 5 or 10 years off in the future, but this method could be painless upon delivery of antigen on either coated solid microneedles or within dissolving microneedles only to the epidermis, which lacks nerve endings," Dr. Weniger said at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

"In theory, it can also be very space efficient for cold chain volume constraints, which is a serious problem as the new prefilled, single-dose packagings for rotavirus vaccine are taking up scarce space in the developing-world vaccine refrigerators. Moreover, such Band-Aid–like delivery systems (called "plasters" in British parlance) are potentially thermostable outside the cold chain. They may be cheaper than needle syringes to dispose of as nonhazardous waste, and in some cases there may be no complex, reusable applicator device to buy, transport, maintain, break, or lose."

Speaking at a later symposium on novel vaccination strategies, Dr. Weniger, an associate editor at the journal Vaccine, and retired former lead for vaccine technology at the Centers for Disease Control and Prevention (CDC), reported that cutaneous vaccination often produced better immune responses than deposition into deeper tissues, thus in some cases permitting dose sparing when vaccine may be scarce or expensive.

He also noted that some new methods of vaccine delivery into or onto the skin – but not patches – share one advantage of the traditional Mantoux method, now used for tuberculosis skin testing and BCG vaccine: the use of existing off-the-shelf vaccines. "The disadvantages of this 100-year-old method are that it’s difficult to do correctly, and local reactions are often more frequent and may be unacceptable if the vaccine contains an irritating adjuvant," he said. "It’s also uncomfortable for the patient."

Newtown, Pa.–based SID Technologies is developing an intradermal injection adapter that attaches to a conventional tuberculin/insulin syringe "to make the Mantoux injection method foolproof," Dr. Weniger said. "Just push it in, and it guides you consistently to the desired bleb or wheal."

The company, which received Small Business Innovation Research (SBIR) funding from the CDC for the technology, is working with West Pharmaceuticals for the developed-world market and with PATH (Program for Appropriate Technology in Health), a Seattle-based nonprofit organization, "to bring this to the developing world for potential cost-saving intradermal administration of expensive rabies and polio vaccines," he said at the meeting, sponsored by the American Society for Microbiology.

The Bioject ID Pen needle-free jet injector, developed by Portland, Ore.–based Bioject Medical Technologies, is anticipated to receive clearance from the Food and Drug Administration (FDA) this year for intradermal delivery. Dr. Weniger described this device as "small, light, powered by metal springs, and featuring single-use autodisabling syringes for 0.05- or 0.1-mL volumes." Studies supported by PATH and the World Health Organization are evaluating its use for delivering rabies and polio vaccines in developing countries.

Another spring-action jet injector product, PharmaJet’s intradermal (ID) model, which also received CDC SBIR contract support, was granted FDA 510(k) clearance in 2011. According to Dr. Weniger, this device, manufactured by Golden Colo.–based PharmaJet, is being used to intradermally administer one of the four candidate dengue vaccines under study in the world. It has been tested in primates, and human trials were launched in 2010. Other clinical trials of the PharmaJet ID are underway in India for delivering rabies and polio vaccines.

The various techniques for cutaneous delivery of vaccines fall into the following categories:

• Mechanical disruption of the stratum corneum. "There are a variety of methods that are used to basically scrape off or abrade that dead layer of skin to allow the vaccine in," explained Dr. Weniger, who is now on the faculty of Chiang Mai University in Thailand. "You can even use cellophane tape applied to the skin and just pull it off a few times. Some researchers have even applied cyanoacrylate superglue and ripped that off, which is probably not painless, he added. There are also microscopic projections which are used to scrape the skin before you apply a drop of vaccine, and you can even use sandpaper friction."

• Coated solid microneedles. This technology involves coating dried vaccines onto microprojections. "When it’s put into the body, within the first few seconds or minutes, the moisture of the body dissolves the vaccine and it begins to be taken up by antigen-processing cells," Dr. Weniger said. "There are but a few human trials to date of which I’m becoming aware."

Fremont, Calif.–based Zosano Pharma created a ZP Patch, which uses an applicator device to push the microneedles into the skin, while St. Paul, Minn.–based 3M is developing a Microstructured Transdermal System. Neither is licensed for vaccine delivery.

