The impressive development speed of tools to combat SARS-CoV-2 has brought the recently established mRNA vaccine technology platform into the spotlight. mRNA vaccines, which contain synthetic SARS-CoV-2 viral RNA encapsulated in lipid nanoparticles (LNP), have proven quite efficacious, with more than 13 B doses ultimately administered. Rather than introducing a pathogen-derived component, mRNA vaccines use a translation-capable RNA strand that allows host cells to autonomously produce a foreign protein. Currently, there are 25 different mRNA vaccines against SARS-CoV-2 that have advanced to clinical trials, of which two, manufactured by Pfizer/BioNTech and Moderna (both lipoplex-based formulations), were found to be approximately 95% efficacious in preventing infection. The design of the COVID-19 mRNA vaccines stems from the attributes of the entry mechanism of the virus into host cells, specifically the viral spike glycoprotein, which binds to angiotensin-converting enzyme 2 (ACE2) [1].
1. Introduction
The COVID-19 pandemic has led to forward thinking regarding the potential risks posed by emerging viral pathogens. Prompt delivery of efficacious vaccines to the general population requires screening concepts that allow rapid adaption of vaccine platforms to emerging viruses. A potential strategy is the design of pre-emptive or pan-vaccines based on broadly neutralizing epitopes. However, prior to human usage, any vaccine concept has to be tested in appropriate animal models and further investigated in the laboratory. Therefore, it seems crucial to establish a vaccine platform that allows such pre-emptive vaccines to be developed effectively in a wholly contained manner inside BSL-2 labs. The enormous success of Pfizer-BioNTech and Moderna mRNA vaccines against COVID-19 has paved the way for mRNA vaccines against other infectious diseases, cancers, and even genetic disorders [2].
1.1. Background on mRNA Technology in Vaccines
Discussed in this section is the extensive and comprehensive knowledge needed to fully comprehend the intricate workings and complexities of this revolutionary and groundbreaking cutting-edge technology. Understanding and embracing this knowledge has the potential to propel and advance the field of medicine into a new era, as it paves the way for the next generation of mRNA vaccines that can effectively target and combat various therapeutic areas. In addition to shedding light on the fundamental principles and foundations underlying the mRNA-LNP vaccine platform, there is a strong emphasis on delving into the rich tapestry of the past, present, and future of mRNA technology in relation to vaccines. By exploring its historical evolution, current advancements, and future prospects, one can truly grasp the immense potential and transformative power that mRNA holds in revolutionizing the field of vaccine development. Recognizing that mRNA is an extraordinary biopharmaceutical product, it is vital to provide a succinct yet enlightening overview of the numerous regulatory aspects intricately associated with the manufacturing process of biopharmaceutical products. By understanding the regulatory landscape, one can navigate the necessary protocols, guidelines, and quality control standards that govern the production and distribution of these innovative medical marvels. This comprehensive understanding is crucial in ensuring the safety, efficacy, and consistent delivery of biopharmaceutical products to patients worldwide. [3][1]
2. Historical Development of mRNA Vaccines
mRNA vaccines and their historical development are explored. With the growing evidence that messenger ribonucleic acid (mRNA) can serve as vaccine triggers, attention was drawn to advances and discoveries made from early research in the late 1970s until vaccines using this technology were developed for the COVID-19 pandemic. Vaccination is one of the most cost-effective means of protection against infectious disease. The concept of vaccination involved the deliberate infection of healthy people with a (weakened) form of a pathogen to elicit protective immunity [1]. Variola (the causative agent of small pox) was the first human pathogen to be used as a vaccine. The introduction of variolation in England and the American colonies in the 1720s and subsequent inoculation campaigns helped eradicate the disease, which led to increased life expectancy in the West and significantly decreased mortality from infectious agents.
