Nanoparticle Vaccine Designed for Direct Delivery to Mucosal Surfaces

Scientists are developing vaccines that can establish a defensive front line at mucosal surfaces to help fight against bacteria and viruses.

Vaccines can be delivered to the lungs using an aerosol spray approach, however, the lungs frequently clear away the vaccine before it can provoke an immune response. To overcome that, engineers from Massachusetts Institute of Technology (MIT; Cambridge, MA, USA) have developed a new type of nanoparticle that protects the vaccine long enough to generate a strong immune response, not only in the lungs, but also in mucosal surfaces far from the vaccination site, such as the gastrointestinal and reproductive tracts.

Such vaccines could help protect against influenza and other respiratory viruses, or prevent sexually transmitted diseases such as HIV, herpes simplex virus and human papilloma virus, according to Dr. Darrell Irvine, an MIT professor of materials science and engineering and biological engineering and the head of the research team. He is also studying the use of the particles to deliver cancer vaccines. “This is a good example of a project where the same technology can be applied in cancer and in infectious disease. It’s a platform technology to deliver a vaccine of interest,” said Dr. Irvine, who is a member of MIT’s Koch Institute for Integrative Cancer Research.

Dr. Irvine and colleagues describe the nanoparticle vaccine in the September 25, 2013, issue of the journal Science Translational Medicine. Only a few mucosal vaccines have been approved for human use; the best-known case is the Sabin polio vaccine, which is administered orally and absorbed in the digestive tract. There is also a flu vaccine delivered by nasal spray, and mucosal vaccines against rotavirus, cholera, and typhoid fever.

To design better ways of delivering such vaccines, the scientists built upon a nanoparticle they developed two years ago. The protein fragments that make up the vaccine are encased in a sphere made of several layers of lipids that are chemically “stapled” to one another, making the particles stronger inside the body. “It’s like going from a soap bubble to a rubber tire. You have something that’s chemically much more resistant to disassembly,” Dr. Irvine stated.

This allows the particles to resist breakdown once they reach the lungs. With this more stable packaging, the protein vaccine remains in the lungs long enough for immune cells lining the surface of the lungs to grab them and deliver them to T cells. Switching on T cells is a vital step for the immune system to form a memory of the vaccine particles so it will be ready to respond again during an infection.

In studies with mice, the researchers found that HIV or cancer antigens encased in nanoparticles were taken up by immune cells much more successfully than vaccine delivered to the lungs or under the skin without being trapped in nanoparticles. HIV does not infect mice, so to evaluate the immune response generated by the vaccines the researchers infected the lab mice with a version of the Vaccinia virus that was engineered to produce the HIV protein delivered by the vaccine.

Mice vaccinated with nanoparticles were able to rapidly contain the virus and prevent it from escaping the lungs. V. virus typically travels to the ovaries soon after infection, but the investigators discovered that the V. virus in the ovaries of mice vaccinated with nanoparticles was undetectable, while considerable viral concentrations were found in mice that received other types of the vaccine.

Mice that received the nanoparticle vaccine lost a small amount of weight after infection but then fully recovered, whereas the viral challenge was 100% lethal to mice who received the non-nanoparticle vaccine. “Giving the vaccine at the mucosal surface in the nanocapsule form allowed us to completely block that systemic infection,” Dr. Irvine said.

The researchers also found a strong memory T cell presence at distant mucosal surfaces, including in the digestive and reproductive tracts. “An important caveat is that although immunity at distant mucus membranes following vaccination at one mucosal surface has been seen in humans as well, it’s still being worked out whether the patterns seen in mice are fully reproduced in humans,” Dr. Irvine remarked. “It might be that it’s a different mucosal surface that gets stimulated from the lungs or from oral delivery in humans.”

The particles also have potential for delivering cancer vaccines, which activate the body’s own immune system to destroy tumors. To assess this, the researchers first implanted the mice with melanoma tumors that were modified to express ovalbumin, a protein found in egg whites. Three days later, they vaccinated the mice with ovalbumin. They found that mice given the nanoparticle form of the vaccine fully rejected the tumors, while mice given the uncoated vaccine did not.

Additional research is needed with more problematic tumor models, according to Dr. Irvine. In the future, tests with vaccines targeted to proteins expressed by cancer cells would be necessary.

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