In 2011, the Soluvia prefilled microinjection system, manufactured by BD Medical of Franklin Lakes, N.J., was approved in the United States for administering a new Fluzone Intradermal vaccine (Sanofi Pasteur) in adults aged 18-64 years. In 2009, it was licensed in the European Union for administration of the same company’s Intanzaand IDfluinfluenza vaccines. The device features a 30-gauge minineedle staked onto a prefilled glass syringe. "The outer diameter of the needle is 0.305 mm, and it projects 1.5 mm outside of the syringe," Dr. Weniger said. "Sanofi Pasteur purchased exclusive worldwide rights to the technology for all commercially sold vaccines."

Another hollow microneedle system under investigation is the MicronJet, manufactured by NanoPass Technologies of Nes Ziona, Israel. This device features an array of 250-mcg-tall microneedles on a Luer-slip syringe adapter. One human trial found that intradermal delivery of 3 or 6 mcg of influenza hemagglutinin yielded similar hemaglutination inhibition antibody titers as intramuscular delivery of 15 mcg (Vaccine 2009;27:454-9).

• Dissolving microneedles. In this approach pioneered at the Georgia Institute of Technology, the antigen/drug is formulated within a solid dissolvable matrix on a patch using biocompatible and nontoxic components, such as carboxymethylcellulose. "Upon dissolution into the body, all the sharps are gone, so there is less of an issue of expensive sharps waste and the cost of disposing of them," Dr. Weniger said. "Other research groups are pursuing this approach, as well."

Other cutaneous vaccine delivery methods are "a bit more futuristic," he said, including kinetic deposition of propelled microparticles, thermoporation, laser light ablation, iontophoresis, chemical enhancers, and sound waves.

Although some of the novel cutaneous delivery systems he discussed might use off-the-shelf liquid products, "others may require extensive, expensive reformulation efforts," Dr. Weniger cautioned.

"Also, regulatory criteria to license annual influenza vaccines may not be biologically relevant for novel nonparenteral routes/antigens. This means that phase III field-efficacy trials may be required to tease out and validate new immunologic correlates of protection."

Even so, the minimally invasive nature of delivering antigen onto or into the skin "means it’s easier to monitor and treat local adverse reactions," he said. "You can see them. You can put topical steroids or other treatments on them to reduce them, and you can hypothesize fewer unanticipated serious adverse events than we’ve seen with other routes."

Another advantage of the cutaneous route is that it’s less dependent on patient cooperation than other novel routes.

"Think of a squirming, uncooperative child unable to swallow capsules, retain oral doses, activate inhalers, or quietly breathe a vaccine mist for an extended time." Dr. Weniger offered. He added that the cutaneous route provides "a relatively sure and certain delivery, compared with oral and respiratory administration."

Dr. Weniger disclosed that he holds stock in Pfizer.

CHICAGO – Of all the novel cutaneous delivery methods being studied for vaccine administration, noninvasive patchlike systems appear to offer the most advantages, according to Dr. Bruce G. Weniger.

"This is maybe 5 or 10 years off in the future, but this method could be painless upon delivery of antigen on either coated solid microneedles or within dissolving microneedles only to the epidermis, which lacks nerve endings," Dr. Weniger said at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

"In theory, it can also be very space efficient for cold chain volume constraints, which is a serious problem as the new prefilled, single-dose packagings for rotavirus vaccine are taking up scarce space in the developing-world vaccine refrigerators. Moreover, such Band-Aid–like delivery systems (called "plasters" in British parlance) are potentially thermostable outside the cold chain. They may be cheaper than needle syringes to dispose of as nonhazardous waste, and in some cases there may be no complex, reusable applicator device to buy, transport, maintain, break, or lose."

Speaking at a later symposium on novel vaccination strategies, Dr. Weniger, an associate editor at the journal Vaccine, and retired former lead for vaccine technology at the Centers for Disease Control and Prevention (CDC), reported that cutaneous vaccination often produced better immune responses than deposition into deeper tissues, thus in some cases permitting dose sparing when vaccine may be scarce or expensive.

He also noted that some new methods of vaccine delivery into or onto the skin – but not patches – share one advantage of the traditional Mantoux method, now used for tuberculosis skin testing and BCG vaccine: the use of existing off-the-shelf vaccines. "The disadvantages of this 100-year-old method are that it’s difficult to do correctly, and local reactions are often more frequent and may be unacceptable if the vaccine contains an irritating adjuvant," he said. "It’s also uncomfortable for the patient."

