Researchers at The University of Texas at Dallas are developing a vaccine delivery system that could boost immune response while eliminating the need for booster shots.

The key is a zinc-based chemical cage called a metal-organic framework that encapsulates a vaccine element, or antigen. In a study published online Jan. 24 and in the Feb. 28 print edition of Chemical Science, researchers demonstrated in mice that as the injected vaccine cage breaks down in the body, it releases the antigen over several days, provoking a more robust immune response than multiple injections of a conventional vaccine.

They also found that the performance of the vaccine delivery mechanism might get a boost from zinc, which is a trace nutrient essential for many biological functions in humans, including maintaining a healthy immune system. Zinc atoms form the structure of the biofriendly, metal-organic cage called zeolitic imidazolate framework-8, or ZIF-8.

“Our delivery system achieved immunity in one dose due to the immunological effects of zinc as well as the sustained release of the vaccine particle from its chemical cage,” said Dr. Jeremiah Gassensmith, corresponding author of the study and an associate professor of chemistry and biochemistry in the School of Natural Sciences and Mathematics.

Vaccines work by introducing a small amount of killed or weakened disease-causing germs, or some of their components, to the body. These antigens prompt the immune system to produce antibodies against a particular disease.

One drawback of modern vaccines is that the antigens break down quickly in the body, so that more than one injected dose is typically required to achieve and maintain immunity. Patient compliance also decreases as the number of booster shots increases.

In previous research in mice, Gassensmith and his colleagues showed that delivering antigens via their zinc-based metal-organic framework provoked a better immune response than conventional delivery methods, but the researchers didn’t test whether zinc played a role.

In the new study, the research team incorporated a model antigen called ovalbumin — egg white protein — into ZIF-8 cages and into a standard delivery system and compared the immune responses to each in mice.

“With the standard vaccine, the antigen cleared the injection site in less than 36 hours, whereas with our method, it hung around for about 21 days. This is significant because the immune system needs time to register whatever it has been exposed to.”

chemistry doctoral student Ryanne Ehrman

“All of the mice that received a single injection using the ZIF-8 delivery method produced more antibodies than three injections using standard vaccine delivery methods,” said Ryanne Ehrman, a chemistry doctoral student in Gassensmith’s lab and co-lead author of the study.

As the ZIF-8 cages degraded, the antigen was released in a controlled, constant manner over several days.

“With the standard vaccine, the antigen cleared the injection site in less than 36 hours, whereas with our method, it hung around for about 21 days,” Ehrman said. “This is significant because the immune system needs time to register whatever it has been exposed to. Our system does that as a single dose, as opposed to multiple boosters.”

The constant supply of antigens promoted the development of germinal centers in the lymph nodes. Germinal centers produce immune cells, which in turn produce the antibodies needed for strong protective immunity, Gassensmith said.

“As the ZIF degraded, we also found higher concentrations of zinc in the lymph nodes. Zinc is known to promote immune activation, so we think its presence there might also be boosting the immune response,” he said.

The ZIF-8 vaccine delivery method has not been tested in humans, but Gassensmith said that in addition to reducing the number of doses a patient might receive, the approach has other potential advantages over conventional vaccines. For example, the formulation is in powder form, and it can be stored and transported at room temperature. The production process is also scalable.

“I was able to produce 20,000 doses just in our lab,” Ehrman said. “That capability scaled to pharmaceutical industry facilities could have important applications if we face another global pandemic.”

Gassensmith said follow-up experiments will determine whether other metals, such as magnesium, used in the cage framework might have an effect on immune response. He noted that aluminum is widely used in conventional vaccine formulations.

Other study authors include co-lead author Olivia Brohlin PhD’21, now a senior scientist in the discovery oncology group at Merck & Co; Fabian Herbert BS’18, PhD’22, a scientist at Eli Lilly and Company; Arun Raja BS’23; Wendy Tang BS’23; chemistry doctoral students Yalini Wijesundara, Sneha Kumari, Orikeda Trashi, Thomas Howlett, Ikeda Trashi, Shailendra Koirala, Noora Al-Kharji, Milinda Senarathna and Laurel Hagge; biology senior Nancy Tran; and Dr. Ronald Smaldone, associate professor of chemistry and biochemistry.

The research was funded by the National Science Foundation and The Welch Foundation.