RNA-Based Vaccines: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Katharine Valéria Saraiva Hodel.

Vaccine development using ribonucleic acid (RNA) has become the most promising and studied approach to produce safe and effective new vaccines, not only for prophylaxis but also as a treatment. The use of messenger RNA (mRNA) as an immunogenic has several advantages to vaccine development compared to other platforms, such as lower coast, the absence of cell cultures, and the possibility to combine different targets.

  • RNA vaccines
  • mRNA vaccines
  • saRNA vaccines

1. Introduction

RNA-based vaccines were among the first to emerge and have become prominent in national immunization programs. RNA vaccine technology builds on the central dogma of molecular biology, in which messenger RNA (mRNA) is the intermediate step between the translation of the encoding DNA and the production of its respective protein. It is a technology that enables the carriage of genetic information directly into the cell, allowing endogenous protein expression instead of administering protein (antigen) as an exogenous entity such as killed or defined subunit platforms [1]. Moreover, due to its capacity to activate various pattern-recognition receptors, RNA can be very immunogenic [2]. Importantly, RNA vaccines can be divided into two main categories, mRNA-based vaccines and those that are considered to be self-amplifying RNA (saRNA) vaccines [3]. A logistical advantage of RNA-based vaccines is that the RNA can be produced in a cell-free environment by in vitro transcription (IVT), removing the need for cultured cells in the manufacturing process and removing the associated quality and safety issues associated with them [4]. In this way, it is possible to perform simple downstream purification to provide rapid and cost-effective manufacturing relative to other vaccine platforms [5]. In addition, several other advantages, such as scalability, flexibility in manipulating antigens of interest, and the induction of both cellular and humoral immunity [6], are inherent to RNA vaccines. These characteristics previously enabled RNA-based vaccines to be evaluated against non-infectious diseases such as cancer and allowed their manufacturers to rapidly respond to emerging infectious agents such as SARS-CoV-2 [7]. For this reason, RNA-based vaccines have become attractive in the pandemic situation, as well as for the therapy of different diseases. 

2. RNA-Based Vaccines

As with other platforms, the development of RNA-based vaccines involves antigen discovery and analysis of the nucleotide sequence that will be translated into the protein of interest. For RNA-based vaccines, screening of modified nucleotides can optimize expression, as can the selection of an appropriate method [7]. Various methods have been used, such as modified nucleosides and the development of nanoparticles capable of stabilizing the RNA and/or improving its cellular uptake and, consequently, improving the overall bioavailability of the RNA cargo [8]. Studies that served as a basis for the development of synthetic RNA vaccines were reported from the end of the twentieth century and were motivated by the 1961 discovery of mRNA [9]. An important milestone for the use of RNA in the pharmaceutical industry occurred in 1989, when researchers from Vical Incorporated and the Salk Institute demonstrated that mRNA introduced by a liposomal nanoparticle could transfect different types of eukaryotic cells [10]. In 1990, Wolff et al. [11] reported that the injection of mRNA without a protective complex could induce protein expression within a few days. The first studies of mRNA and saRNA as vaccines demonstrated cell-mediated and humoral-adaptive immune responses, respectively, against the influenza A virus . This was followed by studies of mRNA as immunotherapies focused on oncology with in vitro and in vivo assays, using both protected or unprotected (“naked”) mRNA [12][13][14]. It is important to note that the basic difference between these two types of RNA is associated with the number of replications and, consequently, the expression of the antigen. By presenting additional sequences in the coding region, saRNA has a self-amplification mechanism, which can result in an increase in the transcription process when compared to mRNA [15]. In addition, mRNA or saRNA are produced by IVT and, besides the advantages mentioned above, the RNA sequence can be easily modified to improve the protein synthesis, such as the addition of a 30 poly(A) tail, a capping approach, and methylated nucleosides or pseudouridine [16]. The amount of protein (antigen) expressed is directly related to the content of mRNA that can enter the intracellular environment. The presence of well-defined mRNA in the cytosol allows the presentation of exogenous and endogenous antigens to occur and can provide activation of the immune system via different pathways [17][18]. However, it has been shown that naked mRNA is more susceptible to enzymatic hydrolysis (especially by omnipresent ribonucleases), which can directly compromise its potency; since any degradation in its structure can result in the incomplete expression of the antigen [19][20]. After this discovery, different studies were conducted to develop delivery vehicles for the mRNA that would protect the molecule from degradation and improve the induction of the immune system [21][22][23]. Thus, several in vivo studies using different types of delivery vehicles have been performed in an attempt to develop a safe and effective RNA vaccine [24][25]. However, some strategies have demonstrated a lack of immunogenicity in primates and humans in contrast to small animal models (also called a “primate barrier”), making the choice of the delivery vehicle an important bottleneck in the clinical use of RNA vaccines [26]. Recently, the use of lipid nanoparticles (LNPs) as a delivery system has been the main focus for RNA vaccine development [27]. In 2007, de Jong et al. [28] demonstrated that LPN-encapsulated antigen can induce a stronger immune response and enhance immune efficacy. Since then, the importance of this delivery system in the development of safe and effective vaccines in different routes of administration has been reported, directly contributing to the advancement in the use of mRNA vaccines. These studies were of great importance in establishing benchmarks for further evaluation and, consequently, assisting in the process of optimizing these vaccines, providing essential safety and immunogenicity, and providing a basis for the production of RNA vaccines in accordance with good manufacturing practices [29][30]. In this context, the most important innovations in RNA-based vaccine technology in recent years have been directed toward the use of optimized RNA sequencing, the application of methods that allow large-scale cGMP production, and the development of efficient and safe materials for RNA delivery [31][32].

