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In the future, vaccines have the potential to be used not only against infectious diseases but also for cancer as a prophylactic and treatment tool, and for elimination of allergens 1 — 3. Prior to the s, vaccines were developed for protection against disease-causing microorganisms. Empirically, inactivated vaccines were produced by heat or chemical treatment, and live attenuated vaccines were generally developed in animals, cell lines or unfavorable growth conditions.

During vaccine development, the mechanisms involved in conferring immunity were unknown. Nevertheless, the use of live attenuated or killed whole organism-based vaccines had enormous success in the control and eradication of a number of severe human infectious diseases, including smallpox, polio, measles, mumps, rubella, and animal infectious disease, such as classic swine fever, cattle plague, and equine infectious anemia.

More recently, live attenuated LAV , subunit and peptide based vaccines have been developed thanks to advancements in molecular biology theory and technologies. The results obtained with LAV vaccination dramatically expanded our knowledge of the mechanisms related to the immune response elicited by these vaccines. For inactivated vaccines, antigen-specific antibodies largely contribute to the prevention and control of microbe-initiated infectious disease.

In addition to specific humoral immune responses. LAVs elicit strong cellular immune responses, which are critical to eradicate many intracellular pathogens. Nevertheless, the failures that are sometimes caused by inactivated vaccines are ascribed to mutation of the surface antigens of pathogens. Additional concerns about LAV applications include the potential to cause disease in immuno-compromised individuals and the possibility of reversion to a virulent form due to the back-mutation, the acquisition of compensatory mutations, or recombination with circulating transmissible wild-type strains 4 , 5.

Vaccination with non-viral delivered nucleic acid-based vaccines mimics infection or immunization with live microorganisms and stimulates potent T follicular helper and germinal center B cell immune response 8 , 9. Furthermore, non-viral delivered nucleic acid-based vaccine manufacturing is safe and time-saving, without the growth of highly pathogenic organisms at a large scale and less risks from contamination with live infectious reagents and the release of dangerous pathogens. Notably, for most emerging and re-emerging devastating infectious diseases, the main obstacle is obtaining a stockpile in a short timeframe Non-viral delivered nucleic acid-based vaccines can fill the gap between a disease epidemic and a desperately needed vaccine From being administrated to antigen expression, DNA vaccine and RNA vaccines are processed through different pathways.

In the steps between immunization with a DNA template and expression of the target antigen, the DNA has to overcome the cytoplasmic membrane and nuclear membrane, be transcribed into mRNA, and move back into the cytoplasm and initiate translation refer to Figure 1. Although promising and with shown safety, well-tolerability and immunogenicity, DNA vaccines were characterized by suboptimal potency in early clinical trials Enhanced delivery technologies, such as electroporation, have increased the efficacy of DNA vaccines in humans 12 , but have not reduced the potential risk of integration of exogenous DNA into the host genome, which may cause severe mutagenesis and induced new diseases 13 , Since naked in vitro transcribed mRNA was found to be expressed in vivo after direct injection into mouse muscle, mRNA has been investigated extensively as a preventive and therapeutic platform 15 — Due to the dramatic development of RNA-based vaccine studies and applications, a plethora of mRNA vaccines have entered into clinical trial The utilization of RNA as a therapeutic tool is not the focus of this manuscript and has been extensively reviewed elsewhere 2 , 19 , In this review, we provide highlights on mRNA vaccines as promising tools in the prevention and control of infectious disease.

Figure 1. MHC, Major histocompatibility complex. Table 1. Although mRNA vaccines were first tested in the early s, these vaccines were not initially extensively utilized due to concerns about their fragile stability caused by omnipresent ribonucleases and small-scale production. Initial demonstration that mRNA stability can be improved by optimization and formulation was published by Ross and colleagues in Since that time, studies on mRNA vaccines have exploded and mRNA can now be synthetically produced, through a cell-free enzymatic transcription reaction.

