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Vaccines work by teaching the immune system to recognize specific molecules, called antigens, from viruses, bacteria, parasites, or other disease-causing organisms. However, some antigens do not produce a strong immune response on their own. Vaccines often include additional substances called adjuvants to help stimulate immunity.
Researchers at the Department of Molecular Biology at Universidad Autónoma de Madrid investigated whether synthetic particles inspired by extracellular vesicles could serve as a new type of vaccine platform.
Extracellular vesicles, or EVs, are small membrane-bound particles naturally released by cells. They carry proteins, RNA, lipids, and other molecules between cells and play an important role in cellular communication. Their ability to interact with immune cells has made extracellular vesicles attractive candidates for vaccine delivery and immune stimulation.
However, natural extracellular vesicles can vary considerably in their composition, which may create challenges for consistent manufacturing and safety. To address these limitations, the researchers created synthetic extracellular vesicle mimetics, or EVMs, designed to reproduce useful features of natural EVs while providing greater control over their composition.
Mimicking a key extracellular vesicle protein
The researchers produced liposomes, artificial vesicles made from defined combinations of lipids, and added part of a protein called CD9 to their surface.
CD9 is a member of the tetraspanin protein family and is commonly found on natural extracellular vesicles. The researchers specifically used the large extracellular loop of CD9, known as CD9-LEL.
They then combined these CD9-containing nanovesicles with antigens from two different pathogens. One was KMP-11, a protein from the parasite Leishmania. The other was the SARS-CoV-2 Spike protein.
Mice were immunized with vesicles containing the antigens alone, CD9-LEL alone, or both CD9-LEL and an antigen. The researchers measured antigen-specific antibodies to determine how strongly the immune system responded.
CD9 increases immune responses to antigens
CD9-LEL by itself did not produce a significant immune response. When it was presented alongside a pathogen antigen, however, antibody responses increased substantially.
KMP-11 alone failed to generate detectable antibodies under the experimental conditions. When KMP-11 was delivered on nanovesicles together with CD9-LEL, the mice developed strong IgG1 and IgG2b antibody responses.
A similar effect was observed with the SARS-CoV-2 Spike protein. Vesicles containing both CD9-LEL and Spike generated higher antibody levels than vesicles carrying Spike alone.
These results suggest that incorporating features of natural extracellular vesicles into synthetic vesicles can help make vaccine antigens more visible to the immune system.
Improving uptake by immune cells
The researchers also investigated how CD9-LEL might improve the immune response.
They found that CD9-LEL increased uptake of the nanovesicles by macrophages. Macrophages are immune cells that can capture foreign material, process antigens, and help present those antigens to other immune cells.
Greater uptake by macrophages may therefore improve antigen presentation and help explain why CD9-containing vesicles generated stronger antibody responses.
Directing different types of immunity
The synthetic vesicles could also be combined with conventional vaccine adjuvants to influence the type of immune response produced.
When the researchers added alum, the response shifted toward IgG1 antibodies, which are associated with a Th2-type immune response. When they added CpG oligonucleotides, production of IgG2a and IgG2b antibodies increased, indicating a stronger Th1-type response.
Being able to influence immune polarization could be important because different pathogens may require different types of immunity for effective protection. Intracellular pathogens, for example, may benefit from stronger Th1 responses.
A synthetic approach inspired by extracellular vesicles
The findings demonstrate how characteristics of natural extracellular vesicles can be incorporated into more controlled synthetic vaccine systems.
Rather than isolating EVs directly from cells, the researchers created liposomes with a defined lipid composition and added a specific EV-associated protein component. This approach could make it easier to manufacture vesicles consistently while still taking advantage of biological features that promote interactions with immune cells.
Because the platform improved immune responses to antigens from both Leishmania and SARS-CoV-2, it may also be adaptable to different pathogens.
Further research will be needed to determine how effectively these extracellular vesicle-inspired particles perform in additional disease models and eventually in humans. However, the ability to improve antigen immunogenicity, enhance immune cell uptake, and adjust the type of immune response makes synthetic EV mimetics a promising platform for future vaccine development.