As diseases were recognized as being caused by microorganisms, the search for protective vaccines started in the mid-19th century. Inoculations with related less virulent animal viruses such as cow pox or equine pox were performed to protect people from small pox. Nevertheless, the virulence of the agents involved led Pasteur in 1881 to his most prominent discovery in microbiology, attenuation. The discovery that non-pathogenic microbes of the same genus as the virulent ones exist led him to produce a rabies vaccine by passing the virus through rabbit spinal cords. By the 1930s, several live vaccines were developed for use in man: for typhoid bacillus, plague bacillus, or for other pathogens. The production of live vaccines, however, is difficult. It requires identifying less virulent strains that still confer protection and a thorough understanding of the virulence factors. The development of procedures for the purification of non-pathogenic microbial fractions or for the inactivation of virulent microbes made possible the use of whole killed microbes as vaccines. Nevertheless, the induction of protective immunity depended on the preservation of intact determinants. To reduce the risks of reactions, the focus shifted to the improvement of the design of classical vaccines. The utilization of surface glycoproteins or non-virulent proteins as vaccines was proposed in the 1980s. With these approaches, the feasibility of the vaccination against a pathogen would depend on the understanding of the humoral onset of the immunity. These efforts led to a persistently active research area in vaccinology of trying to devise safer vaccines by using well-characterized antigenic determinants. Unfortunately, the above-mentioned methods of vaccine design are very conservative in the sense of requiring considerable previous knowledge of the pathogen’s biology and pathogenesis. Moreover, the efficacy of classical vaccines is often poor in immunocompromised hosts, such as the elderly or in individuals infected with HIV. These insufficiencies, together with the growing interest in gene-based research areas, fueled the search for new, non-conventional methods of vaccination. Furthermore, attempts were made to use genetic transfer as a mean for immunization. Even before the emergence of the gene therapy concept, findings in virology and myology during the 1900s led to believe that genetic transfer can readily occur in nature and that naked nucleic acid can enter and be expressed in target cells. The advent of recombinant DNA technology rekindled the interest in understanding the nature of the biologically active agent responsible for genetic transfer. The development of genetically engineered live attenuated vaccines fueled endeavors aimed at using foreign coding sequences for the immunization against persistent viral infections such as HIV. The emergence of candidate vaccines relying on engineered strains sparked speculation about the wider use of these tools. In the mid-1980s, naively injected purified DNA from pathogens were shown to elicit immune responses to these pathogens in mice. Although the concept was rapidly accepted as an ingenious way of vaccination, questions arose regarding the allowable limits on containment in the developed world.
2.1. Early Research and Discoveries
The mid-20th century was a time of scientific discovery and development, including the building blocks of mRNA vaccines. First, the first step came in 1956 when an experiment with hybrid DNA strands in a mouse experiment with a fowl plague virus, a strain of influenza, accentuated the connections between nuclear DNA, cytoplasmic RNA, and surface protein. Also, the team of Sydney Brenner discovered that the genetic code was comprised of coils of three bases using in vitro synthesis of poly-U RNA. Further down the road, Robert W. Holley deciphered the structure and sequence of a yeast tRNA, thus paving the way for similar discoveries for other types of RNA. With this background of knowledge, the background for the advances of mRNA vaccines was set [4].
In 1974, a big year for those early discoveries, the first mRNA isolation occurred. The isolated mRNA from Vesicular Stomatitis Virus in cell extracts directed the synthesis of virus proteins in reticulocyte lysates. In the early 1980s, an unexplained phenomenon followed by an injection of naked mRNA into the cytoplasm of laboratory mice. Soon after, liposome-coated in vitro-transcribed mRNA was capable of inducing the synthesis of proteins in the recipient cells. Later on, mRNA vaccines as an idea included the codon-optimization of mRNA, development of the Polyethylenimine (PEI) polymer, a gold standard in preparing mRNA nanomedicines, and dramatic progress in formulating cationic lipid nanoparticles [3].
2.2. Advances Leading to COVID-19 Vaccines
Advances in Nucleic Acid Vaccines. Over the last two decades, remarkable advances have been made toward the establishment of nucleic acid vaccines, including oligonucleotide-based vaccines such as plasmid DNA- and mRNA-based vaccines, for human use [5]. These advances have encompassed the development of antibiotic-free, animal-component-free, and plasmid construction methods used in DNA vaccines to optimize mRNA transcripts for assembly into lipid nanoparticles (LNPs) for use in mRNA vaccines. Several clinical trials involving mRNA vaccines have been initiated, primarily to prevent cancer, allergies, and infections. EHMC609, a therapeutic mRNA vaccine that targets antigens from HER2-positive cancer cells, was the first mRNA-based therapeutic vaccine to enter a clinical trial, demonstrating the safety of the vaccine in humans. A candidate vaccine targeting Rabies virus glycoprotein mRNA encapsulated in LNPs; however, the vaccine candidate has not yet been tested in humans. mRNA vaccines generated in vitro with high bioproduction yields were developed for a variety of infectious diseases, including Zika virus, seasonal influenza, human immunodeficiency virus (HIV), Middle East respiratory syndrome (MERS) virus, and severe acute respiratory syndrome (SARS).
