Intramuscular injection, commonly referred to as the “jab,” is widely used to deliver vaccines and, currently, is the only route of administration of COVID-19 vaccines. While effective and common, there are challenges with this mode of pharmaceutical delivery. It requires sterile equipment, trained personnel, and can lead to temporary discomfort at the injection site.
Additionally, some people are wary of needle pokes. “Needle phobia” is a bigger problem than people may expect. Estimates project that up to 20% of the world population, or 66 million adults in the U.S., might share this fear at the level of a phobia. In previous years, one in six adults has avoided the flu vaccine due to this phobia. However, needle phobia has not been well studied, and prevalence is hard to estimate because a diagnosis is challenging and these patients may avoid the healthcare system.
These are not trivial issues, and they lead to fewer people being vaccinated, whether it’s against COVID-19 or other diseases. Herd immunity and public safety are at risk when people remain unvaccinated. Furthermore, intramuscular injection is a frequently used route of administration for many other potentially life-saving therapeutics, such as immunotherapies and cancer vaccines.
Consequently, there is considerable public health interest in developing modes of drug delivery that do not use a needle. Here, we elaborate on the state of three of these delivery methods, namely, transdermal, oral, and intranasal.
1. Transdermal Delivery
A. Jet Injection: A jet injector uses a high-pressure stream of liquid to penetrate the outermost layer of the skin to deliver medication to underlying tissues, including the muscle. It was used for mass vaccination against the swine flu outbreak in the U.S. in 1976 (Figure 1). It was later disfavored because of concern for the possibility of transmitting blood-borne viruses.
Recently, that concern has been addressed by the development of a single-use needle-free syringe for the PharmaJet Tropis® injector. As explained in this instructional video, an adapter connects this syringe to a vial of vaccine solution for precisely controlled filling prior to syringe-injector high-pressure delivery of an ultrafine jet of the solution, which painlessly penetrates the skin without using a needle. This device is currently being evaluated in a Phase 1 clinical study by the University of Southampton for vaccination against COVID-19 and other coronaviruses. The study is evaluating needle-free delivery of a vaccine candidate, DIOS-CoVax, in healthy volunteers aged between 18 and 50 in the Southampton area. Participants must have had both doses of a COVID-19 vaccine but not their third dose booster, and will be monitored for approximately 12 months to ensure safety.
FIGURE 1. Jet injector swine flu vaccination in 1976. Taken from wikipedia.org and free to use.
B. Skin Patch: Transdermal delivery using an adhesive patch has been used for years in the form of nicotine patches to quit smoking. In that pharmacological application, nicotine is released slowly. And, because vaccines are generally designed to be rapidly delivered into muscle, patch-based transdermal vaccination necessitates some re-engineering to deliver standard vaccines.
A comparison of new designs for transdermal skin patch vaccine approaches was recently published in PNAS (Caudill et al., 2021). In this study, tiny, painless “microneedles” were designed into transdermal patches (Figure 2) and compared for vaccine delivery efficacy. The faceted microneedle design resulted in ~20% greater surface area, which enhanced the surface coating of model vaccine components.
Utilizing fluorescent tags and whole-body imaging, in vivo cargo retention and bioavailability were evaluated in mice as a function of the delivery route. Compared with a subcutaneous bolus, microneedle transdermal delivery enhanced cargo retention in the skin. Moreover, improved immune cell activation in the draining lymph nodes, a potent humoral immune response, and an effective T-cell response were all observed. Caudill et al. concluded that the 3D-printed microneedle arrays could provide a valuable platform for a noninvasive self-applicable vaccination.
FIGURE 2. Smooth square pyramidal (left) and faceted (center) microneedles for fabrication into a transdermal patch (right). Adapted from Caudill et al. 2021 and commons.wikimedia.org.
2. Oral Delivery
Oral delivery is the most desirable and patient-accepted route of drug administration, with over 60% of commercialized small molecule drug products employing this delivery route (Ramirez et al., 2017). However, due to the obstacles presented by the gastrointestinal system, only a small fraction of currently licensed vaccines are oral formulations. The induction of a robust protective immune response by oral immunization requires
- successful delivery of the intact active antigen through the strongly acidic (pH = 1.5–3.5) stomach to the intestine;
- transport across gel-like mucins and other components of the mucosal barrier (Figure 3), which evolved to prevent the passage of unnatural luminal content (e.g., drugs, vaccines, etc.); and
- subsequent activation of antigen-presenting cells.
FIGURE 3. Physical, biochemical, and immune elements of the intestinal mucosal barrier. See the review by Bischoff et al. 2014 for details. Open Access and free to use.
