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Changing Up the Route of Vaccine Administration

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In these modern times, we have forgotten the diseases of just over a hundred years ago. Most of the world has not seen the paralysis of polio, or the disfiguring rash of smallpox, people have not heard the strange sound from a child with whooping cough. We appreciate the efforts of the scientists and doctors that have developed safe and effective vaccines against these diseases as well as other microorganisms and biological toxins.

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.

Common IM sites include the deltoid muscle in adults and the vastus lateralis muscle in young children and subcutaneous (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, inactivated virus or bacteria, a bacterial toxin, virus like particle or macromolecules, as seen in a 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 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. We have seen, in the news, lines of cars or people rolling up their sleeves, getting a jab, one band-aid and done, next! And although, it is a fast and easy way to get vaccine into the bodies of millions of people, it does have its drawbacks.

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).   

This pandemic has highlighted the logistical challenges in 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.

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 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 vaccine consist of live attenuated virus; therefore, a mucosal COVID-19 vaccine may require a completely different formulation from the current mRNA vaccines.  

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 has seen success with this vaccine in a clinical trial against norovirus, which was able to elicit IgA antibodies.3 Another innovative mucosal vaccine is being developed by Altimmune, Inc., it has developed an intranasal COVID-19 vaccine which is in Phase I trials and shows both IgG and IgA antibody production.4

Intradermal (ID) vaccine delivery via microneedle patches, like mucosal vaccines, do 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.5 The patches can deliver, via a solution, micromolecules or macromolecules, without bleeding, therefore, eliminating the potential for any type of cross-contamination. There are several types of patches and techniques which have 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.5 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).5 Lastly, there is even a version of a microneedle patch that dissolves over time. A recent research paper describes 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.6

During this pandemic, we have seen scientists and researchers work at breakneck speed to deliver a vaccine to help decrease the number of COVID-19 cases. And although there really is no silver lining to a pandemic, we have seen innovation and thinking “outside the box” in efforts to develop vaccines and therapeutic strategies to combat this global health crisis. Any lessons we learn in vaccine delivery systems we can put forward to future pandemics and to fight emerging infectious diseases. 


1. Wu, KJ. You’d rather get a coronavirus vaccine through your nose. The New York Times. https://www.nytimes.com/2020/07/14/health/coronavirus-nasal-vaccines.html. Published July 14, 2020. Accessed May 12, 2021.

2. Zhang L, Wang W and Wang S. Effect of vaccine administration modality on immunogenicity and efficacy. Expert Rev Vaccines. 2015;14(11):1509–1523. doi: 10.1586/14760584.2015.1081067

3. Batty CJ, Heise MT, Bachelder EM and Ainslie KM. 2021. Vaccine formulations in clinical development for the prevention of severe acute respiratory syndrome coronavirus 2 infection. Adv. Drug Deliv. Rev. 2021;169:168–189. doi: 10.1016/j.addr.2020.12.006

4. Tiboni M, Casettari L and Illum L. Nasal vaccination against SARS-CoV-2: synergistic or alternative to intramuscular vaccines? 2021;603:120686. doi: 10.1016/j.ijpharm.2021.120686

5. Giese M. Delivery Technologies. Introduction to Molecular Vaccinology. Springer International Publishing;2016:233-258. doi:10.1007/978-3-319-25832-4_10

6. O’Shea J, Prausnitz MR and Rouphael N. Dissolvable microneedle patches to enable increased access to vaccines against SARS-CoV-2 and future pandemic outbreaks. Vaccines. 2021;9(4):320. doi: 10.3390/vaccines9040320