Researchers from the Massachusetts Institute of Technology have created a way of delivering vaccines directly to lymph nodes in the body - where large populations of immune cells are present. The investigators say distributing vaccines to such areas could help stimulate the body's immune system to attack tumors and enable better delivery of HIV vaccines.
The team's findings were recently published online in the journal Nature. According to the investigators, subunit vaccines - made of protein or sugar fragments - have been successful against some diseases, such as hepatitis and diphtheria. In an attempt to create subunit vaccines for other diseases, researchers have tried using nanoparticles to deliver the vaccines directly to lymph nodes. They have also tried tagging vaccines with antibodies specific to lymph node immune cells in order to push them to lymph node regions.
But the investigators note that it is challenging to get 100% of the vaccine to the lymph nodes. Some of it can escape to the rest of the body and cause negative side effects. With this in mind, the research team decided to adopt an alternative approach.
Vaccine molecule 'hitchhikes' to lymph nodes
Their new method is based on a procedure already used by surgeons, known as "sentinel lymph node mapping." The procedure involves tightly binding an imaging dye to a protein serum, called albumin, that is found in the bloodstream. The dye then builds up in the lymph nodes, which allows surgeons to see the extent of cancer metastasis following tumor removal. The researchers say past studies have shown that immune cells in the lymph nodes catch albumin when foreign particles, such as imaging dye, bind to the protein.
"We realized that might be an approach that you could try to copy in a vaccine - design a vaccine molecule that binds to albumin and hitchhikes to the lymph node," says Darrell Irvine, senior author of the study and professor of biological engineering and materials science and engineering at MIT. "The lymph nodes are where all the action happens in a primary immune response. T cells and B cells reside there, and that's where you need to get the vaccine to get an immune response. The more material you can get there, the better."
Albumin-targeted vaccines triggered strong immune responses
Albumin consists of "binding pockets" that are able to catch fatty molecules. The investigators added a lipid, or a "fatty tail," to protein fragments called peptides, in order to ensure albumin could bind to them. The investigators then created a series of vaccines that targeted certain diseases, such as cervical cancer and melanoma. These were tested on mice. From this, the research team found that each vaccine made a large population of memory T cells that were specific to the viral or tumor peptide.
Of the T cells in the blood, 1 in 3 was found to be a "vaccine-specific T cell." Prof. Irvine says this is something usually only seen with vaccines that are delivered by viruses. Compared with the peptide antigens alone, the albumin-targeted vaccines triggered immune responses that were five to 10 times stronger. Furthermore, the melanoma vaccine was able to slow down cancer growth, while the cervical cancer vaccine reduced tumor size.
New delivery method could improve adjuvant safety
On testing the albumin-targeted vaccines with an adjuvant called CpG - a molecule that strengthens a vaccine's immune response - the investigators found the inflammatory response was significantly higher. The research team notes that with normal vaccines, adjuvants can spread through the bloodstream and prompt inflammation in other areas of the body. But the albumin-targeted vaccines may improve the safety of adjuvants.
"This lymph-node-targeting modification causes pretty much all of the material to get caught in the draining lymph nodes," explains Prof. Irvine, "so that means it's more potent because it's getting concentrated in the lymph nodes, and it also makes it more safe because it's not getting into the systemic circulation." The investigators say they now plan to use the new method to deliver HIV vaccines in nonhuman animal models, as well as create further cancer vaccines, including a vaccine for lung cancer.
Commenting on the overall findings, Pal Johansen, of the University Hospital Zurich, who was not a part of the research team, says: "It certainly is an interesting approach, and the results are very convincing. Both the effect on the stimulated immune responses and the consequential suppression of tumor growth are results that would suggest further development and clinical testing."
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