2.1. RNA Vaccines against Cancer

RNA-based cancer vaccines have been designed to express tumor-associated antigens, resulting in the stimulation of T-cell-mediated immune responses [33]. Acute myeloid leukemia, brain cancer, colorectal cancer, liver metastases, esophagus cancer, glioblastoma, prostate cancer, and melanoma are all examples of clinical conditions targeted by RNA-based cancer vaccine candidates [34], with most applied in a therapeutic rather than a prophylactic manner [35][36]. To date, most RNA-based cancer vaccines have used non-replicating mRNA technology [37][38]. One of the first phase I/II studies involved the direct injection of mRNA into melanoma patients: while a 200-microgram injection of naked mRNA was safe, clinical efficacy was not demonstrated [39]. Soon after, the same group published a phase I/II trial of a protamine-protected mRNA vaccine in metastatic melanoma patients (NCT00204607), demonstrating that protamine-protected mRNA was not only safe but generated more promising clinical efficacy [40]. These trials thereby addressed the reported weakness of RNA based-vaccines being easily degraded by omnipresent ribonucleases and demonstrated the importance of the delivery format in related outcomes, prompting research regarding novel encapsulation/delivery strategies, such as the use of biopolymers, liposomes, or dendritic cells (DCs) [32][41].
Before studies in humans, in vitro and in vivo studies using DCs electroporated with mRNA assessed their ability to trigger potent immune responses against tumor antigens [13]. Boczkowski et al. showed the capacity of RNA-pulsed DC-based vaccines to reduce lung metastases in rats. Early human trials to evaluate mRNA delivery used monocyte-derived DCs transfected ex vivo with antigen-encoding mRNA by electroporation to provide a cell-based vaccine approach, with the cells being re-infused into patients [42]. Since then, many phase I/II clinical trials using this delivery strategy have been published, with prostate cancer, melanoma [43], B-cell lymphoma [44], adenocarcinoma [45], and pancreatic cancer [46] being among the examples of the therapeutic targets.
The RNActive® vaccine platform (WO2002098443, WO2012019780), designed by CureVac, uses an mRNA complex with protamine and naked mRNA, where protamine assists in the process of inducing cellular immunity [47]. Furthermore, it is important to note that the ability to express the antigen within this complex is directly associated with the relationship between the mRNA and the protamine [48]. The platform has proven to be highly versatile, allowing the translation of different antigens of interest. Two cancer vaccines based on this technology have undergone phase 1/2 clinical trials: CV-9104, tested in patients with castration-resistant prostate cancer (NCT01817738) [49] and CV-9201, tested in patients with non-small-cell lung carcinoma (NCT00923312) [50]. 

