In some parts of the world, vaccines have all but wiped out infections such as measles, tetanus, and polio. Yet lack of access to vaccines means that these diseases remain a very real threat in many countries. The COVID-19 pandemic has made vaccine equity’s importance painfully clear: unvaccinated people who contract the disease are fifteen times more likely to die than those who are fully vaccinated (1).

“The pandemic has shown us that everyone is not safe unless everyone has equal access to important life-saving vaccines, given how diseases can spread and evolve in pockets where there are unvaccinated people,” said Courtney Jarrahian, who works on vaccine delivery at the global health nonprofit organization PATH. “Ensuring that everyone, including kids who are in hard-to-reach areas or disadvantaged populations have the same kind of access that the children and adults in high-resource countries have to new and life-saving vaccines is key to ensuring the health of the whole world.”

While the cost of the SARS-CoV-2 vaccines may be a substantial barrier for access in low- and middle-income countries, it’s certainly not the only one. Traditional injectable vaccines, while suitable for many regions, have important shortcomings that can limit access in remote and low-resource settings. Mark Prausnitz, a biomolecular engineer at the Georgia Institute of Technology, described the injectable measles vaccine as “dirt cheap.” Yet, 15 percent of children globally do not receive even the first dose. Tens of thousands of children under the age of five die from this preventable disease each year, almost exclusively in low- and middle-income countries (2).

“There's a huge effort right now in thinking about strategies to identify, reach, and vaccinate those children,” said William Moss, an infectious disease epidemiologist at Johns Hopkins University.

Researchers think that a new vaccine delivery technique called microarray patches, or MAPs, might be a big step forward in increasing vaccine equity. MAPs (sometimes also called microneedle patches) are square or circular patches small enough to fit on a fingertip. On one side, the patches have tens, hundreds, or even thousands of tiny projections, each usually less than one millimeter long, that are either coated with the vaccine or that release the vaccine into the skin as the projections dissolve (3). In many cases, these vaccines are designed to overcome the challenges that traditional intramuscular vaccination presents in low-resource settings.

The MAPs advantage

Many vaccines require an unbroken cold chain to maintain their efficacy. For example, Pfizer recommends that their SARS-CoV-2 mRNA vaccine be stored between -90 and -60 degrees Celsius until the expiration date (or between two and eight degrees Celsius for up to ten weeks); the vaccine must be used within 12 hours once thawed to room temperature and opened (4). But keeping vaccines cold from manufacturing until just before administration is an impossible task in many places.

MAP vaccine designers are acting with this in mind, attempting to create vaccine patches that can be kept at higher temperatures for longer periods of time without losing potency. This ensures that the vaccines can reach remote areas outside the cold chain and makes them easier to use in large scale house-to-house vaccination campaigns. Prausnitz said that the influenza patch his team designed can be stored at 40 degrees Celsius for at least two years.

Unlike intramuscular injections, MAPs do not need to be administered by highly trained healthcare workers. The patches are designed to be easy to use and require extremely minimal training. So minimal, in fact, that patients may even be able to self administer them. Prausnitz’s team showed that antibody titers generated by an influenza MAP vaccine were similar between participants that self administered and those whose vaccine was administered by a nurse (5). Since highly trained healthcare workers are often in short supply in remote regions, this ease of administration could dramatically increase vaccine accessibility.

Another major advantage is that MAPs do not need to be reconstituted or diluted like many injectable vaccines. Prausnitz said that this step is an opportunity for mistakes to be made. “There are various examples where really tragic errors were made; the wrong diluent was used, and people died.” While these errors are extremely rare, they can have outsize effects by undermining trust in vaccines. For example, in 2018, two infants died in Samoa after nurses mistakenly reconstituted a measles, mumps, and rubella vaccine with a muscle relaxant instead of water. Researchers say that this likely contributed to a decline in vaccination rates and a catastrophic measles outbreak on the island in the winter of 2019 (6). 

