Vetting nanoparticle vaccines

New type of nanoparticle holds promise for aerosolized, inhaled vaccines for a variety of diseases

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CAMBRIDGE, Mass.—Vaccines continue to be one of the staples of modern medicine, with ongoing efforts seeking to expand the number of diseases that patients can be vaccinated against. Progress is being made for vaccines against a number of cancer types—with some successes, such as Merck's Gardasil for human papillomavirus (HPV) and cervical cancer—and research is underway by several companies in hopes of a vaccine for dengue fever. And in addition to new diseases to vaccinate against, researchers are also exploring new forms of vaccines, such as ones that can be inhaled.  
So far, only a few vaccines of this type exist, because the lungs tend to clear the vaccine out of the lung before it can engender an immune response. Mucosal vaccines are particularly appealing since many viruses infect humans through the mucosal surfaces in the lungs and gastrointestinal and reproductive tracts.  
Scientists at MIT, led by Darrell Irvine, a professor of materials science, engineering and biological engineering, have engineered nanoparticles that are capable of delivering vaccines while protecting them long enough to allow them to generate an immune response in the lungs as well as in other mucosal surfaces. The new approach builds on a nanoparticle designed by Irvine and his colleagues years ago, in which the protein fragments of the vaccine are surrounded by a sphere consisting of layers of lipids that are chemically bound to one another, making it more durable and resistant to disintegration and thereby giving the immune cells enough time to latch onto the vaccine proteins and deliver them to the T cells to start forming antibodies.  
When tested in mice, the HIV vaccines delivered within the nanoparticles were taken up by immune cells with greater success than vaccines delivered alone. The mice that received the nanoparticles were able to contain the virus—vaccinia, engineered to produce the HIV protein, since HIV does not infect mice—quickly and prevent it from escaping the lungs, with no worse harm than weight loss after infection. Those that received the unprotected vaccine experienced a viral challenge that was 100 percent lethal. In addition, a strong memory T cell presence was observed in the digestive and reproductive tracts as well.  
"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," said Irvine. "It might be that it's a different mucosal surface that gets stimulated from the lungs or from oral delivery in humans."  
So far, only a few mucosal vaccines have been approved for humans, including the Sabin polio vaccine, which is administered orally, as well as a flu vaccine in nasal spray form and mucosal vaccines for cholera, rotavirus and typhoid fever.
Irvine noted that these kinds of vaccines could offer protection against the flu and other respiratory viruses, as well as HIV, herpes simplex virus and HPV. He is also investigating the particles' use in the delivery of cancer vaccines.
"We were particularly surprised at first that the pulmonary vaccination was even more potent than traditional subcutaneous immunization with the same particles," says Irvine. "This is what prompted us to study the mechanisms of how the particles function in the lungs in more detail."
These nanoparticles were also tested in mice for their efficacy against cancer, with encouraging results. Mice were implanted with melanoma tumors designed to express ovalbumin, which they were vaccinated with three days later. The mice that received the nanoparticle vaccine rejected the tumors completely, while those receiving a standard vaccine did not. According to Irvine, further studies will need to be conducted with more challenging tumor models to determine the full potential of this approach with cancer vaccines. He adds that the research team has begun testing this approach with vaccines against HPV, which leads to cervical cancer.
Irvine notes that this technology has been licensed to startup company Vedantra Pharmaceuticals, which is in the process of developing manufacturing in order to move this approach toward clinical testing.
This work appeared in the Sept. 25 issue of Science Translational Medicine, and lead authors for the work are Dr. Adrienne Li and James Moon, a former MIT postdoctoral student. Funding came from the National Cancer Institute, the Ragon Institute, the Bill and Melinda Gates Foundation, the U.S. Department of Defense and the National Institutes of Health.


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