The in vitro transcription reaction includes a linearized plasmid DNA encoding the mRNA vaccine, as a template, a recombinant RNA polymerase, and nucleoside triphosphates as essential components. A cap structure is enzymatically added to the transcriptional product at the end of the reaction or as a synthetic cap analog in a single step procedure.

Finally, a poly A tail will be provided to form a mature mRNA sequence. After transfection, they drive transient antigen expression. In addition to conventional vaccines, there is another mRNA vaccine platform based on the genome of positive strand viruses, most commonly alphaviruses. These mRNA vaccines are based on an engineered viral genome containing the genes encoding the RNA replication machinery whereas the structural protein sequences are replaced with the gene of interest GoI and the resulting genomes are referred as replicons.

These vaccines are named self-amplifying mRNA and are capable of directing their self-replication, through synthesis of the RNA-dependent RNA polymerase complex, generating multiple copies of the antigen-encoding mRNA, and express high levels of the heterologous gene when they are introduced into the cytoplasm of host cells, in a way that mimics production of antigens in vivo by viral pathogens, triggering both humoral and cellular immune responses 22 — Self-amplifying mRNA can be derived from the engineered genomes of Sindbis virus, Semliki Forest virus, Kunjin virus, among others 28 — Compared with the rapid expression of conventional mRNAs, published results have shown that vaccination with self-amplifying mRNA vaccines results in higher antigen expression levels, although delayed in time, which persist for several days in vivo.

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Equivalent protection is conferred but at a much lower RNA dose Due to the lack of viral structural proteins, the replicon does not produce infectious viral particles. Additionally, both conventional mRNA and self-amplifying mRNAs cannot potentially integrate into the host genome and will be degraded naturally during the process of antigen expression.

These characteristics indicate that mRNA vaccines have the potential to be much safer than other vaccines and are a promising vaccine platform. In the process of translation, mRNA purity is critical to determine its stability and protein yield Contamination with dsRNAs, derived from aberrant RNA polymerase activities, leads to the inhibition of translation and degradation of cellular mRNA and ribosomal RNA, thus decreasing protein expression by interrupting the translation machine. The removal of dsRNA can increase translation dramatically Additionally, codon optimization is a popular method to avoid rare codons with low utilization, to increase protein production, mRNA abundance and stability 46 — Thanks to advancement in RNA biology understanding, several methods can be employed to increase the potency of mRNA vaccines, including sequence optimization and usage of modified nucleosides.

During the in vitro transcription of mRNA, immature mRNA would be produced as contamination which inhibited translation through stimulating innate immune activation. Currently, most vaccines in use, with the exception of some animal vaccines, need to be transported and stored in an uninterrupted cold-chain process, which is prone to failure, especially in poor rural areas of tropical countries; these requirements are not being met by available effective vaccines to prevent and control infectious diseases.

Therefore, the development of thermostable vaccines has been gaining interest. Optimization in formulation of synthetic mRNA vaccines have shown that it is possible to generate thermostable vaccines. After being transfected, these mRNAs expressed high levels of proteins and conferred highly effective and long-lasting immunity in newborn and elderly animal models These intriguing approaches would be discussed in delivery methods.

During the last two decades, mRNA vaccines have been investigated extensively for infectious disease prevention, and for cancer prophylaxis and therapy. Much progress has been made thus far 19 , Cancer mRNA vaccines were designed to express tumor-associated antigens that stimulate cell-mediated immune responses to clear or inhibit cancer cells Most cancer vaccine are investigated more as therapeutics than prophylactics and have been reviewed elsewhere 20 , 60 , As previously described the production procedure to generate mRNA vaccines is entirely cell-free, simple and rapid if compared to production of whole microbe, live attenuated and subunit vaccines.

This fast and simple manufacturing process makes mRNA a promising bio-product that can potentially fill the gap between emerging infectious disease and the desperate need for effective vaccines. Currently, all components needed for mRNA production are available at the GMP grade; however, some components are supplied at a limited scale. A great deal of research has been initially conducted on the development of cancer mRNA vaccines and has demonstrated the feasibility of producing clinical grade in vitro transcribed RNA Several projects on mRNA vaccines against infectious disease have also been conducted, although clinical evaluation is still limited.

