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Summer 2020 - Vaccines

Exploring New Vaccine Delivery Methods

Some promising new methods for delivering vaccinations could mean a pain-free alternative, the elimination of accidental needlesticks and reduced risk of infections.

LET’S BE HONEST: Many if not most healthcare professionals secretly wish they had Dr. McCoy’s hypospray device for delivering vaccinations on the TV show “Star Trek.” Painless and risk-free, the make-believe hypospray is the perfect delivery method for vaccines: Just place the nozzle against the patient’s arm, and it shoots the dose through clothing and skin with no puncture wound, pain or bleeding.

Unfortunately, today’s real-world administration of vaccines is not as easy. With nearly all vaccines using a weakened or dead microbe (or part of one) to stimulate the patient’s immune system, oral application is often not viable: Many microbes would simply be digested in the stomach and never promote the desired immune response. So most vaccines need to be placed directly into the bloodstream or muscle tissue to be effective. And while inhalers and patches are increasingly an option to administer vaccines, the fact remains that the hypodermic needle is still the dominant method of injection.

Interestingly, the writers of “Star Trek” based their make-believe hypospray device on a real-life (but ultimately flawed) device developed a few years before the series debuted in 1966: the jet injector, developed to replace the hypodermic syringe. The fact that we’re still using hypodermic needles to administer the vast majority of vaccines a half-century after the jet injector was introduced to replace the needle shows just how difficult advancing the state of the art of vaccination can be.

The good news is new methods of administering vaccines continue to be introduced, and for good reason: Each year, more than 12 billion injections are given by medical professionals around the globe. Roughly 385,000 of those result with a healthcare professional experiencing an accidental needlestick with the risk of poisoning and/or infection.1 Yet another risk is present: Fear of needles and the pain they cause can lead patients to avoid lifesaving vaccinations.2

Origins of the Needle

As pharmacology began its first stirrings in the late Middle Ages, efforts to deliver drugs directly to the tissue or bloodstream were also undertaken. While most early drugs were designed to be taken orally or rectally, or applied topically, there were some attempts to find a more efficient method of delivery. Unfortunately, early needles — perhaps inspired by the fangs of snakes, which the ancients had known were able to deposit venom directly into muscle tissue or the circulatory system — were crude, large and more painful than our modern versions.

The first serious study of using a needle to deliver medicine into the body was not undertaken until 1656, when Christopher Wren improvised a hypodermic syringe and needle from an animal bladder and a goose quill. His experiments on dogs were noted, but the technique was not adopted.3

Some 200 years later, three developments occurred in short succession that made the modern needle a viable delivery method:

  • Irish physician Francis Rynd, MD, administered morphine under the skin of a patient in May 1844 using a hollow needle, and he reported the patient’s pain subsided more quickly and for longer than using other methods.4
  • French veterinarian Charles Gabriel Pravaz connected a needle to a syringe at his Lyon laboratory in 1853, using it to inject iron chloride into an aneurysm.5
  • A little later that same year, Scottish physician Alexander Wood, MD, independently developed his own syringe and needle and used it to administer morphine.5

At that time, however, the syringe was ahead of its time since fewer than 2 percent of drugs were available in an injectable form as recently as 1905.6 However, the rapid development of vaccines in the 20th century quickly made the needle the best available delivery method since most vaccines could not be effectively administered orally. With new immunizations against typhoid fever, tuberculosis, whooping cough (pertussis), tetanus and diphtheria, the use of hypodermic needles exploded in the years before and after World War I.

Replacing the Needle

Despite its widespread use, there were so many disadvantages associated with the needle that it was viewed as an imperfect delivery method almost from its beginning. Shortcomings included risk of infection if a needle wasn’t kept sterile, single-use delivery (the World Health Organization reports unsafe reuse of needles is a massive issue in developing nations7), the challenge of safe disposal and the fear of needles by many patients. Additionally, almost from its introduction, the needle was associated with narcotic addiction. Even Dr. Wood, who helped invent the syringe, was reported to have become addicted to the morphine he prescribed and administered to his patients.6 Consequently, during the six decades following the needle’s invention, the search to replace it was in motion.

An early attempt at replacement occurred when French factory workers experienced needle-less injections by accident when using high-powered grease guns as early as the late 1800s. Doctors who examined them after these accidents noticed there were grease deposits under the skin. Then, in 1935, an American mechanical engineer, Arnold K. Sutermeister, witnessed such an accident and worked with John Roberts, MD, to design a prototype jet injector for medical use.8 Twelve years later, a working model designed by Marshall Lockhart was introduced for clinical testing, and he named the device the hypospray, which lived on in “Star Trek.”

A slightly different design of a jet injector was adopted by the Army’s Medical Corps in 1961 for vaccinations. That same year, the U.S. Centers for Disease Control and Prevention adopted similar technology for its mass civilian immunization program against polio.