Advances Leading to COVID-19 Vaccines. The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019 precipitated the COVID-19 pandemic, resulting in millions of infections and deaths worldwide. Rapid development and deployment of safe and effective vaccines are urgently needed to ameliorate the pandemic and facilitate recovery from its impact. Notably, years of efforts in canonical drug and vaccine development for SARS-CoV-1 and other related coronaviruses culminated in the development of viable safe and effective mRNA vaccines against the COVID-19-causing SARS-CoV-2 viruses within 11 months of the release of the viral genome sequence [3]. mRNA vaccines have emerged as one of the most promising strategies to develop effective vaccines, especially against infectious diseases. Stability of RNA is crucial for the application of such vaccines.
3. Mechanism of Action
Newly-designed vaccines often come with a sense of skepticism; many people remember the panic of the swine flu vaccine back in the 1990s that was withdrawn after a few years of use, or the early days of the HPV vaccine. However, the exploratory nature of DNA and especially mRNA constructs is relatively new to the vaccine front. Safety and efficacy concerns with live attenuated and inactivated vaccine platforms offer a chance for mRNA-based technologies to shine. The novel candidate BNT162b2 vaccine sought to address these concerns by developing an mRNA construct expressing the SARS-CoV-2 S glycoprotein. This construct was then packaged into lipid nanoparticles (LNPs) for delivery. Observations of rVSV-SARS-CoV-2(S) challenged mice immunized with LNP-mRNA |vaccine models showed robust immunogenicity with neutralizing humoral antibody responses, polyfunctional T cell responses, and protection from progressive disease [1].
In all these capacities, mRNAs mimic viral transcripts. Once delivered, their translation is recognized by cellular machinery, allowing for rapid amplification of the target antigen. Diverse antigenicity profiles across different cellular compartments elicit varied T cell responses. Initial uptake by professional antigen presenting cells (APCs) provokes a powerful and unique immune response. This response is then propagated to bystander cells, which leads to even wider antigen amplification and a more thorough immune response. FLAcc is composed of cis-acting elements from West African Ebola virus and foot-and-mouth disease virus that exert an influence on the inherent stability of rRNA, and its effect was confirmed with opposition to the translation of both β-globin and enhanced green fluorescent protein mRNAs [6].
3.1. mRNA Delivery and Translation
Cellular entry of free mRNA into mammalian cells is a post-transcriptional multi-step process that includes mRNA transport, delivery to subcellular compartments, escape from the endosomal network, and translation into proteins. The notion of chemotransport of mRNA (to be enclosed in liposomes or other particulate carriers to cells) has emerged beyond just oligodeoxyribonucleotides (ODN) and has become more important for the clarity of the latter. Recent advances in new 2-3D mathematical models and experiments help clarify much of the cross-talks between lipid membrane and ODN/mRNA leading to endosome escape [7].
The understanding of the first step which includes the transport process of the mRNA (transportation in the cytoskeleton, diffusion, and drift) and the cellular events (the competition between diffusion and binding via electrostatics in the cellular surface area, adherence on the surface of cells, and so on) has blossomed recently. Today, it is clearer that the floating mRNA/drug mass will not be simply sucked by the porous cell surface, and/or attach to the cellular membrane like a barnacle in the sea where much of the cargo will be lost; rather it needs to overcome a binding energy barrier on the order of some tens of kBT before strong appropriation will happen. For the “enemy” drugs, the cell senses their presence and will need to undergo extra cellular events such as endocytosis in a timely manner as a kind of cellular immune surveillance [2]. On the other hand, the injectable mRNA drug mass would be relatively tiny (in the range of pico- to nano-moles each time) compared to the cell-free surrounding liquid medium where the average waiting time for one mRNA/drug into a given cell in the sigmacell level could take much longer than the physiological time scale of the cellular events in the cellular surroundings. This has led to a concern of how to improve its efficiency uptake by cells, and it can now be more clear-cut and mathematically modelable.