For example, several RNA-based vaccine platforms have been utilized for the development of influenza vaccines. Several published results showed that RNA-based influenza vaccines induce a broadly protective immune response against not only homologous but also hetero-subtypic influenza viruses 62 — Influenza mRNA vaccines hold great promises being an egg-free platform, and leading to production of antigen with high fidelity in mammalian cells. Recent published results demonstrated that the loss of a glycosylation site by a mutation in the hemagglutinin HA of the egg-adapted H3N2 vaccine strain resulted in poor neutralization of circulating H3N2 viruses in vaccinated humans and ferrets.

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In contrast, the process of mRNA vaccine production is egg-free, and mRNA-encoded proteins are properly folded and glycosylated in host cells after vaccine administration, thus avoiding the risk of producing incorrect antigens 67 , Pulido et al. Saxena and colleagues demonstrated that a self-amplifying mRNA vaccine encoding rabies virus glycoprotein induced an immune response and provided protection in mice and could potentially be used to prevent rabies in canine Recently, VanBlargan et al.

As described previously, modification of nucleosides and optimization of codons can avoid recognition by innate immune sensors to improve translation efficiency. In Table 2 , studies conducted with nucleoside modified and non-modified mRNA vaccines for infectious disease are summarized 52 , 58 , 72 — Table 2. Nucleoside modified or non-modified mRNA vaccines against infectious diseases. Besides being used as vaccine, mRNA could also be deployed for therapeutic purposes. Interestingly, a recent publication by Pardi and colleagues showed that the adnimistration of mRNA encoding the light and heavy chains of a broadly neutralizing anti-HIV antibody encapsulated in lipid nanoparticles LNPs protected humanized mice from intravenous HIV challenge The data suggest that the utilization of nucleoside-modified mRNA can be expanded for passive immunotherapy against HIV, cytomegalovirus CMV , human papiloma virus, etc.

Self-amplifying mRNA vaccines enable large amounts of prompt antigen expression and potent T cellular immune responses.

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In Table 3 , we summarize publications on self-amplifying mRNA vaccines for infectious disease, delivered as viral replicon particles or synthetic formulated mRNA 80 , 82 — 85 , 87 , 91 , The administration route and formulation of mRNA vaccines are crucial to determine the kinetics and magnitude of antigen expression as well as the potency of the immune response. For example, intravenous administration of unmodified naked mRNA resulted in rapid digestion by ribonucleases and stimulation of the innate immune response, but these limitations can be overcome by appropriate delivery systems and mRNA modifications Direct intramuscular i.

Multiple reports have been recently published and showed that a variety of antigens can be expressed with high efficiency and induced potent humoral and cellular immune responses after mRNA vaccination. Lipid nanoparticles LNP loaded with nucleoside modified conventional mRNA encoding firefly luciferase have been used, for example, to examine the influence of route of administration on kinetics of antigen expression Both i. In a phase I clinical trial, CV showed long-term safety and immunogenicity against the rabies virus at alow dose. No differences were observed in terms of safety between i.

However, when neutralizing antibody titers induced by CV were evaluated, needle-free administration was superior to injection with a needle In an influenza vaccine test, the intranodal i. Combination with two or more delivery methods have been explored and employed in cancer mRNA vaccine development. The combination of i. Further studies demonstrated that i.

However, i. Altogether, these results highlight the importance of the delivery route for effective mRNA vaccines. Similarly, Fleeton et al. Geall and colleagues showed that i. Delivery tools are equally important in the effectiveness of mRNA vaccines. Ideally, the delivery vehicle should protect RNA against potential digestion by ribonuclease and confer efficient target cell uptake, easy dissociation of RNA cargo from the vehicle and escape from the endosome.

