1. INTRODUCTION:

Infectious diseases have gained much attention of scientists since past several centuries. Many more attempts had been made to control such disease. In ancient era various practices were performed in Indian and Chinese traditional medicinal systems to control dried infectious disease. Number of vaccines and vaccine candidates were discovered and emerged into the market in past two centuries. Vaccination is a great and cost-effective approach to the prevention of disease, particularly infectious diseases¹. Vaccines development has huge historical background and various researchers contributed in it.

Dawn of Vaccination began in year 1796, when Edward Jenner realized that, following exposure to cowpox, milkmaids were protected from smallpox. Jenner explicated that exposure to cowpox could therefore also furnish protection in humans from smallpox^2,3. Jenner scraped cowpox matter from Sarah Nelmes' arm and injected it to the skin of James Phipps, an 8-year-old child⁴. Jenner now had enough empirical proof of smallpox immunity². Since then various infectious, parasitic, and non-infectious diseases, such as cancer and Alzheimer’s disease were encountered by different vaccines. In the year 1803, the phrases “vaccine” and “vaccinate” were coined. Vaccinae is come from the Latin terms vaccinus, which means "pertaining to cows, from cows," and vacca, which means "cow."^5,6.

Vaccines can be divided into different subgroups based on their origin and fabrication method². Vaccines are presently accesible in eight various sections⁷. Live-attenuated vaccines are Available since the 1950s. Live attenuated vaccines (LAVs) are made from disease-causing organisms (viruses or bacteria) that were weakened in the laboratory. In a vaccinated person, they will grow, nonetheless, it is because they are frail, they will produce no or very minimal sickness⁸. The use of live attenuated bacteria started with Louis Pasture's discovery of attenuation and immunogenicity of chicken Cholera culture in 1879³. These vaccines contain an attenuated form of the living microbe that can induce immunity but not cause the disease. These vaccines confer lifetime immunity with only a single dosage or two triggering cellular and antibody responses that are powerful⁹. Measles, mumps, and rubella virus vaccine is a live attenuated vaccine made up of weakened Measles virus strains such as Rubella, Rubula, and Rubeola. Inactivated or “killed” vaccines contain killed form the germ that is provokes a disease. Inactivated vaccines typically do not provide immunity (protection) as strong as live vaccines. In this vaccine the microbes are completely inactivated or practically killed with chemicals heat, or radiation. Even so, the antigen, the membrane and genetic material of microbes remain intact. The dead microbes in the inactivated vaccine are incapable of mutating back to their virulent form; making these vaccines can be stored at room temperature. However, these vaccines required several additional doses to maintain immunity in host system as compared to live attenuated vaccine because they energise an immune system that isn’t working as well^2;9. Toxoid vaccines be using a toxic substance created by the bacteria that causes the sickness. The bacterial exotoxin is purified to make them. Rather than the germ itself, they develop immunity to the elements of the germ that cause disease. That is, rather than attacking the entire germ, the immune system targets the toxin. Recombinant vector vaccines, carbohydrate-based vaccines, Conjugated vaccines, Subunit vaccines, nucleic acid–based vaccines. The appearance and spread of a new form of respiratory coronavirus in the current pandemic (severe acute respiratory syndrome, SARS, CoV, or 2019 novel CoV) recalls the last two encounters with CoV, namely SARS-CoV and Middle East Respiratory Syndrome Coronavirus (MERS-CoV). The development of viable vaccinations for SARS-CoV or MERS was delayed or abandoned once the pandemic was under control. Following the H1N1 pandemic, a rigorous review of pandemic preparedness was published, stressing the failure to provide adequate vaccines where they were needed, and which had not been done prior to the importance of SARS-CoV. This has caused a delay in the discovery and formulation of candidate vaccines for SARS-CoV2, necessitating a massive effort from both the public (academic institutions and government agencies) and private (industry) sectors to accelerate vaccine development. The current pandemic has also brought to light the difficulties of timely vaccination distribution for seasonal flu and other infections, together with the troublesome "cold chain." These issues are strongly reliant on vaccination formulations and features, and thus on pharmaceutical research and innovation⁷. Traditional vaccine approaches, such as live attenuated vaccine, inactivated vaccine and subunit vaccine provide long-term protection against a wide range of hazardous diseases, although mRNA vaccines represent promising alternative to conventional vaccine strategies owing to the fact that high potency, capacity of rapid development, cell-mediated immunity, potential low-cost, simplified production process and safe administration^10,11. Pfizer and Moderna vaccines have been approved for emergency use by the US Food and Drug Administration and comparable authorities around the world, bringing mRNA vaccines to the attention of the world. mRNA is new type of vaccine that arouse an immune response by transfecting synthetic mRNA encoding viral antigens into human cells^12,13,14.