3.2. Immune Response Activation
One of the most important advantages of mRNA vaccines is their ability to activate the immune response and induce immunity. Generally, the immune response can be divided into two branches: the humoral arm, comprising B cells and antibodies, which neutralize pathogens and prevent infection, and the cellular branch, comprising CD4+ and CD8+ T lymphocytes, which can kill infected cells and act in concert with other immune cells to eradicate the pathogen. Upon first exposure to a pathogen, the body utilizes the innate immune system to recognize conserved molecular patterns associated with pathogens, such as nucleic acids, lipids, and polysaccharides. This leads to the activation of antigen-presenting cells, primarily dendritic cells (DCs), which promote the acquisition of antigenic material and express costimulatory and MHC molecules. The subsequent migration of activated DCs to the draining lymph node (dLN) stimulates antigen-specific T cells and B cells, inducing adaptive immunity [1]. While DNA vaccines rely on the uptake of naked DNA by cells, which then transcribe and translate the encoded antigens in the cytoplasm, mRNA vaccines, which transport the in vitro transcribed mRNA into the target cells, also harness the intrinsic endosomal uptake pathways to recognize the vaccine components. The recognition of the mRNA constituents by cellular sensors stimulating innate immunity (e.g., Toll-like receptors (TLR)) and the cytoplasmic routing of mRNA employing chaperones and helicases that eventually promote translation and the peptidation of the MHC Class I and II pathways are striking similarities between both vaccine technologies [8]. Hence, mRNA vaccines can be viewed as a unique platform to activate and control the immune response to elicit the desired adaptive immunity.
4. Advantages and Challenges of mRNA Vaccines
Vaccination is one of the safest and most successful medical interventions for preventing the severe outcome of infectious diseases. In addition to the established inactivated and live attenuated vaccine platforms, there is a growing interest in novel vaccine designs, and with it, flexibility in the administration of vaccination routes and vaccination types regarding safety. Recently discovered, and rapidly developed COVID-19 mRNA vaccines paved the way to use novel platforms and technologies that make a rapid response to outbreaks possible. Nucleic acid-based (including both mRNA- and DNA-plasmid-based) vaccines are promising vaccines for human infectious diseases in terms of safety, production, and rapid development [3]. Drugs and vaccines are widely used big pharmaceutical companies in the world. For any vaccine platform technology, mRNA constructs are used as a therapeutic approach to infectious diseases in plants and animals. Exploitation of mRNA vaccine platforms is more cost-effective and are satisfactory immunogen. To construct suitable mRNA vaccine candidates, selection of mRNA transgene is essential (i.e. immune-enhancing capability, modulation, and durability of immune response).
Vaccines against infectious diseases have been mainly focused for long, however, this paradigm changed hugely after the emergence of SARS-CoV-2. The rapid development of mRNA technologies of COVID-19 vaccines encouraged the exploration of this technology in infectious diseases other than COVID-19 as well as non-infectious diseases like cancers [9]. mRNA vaccines platform has a pertinent potential for a wide range of vaccine targets. Enhanced potency of current mRNA vaccine technology is desired to ensure a spectacular safety record and the success of any worldwide vaccination campaign. Understanding the mechanism of intracellular transcription and translational events may facilitate an answer to the question of why mRNA vaccine potency varies widely. On the other hand, numerous studies are under progress to sharply tune these processes via optimization of different formulations such as LNPs and lipids. Moreover, various technologies currently under development can help to formulate a vaccine regimen that will generate a particular type of immune response (i.e. inhibiting Th1, Th2, and Th17 response) by precisely modulating the vaccine CIDAs (chemokines, cytokines, immune activator/inhibitor) blend, their concentration, and the delivery route. Despite several mRNA vaccination success stories in recent years, vaccine efficacy must still be proved and justified using solid scientific evidence.