Newtown, Pa.–based SID Technologies is developing an intradermal injection adapter that attaches to a conventional tuberculin/insulin syringe "to make the Mantoux injection method foolproof," Dr. Weniger said. "Just push it in, and it guides you consistently to the desired bleb or wheal."

The company, which received Small Business Innovation Research (SBIR) funding from the CDC for the technology, is working with West Pharmaceuticals for the developed-world market and with PATH (Program for Appropriate Technology in Health), a Seattle-based nonprofit organization, "to bring this to the developing world for potential cost-saving intradermal administration of expensive rabies and polio vaccines," he said at the meeting, sponsored by the American Society for Microbiology.

The Bioject ID Pen needle-free jet injector, developed by Portland, Ore.–based Bioject Medical Technologies, is anticipated to receive clearance from the Food and Drug Administration (FDA) this year for intradermal delivery. Dr. Weniger described this device as "small, light, powered by metal springs, and featuring single-use autodisabling syringes for 0.05- or 0.1-mL volumes." Studies supported by PATH and the World Health Organization are evaluating its use for delivering rabies and polio vaccines in developing countries.

Another spring-action jet injector product, PharmaJet’s intradermal (ID) model, which also received CDC SBIR contract support, was granted FDA 510(k) clearance in 2011. According to Dr. Weniger, this device, manufactured by Golden Colo.–based PharmaJet, is being used to intradermally administer one of the four candidate dengue vaccines under study in the world. It has been tested in primates, and human trials were launched in 2010. Other clinical trials of the PharmaJet ID are underway in India for delivering rabies and polio vaccines.

The various techniques for cutaneous delivery of vaccines fall into the following categories:

• Mechanical disruption of the stratum corneum. "There are a variety of methods that are used to basically scrape off or abrade that dead layer of skin to allow the vaccine in," explained Dr. Weniger, who is now on the faculty of Chiang Mai University in Thailand. "You can even use cellophane tape applied to the skin and just pull it off a few times. Some researchers have even applied cyanoacrylate superglue and ripped that off, which is probably not painless, he added. There are also microscopic projections which are used to scrape the skin before you apply a drop of vaccine, and you can even use sandpaper friction."

• Coated solid microneedles. This technology involves coating dried vaccines onto microprojections. "When it’s put into the body, within the first few seconds or minutes, the moisture of the body dissolves the vaccine and it begins to be taken up by antigen-processing cells," Dr. Weniger said. "There are but a few human trials to date of which I’m becoming aware."

Fremont, Calif.–based Zosano Pharma created a ZP Patch, which uses an applicator device to push the microneedles into the skin, while St. Paul, Minn.–based 3M is developing a Microstructured Transdermal System. Neither is licensed for vaccine delivery.

In 2011, the Soluvia prefilled microinjection system, manufactured by BD Medical of Franklin Lakes, N.J., was approved in the United States for administering a new Fluzone Intradermal vaccine (Sanofi Pasteur) in adults aged 18-64 years. In 2009, it was licensed in the European Union for administration of the same company’s Intanzaand IDfluinfluenza vaccines. The device features a 30-gauge minineedle staked onto a prefilled glass syringe. "The outer diameter of the needle is 0.305 mm, and it projects 1.5 mm outside of the syringe," Dr. Weniger said. "Sanofi Pasteur purchased exclusive worldwide rights to the technology for all commercially sold vaccines."

Another hollow microneedle system under investigation is the MicronJet, manufactured by NanoPass Technologies of Nes Ziona, Israel. This device features an array of 250-mcg-tall microneedles on a Luer-slip syringe adapter. One human trial found that intradermal delivery of 3 or 6 mcg of influenza hemagglutinin yielded similar hemaglutination inhibition antibody titers as intramuscular delivery of 15 mcg (Vaccine 2009;27:454-9).

• Dissolving microneedles. In this approach pioneered at the Georgia Institute of Technology, the antigen/drug is formulated within a solid dissolvable matrix on a patch using biocompatible and nontoxic components, such as carboxymethylcellulose. "Upon dissolution into the body, all the sharps are gone, so there is less of an issue of expensive sharps waste and the cost of disposing of them," Dr. Weniger said. "Other research groups are pursuing this approach, as well."

