Vaccine News: Harvard Study Leads To a More Effective And Safer Vaccine Platform Utilizing Red Blood Cells To Elicit Specific Immune Responses
: Researchers from Harvard’s Wyss Institute for Biologically Inspired Engineering and John A. Paulson School of Engineering and Applied Sciences (SEAS) along with support from Perelman School of Medicine, University of Pennsylvania, have developed a platform technology that uses red blood cells to deliver antigens to antigen-presenting cells (APCs) in the spleen, generating an immune response.
Unknown to many, red blood cells do more than shuttle oxygen from our lungs to our organs, they also help the body fight off infections by capturing pathogens on their surfaces, neutralizing them, and presenting them to immune cells in the spleen and liver. The study team has harnessed this innate ability in the building of their vaccine platform.
The study team summarized their findings,”Erythrocytes naturally capture certain bacterial pathogens in circulation, kill them through oxidative stress, and present them to the antigen-presenting cells (APCs) in the spleen. By leveraging this innate immune function of erythrocytes, we developed erythrocyte-driven immune targeting (EDIT), which presents nanoparticles from the surface of erythrocytes to the APCs in the spleen. Antigenic nanoparticles were adsorbed on the erythrocyte surface. By engineering the number density of adsorbed nanoparticles, (i.e., the number of nanoparticles loaded per erythrocyte), they were predominantly delivered to the spleen rather than lungs, which is conventionally the target of erythrocyte-mediated delivery systems. Presentation of erythrocyte-delivered nanoparticles to the spleen led to improved antibody response against the antigen, higher central memory T cell response, and lower regulatory T cell response, compared with controls. Enhanced immune response slowed down tumor progression in a prophylaxis model. These findings suggest that EDIT is an effective strategy to enhance systemic immunity.”
The study findings are published in the peer reviewed journal: Proceedings of the National Academy of Sciences (PNAS). https://www.pnas.org/content/117/30/17727
The new platform has successfully demonstrated the slowing of the growth of cancerous tumors in mice, and could also be used as a biocompatible adjuvant for a variety of vaccines
The new technology platform has been named Erythrocyte-Driven Immune Targeting (EDIT).
Senior author Professor Dr Samir Mitragotri, Ph.D., a Wyss Core Faculty member who is also the Hiller Professor of Bioengineering and Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS told Thailand Medical News, “The spleen is one of the best organs in the body to target when generating an immune response, because it is one of the few organs where red and white blood cells naturally interact.”
He added, “Red blood cells’ innate ability to transfer attached pathogens to immune cells has only recently been discovered, and this study unlocks the door to an exciting array of future developments in the field of using human cells for disease treatment and prevention.”
Utilizing red blood cells as delivery vehicles for drugs is not a new idea, but the vast majority of existing technologies target the lungs,
because their dense network of capillaries causes cargoes to shear off of red blood cells as they squeeze through the tiny vessels.
The study team first needed to figure out how to get antigens to stick to red blood cells strongly enough to resist shearing off and reach the spleen.
The team coated polystyrene nanoparticles with ovalbumin, an antigenic protein known to cause a mild immune response, then incubated them with mouse red blood cells. The ratio of 300 nanoparticles per blood cell resulted in the greatest number of nanoparticles bound to the cells, retention of about 80% of the nanoparticles when the cells were exposed to the shear stress found in lung capillaries, and moderate expression of a lipid molecule called phosphatidyl serine (PS) on the cells’ membranes.
Dr Anvay Ukidve, a graduate student in the Mitragotri lab and co-first author of the paper said, “A high level of PS on red blood cells is essentially an ‘eat me’ signal that causes them to be digested by the spleen when they are stressed or damaged, which we wanted to avoid. 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,”
In order to test that hypothesis, the study team injected red blood cells coated with their nanoparticles into mice, then tracked where they accumulated in their bodies.
It was found that 20 minutes after injection, more than 99% of the nanoparticles had been cleared from the animals’ blood, and more nanoparticles were present in their spleens than their lungs.
Interestingly, the higher nanoparticle accumulation in the spleen persisted for up to 24 hours and the number of EDIT red blood cells in the circulation remained unchanged, showing that the red blood cells had successfully delivered their cargoes to the spleen without being destroyed.
Upon having confirmed that their nanoparticles were successfully delivered to the spleen in vivo, the study team next evaluated whether the antigens on the nanoparticles’ surfaces induced an immune response.
Animal models (mice) were injected with EDIT once a week for three weeks, and then their spleen cells were analyzed. Treated mice displayed 8-fold and 2.2-fold more T cells displaying the delivered ovalbumin antigen than mice that were given “free” nanoparticles or were untreated, respectively. Mice treated with EDIT also produced more antibodies against ovalbumin in their blood than either of the other groups of mice.
in order to evaluate if these EDIT-induced immune responses could potentially prevent or treat disease, the study team repeated their three-week prophylactic injection of EDIT into mice, then inoculated them with lymphoma cells that expressed ovalbumin on their surfaces.
It was found that the mice that received EDIT had about three-fold slower tumor growth compared with the control group and the group that received free nanoparticles, and had lower numbers of viable cancerous cells. This outcome significantly increased the window of time during which the tumor could be treated before the mice succumbed to the disease.
Dr Zongmin Zhao, Ph.D., a Postdoctoral Fellow in the Mitragotri lab and co-first author of the paper added, “EDIT essentially is an adjuvant-free vaccine platform. 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. 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
The study team is continuing to work on understanding exactly how an immune response that is specific to the antigen presented by EDIT is generated by the spleen’s APCs, and plans to test it with other antigens beyond ovalbumin.
The team hopes to use this additional insight to drive their pursuit of the optimal clinical setting(s) for the technology.
The Wyss Institute’s Founding Director Dr Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology
at Harvard Medical School and Boston Children’s Hospital, and Professor of Bioengineering at SEA said, “The human body is a treasure trove of elegant solutions to healthcare problems, and while medicine has come a long way in understanding those mechanisms, we are still in the early stages of being able to harness them to improve the length and quality of human life. This research is an exciting step forward toward that goal, and could dramatically change how immune responses are modulated in patients.”
Thailand Medical News would like to further add that with new emerging studies showing the possible adverse effects from using AAV (Adeno-associated viral) vectors to deliver vaccines, which is unfortunately being used in most of the current COVID-19 vaccines in phase 3 trials, this new platform might be a safer alternative to explore. https://www.thailandmedical.news/news/breaking-covid-19-vaccine-exclusive-possible-dangers-of-using-adeno-associated-virus-aav-vectors-for-covid-19-vaccines-
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