4.1. Advantages of mRNA Technology
Synthetic vaccines are a promising approach for a mRNA-based immunization strategy. Subunit vaccines consist of only a few proteins, and some of them are unable to induce stable adaptive immune responses, such as hepatitis B virus (HBV) or human papillomavirus (HPV) proteins. The initial protein delivery into antigen-presenting cells (APCs), preferably in their native folded state, is of crucial importance in all vaccine development approaches. Because the subunits of the common vaccines are either produced by recombinant technology or purified from natural sources, such proteins are non-pathogenic by definition [3]. The cellular mechanism(s) of transport of proteins in APCs as non-pathogenic particles is also being intensively studied. Peptide-based vaccines consist of the shortest T-helper cell epitopes plus a few MHC class I-restricted CTL epitopes. This approach might be applicable to the present known oncogenic viruses, including cervical cancer vaccination in women.
mRNAs are stabilizing agents of the existing vaccines or adjuvants that assist in the improvement of immune responses. Liposomes are known to induce the “double-stranded (ds) structural change” of proteins. It can theoretically initiate the immune responses in all important stages [9]. Poly (lactic-co-glycolic acid) or polymeric nanoparticles are discussed as structures that can be delivered via the intranasal route, leading to the stimulation of specific immune responses. Nanoparticle carriers are being developed in some present controlled or sustained delivery vaccine strategies. However, vaccine efficacy has not yet been sufficiently demonstrated. The present nanoparticles released viral particles in circulation immediately. Robust vaccine immunogenicity and efficacy rely on these structures passing through the first line of cellular defense formed by macrophages and dendritic cells localized near the site of application.
4.2. Challenges and Limitations
The challenges and limitations of mRNA vaccines are considered. As previously mentioned, mRNA vaccines are a new and exciting technology. However, there are challenges and limitations confronting them. The vast majority of vaccine studies focused on the SARS-CoV-2 virus concentrate on the design, efficacy, and safety aspects of vax. These are extremely important topics. However, mRNA vaccines are a new technology, and they operate differently than existing platforms, so technological aspects of mRNA vaccines are examined [1]. There are challenges and limitations regarding delivering mRNA and formulating it into an effective vaccine. Consideration is also given to issues concerning the stability of the vaccines and the possibility of production interruptions. Finally, biosafety issues, risk assessments, and annoying rumors that need to be addressed are examined [3].
Disadvantages of mRNA vaccines against SARS-CoV-2 Due to the scale of the ongoing pandemic, the accelerated development of mRNA vaccines against the SARS-CoV-2 virus has been phenomenal. Nevertheless, there are disadvantages to the current mRNA vaccines, ranging from the technological aspects of designing and producing them to practical issues regarding logistics, safety concerns, and occasionally disturbing misinformation. In addition to the anticipated short-term side effects, concerning safety signals might arise involving mRNA vaccines. Media reports of suspected but seldom documented onset of very rare cases of myocarditis and pericarditis disorders, mainly occurring in young men after the second mRNA vaccination, are being scrutinized. With respect to current vax strategies worldwide that involve the administration of mRNA against the Spike protein (S), evolutionary considerations might lead to the emergence of more virulent SARS-CoV-2 variants.
5. Applications Beyond Infectious Diseases
The initial applications for mRNA, however, focused primarily on infectious diseases. As vaccine developers learned about the strengths of mRNA technology, pipelines were broadened beyond infectious diseases and into cancers, autoimmune diseases, allergies, and even cardiovascular diseases, all of which have vastly different mechanisms and challenges than infectious diseases [10].
With a vaccine approach to infectious diseases, a pathogen-associated antigen is typically expressed for immune system screening, either to develop neutralizing antibodies to infection or immune memory to protect against future infection. Such an approach with mRNA is currently being explored in Phase I trials for various cancers, where personalized mRNA vaccines encoding neoepitopes arising from somatic mutations in tumors are administered to patients to enrich the neoepitope-specific T cell repertoire and restore tumor immunity. This is generally done in combination with check-point inhibitors to modulate the immunosuppressive environment. Although such approaches have been studied for decades with different technologies, including peptides, proteins, and DNA, low immunogenicity, limited T cell repertoire coverage, and difficulty targeting multiple neoepitopes have thus far resulted in a modest benefit for overall survival [9]. Further, cancer vaccines would be of little use for patients with advanced-stage cancer, where curative intent is generally not possible, and focus on relief of pain and suffering. Thus, creating an agent that can broadly cross-boost immunity against a wide variety of cancer-associated antigens and protect irrespective of tumor antigen expression becomes an urgent and compelling challenge.
