New Harvard vaccine technique coats red blood cells in nanoparticles
Researchers at Harvard have developed a new platform for producing vaccines – and the secret ingredient is blood. The technique involves loading red blood cells with antigens that they can then use to generate a specific immune response, and tests in mice have shown it is effective in slowing the growth of cancer.
Red blood cells are best known for their important work in shuttling oxygen from the lungs around the body, but it turns out that’s not the only cargo they can carry. In recent years, scientists have found ways to attach chemical payloads to them, like drugs or antibodies, which can then be delivered to specific organs or tissues.
For the new study, researchers at Harvard’s Wyss Institute built on this base, with the spleen as the target. Since this vital organ is one of the few places in the body where red and white blood cells interact directly, it should help launch a stronger immune response to a given pathogen.
Red blood cells have a secondary function of carrying neutralized pathogens to the spleen, where they’re passed onto antigen-presenting cells (APCs). From there, white blood cells learn to recognize these antigens, which are the molecules of a pathogen that the body uses to launch a counter-attack. This improves the immune response against those pathogens.
The new system, named Erythrocyte-Driven Immune Targeting (EDIT), exploits this. The problem is that normally, the payload is sheared off as red blood cells squeeze through narrow capillaries in the lungs, so much of it never reaches the spleen. But the team developed a way to stick antigen nanoparticles to red blood cells firmly enough to reach their destination.
In this case, the nanoparticles were made of polystyrene, and coated with an antigenic protein called ovalbumin. The red blood cells also had to express a lipid molecule called phosphatidyl serine (PS) in just the right amounts – too much and the spleen would register the cells as damaged and destroy them.
“We hoped that a lower amount of PS would instead temporarily signal ‘check me out’ to the spleen’s APCs, which would then take up the red blood cells’ antigen-coated nanoparticles without the cells themselves getting destroyed,” says Anvay Ukidve, co-first author of the study.
The team ran tests on mice. First they incubated their antigen-loaded nanoparticles with mouse red blood cells, and found that a ratio of about 300 nanoparticles to one red blood cell was enough to ensure that at least 80 percent stayed stuck to their surface.
Next, they injected the concoction into mice, and tracked where the nanoparticles ended up. After 20 minutes, almost all of the nanoparticles had been cleared from the animals’ blood, with more accumulating in the spleen than the lungs.
This abundance in the spleen remained for 24 hours after injection, and importantly the team found that the amount of EDIT red blood cells in the body didn’t change. That shows that they weren’t being destroyed by the spleen.
In the next tests, the researchers checked whether this technique actually induced a stronger immune response. The team gave two groups of mice a treatment once a week for three weeks, and then analyzed their spleen to check how many T cells were displaying the ovalbumin antigen.
Mice that had received the EDIT treatment had eight times more ovalbumin T cells than mice that had just received the nanoparticles not attached to red blood cells. This number was also 2.2 times higher than in mice that had received no treatment. More antibodies against ovalbumin were also found in the blood of the EDIT mice than the others.
Finally, the researchers investigated how effective the technique might be against disease. The team again gave groups of mice the EDIT treatment over three weeks, then injected the animals with lymphoma cells that expressed ovalbumin.
Sure enough, tumors grew three times slower in mice that had received EDIT than in the control or free nanoparticle groups. The EDIT mice also had lower numbers of viable cancer cells in their bodies.
The team says that the new technique could be used as a new delivery system for vaccines targeting a range of infections and illnesses. But the real advantage is that it works without adjuvants – agents added to vaccines to boost the immune response – which could help speed up vaccine development.
"Part of the reason why vaccine development today takes so long is that foreign adjuvants delivered along with an antigen have to go through a full clinical safety trial for each new vaccine,” says Zongmin Zhao, co-first author of the study. “Red blood cells have been safely transfused into patients for centuries, and their ability to enhance immune responses could make them a safe alternative to foreign adjuvants, increasing the efficacy of vaccines and speed of vaccine creation.”
Of course, for now the research remains only in mice, but the team plans to continue the work to gain a better understanding of how the system works, and test it against other antigens.
The research was published in the journal PNAS.