2. Human Immune System:

The immune system is a group of cells, chemicals and processes that work together to protect the skin, respiratory passage, intestinal tract and other areas from foreign antigens, such as microbes, viruses, cancer cells, and toxins. Innate immunity is the body’s first line of defence against an invading pathogen. It is an antigen-independent defence mechanism that the host employs immediately or within hours of encountering an antigen. The innate immune response lack immunologic memory, it will be unable to recognize or memorize the same pathogen if body is exposed to it again in the future. Adaptive immunity, on the other hand, is antigen-dependent and antigen-specific, implying a time lag between antigen exposure and peak response. Memory is a key feature of adaptive immunity, as it allows the host to build a more quick and effective immune response when exposed to the antigen again¹⁵.

Figure 1 Innate and adaptive immune system.

2.1 Innate Immunity:

The key function of innate immunity is the rapid recruitment of immune cells to areas of infection and inflammation by means of production of cytokines and chemokines. Phagocytes (macrophages and neutrophils), dendritic cells, mast cells, basophils, eosinophils, natural killer (NK) cells, and innate lymphoid cells are an element of the innate immune system (Fig.1). Macrophages and neutrophils both have the same purpose: to engulf (phagocytosis) microorganisms and kill them via numerous bactericidal routes. Unlike neutrophils, which are short-lived cells, macrophages are long-lived cells that participate in phagocytosis and antigen presentation to T cells¹⁵. Dendritic cells phagocytose and act as APCs, initiating the adaptive immune system and serving as a vital link between innate and adaptive immune system. Natural killer cells are chief in the rejection of tumor and the elimination of virus-infected cells. NK cells are also a major generator of interferon gamma, a cytokine that aids in the mobilization of APCs and the establishment of efficient antiviral immunity¹⁶.

2.2 Adaptive Immunity:

The development of adaptive immunity is aided by the innate immune system's actions, which is critical when innate immunity is ineffective in eliminating infectious agents. The adaptive immune response's main functions are to recognize and identify certain "non-self" antigens from "self" antigens. The cells of adaptive immunity includes antigen-specific T cells, which are stimulated to proliferate through the action of APCs, and B cells (Fig.1), which alter into plasma cells to produce antibodies¹⁵.

2.3 T cells and APCs:

T cell that develops in the bone marrow from hematopoietic stem cells and migrates to the thymus. To detect a specific antigen, T cells need the help of APCs (typically dendritic cells, but sometimes macrophages, B cells, fibroblasts, and epithelial cells). On the surface of APCs, a protein complex known as the major histocompatibility complex (MHC) is expressed. T cells become activated when they come into contact with a digested APC and antigen and is displaying the correct antigen fragment (peptides) bound to its MHC molecule. T cell movement throughout the body (via the lymphatic system and blood stream) and their concentration (together with APCs) in lymph nodes improve the chances of the right T cell coming into touch with an APC carrying the proper peptide MHC complex. The TCR is stimulated by the MHC antigen complex, and T cells emit cytokines that assist to govern the immunological response. As a result of the antigen presentation process, T cells are stimulated to differentiate into either cytotoxic T cells (CD8 + cells) or T helper (Th) cells (CD4 + cells). CD8+ cytotoxic T cells are solely accountable for the decimation of infected cells with foreign agents such as viruses, including tumor cells that express antigens. They are triggered when their TCR has an interaction with a peptide bond on the MHC class I molecule. Effector cells are produced by the clonal proliferation of cytotoxic T cells, which release a substance that causes apoptosis of target cells. CD4+ Th cells are crucial in developing and optimizing the immune response. These cells have very little cytotoxic or phagocytic potential, hence they cannot destroy infected cells or remove pathogens directly. However, they “mediate” the immune response by directing other cells to carry out these functions and regulating the sort of immunological response that arises. TCR recognition of antigen bound to class II MHC molecules activates Th cells, which in turn activates APCs. The regulatory T cell (T reg), a subgroup of CD4+ T cells, also plays a function in immune response. T regulatory cells limit and inhibit immune responses, potentially regulating irrational responses to self-antigens and the development of autoimmune diseases.^15,17.

