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Changing Up the Route of Vaccine Administration
The COVID-19 pandemic highlighted the need for alternative vaccine delivery options.

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Vaccines can be broadly categorized as preventive or therapeutic. For example, some are administered to individuals to protect against infection and disease from viruses, bacteria or bacterial toxins (preventive vaccines). Therapeutic vaccines, on the other hand, are administered to patients who have already been affected by a disease (e.g., cancer) and are designed to strengthen the immune response. For this discussion, we will focus on vaccines against a biological entity. The optimal vaccine must be immunogenic, safe, effective at preventing disease and, in a best-case scenario, heat-stable with no need for cold storage. However, the vaccine can only be effective if we get it into an individual, so that it may initiate an immune response and thus lead to immunological memory.
The most common method to “get” the vaccine into individuals to elicit a robust immune response is via an intramuscular (IM) or subcutaneous (SC) injection. The vaccine response begins with inflammation resulting from skin injury by the needle. Briefly, professional antigen presenting cells (APC), such as dendritic cells, take up the vaccine antigen, process it and present it to T cells and B cells, which – through a process that is both complicated and elegant, involving a myriad of chemicals and cell types, numerous proteins and signals – eventually leads to the generation of memory immune cells. At some time in the future, if the immune system encounters this same antigen, immune memory will respond quickly to the threat and prevent subsequent infection and disease.
Drawbacks to traditional intramuscular injections
Common IM sites include the deltoid muscle in adults and the vastus lateralis muscle in young children. SC sites include the outer aspect of the upper arm in adults or the anterolateral thigh in young children. The vaccine is often formulated to accommodate the use of a syringe; therefore, it is in a solution that often requires cold storage. The vaccine can be formulated as a whole-killed virus, an inactivated virus or bacteria, a bacterial toxin, a virus-like particle or macromolecules, as seen in an mRNA virus. Additionally, an adjuvant may be added to enhance the immune response. The vaccine solution is manufactured and aliquoted into glass vials with rubber tops, so a needle could be inserted to remove the appropriate amount of vaccine for administration. The four primary vaccines developed to address the SARS-CoV-2 (COVID-19) pandemic – Moderna, Pfizer–BioNTech, Johnson & Johnson and Oxford–AztraZeneca (Vaxzevria) – are administered IM into the deltoid muscle of the upper arm. During the COVID-19 pandemic, we saw, in the news, lines of cars with people rolling up their sleeves, getting a jab, one band-aid and done, next! Although this is a fast and easy way to get the vaccine into the bodies of millions of people, it does have its drawbacks.

Common IM sites include the deltoid muscle in adults and the vastus lateralis muscle in young children and SC sites include the outer aspect of the upper arm in adults or the anterolateral thigh in young children. Credit: iStock.
The first drawback is the need for cold storage; the vaccine must be maintained in either frozen storage, defrosted and/or kept cold until injection into a patient’s arm. Other disadvantages with IM and SC injections include the need for medical personnel to perform the actual injection; risk of accidental needle stick (it may be small with designs of syringe and needles, but it is not zero) and the needle must be properly disposed of in biohazard sharps (must never be reused).
The pandemic highlighted the logistical challenges in the access and distribution of COVID-19 vaccines. There are areas of the world where there is a scarcity of medical personnel, syringes and needles, freezers (also electricity), even ice and ice chests to maintain the viability of the vaccines. For these reasons, it is incumbent upon the research community to develop alternative methods to deliver the vaccine, which, of course, may likely require a different formulation to ensure a safe and effective immune response. Alternative delivery options may include intranasal delivery, oral delivery or microneedle patches.
Alternative vaccine administration options
Mucosal vaccine administration is a good option to protect against viruses or bacteria that enter through the mucosa, such as the coronavirus, “Knowing how potent mucosal responses can be against a viral pathogen, it would be ideal to be thinking about mucosal vaccines,” said Akiko Iwasaki , an immunologist at Yale.1 Examples of mucosal vaccines that have a proven record of safety and protection are the oral polio vaccine (OPV) and the FluMist® Quadrivalent intranasal vaccine, both of which consist of a live attenuated virus. Traditional needle vaccination does not generally elicit a strong mucosal response; however, mucosal delivery may elicit both a systemic and mucosal response with production of IgA antibodies, which are important in mucosal immunity.2 Most mucosal vaccines consist of live attenuated virus; therefore, a mucosal COVID-19 vaccine may require a completely different formulation from the current mRNA vaccines.