2.2. RNA Vaccines against Non-Infectious Diseases

In addition to the applications in cancer, it is important to mention that RNA-based vaccines also have a great potential to be applied to the treatment and prophylaxis of non-infectious diseases, such as autoimmune and allergic diseases [51][52]. These diseases, while apparently diverse, share a common characteristic of an undesired and inappropriate immune response. Therefore, in a different way than the approach used for non-infectious disease and cancer, which is based on the principle that RNA, together with its formulation, provides immune stimulations of T-cell and antibody responses [32], in the case of non-infectious diseases, the goal is to suppress an immune response.
Companies specializing in therapeutics with mRNA have sought solutions to a wide range of health conditions. When it comes to autoimmune disorders, previous studies have shown that mRNA therapy has a high potential application in the treatment of these diseases [53][54][55]. It is important to note that there are over 100 distinct autoimmune disorders, and they are highly complex, where for each one, there may be a different treatment approach [56]. In general, for autoimmune disease applications, an mRNA-based vaccine acts by suppressing antigen-specific immune responses [51]. A recent study performed by BioNTech RNA Pharmaceuticals researchers [51] described the disease-suppressing effects of a non-inflammatory mRNA vaccine in mice models of multiple sclerosis. It was demonstrated that the delivery of the autoimmune target antigen by the mRNA vaccine candidate into antigen-presenting cells in the lymph nodes resulted in the prevention of disease symptoms, a reduction in the disease progression, and the restoration of motor functions [51]. This study highlights that mRNA therapy has the potential to treat autoimmune diseases by increasing immune cell tolerance and consequently reducing damage without jeopardizing the immune system functions. Another important approach for mRNA-based vaccines in the autoimmune disease context relies on the application of mRNA to encode the immunomodulation of signal molecules such as cytokines. Veiga et al. demonstrated the application of mRNA encoding IL-10 as an alternative to traditional recombinant protein therapies in inflammatory bowel diseases. The expression of IL-10 in target cells resulted in a significant decrease in pathological symptoms and in the severity of intestinal inflammation. It is important to mention Moderna’s potential mRNA medicine, mRNA-6231, which was designed to trigger peripheral tolerance pathways to restore immune homeostasis and reduce autoimmune pathology by buffering autoimmune activation. mRNA-6231 encodes for IL-2, which mutein designs to activate and expand regulatory T cells, buffering the immune response [57]. The clinical trial to evaluate the safety and tolerability of mRNA-6231 is underway (NCT04916431).
When it comes to RNA-based vaccine applications for allergic diseases therapy, in contrast to cancer or autoimmune diseases applications, vaccination against allergy does not involve the administration of self-antigens [56]. It is generally accepted that allergic reactions are triggered by recurring exposure to allergens that will lead to the production of allergen-specific IgE antibodies and the subsequent activation of inflammatory cell responses by allergen–IgE immune complexes [58]. Therefore, allergic diseases are treated with allergen-specific immunotherapy since this is the treatment that can alter the immunological basis of allergic diseases with long-term effects, and no preventive vaccination against type I allergy is available [59][60][61]. mRNA-based vaccines are studied as an alternative for allergen-specific immunotherapy since, through this technology, it is possible to deliver the allergen in a pure form and in lower doses, therefore decreasing the risk of anaphylactic side effects caused by pre-existing IgE and the occurrence of the production of any novel allergen-specific to IgE. Roesler et al. demonstrated that mRNA vaccine expression of important 29 allergens could protect the induction of IgE in animal models. In this study, the benefits of mRNA vaccination were also seen in the downregulation of inflammatory lung parameters [62]. Moreover, Hattinger et al. [63] demonstrated that vaccination with mRNA vaccines was responsible for preventing an allergen-specific response by immunomodulating the TH2-type response by suppressing TH2 cytokines, eosinophils, and IgE expression, and increasing TH1-type parameters.