2.4. B cells:

B cells originate from hematopoietic stem cells in the bone marrow and leave with either a unique antigen-binding receptor on their membrane after maturation. Unlike T cells, B cells can detect antigens without any need for APCs even though they have unique antibodies on their cell surface. The generation of antibodies against foreign antigens is the main purpose of the B cell. B cells multiply and mature into antibody-secreting plasma cells or memory B cells when they are stimulated by foreign antigens for which they contain an antigen specific receptor. Memory B cells are “long-lived” survivors of previous infections, retaining antigen-binding receptor expression. These cells can be triggered to produce antibodies and eliminate antigen upon re-exposure^15,16.

3. mRNA Vaccines:

The concept of genetic (DNA and RNA) vaccines was proposed decades ago in the goal of improving a flexible, easy-to-produce, safe, and effective vaccine class. Until the late 2000s, the priority was on establishing DNA-based approaches¹⁸. Brenner et al. discovered mRNA in 1961, a hereditary substance intermediate in the central dogma¹⁹. mRNA vaccines have depicted a number of distinct advantages over conventional vaccines. First safety, as mRNA is a non-infectious, non-integrating manifesto, there is no potential risk of infection or insertional mutagenesis. Second efficacy, innumerable alteration assembles mRNA more stable and highly translatable. mRNA has self-adjuvant properties, causing a strong and long-lasting adaptive immune response via type I IFN. Third, mRNA vaccines can more efficiently express target proteins because they are expressed in the cytoplasm rather than the nucleus^11,12. In 1990, in vitro-transcribed mRNA was successfully expressed in mouse skeletal muscle cells via direct injection, establishing the first successful attempt at in vivo mRNA expression and demonstrating the feasibility of mRNA vaccine development. Since then, research into mRNA structure and other related technologies has advanced at a rapid pace. Several development constraints caused by mRNA instability, high innate immunogenicity, and inefficient in vivo delivery have been overcome, and mRNA vaccines are now widely studied in a variety of diseases ¹⁰. Initially, much research was conducted on the development of cancer mRNA vaccines, demonstrating the feasibility of producing clinical grade in vitro transcribed RNA. Several studies on mRNA vaccines against infectious diseases have also been carried out, though clinical trials are still limited. For example, Several RNA-based vaccination systems have been used to generate influenza vaccines. RNA-based influenza vaccines generate a broadly protective immune response against both homologous and hetero-subtypic influenza viruses, according to several published studies. Influenza mRNA vaccines show significant promise as an egg-free platform that can produce high-fidelity antigen in mammalian cells. According to new research, the lack of a glycosylation site in the hemagglutinin (HA) of the egg-adapted H3N2 vaccine strain resulted in poor neutralisation of circulating H3N2 viruses in vaccinated humans and ferrets. mRNA vaccine synthesis, on the other extreme, is egg-free, and mRNA-encoded proteins are folded and glycosylated appropriately in host cells following vaccination injection, reducing the possibility of generating erroneous antigens. In the veterinary field, mRNA has been employed to prevent animal infectious diseases. This mRNA vaccination elicited a substantial humoral immune response against both POWV strains and the distantly related Langat virus. As previously demonstrated, modification of nucleosides and codon optimization, can improve translation efficiency by avoiding detection by innate immune sensors³⁴. mRNA vaccines can be categorized into two types: (a) nonreplicating and (b) self-amplifying (also known as self-replicating and replicon) mRNA vaccines. While both types of vaccines share a common structure in mRNA constructs, self-amplifying RNA vaccines contain additional sequences in the coding region for RNA replication¹³. Some key advancements regarding mRNA vaccine is presented in Fig. 2.

3.2. Administration sites for mRNA Vaccines:

The first vaccine were done by scarification of the skin (ie, disruption of the skin’s epidermal layer), most modern vaccines are delivered by means of hypodermic needle and syringe into muscle (i.m.), subcutaneous tissue (s.c.), or skin (i.d.). Vaccines can also be administered by the mucosal route (i.e., orally or nasally), though this method necessitates the use of special formulations to prevent antigen degradation. This is especially the case for oral administration because of the hostile environment that the vaccine must endure within the gastrointestinal system while yet allowing for adequate absorption and avoiding low bioavailability. Since there are so many different vaccinations, several delivery methods are required depending on the vaccine's composition, cellular absorption, or tissue vascularity¹⁸. The following is a list of vaccination routes ³⁸:

a) Intramuscular Immunizations

b) Subcutaneous Immunizations

c) Cutaneous Immunizations

d) Mucosal Immunizations

e) Intranasal Immunizations

4. Immunological Perspective of MRNA:

Based on its self-adjuvanting effect, mRNA can reveal some properties similar to the mRNA virus when it seems like the vector of exogenous genes. In this case, antigen-presenting cells (APCs) detected by mRNA, which activates patterns recognition receptors (PRRs) including Toll-like receptor TLR3, TLR7, and TLR8. In the cytoplasm, double-stranded RNA (dsRNA) can interact to a Retinoic acid inducible gene I (RIG-I)-like receptor, inducing APC maturation, pro-inflammatory cytokine secretion, and type I interferon (IFN) secretion. However, peptide or protein antigens in subunit vaccines are often unable to activate PRRs, adjuvants that can begin and sustain adaptive immune responses are needed to attain the ultimate goal of carrying out the body's immunological response to subunit vaccines. As a result, the strong adaptive immune response and self-adjuvanting properties of mRNA can provide a significant advantage in mRNA vaccines¹⁰.

Type I interferons (IFNs) play an major role in the immune response to mRNA vaccines. In the context of self-amplifying mRNA vaccines, type I IFN has been shown to have a detrimental impact. According to Pepini et al, Blocking the function of the type I IFN receptor increased both mRNA-encoded protein expression with antigen-specific antibody and CD8+ T cell responses. In contrast, Kranz et al. discovered that type I IFN signaling was required for optimal antitumor immunity elicited by an unmodified mRNA-LNP vaccine. Taken together, it appears that type I IFNs may be harmful to some types of mRNA vaccines. The kinetics or magnitude of antigen presentation on MHC class I and II, contributions from other innate immune system components (NK cells, neutrophils, macrophages, etc.), and the cytokine milieu induced by the mRNA and/or the delivery material all play a significant role in the B or T cell response to all mRNA vaccines³⁸.

The paradigm of vaccination is the establishment of antibodies and cytotoxic T cells to create a long-term immunisation against one or more antigens specific for a pathogen or cancer cell. The strategy can be split into three steps: (a) antigen and adjuvant uptake by antigen presenting cells (APCs), (b) APC maturation, and (c) antigen-specific priming B and T cells with the generation of antibodies and cytotoxic T cells APCs are immature dendritic cells, macrophages, B cells, or even immune fibroblasts, which can take-up antigens and are activated by endogenous or exogenous danger signals. Once activated, APCs, particularly dendritic cells, develop a mature phenotype while converting antigens into peptides suitable for expression on MHC I or II. At the same time, the APC emits co-stimulatory signals (e.g., CD80 or 86) and secretes pro-inflammatory cytokines. Ultimately, naive T cells interact with MHC to become cytotoxic or helper T cells. B cells become activated when their B cell receptor (BCR) interferes with soluble or bound antigens, ensuing in differentiation into plasma or memory B cells and the production of antigen-specific antibodies. Besides that, the activation process can be dependent on the presence of helper T cells or can occur in the absence of any other signal. Antibodies can fight viral infections by attaching to the virus's surface, causing steric hindrance, preventing viral infection in cells, preventing virus release from infected cells, blocking hemagglutinin cleavage, activating complement, and fagging the virus to phagocytes for elimination (Fig.3) Cytotoxic T cells are responsible for recognising and killing virus-infected or cancer cells, as well as releasing interferon and tumour necrosis factor. The preference of vaccine, antigen, adjuvant, and route of administration all dictate the quality and magnitude of the immune response primed, and even the duration of the immunological memory³⁷.

5. Delivery Strategies For mRNA vaccines:

Researchers have looked into a variety of approaches for delivering mRNA vaccines. Delivery carriers, such as lipid-derived and polymer-derived materials, for example, have drastically boosted cellular uptake of RNAs, garnering a lot of interest in recent years. Free mRNA vaccinations were also distributed³⁸. Furthermore, dendritic cells were ex vivo loaded with mRNA vaccines and transferred to the hosts³⁹.

5.1. Lipid-based delivery:

Lipids, lipid-like substances, and lipid derivatives have all been used to make lipid and lipid-derived nanoparticles (LNPs) for in vivo mRNA vaccine delivery³⁹. A cationic or ionizable lipid, cholesterol, a helper phospholipid, and a polyethylene glycol (PEG) lipid are the most common components. Although cationic lipids can effectively interact with anionic RNA molecules, their persistent positive charge renders them more hazardous. Ionizable lipids encapsulate RNA under acidic conditions while maintaining a neutral or weakly cationic surface charge at physiological pH, minimising non-specific lipid-protein interactions and enabling RNA release in the cytoplasm¹⁰. The PEG-lipid conjugates have the potential to stabilise nanoparticles during synthesis and offer a hydrophilic outer layer that extends circulation time after in vivo delivery ³⁹. LNPs have also been utilized in the treatment of cancer (B16F10 melanoma). IM, ID, SC, IN, and IV injection are all options for lipid-based mRNA vaccine delivery. LNP-based vaccines based on modified mRNA elicited a strong immune response^34,40.

