A team at the Massachusetts Institute of Technology (MIT) is working on COVID-19 RNA vaccine optimisation to try and improve immune responses at lower doses. Results, published in Nature Biomedical Engineering suggest that their attempts to engineer both the nanoparticles used to deliver the COVID-19 antigen and the antigen itself, have boosted the immune response. The study describes the use of a “multiply adjuvanted mRNA vaccine”, comprising lipid nanoparticles encapsulating an mRNA-encoded antigen, optimised for efficient mRNA delivery and the “enhanced activation of innate and adaptive responses”.  

Building better 

Despite the recent success of RNA vaccines there is always room for improvement, and this vaccine strategy has the potential to reduce costs and dosage as well as leading to longer-lasting immunity. Furthermore, the possibility of intranasal delivery offers greater immune responses and easier administration solutions.  

Professor Daniel Anderson of MIT’s Department of Chemical Engineering, the Koch Institute for Integrative Cancer Research, and Institute for Medical Engineering and Science (IMES), hopes that intranasal vaccination will “kill” the virus at the “mucus membrane”. Additionally, they may be “easier to administer” as they “don’t require an injection”.  

The study 

Although the original COVID-19 vaccines induced strong immune responses, the MIT team hoped to improve them by engineering them to have “immune stimulatory properties”. Thus, they employed two different strategies. The first involves a protein called C3d, part of an “arm” of the immune response known as the complement system. These proteins help to fight infection, with C3d binding to antigens and amplifying the antibody response against them.  

Graduate student Allen Jiang describes how the realisation of the “promise of mRNA technologies” enabled the team to explore C3d’s role as an adjuvant in mRNA vaccine systems. Therefore, the researchers engineered the mRNA to encode the C3d protein fused to the antigen, so both components were produced as one protein by cells that received that vaccine.  

The second phase involved the modification of the lipid nanoparticles used to deliver the RNA vaccine, so that alongside supporting RNA delivery the lipids stimulated a stronger immune response. To find the most effective lipids, the team created a library of 480 lipid nanoparticles with different types of chemistries. These were all “ionisable”, becoming positively charged upon entry to acidic environments.  

Professor Anderson commented that although they “understood that nanoparticles themselves could immunostimulatory”, they weren’t sure “what the chemistry was that was needed to optimise that response”.  

“Instead of trying to make the perfect one, we made a library and evaluated them, and through that we identified some chemistries that seemed to improve their response.”  
Intranasal vaccines 

The next step was to test the vaccine in mice. Mice injected with the vaccine produced 10 times more antibodies that mice given unadjuvanted COVID-19 RNA vaccines. The vaccine also encouraged a stronger T cell response. Former postdoc Dr Bowen Li suggested that demonstrating a “synergistic boost in immune responses” prompted the team to investigate the “feasibility of administering this new RNA vaccine platform intranasally”. This takes into account the “challenges presented by the mucociliary blanket barrier in the upper airways”.  

This method of administration demonstrated a “similarly strong immune response” in the mice. If developed for use in people, such a vaccine could potentially provide greater protection. Anderson’s lab is now exploring the platform’s possible uses in other RNA vaccines, including cancer vaccines.  

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