Other cutaneous vaccine delivery methods are "a bit more futuristic," he said, including kinetic deposition of propelled microparticles, thermoporation, laser light ablation, iontophoresis, chemical enhancers, and sound waves.

Although some of the novel cutaneous delivery systems he discussed might use off-the-shelf liquid products, "others may require extensive, expensive reformulation efforts," Dr. Weniger cautioned.

"Also, regulatory criteria to license annual influenza vaccines may not be biologically relevant for novel nonparenteral routes/antigens. This means that phase III field-efficacy trials may be required to tease out and validate new immunologic correlates of protection."

Even so, the minimally invasive nature of delivering antigen onto or into the skin "means it’s easier to monitor and treat local adverse reactions," he said. "You can see them. You can put topical steroids or other treatments on them to reduce them, and you can hypothesize fewer unanticipated serious adverse events than we’ve seen with other routes."

Another advantage of the cutaneous route is that it’s less dependent on patient cooperation than other novel routes.

"Think of a squirming, uncooperative child unable to swallow capsules, retain oral doses, activate inhalers, or quietly breathe a vaccine mist for an extended time." Dr. Weniger offered. He added that the cutaneous route provides "a relatively sure and certain delivery, compared with oral and respiratory administration."

Dr. Weniger disclosed that he holds stock in Pfizer.

CHICAGO – Of all the novel cutaneous delivery methods being studied for vaccine administration, noninvasive patchlike systems appear to offer the most advantages, according to Dr. Bruce G. Weniger.

"This is maybe 5 or 10 years off in the future, but this method could be painless upon delivery of antigen on either coated solid microneedles or within dissolving microneedles only to the epidermis, which lacks nerve endings," Dr. Weniger said at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

"In theory, it can also be very space efficient for cold chain volume constraints, which is a serious problem as the new prefilled, single-dose packagings for rotavirus vaccine are taking up scarce space in the developing-world vaccine refrigerators. Moreover, such Band-Aid–like delivery systems (called "plasters" in British parlance) are potentially thermostable outside the cold chain. They may be cheaper than needle syringes to dispose of as nonhazardous waste, and in some cases there may be no complex, reusable applicator device to buy, transport, maintain, break, or lose."

Speaking at a later symposium on novel vaccination strategies, Dr. Weniger, an associate editor at the journal Vaccine, and retired former lead for vaccine technology at the Centers for Disease Control and Prevention (CDC), reported that cutaneous vaccination often produced better immune responses than deposition into deeper tissues, thus in some cases permitting dose sparing when vaccine may be scarce or expensive.

He also noted that some new methods of vaccine delivery into or onto the skin – but not patches – share one advantage of the traditional Mantoux method, now used for tuberculosis skin testing and BCG vaccine: the use of existing off-the-shelf vaccines. "The disadvantages of this 100-year-old method are that it’s difficult to do correctly, and local reactions are often more frequent and may be unacceptable if the vaccine contains an irritating adjuvant," he said. "It’s also uncomfortable for the patient."

Newtown, Pa.–based SID Technologies is developing an intradermal injection adapter that attaches to a conventional tuberculin/insulin syringe "to make the Mantoux injection method foolproof," Dr. Weniger said. "Just push it in, and it guides you consistently to the desired bleb or wheal."

The company, which received Small Business Innovation Research (SBIR) funding from the CDC for the technology, is working with West Pharmaceuticals for the developed-world market and with PATH (Program for Appropriate Technology in Health), a Seattle-based nonprofit organization, "to bring this to the developing world for potential cost-saving intradermal administration of expensive rabies and polio vaccines," he said at the meeting, sponsored by the American Society for Microbiology.

The Bioject ID Pen needle-free jet injector, developed by Portland, Ore.–based Bioject Medical Technologies, is anticipated to receive clearance from the Food and Drug Administration (FDA) this year for intradermal delivery. Dr. Weniger described this device as "small, light, powered by metal springs, and featuring single-use autodisabling syringes for 0.05- or 0.1-mL volumes." Studies supported by PATH and the World Health Organization are evaluating its use for delivering rabies and polio vaccines in developing countries.