While the various jet injectors all avoided use of a needle, instead using high-pressure air to force a thin stream of liquid medication through the skin into the tissue beneath, these devices also had drawbacks. First, they weren’t noticeably less painful than a needle, and because they breached the skin, occasional infections still occurred. Second, the blowback from the small wound created at the injection site could infect the applicator with fluids from one patient that could be inadvertently injected into subsequent patients.9

By the 1990s, the jet injector in its original form was no longer being used by the military since its drawbacks outweighed its efficiencies. However, the goal of a painless, safe and efficient method of administering vaccines was no less urgent.


The use of adhesive patches to deliver medication through the skin is now known to most laypeople due to the popularity of contraceptive patches to prevent pregnancy and nicotine patches for smokers trying to wean themselves off their addiction (a product popularly known as “the patch”).

Originally introduced in 1979 to apply scopolamine for motion sickness,10 transdermal patches offer several advantages over hypodermic syringes or jet injectors: less pain, lower fear threshold, no risk of cross-contamination or infection, less risk to medical staff and safer disposal. They can also reduce office visits since the patches can be delivered to patients who can then apply them themselves.

There is continued research studying whether delivering vaccines via skin patches can be as effective as pharmaceutical patches. Currently, anthrax11 and influenza (flu)12 are both being studied as candidates. But these studies have identified some challenges. Namely, dosage control is more difficult, and a longer period of time is required to administer the full dose to obtain full immunization.11 Further, as with oral delivery, patches encounter the body’s own first-line defenses — the skin’s resistance to invasion — limiting the types of material that can be delivered via patch to those molecules small enough to pass through the skin.13

However, a new technology may offer a way around the skin’s defenses: patches that utilize dissolving microneedles. This technology creates tiny hollow needles made of sugars and polymers that penetrate the skin with an encapsulated dose before breaking down and releasing the vaccine.14 Early studies with seasonal flu vaccines show promise,15 and patients report no pain with the microneedles.

Ongoing research at Rutgers University is utilizing 4-D printing (in which 3-D printed materials are designed to change shape after the printing process is complete) to create microneedles that mimic natural shapes known to penetrate the skin (basing the shape on microscopic parasites with backward-facing barbs).16

Inhalers Just as smoking cessation programs have made “the patch” popular as an alternative form of delivery, the asthma inhaler introduced many laypeople to the concept of administering drugs via the lungs or nasal passages. While people have ingested drugs via their lungs by smoking for thousands of years, the modern application of therapeutic drugs via the lungs began in 1956 with the introduction of the metered dose inhaler.17 Today, new inhalers are available to deliver a variety of drugs outside asthma relief, from insulin to loxapine.18

The use of inhalers to deliver vaccines has shown great promise. Inhalers bypass the issues in both oral and injection delivery methods. The lungs and nasal cavity offer a fast, efficient path to the blood supply without any of the body’s more stringent defense mechanisms coming into play. Compared to injections, delivering a vaccine via the lungs may increase the body’s mucosal immune response, resulting in higher overall immunological protection.18 And, similar to patches, inhalers can reduce demand for office visits since patients can self-apply.

Currently, seasonal flu vaccines in the United Kingdom are primarily given to children via a nasal application.19 This method is also licensed for use in individuals from 2 years up to 49 years old in the United States.

Yet, while delivery via the lungs or nasal cavity offers many advantages over other methods, there are challenges. First, different medications may require different inhaler designs to properly transport the substance through the mouth and airways into the lungs. Even with existing asthma and chronic obstructive pulmonary disease medications, there are a variety of different types of inhalers, from aerosols to nebulizers. Second, patients must be taught the proper technique for using these different types of inhalers since poor technique can negatively impact dosage and effectiveness.17 Third, inhalers should not be shared between patients, which can drive up the total infrastructure cost of using them — a consideration in countries lacking financial resources. Lastly, an inhaled version of a drug will generally have a different composition than the injected formula, creating additional costs.

New Approaches to Oral Delivery

While oral delivery of most vaccines has been historically challenging due to the gastric acids’ tendency to break down the proteins of the attenuated microbes, encapsulated edibles offer a delivery method that carries the vaccine past the toxic environment of the stomach before releasing the contents in the intestinal tract, where it can be absorbed into the bloodstream.20

Perhaps the most unusual of these new oral delivery methods is the RaniPill, which recently passed Phase I clinical testing.21 The RaniPill contains a small balloon-powered syringe in a dissolvable capsule. Once delivered to the small intestines, the capsule dissolves, and the syringe injects the dose into the intestine wall, which lacks pain receptors that make an injection into the skin so painful. In clinical tests, subjects reported not noticing any pain from the process, outside of the discomfort of swallowing a larger-than-normal pill.