2.3. RNA Vaccines against Infectious Diseases

In addition to the push for RNA-based vaccines to fight cancer and non-infection diseases, in recent years, the use of these platforms has gained prominence against infectious agents, especially against emerging infectious diseases such as those caused by the Zika virus, Zaire Ebolavirus, and coronavirus [15]. In general, RNA-based vaccines against pathogens are developed through four main steps: (1) construction of an optimized sequence (capable of enhancing immunogenicity) of antigen-encoding mRNA based on the selected antigen(s) of the target pathogen; (2) determination of the delivery material, in either the presence or absence of adjuvant molecules, and influenced by the route of administration; (3) demonstration of the in vivo expression of the encoded antigen); and (4) evaluation of immune induction [34][64]. Unlike the predominance of the conventional mRNA approach against cancer vaccines, saRNA technology has been more widely evaluated against infectious diseases [65]. saRNA replicons are created by replacing the structural genes of, typically, an alphavirus (such as Semliki Forest virus (SFV), Sindbis virus (SINV), or Venezuelan equine encephalitis virus (VEEV) with the gene for the antigen of interest. It is important to note that the absence of endogenous viral structural genes in the replicons means that the production of infectious virions or virus-like vesicles in individuals after vaccination is negated, increasing the safety profile when compared to vaccine technologies such as attenuated virus [64]. When delivered into the cytoplasm of target cells, saRNA becomes capable of amplifying the mRNA to express the target antigen at very high levels [64][66][67]. Through this self-amplification system, it has already been estimated that 200,000 copies of RNA can be made from a single saRNA molecule, resulting in higher levels of protein expression relative to those achieved by conventional mRNA (Figure 1) [68]. Thus, vaccines based on saRNA technology can induce high levels of immunity even when administered in low amounts [69].
Vaccines 09 01345 g001 550
Figure 1. Overview of mRNA and saRNA-based vaccine mechanisms for protein production. Adapted from Maruggi et al. [64]. GoI, gene of interest; MHC, major histocompatibility complex; nsPs, nonstructural proteins. Created with BioRender.com (accessed on 30 September 2021).
RNA-based vaccines have been used to deliver bacterial and parasite genes but, except for vaccine candidates for Chlamydia trachomatis [70], most of these remain in pre-clinical or early clinical stages of development (e.g., those against the protozoan Toxoplasma gondii [71], Plasmodium [72], and Leishmania donovani [73]). Recently, Raj et al. [74] developed an RNA vaccine for the expression of the glutamic-acid-rich protein (PfGARP) of Plasmodium falciparum and showed that it induced antibody formation in vitro assays and in a non-human primate challenge model. Maruggi et al. [75] reported that saRNA vaccines based on bacterial antigens from Group A (GAS) and Group B (GBS) Streptococci induced protective efficacy in mice through the induction of functional antibodies. RNA-based vaccines have advanced further in the context of viral infections, most notably for SARS-CoV-2 but also including other respiratory viruses (SARS-CoV-1) [76], insect-transmitted viruses (Zika, dengue, and Chikungunya) [77][78][79], animal-transmitted viruses (rabies) [80], as well as viruses transmitted by direct contact with humans or their fluids (e.g., Ebola [81], herpes (herpes simplex virus and human cytomegalovirus) [82][83], and HIV [84]. A pioneering study involving RNA vaccines for infectious agents was conducted by Fleeton et al. [85] against three viruses: influenza A virus, a tick-borne flavivirus (louping ill virus), and respiratory syncytial virus (RSV). In vivo experiments with a mouse model showed that the RNA vaccine encoding the envelope proteins of the three viruses afforded protection against each virus evaluated [85]. Just over a decade later, Petsch et al. [86] published important preclinical data on RNActive® platform-based influenza A virus infection vaccines, demonstrating that the vaccines promoted balanced, long-lived, and protective immunity against infection with influenza A virus in both small animals (mice and ferrets) and large animals (pigs) [86]. RNA vaccines can induce protective immunity against several influenza viruses and prolong the immune responses [16][87], and RNA-based vaccines are now being considered as alternatives that could overcome the bottlenecks typically faced by the conventional influenza vaccine.

However, the pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) brought about one of the important milestones within this context, as for the first time vaccines based on RNA technology were approved for use in humans [88]. The vaccines in question are BNT162b2 (Comirnaty)  and mRNA-1273 (Spikevax), which use an mRNA capable of encoding part of the SARS-CoV-2 S-glycoprotein, which ultimately triggers an immune response against viral infection [89]. 

 

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