Nevertheless, encouraging findings were reported by Keikha et al. in 2021 for oral delivery of a novel type of self-amplifying RNA (saRNA) vaccine against COVID-19.
Briefly, a lipid nanoparticle (LNP) formulation was used to encapsulate a saRNA fusion construct comprised of coding sequences for both SARS-CoV-2 spike protein antigen and Norovirus structural protein for evaluation in mice. This unique design combined the known (McKay et al., 2020) low-dose potency of an LNP/saRNA SARS-CoV-2 spike protein vaccine in mice with the known (Green et al., 2020) GI-tropism of Norovirus structural proteins to selectively deliver the spike immunogen to cells in the GI system.
Encouragingly, oral vaccination of mice led to robust production of antibodies that neutralized two SARS-COV-2 variants. However, the authors noted the following limitations of this study: there was no measurement of the durability of responses for antibodies and T-cell responses, and there was no head-to-head comparison with any of the conventional mRNA vaccines for COVID available at that time.
In closing this section, it should be mentioned that BioNTech announced on April 11, 2022, an exclusive research collaboration with Matinas BioPharma to evaluate novel formulations for oral mRNA vaccines. Although no technical details were provided, a Matinas video and poster discuss using calcium-phospholipid nanocrystals for oral drug delivery.
Finally, TriLink’s March 2022 Research Spotlight featured a very different approach to oral delivery, wherein mRNA formulated with non-lipid polymers was delivered directly into gastric tissue by ingestible “milli-injector” capsules.
3. Intranasal Delivery
The respiratory epithelium is the cellular ciliated lining of most of the respiratory tract. It functions to moisten and protect the airways (Figure 4). It also acts as a barrier to potential pathogens and foreign particles via mucus secretion and mucociliary clearance.
FIGURE 4. Respiratory system and respiratory epithelium. Taken from commons.wikimedia.org and free to use.
Nanotechnologies for delivering mRNA vaccines to the nasal and pulmonary mucosa were recently comprehensively reviewed (Tang et al., 2022) and are an active area of investigation. Successful delivery of mRNAs within the airway is exceptionally challenging because of the complex structures and microenvironments of the respiratory tract, which has evolved to remove foreign particles (Figure 5) proficiently. There is only one approved nasally administered vaccine (Flumist®). It is based on a live attenuated virus because only virus-based delivery systems have achieved strong respiratory mucosal immune responses.
In the face of these challenges, promising advances for nasal vaccine delivery have been reported. For example, Hassan et al. (2020) found that a single intranasal dose of an adenovirus-vectored vaccine encoding the SARS-CoV-2 spike antigen induced high levels of neutralizing antibodies and almost entirely prevented infection in both the upper and lower respiratory tracts. In addition to this type of prophylactic efficacy, there are promising results for cancer immunotherapy using intranasal delivery.
Researchers showed the first proof-of-concept for mRNA-based cancer immunotherapy via intranasal delivery of a novel liposome-protamine complex (LPC). Protamine is a positively charged polycation known to self-assemble with polyanionic RNA to form compressed, nano-sized particles that can be used for the transfection of cells. Mai et al. (2020) hypothesized that nanoparticles of protamine/mRNA could be encapsulated into liposomes more efficiently than conventional direct incorporation of free, non-complexed mRNA.
To test these hypotheses, Mai et al. used in vitro transcribed mRNA encoding enhanced green fluorescent protein (eGFP) and tumor-associated cytokeratin 19 (CK19), a cell differentiation-specific protein widely distributed on epithelial cell membranes and prevalent in lung cancer cells. The CK19 protein could potentially be used as an antigen for targeted immunotherapy against lung cancer.
After liposome preparation, mice received a subcutaneous injection of murine Lewis lung carcinoma cells, a highly tumorigenic cell line (reviewed by Kellar et al., 2015). Once the tumor reached the desired volume, the mice were immunized intranasally with 10 μg of LPC/CD19 mRNA or various controls. This immunization procedure was repeated three times at 1-week intervals, and the volume of the tumor was recorded at two-day intervals. Final-day tumor volumes, compared with PBS, indicated a ~2-fold reduction in tumor size for LPC/CD19 mRNA vaccinated mice.
Concluding Comments
Further development and clinical evaluation of all the aforementioned new formulations and devices will take time. Although still early, the Phase 1 study using an already available jet injector for intradermal delivery of antigens for vaccination against COVID-19 provides hope for a jab-free mode of administration available in the future.
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