Overcoming the barrier of the cytoplasmic membrane and avoiding digestion by RNases are the initial steps for efficient RNA delivery into target cells. The final important requirements for an optimal delivery vehicle are a lack of both toxicity and immune stimulation. In initial studies, mRNA synthesized in vitro was directly injected into animals. Subsequently, mRNA vaccines formulated in liposomes were confirmed to induce a virus-specific anti-influenza cytotoxic T lymphocyte CTL immune response in mice Several methods have been explored to increase delivery efficiency and great progress has been made in the field of designing delivery vehicles form RNA vaccines — In addition to the physical methods of gene guns and electroporation, mRNA vaccines have been delivered into the cytoplasm by cationic lipids and polymers.

Cationic nano-emulsion formulated mRNA was also shown to induce a potent immune response 8 , 23 , However, several of these delivery vehicles demonstrated toxicity in vivo , which may limit their use in humans New platforms were developed as transportation tools for mRNA vaccines to avoid the limitation of toxic chemical transfection reagents. Most of these platforms utilized LNPs based on modified cationic lipid or lipid polymers. Several groups have utilized lipids or polymers as a platform to deliver mRNA vaccines against HIV-1 by a subcutaneous route, which efficiently elicited HIV-specific CD4 and CD8 T cell responses, or by an intranasal route, which induced an antigen-specific immune response 73 , , Lipid-encapsulated mRNA of influenza HA gene segments was also tested and showed T cell activation following a single dose No vaccine is available to prevent this mosquito-borne disease and the recent epidemic has caused worldwide concern.

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Modified mRNA-based vaccines formulated with LNPs elicited robust immune responses and protected guinea pigs from Ebola virus disease as well Intravenous i. A plethora of studies have shown that self-amplifying mRNA encapsulated in LNP induced potent cellular and humoral immune responses by different administration routes 19 , , LNP formulated self-amplifying mRNA vaccines encoding influenza virus antigens resulted in potent T and B cell immune responses and conferred protection against homologous and heterologous influenza virus challenges as well 63 , 65 , Cell penetrating peptides CPPs , a type of cationic peptide, represent promising tools for mRNA delivery into intracellular target sites.

Protamine is an arginine-rich cationic peptide that can bind to mRNA and transport it into cytoplasm. Protamine was extensively used as a delivery system for cancer and viral mRNA vaccines. The self-adjuvanted RNActive vaccine platform was created with protamine and has demonstrated potency against various infectious diseases and cancers 76 , 77 , Recently, Coolen and colleagues designed innovative delivery platform consisting of poly lactic acid and cationic-penetrating peptides as mRNA condensing agent.

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This nano-complexes were taken up by dendritic cells induced strong protein expression and innate immune response Chahal et al. Additional new modified nanoparticles are currently being investigated, such as polyplexes, nanoplexes and porous polymer scaffold-mediated delivery — Although great advances have been achieved in the development of delivery tools, the ideal platform maybe a combination of different mRNA delivery tools and more efforts in understanding mechanism of action might be required. The immune response mechanism instigated by mRNA remains to be elucidated. The process of mRNA vaccine recognition by cellular sensors and the mechanism of sensor activation are still not clear.

TLR7 activation can increase antigen presentation, promote cytokine secretion and stimulate B cell responses Natural exogenous mRNA stimulates strong induction of type I INFs and potent inflammatory cytokines, which instigate T and B immune responses but may negatively affect antigen expression — In this method, proximity ligation assays PLAs was employed TLR7 activation leads to upregulation of chemokines, which in turn recruit innate immune cells such as DCs and macrophages to the site of injection On the other hand, an early shut-down of antigen expression after the mRNA vaccination due to PRRs activation might be detrimental.

The negative impact from excessive IFN activation could derive not only from preventing RNA amplification, in case of self-amplifying mRNA vaccines, and expression, but also at the level of T cells. T cell inhibition could prevail if triggering of type I IFN receptors precedes that of T cell receptors.

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For an instance, i. Furthermore, some publications have shown that purity and delivery systems affect the immune response stimulated by mRNA vaccines More interestingly, a recent study showed that modified mRNA encapsulated into LNPs has an adjuvant effect and induces a potent T follicular helper response and a large number of germinal center B cells with long-living, high affinity neutralizing antibodies Administration route and vaccine formulation determine the peak of antigen expression, which is another way to modulate the immune response 94 , , Liang et al.

