Many vaccines, including vaccines for hepatitis B and whooping cough, consist of fragments of viral or bacterial proteins. These vaccines often include other molecules called adjuvants, which help to spice up the immune system’s response to the protein.
Most of those adjuvants consist of aluminum salts or other molecules that provoke a nonspecific immune response. A team of MIT researchers has now shown that a variety of nanoparticle called a metal organic framework (MOF) may also provoke a robust immune response, by activating the innate immune system — the body’s first line of defense against any pathogen — through cell proteins called toll-like receptors.
In a study of mice, the researchers showed that this MOF could successfully encapsulate and deliver a part of the SARS-CoV-2 spike protein, while also acting as an adjuvant once the MOF is broken down inside cells.
While more work can be needed to adapt these particles to be used as vaccines, the study demonstrates that this kind of structure might be useful for generating a robust immune response, the researchers say.
“Understanding how the drug delivery vehicle can enhance an adjuvant immune response is something that could possibly be very helpful in designing recent vaccines,” says Ana Jaklenec, a principal investigator at MIT’s Koch Institute for Integrative Cancer Research and one among the senior authors of the brand new study.
Robert Langer, an MIT Institute Professor and member of the Koch Institute, and Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School, are also senior authors of the paper, which appears today in Science Advances. The paper’s lead creator is former MIT postdoc and Ibn Khaldun Fellow Shahad Alsaiari.
Immune activation
On this study, the researchers focused on a MOF called ZIF-8, which consists of a lattice of tetrahedral units made up of a zinc ion attached to 4 molecules of imidazole, an organic compound. Previous work has shown that ZIF-8 can significantly boost immune responses, but it surely wasn’t known exactly how this particle prompts the immune system.
To attempt to figure that out, the MIT team created an experimental vaccine consisting of the SARS-CoV-2 receptor-binding protein (RBD) embedded inside ZIF-8 particles. These particles are between 100 and 200 nanometers in diameter, a size that enables them to get into the body’s lymph nodes directly or through immune cells comparable to macrophages.
Once the particles enter the cells, the MOFs are broken down, releasing the viral proteins. The researchers found that the imidazole components then activate toll-like receptors (TLRs), which help to stimulate the innate immune response.
“This process is analogous to establishing a covert operative team on the molecular level to move essential elements of the Covid-19 virus to the body’s immune system, where they will activate specific immune responses to spice up vaccine efficacy,” Alsaiari says.
RNA sequencing of cells from the lymph nodes showed that mice vaccinated with ZIF-8 particles carrying the viral protein strongly activated a TLR pathway often known as TLR-7, which led to greater production of cytokines and other molecules involved in inflammation.
Mice vaccinated with these particles generated a much stronger response to the viral protein than mice that received the protein by itself.
“Not only are we delivering the protein in a more controlled way through a nanoparticle, however the compositional structure of this particle can be acting as an adjuvant,” Jaklenec says. “We were capable of achieve very specific responses to the Covid protein, and with a dose-sparing effect in comparison with using the protein by itself to vaccinate.”
Vaccine access
While this study and others have demonstrated ZIF-8’s immunogenic ability, more work must be done to judge the particles’ safety and potential to be scaled up for large-scale manufacturing. If ZIF-8 just isn’t developed as a vaccine carrier, the findings from the study should help to guide researchers in developing similar nanoparticles that could possibly be used to deliver subunit vaccines, Jaklenec says.
“Most subunit vaccines often have two separate components: an antigen and an adjuvant,” Jaklenec says. “Designing recent vaccines that utilize nanoparticles with specific chemical moieties which not only aid in antigen delivery but may also activate particular immune pathways have the potential to reinforce vaccine potency.”
One advantage to developing a subunit vaccine for Covid-19 is that such vaccines are often easier and cheaper to fabricate than mRNA vaccines, which could make it easier to distribute them world wide, the researchers say.
“Subunit vaccines have been around for a very long time, and they have an inclination to be cheaper to supply, in order that opens up more access to vaccines, especially in times of pandemic,” Jaklenec says.
The research was funded by Ibn Khaldun Fellowships for Saudi Arabian Women and partially by the Koch Institute Support (core) Grant from the U.S. National Cancer Institute.