Furthermore, MAPs are packaged individually, which can keep valuable vaccine doses from being wasted. Injectable vaccines often come in multidose vials, which may need to be used within hours of opening, possibly leading to waste (7). Fear of wastage can also have substantial effects on vaccinations, said Jarrahian. “Health workers may refuse to open a new vial if there aren't enough children present or may only offer the vaccination one day a week so they can group people,” she said. “And that leads to missed opportunities where a mother has brought her child in to be vaccinated, but it's not the right day. So, they get sent home and told to come back. And you don't know if they will come back.”

Finally, MAPs may also reduce the pain and fear that can occur with traditional intramuscular injections. The majority of children are afraid of needles, but this fear affects adults too; as many as 16 percent of adults avoid influenza vaccinations just to avoid injections (8). Moss, the epidemiologist, vouches for the benign nature of MAP application.

“These are pretty painless,” he said. “I've actually had one — without the vaccine — put on my skin and you can hardly even feel it. It's just like a Band-Aid being put on.”

Skin deep

Can a microneedle that barely penetrates the skin really be strong enough to elicit full-body immunity? After all, many pathogens enter the body through the respiratory or gastrointestinal tract, not the skin.

The skin is the body's first line of defense. It's evolved over time to be incredibly responsive to any outside injuries. It's one of the most immunologic tissues in our body, which makes it an ideal target for vaccines.
- Louis Falo, University of Pittsburgh

In theory, skin should be an optimal vaccination site. “The skin is the body's first line of defense. It's evolved over time to be incredibly responsive to any outside injuries,” said Louis Falo, a skin immunology researcher at the University of Pittsburgh. “It's one of the most immunologic tissues in our body, which makes it an ideal target for vaccines.”

However, it was not immediately clear how skin-deep vaccinations would work in practice.

“There's always been a question about what the potency of a vaccine would be if delivered to skin in distant tissues in the body,” said Falo.

Falo’s work shows that skin-administered vaccines can, in fact, produce immunity in distant regions of the body. Falo’s team created a MAP that contains a SARS-CoV-2 vaccine along with an adjuvant to boost the immune response. Like other SARS-CoV-2 MAPs, this patch produced a robust antibody response in mouse serum. But Falo’s team took their testing one step further and demonstrated that the vaccine also induced an immune response in lung mucosa, which is important for protection from respiratory viruses. Importantly for vaccine accessibility, this formulation of the vaccine was still effective even after one month stored at room temperature (9). Falo said that his team plans to test this vaccine in nonhuman primates next.

From mice to men (and women)

So far, MAP vaccines have demonstrated efficacy in rodent models of a variety of infectious diseases, including dengue virus, polio virus, and rotavirus (10,11). MAP vaccines for hepatitis B and human papillomavirus made it over the next hurdle, inducing protective responses in rhesus macaques (12,13).

However, human trials will be the true test. So far, phase 1 trials of two different influenza MAP vaccines look promising: the patches produced only mild side effects (like tenderness or itchiness) and immune responses produced by the MAPs were similar to (or sometimes even better than) those elicited by intramuscular injection, likely indicating equivalent protection from infection (5,14).

More clinical trials are in progress: SARS-CoV-2 MAP vaccine trials are currently recruiting in The Netherlands and Australia, while a larger phase 1/2 trial is putting a measles and rubella MAP vaccine to the test in The Gambia (15–17).

However, researchers say it may be difficult to proceed to phase 3 trials and widespread use. “The bottleneck to further development is having a manufacturing facility big enough for phase 3 clinical trials,” said Jarrahian. Since manufacturing MAPs is very different from manufacturing other vaccines, substantial upfront investments will have to be made.

Prausnitz said that developing the public’s understanding and trust in this new technology will also take time. Paradoxically, he said, MAPs’ subtle and painless nature could undermine trust in their efficacy, especially when people are used to intramuscular vaccines, which produce more obvious sensations. “There’s this issue of introducing a technology that is supposed to be powerful, but appears very meek and mild.”

Nevertheless, researchers believe that with more data, manufacturing investments, and time, these vaccines could be a game changer for vaccine equity and save lives all over the world.