5.1. Cancer Immunotherapy
Focusing on cancer immunotherapy, mRNA research and on-going trials stand in the domain of infectious diseases. However, the prospects for mRNA to combat cancer are immense and it is anticipated to embrace innovation and adventure in a world beyond COVID-19. Indeed, mRNA as an innovative ammo for vaccination in infectious diseases eradication has other existent revolutionary applications, such as immunomodulation in cancer, autoimmune and genetic diseases. Nonetheless, the effects of mRNA extensibility in other diseases arena are blotted and so far limited. As an alternative to anti-pathogen prophylaxy, the harnessing of mRNA for cancer vaccination is conceived as a simple “vaccine manufacturing”. Cancer vaccination by mRNA has unfolded various parallel innovative tools and approaches providing the conception to usher the fight against cancer with cutting-edge avenues of immunotherapy. Cancer vaccination with mRNA is envisaged as an innovative and attractive approach, revolutionizing the concept of vaccination itself in the domain of vaccinology.
Since the first introduction of mRNA vaccines in 1993 to activate immune response in vivo, mRNA quickly became the spotlight of cancer immunotherapy [11]. The earliest mRNA vaccines were all based on virus genomes, and a liposome-mRNA vaccine that could induce cognate cytotoxic T cells also resulted in the destruction of melanoma cancer cells was developed afterwards. Over the past decades, mRNA vaccines have demonstrated great advantages over conventional vaccines and thus have been established as novel strategies in cancer therapies. To date, replicating modified mRNA, unmodified mRNA and virus-derived mRNA are the three main types of mRNA vaccines in the application of cancer immunotherapy. In this research, this paper comprehensively reviews the potentialities and challenges of these three kinds of mRNA vaccines including delivery, expression, safety, stability and persistence [12]. The perspectives of mRNA vaccines in cancer immunotherapy are also addressed.
5.2. Allergy Treatments
Anaphylaxis, a severe and potentially life-threatening hypersensitivity reaction, can occur following exposure to allergens, such as foods, venom, and drugs. The involvement of IgE antibodies and mast cells in allergy has been known since the 1960s [13]. Treatment options for allergic diseases are limited and provide only symptomatic relief. Only a few approaches are available for the causal treatment of allergy. Traditional forms of allergen immunotherapy have largely focused on parenteral formulations of whole allergens, such as in allergen subcutaneously injected allergen immunotherapy (SCIT) or sublingual immunotherapy (SLIT). These approaches are long-term treatments and require several months or even years of ongoing treatment. The main aim of allergen immunotherapy is the switch from an allergen-driven Th2-dominated response to a more tolerant Th1/Th0-dominated immune reaction.
Innovative approaches incorporating mRNA vaccine technology have been suggested to facilitate new strategies in the field of allergy immunotherapy. mRNA vaccines encoding allergens or regulatory proteins can be simply synthesized and prepared in large quantities, whereas the production of proteins requires purification processes. mRNA vaccines are non-infectious and non-integrating; thus, there is no risk of insertional mutagenesis. Moreover, naked mRNA and mRNA in pDNA vaccination do not trigger antibodies against the vector but only respond to the encoded antigen. Preclinical studies demonstrate that a one-shot treatment of RNAs coding for a model allergen can prevent the development of IgE sensitization in mice. The immediate inhibition of allergic skin reactions in a wheal-and-flare model confirmed the restoration of tolerance against allergens [2].
6. Regulatory Considerations
The rapid advancement of mRNA vaccine technology has led to groundbreaking developments in the field of immunization, but the need for robust regulatory mechanisms for vaccine approval and safety monitoring is more crucial than ever. Regulatory bodies have devised approval processes that scrutinize not only raw data but also the trial infrastructure, ensuring data integrity, methodology robustness, and participant safety prior to any vaccination [1]. In the United States, mRNA vaccines like BNT162b2 (Pfizer/BioNTech) and mRNA-1273 (Moderna) received Emergency Use Authorization (EUA). This was possible due to rapid clinical developments stemming from lymph node and splenocyte studies under the Complications of Treatment (CoT) model. The safety, immunogenicity, and persistence of the two-dose BNT162b2 and mRNA-1273 vaccines were evaluated at the 10-μg and 30-μg doses, respectively, using a luminescent SARS-CoV-2 challenge. Based on a thorough review of the vaccines’ safety and effectiveness data, the vaccinated nonhuman primates exhibited robust protection against mild-to-moderate SARS-CoV-2 infection, leading to an exceptional EUA approval timeframe of approximately 8 months.
