Nucleic acid vaccines: prospects for non-viral delivery of mRNA vaccines

Abstract

The prospects for mRNA vaccines are very promising. Like other types of nucleic acid vaccines, mRNA vaccines have the potential to combine the positive attributes of live attenuated vaccines while obviating many potential safety limitations. Although data from initial clinical trials appear encouraging, mRNA vaccines are far from a commercial product. These initial approaches have spurred innovations in vector design, non-viral delivery, large-scale production and purification of mRNA to quickly move the technology forward. Some improvements have already been tested in preclinical models for both prophylactic and therapeutic vaccine targets and have demonstrated their ability to elicit potent and broad immune responses, including functional antibodies, type 1 T helper cells-type T cell responses and cytotoxic T cells. Though the initial barriers for this nucleic acid vaccine approach seem to be overcome, in our opinion, the future and continued success of this approach lies in a more extensive evaluation of the many non-viral delivery systems described in the literature and gaining a better understanding of the mechanism of action to allow rational design of next generation technologies.

Induction of Broad-Based Immunity and Protective Efficacy by Self-amplifying mRNA Vaccines Encoding Influenza Virus Hemagglutinin

“…Thus, RNA replicon-based vaccines are amplified in the cells of the vaccinated hosts, permitting the expression of the vaccine antigen, without generating virus particles. Furthermore, in the process of amplification of their genomes, RNA replicons engage pattern recognition receptors in the host cell, adjuvanting the responses to the encoded immunogen (45)(46)(47). Although both mRNA-and replicon RNA-based vaccines were shown to elicit antigen-specific antibody and cellular immune responses against several pathogens (44,(48)(49)(50)(51), the self-amplifying nature of replicon-based vaccines is likely to result in higher levels of antigen expression and in a more effective engagement of innate immune responses than mRNA-based vaccine candidates.…”

Vaccines ‘on demand’: science fiction or a future reality

“…For example, based on animal testing,~1 Â 10 4 to 1 Â 10 5 times as much RNA by non-viral delivery is required to achieve equivalent potency compared to viral delivery [3]. Therefore, if needed, there is much room for improvement to increase the efficiency of non-viral RNA delivery.…”

“…One potential solution would be to produce preventive or therapeutic vaccines 'on demand,' though sufficient pace and scale have not been feasible so far. Self-amplifying mRNA vaccines [3,4], currently in development at Novartis Vaccines, are produced using a generic manufacturing platform utilizing completely synthetic methods and have potential to meet this aim.…”

Self-Amplifying mRNA Vaccines

“…Although each of these platforms has demonstrated some advantages, no vaccine using these technologies, has been licensed for human use (Kutzler & Weiner, 2008;Liu, 2011;Sardesai & Weiner, 2011). More recently, mRNA-based vaccines have emerged as potential alternatives and may offer certain advantages over their DNA-based counterparts (Deering, Kommareddy, Ulmer, Brito, & Geall, 2014;Geall, Mandl, & Ulmer, 2013;Kallen et al, 2013). Historically, this approach has been overlooked due to skepticism regarding mRNA stability and the perception that the barriers in large-scale commercial production were insurmountable.…”