Self-Amplifying RNA Vaccines Give Equivalent Protection against Influenza to mRNA Vaccines but at Much Lower Doses

Abstract

New vaccine platforms are needed to address the time gap between pathogen emergence and vaccine licensure. RNA-based vaccines are an attractive candidate for this role: they are safe, are produced cell free, and can be rapidly generated in response to pathogen emergence. Two RNA vaccine platforms are available: synthetic mRNA molecules encoding only the antigen of interest and self-amplifying RNA (sa-RNA). sa-RNA is virally derived and encodes both the antigen of interest and proteins enabling RNA vaccine replication. Both platforms have been shown to induce an immune response, but it is not clear which approach is optimal. In the current studies, we compared synthetic mRNA and sa-RNA expressing influenza virus hemagglutinin. Both platforms were protective, but equivalent levels of protection were achieved using 1.25 μg sa-RNA compared to 80 μg mRNA (64-fold less material). Having determined that sa-RNA was more effective than mRNA, we tested hemagglutinin from three strains of influenza H1N1, H3N2 (X31), and B (Massachusetts) as sa-RNA vaccines, and all protected against challenge infection. When sa-RNA was combined in a trivalent formulation, it protected against sequential H1N1 and H3N2 challenges. From this we conclude that sa-RNA is a promising platform for vaccines against viral diseases.

Emerging Technologies for Low‐Cost, Rapid Vaccine Manufacture

“…Thus, current research focuses on using RNA‐dependent RNA polymerase (aka. replicase) based RNA vaccines . In the case of these replicase‐based RNA vaccines, first the replicase is expressed and this allows the amplification of RNA template .…”

Influenza vaccine: Where are we and where do we go?

“…Owing to fewer regulatory tests and being products with invariant base regardless of the type of pathogen, a large body of evidence have nominated nucleic acid‐based vaccines as encouraging vaccine candidates …”

“…Third, production: mRNA vaccines are capable of being produced in a rapid, cheap, and scalable manner, mainly because of the high yields of in vitro transcription reactions . As toxic chemicals are not used in manufacturing of mRNA, there is no possibility of common risks associated with other vaccine platforms . However, possible undesired consequences such as fever can originate from the extreme induction of type I interferons and proinflammatory cytokines, mediated by some RNA vaccines.…”

“…Intracellular replication of RNA which encodes antigen guarantees the highly effective antigen production from an extremely small dose of self‐amplifying RNA vaccine. SAM vaccines are capable of self‐production of adjuvants, intermediates of replication, and the rest of contributory motifs in their high potency …”

“…A number of delivery formulation platforms have been explained to enhance the RNA vaccination, including PEI‐based delivery vehicles . Furthermore, a validated adjuvant strategy is TriMix, which is formed by a combination of mRNAs encoding three immune activator proteins: CD70, CD40 ligand (CD40L), and constitutively active TLR4.…”