Research from the Washington University School of Medicine in St. Louis suggests that beyond providing individual immunity, mucosal vaccines may also help contain the spread of respiratory infections. Published in the journal Science Advances, the study found that hamsters vaccinated with a nasal COVID-19 vaccine that developed infections did not pass the virus on to others, breaking the cycle of transmission.3
Vaxart, a US company, is developing an oral COVID-19 vaccine, which is a lyophilized form of the virus in an adenovirus vector and adjuvant. It is coated with a microcrystalline cellulose/starch that can resist the acidic stomach environment, but dissolves in the higher pH of the intestines. Vaxart observed initial success with this style of vaccine in a clinical trial against norovirus, which was able to elicit IgA antibodies.4 Vaxart has since begun a Phase 2b clinical trial evaluating its oral pill COVID-19 vaccine candidate. The study is designed to evaluate the relative efficacy, safety and immunogenicity of the vaccine candidate compared to an approved mRNA COVID-19 vaccine in adults who have previously been vaccinated against COVID-19.
Another mucosal vaccine was being developed by Altimmune, Inc., which had developed an intranasal COVID-19 vaccine that showed both IgG and IgA antibody production in preclinical trials.5 However, in Phase 1 clinical trials, the vaccine failed to stimulate an adequate immune response in healthy volunteers. As a result, the company discontinued further development of the vaccine to focus its resources on its ongoing obesity and liver programs.
Intradermal (ID) vaccine delivery via microneedle patches, like mucosal vaccines, does not require medical personnel to administer, or syringes and hypodermic needles. Microneedle patches deliver the vaccine antigen into the dermis and epidermis and to the APCs therein. Since the skin is densely packed with APCs, a smaller amount of vaccine may be sufficient to get a comparable response as seen in IM or SC administration. ID vaccination using microneedles are typically manufactured as a patch with micro projections ranging in height from 25–2000 µm and attached to a micro platform.6 The patches can deliver, via a solution, micromolecules or macromolecules, without bleeding, therefore, eliminating the potential for any type of cross-contamination.
Several types of patches and techniques have the potential to deliver a COVID-19 vaccine. In the “poke and patch” approach, the skin is poked with a small patch embedded with microneedles. Once removed, the vaccine is then topically applied to the “damaged” skin. In the “coat and poke” method, microneedles are loaded with vaccine, placed on the skin, creating micro holes in which the vaccine can be delivered.6 Lastly, there is a version of a microneedle patch that dissolves over time. A research paper, published in the journal Vaccines, described efforts to develop a dissolvable microneedle patch coated with the SARS-CoV-2 spike protein. The advantages of this innovative vaccine technology include no need for cold storage, no need for sharps disposal and very little vaccine waste.7
Through Project NextGen, the National Institute of Allergy and Infectious Diseases (NIAID) aims to accelerate the development of the next generation of COVID-19 vaccines that are ready for clinical evaluation. Included in the project is Gylden Pharma’s CoronaTcP™ vaccine, a T-cell priming vaccine designed to be broadly effective against Betacoronavirus infections. One of the key features of the vaccine is the use of a microneedle patch to achieve transdermal administration.
Discussing the benefits of intradermal delivery, Professor Thomas Rademacher, co-founder, executive director and CEO at Gylden Pharma Limited, previously told Technology Networks, “If you vaccinate into the epidermis, a signal tells T cells to home in on the infected organs, so you get tissue-resident T cells. The epidermis is also directly connected to the draining lymph nodes. It's a skin lymphatic injection, which was never possible before the development of microneedle technology.”
During the COVID-19 pandemic, we saw scientists and researchers work at breakneck speed to deliver a vaccine to help decrease the number of COVID-19 cases. Although there is no silver lining to a pandemic, we did see innovation and thinking “outside the box” in efforts to develop vaccines and therapeutic strategies to combat the global health crisis. Any lessons we learnt in vaccine delivery systems, we can now put forward to future pandemics and to fight emerging infectious diseases.