Essential facets of mRNA vaccine safety monitoring have also emerged as demands on regulatory bodies have increased. Monitoring after marketing authorization became more than a safety assurance strategy; it evolved to ensure the safety and effectiveness of treatments authorized to address public health emergencies. This section summarizes the state of the art as of early 2022 of the postmarket surveillance of large-scale COVID-19-vaccine immunization campaigns [3]. Various efforts to fill identified knowledge gaps in terms of addressing potential safety signals, including advances in the implementation of social listening strategies, and discuss how the knowledge generated in the context of COVID-19 might influence the future direction of postmarket surveillance for new therapeutics going forward are covered.
6.1. Approval Processes and Safety Monitoring
The goal of vaccine development is the creation of safe, efficacious, and high-quality preparations. Development of a new vaccine candidate typically consists of laboratory and animal studies in preclinical phases, labor-intensive large-scale testing in clinical phases, and production in good manufacturing practice (GMP) quality standards. Following initial market authorization in certain countries or regions, further studies (phase IV or post-marketing studies) are performed. These studies explore safety, immunogenicity, and effectiveness in a broader population and the implications for current vaccination strategies. Due to their rapid development and approval, mRNA vaccines also generated discussions on the clinical trial protocols used, the biomarker thresholds required for safety and immunogenicity, and aspects of supply chain and logistics [3].
Broad and continuous safety monitoring is an integral part of the approvance of any vaccine. All authorized vaccines have passed preclinical and clinical trials, in which estimated risks were evaluated. Monitoring systems are set in place to identify possible unobserved events following licensure and prolonged vaccination effort. The past decades have shown that, irrespective of vaccine platform, signs of underreported adverse events or new safety signals arising from the vaccination program become visible within the first six months [14]. Hence, once guaranteed relative low risk and a high-benefit-to-risk-ratio by the estimated prior knowledge, any vaccine undergoes safety surveillance. In addition to national SAFETY and effectiveness databases, the World Health Organization (WHO) encourages the establishment collaboratives for signal detection, such as the Global Vaccine Safety Initiative, Pilot Global Vaccine Safety Initiative, and Global Vaccine Safety New Initiative.
7. Global Access and Equity
Many mRNA technologies were developed under the auspices of COVID-19 vaccine candidate pipeline programs, however, equitable access to these robust and promising technologies remains a significant challenge. Efforts have been made to facilitate the global transfer of mRNA technologies, know-how and upskilling and ensure that developing areas have access to these technologies to manufacture vaccines locally. Inequitable access to COVID-19 therapeutics and vaccines globally is concerning, especially after discovering a host of new and concerning variants [2]. As of mid-April 2022, 75% of COVID-19 vaccine doses had been administered in high-income countries, whereas only 0.5% of doses had been administered in low-income countries, despite international efforts to work towards equitable access.
Even with existing access to mRNA technology in various developing countries, vaccine rollout has been slowed due to concerns about equitable access stemming from both affordability issues as well as logistical barriers. Current DNA & protein-based immunization strategies are highly dependent on cold chain processes — stringent refrigerative conditions for transport, storage and distribution [15]. DNA & protein-based vaccine candidates have environmentally compatible alternatives that do not require severe temperature control, yet since mRNA vaccines are nucleic acid-based therapeutics, they remain limited to ultra-cold environments of -70 degrees Celsius. This creates an expensive, inflexible and energy-consuming logistical hurdle for the already strained global immunization infrastructure. Highly-developed low-income countries are consequently at a much greater disadvantage with regards to the storage, transport, and distribution of mRNA vaccines. If mRNA-based immunization on a global scale is to be possible, the mRNA platform must therefore be able to be developed into a more robust technologically as well as a distributively flexible system, namely with special regard for at least a 2-8 degrees Celsius refrigerative range compatible with that of existing vaccines.
