ABSTRACT
What can we expect from mRNA vaccines going forward? A brief history of mRNA vaccines Experiments showing that mRNA could be introduced into cells to generate an immune response against the encoded protein date to the 1990s, although technical challenges including the biological instability of mRNA and the induction of undesirable inflammatory responses by unmodified nucleic acid hampered development of this technology into clinical application.3,4 Advances including chemical modifications to the nucleo-side constituents of the mRNA polymer and the use of a lipid outer coating for delivery of the mRNA formed the basis for this technology to enter human studies.5,6 These changes led to increased production of the target protein after inoculation with fewer inflammatory adverse effects (AEs), while retaining induction of an immune response.7-9 These technologic advances were the basis for the COVID-19 mRNA vaccines in widespread use today. The sequence of events that leads to induction of effective immunity includes the following: O Creation of a nucleic acid sequence that results in production of the protein or a part of the protein against which a specific immune response is desired (immunogen) O Delivery of that sequence into the cell to engage the cellular machinery for producing the immunogen O Induction of inflammatory pathways to stimulate adaptive immunity leading to antibodies and T cells that respond to the immunogen Immune protein sensors that initiate inflammation are present in all cell types. A killed virus vaccine platform is the basis for Sinopharm and Coro-naVac vaccines developed in China and the BBV152 vaccine made in In-dia.15 Vaccines based on this plat form have been given to billions of individuals worldwide.16 Manufacture of these vaccines early in the pandemic required the ability to grow infectious viruses in a controlled setting, which unlike manufacture of mRNA vaccines carries nonzero transmission risk. Because these vaccines do not produce proteins in the immunized individual, they tend to be better at inducing antibody-based protection than cellular responses.