The i. Furthermore, only skin monocytes and DCs showed evidence of antigen translation at day 9, indicating prolonged antigen availability after i. A better elucidation of the sequence of events leading to mRNA translation and immune activation will help engineer mRNA vaccines to induce the correct balance of type I IFN induction, positively affecting vaccine outcome. Compared with the prophylactic and therapeutic application of mRNA in cancer, clinical trials of mRNA vaccines for infectious disease are still in their early age.

In a recent clinical trial of protamine complexed mRNA vaccine against rabies virus, the results showed that RNA complexed with protamine is safe and well-tolerated in vivo , but efficacy was highly dependent on the dose and route of administration. The efficacy of administration with a needle-free device was much better than with direct needle injection 57 , A plethora of publications have shown that mRNA-based vaccines are a promising novel platform that is high flexible, scalable, inexpensive, and cold-chain free.

Most importantly, mRNA-based vaccines can fill the gap between emerging pandemic infectious disease and a bountiful supply of effective vaccines. A variety of preclinical and clinical projects have made enormous strides toward the conceivable application of mRNA vaccines and have suggested that mRNA-based prophylaxis and therapy can be translated to human applications.

Although in medical application, magnitude of responses was lower than predicted from than those observed into animal models, the results of pilot clinical trials have shown good tolerability and that mRNA vaccination can induce antigen-specific T and B cell immune responses 57 , Therefore, mRNA holds great promises, but further insights into the mechanism of action and potency are still needed for full development of mRNA vaccines. The exploration of new strategies is needed to create applicable mRNA vaccines and to decrease the dose.

Study demonstrated removal of dsRNA contaminants by high performance liquid chromatography purification of in vitro transcribed mRNA prolonged the translation Research has demonstrated that modified nucleoside decreases the innate immune response and enhances protein expression. However, improper incorporation of modified nucleosides can have a negative impact on transcription products and increase costs. Based on the results of the above described studies, a better understanding of the mechanism of action of mRNA vaccines, the identification and development of a new delivery system, and improvement of mRNA vaccine design will be attained The growing body of preclinical and clinical results demonstrates that prophylaxis and therapy with mRNA promises to be useful for preventing infectious disease and treating tumors and that mRNA vaccines are safe and tolerated in animal models and humans.

Additionally, future improvements should increase antigen-specific immune responses and the magnitude of memory immune cell responses, including memory B and T cell responses. Although mRNA vaccine technology has still not extensively tested in humans, publications of preclinical and early clinical tests have emerged in recent years, in which promising results were reported. This evoked the momentum of biocompanies to commercialize mRNA vaccines with great enthusiasm , Some private funding resources and institutes have supported the research and development of mRNA vaccines , Despite the need for further optimization of manufacturing processes to generate mRNA vaccines, these processes hopefully will be streamlined to be establish large-scale production.

It is just a matter of time for RNA vaccines to be used in humans and animals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Immunocastration of goats using anti-gonadotrophin releasing hormone vaccine. Cuzick J. Preventive therapy for cancer. Lancet Oncol.

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Int J Infect Dis. Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies. Nat Commun. Hum Vaccin Immunother. New vaccine technologies to combat outbreak situations. Front Immunol. DNA vaccines: ready for prime time? Nat Rev Genet. Sci Transl Med. RNA: the new revolution in nucleic acid vaccines.

Semin Immunol. Direct gene transfer into mouse muscle in vivo. PubMed Abstract Google Scholar. Mechanism of action of mRNA-based vaccines. Expert Rev Vaccines. Developing mRNA-vaccine technologies. RNA Biol. Kallen KJ, Thess A. A development that may evolve into a revolution in medicine: mRNA as the basis for novel, nucleotide-based vaccines and drugs. Ther Adv Vaccines. Nat Rev Drug Discov. Recent Results Cancer Res. Not every article in a journal is considered primary research and therefore "citable", this chart shows the ratio of a journal's articles including substantial research research articles, conference papers and reviews in three year windows vs.

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