7.1. Challenges in Distribution and Storage
Distribution and storage represent one of the most complex challenges needing to be addressed. Inequitable access to vaccines is not only a function of costs and prioritisation in national vaccination strategies, but also a result of who has the required infrastructure to deliver, store and manage these vaccines post-complication. Complexity increased manifold, given that vaccines need to be distributed globally. Some islands and landlocked countries might need to import these vaccines using air freight, and countries need to work closely with airlines who have historically never transported vaccines [16]. Therefore, there is no guarantee, based solely on purchase agreements, that vaccines will be readily available to those countries that need it. Time is of the essence.
Minimal delays during distribution and storage are paramount, especially given that many vaccines need to be kept cold. Stresses experienced during the distribution chain include temperature variations, transport vibrations and shocks, and exposure to humidity or light. Distribution concerning mRNA-LNP vaccines (lipid-nanoparticle encapsulated mRNA vaccines) remains largely unchartered territory, and much remains unclear. Vaccine stabilisation during storage and screening of conditions will have to be determined. How these biopharmaceuticals survive rough shipping scenarios, such as common shocks experienced during land transport, remains unknown [17].
8. Future Directions in mRNA Technology
Looking ahead, there are several potential future directions for mRNA technology. The first is improving vaccine design. New mRNA vaccine candidates for other infectious diseases, including HIV, flu, RSV, Zika, HPIV, and other viruses are being tested in clinical and preclinical studies. It is expected that many of these new candidates will use optimizations and formulations from the SARS-CoV-2 vaccine development, thereby speeding up their development [18]. The second is novel applications of mRNA, including engineered cell therapies, mRNA vaccines for cancer, replacement of missing proteins, or mRNA gene editing. There remains an emphasis on preclinical research studying delivery efficiency, safety, efficacy, and stability of these new mRNA-based modalities. Finally, there are new computational virology approaches for modeling RNA structures and interactions with RNAPs, ribosomes, or immune sensors. Improvements in speed, accuracy, and usability of these models will enhance the impact on all RNA-based research areas. Although genetic vaccines comprise only a small fraction of the vaccine market now, the success of mRNA vaccines in the COVID-19 pandemic will likely increase interest and investment in other genetic vaccines. There is optimism that this technology will become even more effective and precise, creating engineered vaccines more quickly tailored to emerging diseases. Ultimately, this approach has great potential for revolutionizing vaccination.
8.1. Enhancements in Vaccine Design
Emerging advancement and innovations in vaccine design is presented specifically focusing on mRNA-based vaccine development. Decoding pathogens’ genomes has enabled synthetic antigen design to develop a new class of recombinant vaccines. New technology platforms are being developed to improve the safety and efficacy of classical vaccine strategies. An overview of the design principles of vaccine platforms and their use to respond to emerging diseases is outlined. Improved decoding of pathogen genome sequences necessitates the new paradigm of vaccine development built upon universal space/synthetic platforms that will have a meaningful impact on developing future vaccines [3].
Same methodology can be employed using the uncovered knowledge of transmission pathways and zoonotic reservoirs for vaccine development against missed outbreaks. New approaches to design and manufacture the next generation vaccines based on synthetic platforms that will enhance the safety and efficacy are proposed. Novel designer adjuvants will be in particular focus to modify the immunogenicity of vaccine platforms [9].
9. Conclusion and Implications for Public Health
Reflections on the implications of mRNA technology for public health are provided, along with a summary of the key insights and challenges to be considered. Numerous prominent infectious diseases and viruses take center stage in public health discussions, including the coronavirus that causes COVID-19. Recently, vaccines using mRNA technology for public use were rolled out in many nations in a race to ward off a pandemic. However, a question looms: what now? Could this technology be used to ward off other diseases and viruses? The answer, indeed, is yes. In fact, mRNA technology has the potential to be utilized beyond infectious, viral diseases, impacting health care even more. The implications of mRNA vaccines reach as far as cancer, driving personal health care, and targeting any infectious disease with a strong and safe vaccine in months rather than years [5].
Planning is underway to expand usage of mRNA vaccines in health care settings globally. However, challenges remain in development days, safety, and acceptance. Herd immunity is critical for mRNA vaccines or any vaccine’s success, especially in infectious disease. Some potential users are hesitant toward vaccines in general, especially newer designs like those utilizing mRNA technology. Their hesitation is born from deep-seated conspiracy theory and skepticism, and it should be taken seriously. Efforts to blunt mRNA technology’s political affiliation should be of utmost importance [18].
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