Another research direction is to use genetically engineered plant compounds to achieve the same effect by fine-tuning the formulation to withstand the stomach’s environment and then dissolve in the intestines.22

As with inhaled vaccines, studies indicate orally delivered vaccines can increase mucosal immunities in comparison to injections.22

Revisiting the Jet Injector

Jet injectorWhile the original jet injector is no longer considered an acceptable form of delivery, engineers have continued to fine-tune the basic concept of using a high-pressure stream to inject without a needle. Like the hypodermic needle, the jet injector offers tremendous advantages over other methods in terms of dosage control, immediacy of application and control of rate of diffusion.

Today, the main change from the original design is the use of disposable components to prevent cross-contamination between patients. While the main compressor is reused, the tip is disposed of, much as needles have one-time use with a traditional syringe.23 This means any blood or tissue splatter is safely removed from the equipment, and a fresh unused applicator is used for the next patient.

However, a 2015 study conducted in India that examined the use of disposable-syringe jet injectors for the delivery of the DTP-HB-Hib vaccine was halted early due to a high incidence of adverse reactions at the injection site. The study results, published last year, indicate the vaccine itself worked as well as the same formula delivered by hypodermic needle. However, the negative reaction (bleeding, discoloration, nodules) to the injection method needs further investigation.24

Another innovation under way is use of a combustible propellant to drive the liquid stream through the injector nozzle. It is believed this will provide greater control over the nozzle velocity, as well as add flexibility for different applications.25

Looking Ahead

While jet injectors, skin patches, inhalers and oral vaccines are all currently approved for use (at least in some countries), additional new methods of delivery continue to be explored.25

  • Sonophoresis uses ultrasound to weaken the skin’s structure to allow for a medication to penetrate the skin’s defenses.25 Several studies are proceeding on using this to deliver medications; however, vaccine delivery remains over the horizon for now.
  • Iontophoresis or electroporation applies an electrical current to an area of the skin to make it permeable, similar to sonophoresis. It has been successfully tested in animals.26
  • Elastic liposomes can be structured as a hollow carrier that can pass through cell membranes.27

Oral and inhaled delivery options for most existing vaccines are currently undergoing clinical study. In fact, vaccines that can currently only be administered via injection should have multiple application options in the near future. For instance, tuberculosis, typhoid fever, shigella and cholera all have alternative delivery methods currently under study.

Fortunately, with such promising new delivery methods for vaccinations, patients who avoid vaccines for fear of needles are unlikely to have to face that dilemma in years to come.


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  13. Lahiji SF, Kim Y, Kang G, et al. Tissue Interlocking Dissolving Microneedles for Accurate and Efficient Transdermal Delivery of Biomolecules. Scientific Reports, May 27, 2019. Accessed at
  14. Ita K. Dissolving Microneedles for Transdermal Drug Delivery: Advances and Challenges. Biomedicine & Pharmacotherapy, September 2017. Accessed at
  15. Researchers Develop Microneedle Patch for Flu Vaccination. National Institutes of Health, June 27, 2017. Accessed at
  16. Rutgers University. An Alternative to Painful Hypodermic Needle Drug Delivery? Technology Networks, Feb. 5, 2020. Accessed at
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  18. De Boer A and Hagedoorn P. The Role of Disposable Inhalers in Pulmonary Drug Delivery. Expert Opinion on Drug Delivery, Volume 12, 2015. Accessed at
  19. Nasal and Systemic Immune Responses to Nasal Influenza Vaccine., Oct. 1, 2019. Accessed at
  20. Feibus M. Afraid of Needles? These Start-Ups Are Working on Alternatives. USA Today, July 8, 2018. Accessed at
  21. Hargreaves B. RaniPill Passes Phase I Test for Orally Delivered Biologics., Feb. 5, 2020. Accessed at
  22. Criscuolo E, Caputo V, Diotti RA, et al. Alternative Methods of Vaccine Delivery: An Overview of Edible and Intradermal Vaccines. Journal of Immunology Research, 2019. Accessed at
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  24. Bavdekar A, Malshe N, Ravichandran L, et al. Clinical Study of Safety and Immunogenicity of Pentavalent DTP-HB-Hib Vaccine Administered by Disposable-Syringe Jet Injector in India. Contemporary Clinical Trials Communications, June 2019. Accessed at
  25. Miyazaki H, Atobe S, Suzuki T, et al. Development of Pyro-Drive Jet Injector with Controllable Jet Pressure. Journal of Pharmaceutical Sciences, July 2019. Accessed at S002235491930139X#bib1.
  26. Parry N. A Review of Transdermal Vaccine Delivery. Contagion Live, Oct. 10, 2016. Accessed at
  27. Hussain A, Singh S, Sharma D, et al. Elastic Liposomes as Novel Carriers: Recent Advances in Drug Delivery. International Journal of Nanomedicine, July 17, 2017. Accessed at
Jim Trageser
Jim Trageser is a freelance journalist in the San Diego, Calif., area.