Since the SARS-CoV-2 outbreak in the late 2019, we have witnessed significant global efforts that led to the development and approval of several vaccines against the virus. This unprecedented achievement demonstrated the power of science and technology in facing new threats and protecting public health.

Challenges with vaccine equity, among other factors, mean that roughly 30% of the global population — mostly concentrated in low-income countries — remains nonetheless unvaccinated against SARS-CoV-2.

The most efficacious of the COVID-19 vaccines were the mRNA vaccines developed by Pfizer and Moderna. However, their expense, challenges in their storage, and supply chain issues impacted vaccine inequity across the globe. The situation is exacerbated by the fact that multiple doses of the vaccine are needed in order to maintain protection.

Now, new research from the laboratory of Eric Appel, assistant professor of materials science and engineering at Stanford University, shows that using a type of hydrogel — a solid-liquid hybrid material with high contents of water — to administer COVID-19 vaccines reduces the number of shots needed to a single dose.

“There is a lot of interest in a vaccine delivery platform [like our hydrogels] that can eliminate the need for booster shots and still achieve vaccine efficacy in a global health perspective,” said Ben Ou, Ph.D. student in Appel’s lab and first author of the publication in Advanced Healthcare Materials. “This research can help our preparedness for future pandemics, where the hydrogel platform can be employed to potentially help speed up the vaccination process worldwide.”

A slow release gel

While the term “hydrogels” may sound unfamiliar, most of us have already encountered them in the form of hand sanitizer or gelatin desserts. “Whether you’re talking about Jello, hair gel, or our hydrogels, they are all primarily water with a small amount of [fibers called] polymers,” said Appel.

In the study, the polymer used to build the hydrogel was cellulose, which forms a mesh that holds the structure together, creating something that isn’t fully a liquid but isn’t quite fully a solid either.

The hydrogel is also injectable because the mesh is dynamic and non-covalent, meaning that it is more like velcro than glue. “When you push on the syringe plunger, the velcro peels apart […] and the material easily flows through the needle,” said Appel. “Once the materials leave the syringe, […] the molecular velcro instantaneously snaps back together to give you a solid-like gel again.”

Inside the injectable hydrogels are incredibly small particles called nanoparticles that contain the vaccine’s active ingredient, a portion of the SARS-CoV-2 spike protein, RBD. The virus uses this protein as a “key” to enter cells, however, the vaccine hydrogel uses it to train our immune systems to recognize and attack incoming viruses.

The nanoparticles are engulfed and protected by the hydrogel, which once injected under the skin, takes weeks to dissolve. Unlike current vaccines that are administered in a soluble formula and dissolve quickly, the slow release of vaccines in hydrogels mimics natural infections in which viral materials can be present for several weeks.

Tests in mice demonstrated faster, higher, and more durable immunity after a single shot of the hydrogel vaccine than in standard liquid-delivery vaccines. “We are actively studying the long-term durability of vaccine immune responses and we are confident that immunity can last over a year, if not longer,” said Ou. Even more, animals vaccinated with the hydrogel platform developed antibodies that were effective against SARS-CoV-2 variants of concern, such as Delta and Omicron, which are known to escape the immune response.

According to Hirak Patra, associate professor in nanomedicine and regenerative medicine at the University College London who was not involved in the study, this is a “proof of concept” study, with the real challenge being to now translate it to biocompatibility and the sustained immunization in humans.

“At this stage […] it will be hard to predict if a similar response is expected in humans,” said Patra, who indicated that it is difficult to predict how the human immune system will respond to the hydrogel. According to him, further complications, such as blood clotting, should also be assessed before using these materials in clinical settings.

Getting ready for the next pandemic

Appel and his team hope that their “gel vaccine platform can reach the human clinical trial stage in the next years” and remain optimistic about its future prospects.

They are encouraged by the positive outcomes observed in their studies so far and believe that further advancements can be made to bring this technology closer to clinical application. “We have not seen any complications from our studies in animals and every component of the hydrogels is made with materials that are consider as GRAS [generally recognized as safe] materials by the FDA.”

The researchers are also thinking about applications of their hydrogel vaccine delivery platform beyond just COVID-19. “We showed that we can incorporate diverse vaccines in the hydrogel and, with just one injection, generate potent, broad, and durable vaccine immune responses,” said Ou. “This means that when a new unknown pathogen emerges, we can quickly employ our hydrogel with any vaccine candidate and use it as a platform for single immunization.”

Improving the capability to respond to an unforeseen outbreak is, indeed, one of the priorities and recommendations of the World Health Organization, which, since the outbursts of Ebola and Zika epidemics, has launched a plan to develop vaccines within the first 100 days of a hypothetical public health crisis.

Proof of concept for mRNA vaccines were developed during this time and were key to fighting the COVID-19 pandemic. Hydrogels might be an excellent platform to tackle the next one. “Perhaps we can see a vaccine technology meeting all the criteria — single dose, cheap, and not dependent on the cold chain — by the end of this decade,” concluded Ou.

Reference: Ben S. Ou et al., Broad and Durable Humoral Responses Following Single Hydrogel Immunization of SARS-CoV-2 Subunit Vaccine, Advanced Healthcare Materials (2023). DOI: 10.1002/adhm.202301495

Feature image credit: Afif Ramdhasuma on Unsplash