Another spring-action jet injector product, PharmaJet’s intradermal (ID) model, which also received CDC SBIR contract support, was granted FDA 510(k) clearance in 2011. According to Dr. Weniger, this device, manufactured by Golden Colo.–based PharmaJet, is being used to intradermally administer one of the four candidate dengue vaccines under study in the world. It has been tested in primates, and human trials were launched in 2010. Other clinical trials of the PharmaJet ID are underway in India for delivering rabies and polio vaccines.

The various techniques for cutaneous delivery of vaccines fall into the following categories:

• Mechanical disruption of the stratum corneum. "There are a variety of methods that are used to basically scrape off or abrade that dead layer of skin to allow the vaccine in," explained Dr. Weniger, who is now on the faculty of Chiang Mai University in Thailand. "You can even use cellophane tape applied to the skin and just pull it off a few times. Some researchers have even applied cyanoacrylate superglue and ripped that off, which is probably not painless, he added. There are also microscopic projections which are used to scrape the skin before you apply a drop of vaccine, and you can even use sandpaper friction."

• Coated solid microneedles. This technology involves coating dried vaccines onto microprojections. "When it’s put into the body, within the first few seconds or minutes, the moisture of the body dissolves the vaccine and it begins to be taken up by antigen-processing cells," Dr. Weniger said. "There are but a few human trials to date of which I’m becoming aware."

Fremont, Calif.–based Zosano Pharma created a ZP Patch, which uses an applicator device to push the microneedles into the skin, while St. Paul, Minn.–based 3M is developing a Microstructured Transdermal System. Neither is licensed for vaccine delivery.

In 2011, the Soluvia prefilled microinjection system, manufactured by BD Medical of Franklin Lakes, N.J., was approved in the United States for administering a new Fluzone Intradermal vaccine (Sanofi Pasteur) in adults aged 18-64 years. In 2009, it was licensed in the European Union for administration of the same company’s Intanzaand IDfluinfluenza vaccines. The device features a 30-gauge minineedle staked onto a prefilled glass syringe. "The outer diameter of the needle is 0.305 mm, and it projects 1.5 mm outside of the syringe," Dr. Weniger said. "Sanofi Pasteur purchased exclusive worldwide rights to the technology for all commercially sold vaccines."

Another hollow microneedle system under investigation is the MicronJet, manufactured by NanoPass Technologies of Nes Ziona, Israel. This device features an array of 250-mcg-tall microneedles on a Luer-slip syringe adapter. One human trial found that intradermal delivery of 3 or 6 mcg of influenza hemagglutinin yielded similar hemaglutination inhibition antibody titers as intramuscular delivery of 15 mcg (Vaccine 2009;27:454-9).

• Dissolving microneedles. In this approach pioneered at the Georgia Institute of Technology, the antigen/drug is formulated within a solid dissolvable matrix on a patch using biocompatible and nontoxic components, such as carboxymethylcellulose. "Upon dissolution into the body, all the sharps are gone, so there is less of an issue of expensive sharps waste and the cost of disposing of them," Dr. Weniger said. "Other research groups are pursuing this approach, as well."

Other cutaneous vaccine delivery methods are "a bit more futuristic," he said, including kinetic deposition of propelled microparticles, thermoporation, laser light ablation, iontophoresis, chemical enhancers, and sound waves.

Although some of the novel cutaneous delivery systems he discussed might use off-the-shelf liquid products, "others may require extensive, expensive reformulation efforts," Dr. Weniger cautioned.

"Also, regulatory criteria to license annual influenza vaccines may not be biologically relevant for novel nonparenteral routes/antigens. This means that phase III field-efficacy trials may be required to tease out and validate new immunologic correlates of protection."

Even so, the minimally invasive nature of delivering antigen onto or into the skin "means it’s easier to monitor and treat local adverse reactions," he said. "You can see them. You can put topical steroids or other treatments on them to reduce them, and you can hypothesize fewer unanticipated serious adverse events than we’ve seen with other routes."

Another advantage of the cutaneous route is that it’s less dependent on patient cooperation than other novel routes.

"Think of a squirming, uncooperative child unable to swallow capsules, retain oral doses, activate inhalers, or quietly breathe a vaccine mist for an extended time." Dr. Weniger offered. He added that the cutaneous route provides "a relatively sure and certain delivery, compared with oral and respiratory administration."

Dr. Weniger disclosed that he holds stock in Pfizer.