Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines

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.

Self-Amplifying RNA Vaccines for Venezuelan Equine Encephalitis Virus Induce Robust Protective Immunogenicity in Mice

“…Alternatively, we speculate that the lower potency of a highly attenuated or inactivated VEE RNA vaccine could be overcome by further improvement of the synthetic non-viral delivery system, for example, by optimizing CNE specifically for VEEV SAM vaccine or utilizing alternative delivery strategies such as LNPs. 8,10,42,43 On a related note, the attenuated LAV m -CNE vaccine was significantly less immunogenic than the parental LAV-CNE vaccine, whereas LAV m -VRPs was similar to LAV-VRPs. It is possible that the VRP presents glycoproteins authentically to allow for more efficient uptake of the particles as compared to CNE so that both LAV m -VRPs and LAV-VRPs could efficiently launch to induce robust immune responses.…”

“…Nucleic-acid-based vaccines have the benefits of a generic delivery platform and in situ expression of the antigens. [7][8][9][10][11][12][13][14] Moreover, immunization with nucleic acid vaccines can mimic natural infections by live or attenuated organisms, inducing both humoral and cellular immunity. 7,15 Vaccine platforms derived from a replicating RNA viral genome are particularly attractive because replicating RNA itself potently stimulates the innate immune system by engaging pattern recognition receptors.…”

Advances in RNA Vaccines for Preventive Indications: A Case Study of a Vaccine against Rabies

“…A key observation made by Geall et al [40] was that replicating nonmodified mRNA molecules formulated as lipid nanoparticles (LNPs) were able to induce protective immune responses in mice against respiratory syncytial virus (RSV). The impact of LNP encapsulation of the rabies RABV-G nonreplicating mRNA proven in the studies described above was investigated by Lutz et al [41]. Initially they investigated the effect of LNP on the activation of the innate immune system by measuring cytokine and chemokine concentrations following intramuscular injection into mice.…”

Unlocking the potential of vaccines built on messenger RNA

“…CureVac has since altered its delivery platform and restarted human trials with a vaccine candidate that is encased in lipid nanoparticles. As the company's scientists reported in 2017, this change enhances the cellular uptake of the mRNA sequences, so the same level of antibody and T-cell responses can be achieved in mice and monkeys using a tiny fraction of the dose 7 .…”