References

1. CDC. COVID Data Tracker. Centers for Disease Control and Prevention (2020). at <https://covid.cdc.gov/covid-data-tracker>
2. Sbarra, A. N. et al. Mapping routine measles vaccination in low- and middle-income countries. Nature  589, 415–419 (2021).
3. Peyraud, N. et al. Potential use of microarray patches for vaccine delivery in low- and middle- income countries. Vaccine  37, 4427–4434 (2019).
4. Pfizer-BioNTech COVID-19 Vaccine: Storage and Handling Summary. 1
5. Rouphael, N. G. et al. The safety, immunogenicity, and acceptability of inactivated influenza vaccine delivered by microneedle patch (TIV-MNP 2015): a randomised, partly blinded, placebo-controlled, phase 1 trial. The Lancet  390, 649–658 (2017). 
6. Isaacs, D. Lessons from the tragic measles outbreak in Samoa. Journal of Paediatrics and Child Health  56, 175–175 (2020).
7. MMR vaccine,vial of 10 doses. at <https://supply.unicef.org/s359343.html>
8. McLenon, J. & Rogers, M. A. M. The fear of needles: A systematic review and meta-analysis. J Adv Nurs  75, 30–42 (2019).
9. Balmert, S. C. et al. A microarray patch SARS-CoV-2 vaccine induces sustained antibody responses and polyfunctional cellular immunity. iScience  25, 105045 (2022).
10. Choo, J. J. Y. et al. A chimeric dengue virus vaccine candidate delivered by high density microarray patches protects against infection in mice. npj Vaccines  6, 1–10 (2021).
11. Moon, S.-S. et al. Microneedle patch as a new platform to effectively deliver inactivated polio vaccine and inactivated rotavirus vaccine. npj Vaccines  7, 1–9 (2022).
12. Choi, Y. H. et al. Feasibility of Hepatitis B Vaccination by Microneedle Patch: Cellular and Humoral Immunity Studies in Rhesus Macaques. J Infect Dis  220, 1926–1934 (2019).
13. Meyer, B. K. et al. Immune response and reactogenicity of an unadjuvanted intradermally delivered human papillomavirus vaccine using a first generation Nanopatch^TM in rhesus macaques: An exploratory, pre-clinical feasibility assessment. Vaccine X  2, 100030 (2019).
14. Forster, A. H. et al. Safety, tolerability, and immunogenicity of influenza vaccination with a high-density microarray patch: Results from a randomized, controlled phase I clinical trial. PLOS Medicine  17, e1003024 (2020).
15. Aheroukens. Establishing Immunogenicity and Safety of Needle-free Intradermal Delivery by Solid Micro Needle Skin Patch of mRNA SARS-CoV-2 Vaccine as a Revaccination Strategy in Healthy Volunteers. (clinicaltrials.gov, 2022). at <https://clinicaltrials.gov/ct2/show/NCT05315362>
16. Vaxxas Announces Initiation of Phase I Clinical Study of First Needle-Free COVID-19 Vaccine (HexaPro) Delivered Using High-Density Microarray Patch (HD-MAP). (2022). at <https://www.businesswire.com/news/home/20221108005505/en/Vaxxas-Announces-Initiation-of-Phase-I-Clinical-Study-of-First-Needle-Free-COVID-19-Vaccine-HexaPro-Delivered-Using-High-Density-Microarray-Patch-HD-MAP>
17. Adigweme, I. et al. Study protocol for a phase 1/2, single-centre, double-blind, double-dummy, randomized, active-controlled, age de-escalation trial to assess the safety, tolerability and immunogenicity of a measles and rubella vaccine delivered by a microneedle patch in healthy adults (18 to 40 years), measles and rubella vaccine-primed toddlers (15 to 18 months) and measles and rubella vaccine-naïve infants (9 to 10 months) in The Gambia [Measles and Rubella Vaccine Microneedle Patch Phase 1/2 Age De-escalation Trial]. Trials  23, 775 (2022).