Abstract
mRNA represents a promising new vaccine technology platform with high flexibility in regard to development and production. Here, we demonstrate that vaccines based on sequence optimized, chemically unmodified mRNA formulated in optimized lipid nanoparticles (LNPs) are highly immunogenic and well tolerated in non-human primates (NHPs). Single intramuscular vaccination of NHPs with LNP-formulated mRNAs encoding rabies or influenza antigens induced protective antibody titers, which could be boosted and remained stable during an observation period of up to 1 year. First mechanistic insights into the mode of action of the LNP-formulated mRNA vaccines demonstrated a strong activation of the innate immune response at the injection site and in the draining lymph nodes (dLNs). Activation of the innate immune system was reflected by a transient induction of pro-inflammatory cytokines and chemokines and activation of the majority of immune cells in the dLNs. Notably, our data demonstrate that mRNA vaccines can compete with licensed vaccines based on inactivated virus or are even superior in respect of functional antibody and T cell responses. Importantly, we show that the developed LNP-formulated mRNA vaccines can be used as a vaccination platform allowing multiple, sequential vaccinations against different pathogens. These results provide strong evidence that the mRNA technology is a valid approach for the development of effective prophylactic vaccines to prevent infectious diseases.
Highlights
The introduction of prophylactic vaccination has been one of the most effective medical interventions to fight and eradicate infectious diseases
We used in our study unmodified, sequence-optimized mRNA formulated with an optimized lipid nanoparticles (LNPs) consisting of an ionizable amino lipid, phospholipid, cholesterol and a polyethylene glycol (PEG) containing lipid
DISCUSSION mRNA is a very promising and versatile vaccination approach, important given the experiences with early DNA vaccines which showed promising results in small animals that were difficult to translate into clinical success.[28]
Summary
The introduction of prophylactic vaccination has been one of the most effective medical interventions to fight and eradicate infectious diseases. The continuous threat of infectious agents for which no vaccine exists and the introduction of new pathogens into the human population emphasize the need for the development of novel safe vaccines and even vaccine platforms capable of rapidly responding to those needs. These vaccine platforms should be highly versatile at minimal development and production costs. These data reveal a gap between selfamplifying and non-replicating mRNA, which cannot be closed only by formulation This demonstrates a clear need to optimize the mRNA itself to obtain sufficient expression levels.
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