5.2. Polymer-based delivery:

Polymeric materials, including as polyamines, dendrimers, and copolymers, are functional materials that can transport mRNA vaccines. Polymers, like functional lipid-based carriers, can protect RNA from RNase-mediated degradation while simultaneously allowing for intracellular transport. Polymer-based mRNA nanoparticles, on the other hand, exhibit a significant polydispersity in their composition³⁹. One of the most commonly utilised cationic polymers for gene and oligonucleotide delivery is polyethylenimine (PEI). A self-amplifying mRNA encoding influenza virus hemagglutinin and nucleocapsid was integrated into nanoparticles using linear PEI for boosting the efficacy of mRNA vaccines¹⁸. mRNA vaccines were also delivered using anionic polymers like PLGA. Because an anionic polymer was unable to encapsulate the negatively charged mRNA molecules effectively, cationic lipid components were added to construct lipid–polymer hybrid formulations. In general, preclinical investigations demonstrated that mRNA vaccines delivered by polymer materials had therapeutic effects. For clinical translation of polymer-based mRNA vaccines, new functional polymers with improved biodegradability and delivery efficiency are required³⁹.

5.3. Peptide-based delivery:

Positively charged peptides should be used as the primary carrier for RNA delivery. Many lysine and arginine residues in cationic peptides provide positively charged amino groups, allowing them to bind with nucleic acids via electrostatic interactions. Protamine is also utilised to deliver mRNA vaccines via peptides⁴¹. Protamine is a cationic peptide that has been utilised in a number of early trials to deliver mRNA vaccines. Protamine has two properties that make it a good candidate for mRNA vaccines. Protamine, for starters, protects mRNA. Second, the protamine-mRNA combination functions as an adjuvant. The protamine-mRNA complex is immunogenic through activation of TLR7³⁹. Another approach is to employ peptides as the immunogenic, as they have a simpler and more stable structure than proteins. Due to the short length of amino acid sequences giving epitopes to immune cells, peptides frequently suffer from poor immune activation.

5.4. Virus like Particles (VLPs):

Virus-like particles (VLPs) can be created to express the native virus's surface proteins or nucleic acid sequences without causing infection or reproduction. Although VLPs are recombinant protein vaccines, they frequently retain the original structure of virion, making them superior in terms of antigenicity and immunogenicity to other subunit protein vaccines⁴¹. VLPs have shown high adjuvanticity for DNA vaccines administered via nasal route⁴². Viral particles can package and deliver antigen-encoding self-amplifying mRNA into the cytoplasm in a process known as virus-like self-amplifying mRNA particle, also known as virus-like replicon particle (VRP). VRP vaccines were developed using a variety of ssRNA viruses, including alphaviruses, flaviviruses, measles viruses, and rhabdoviruses. The development of antibodies against viral vectors, which has been reported in multiple clinical trials, is a challenge for VRP-based mRNA vaccines³⁹.

6. Regulatory Aspects of mRNA Vaccines:

Regulatory issues such as the quality of the starting materials, consistency of manufacture, demonstrated evidence of safety and efficacy during pre-clinical studies, clinical trials, and post-marketing surveillance are all involved in the approval of mRNA vaccines, just as they are with any other vaccine. Regulatory difficulties regarding the manufacture, quality control, and safety of mRNA vaccines have been highlighted in recent studies⁷. Today, Vaccines are one of the most complex pharmaceuticals available in market. Vaccines are also regulated by pharmaceutical law. Informed decision making for vaccines requires regulatory expertise. Evaluating their benefit-to-risk ratio requires an understanding of, first, biological production and quality control processes and, second, the implications (in the case of preventive vaccines) of administering products derived from living systems, often to very young infants, at a population scale. Regulatory authorities must always be ready to evaluate new information on potential or real risks and benefits of vaccines and to change decisions as needed⁴³. Vaccines are a unique class of pharmaceutical products because vaccines meet the statutory definitions of both a drug as well as a biological product. According to the Food, Drug, and Cosmetic Act (FD&C Act) drugs are defined as, “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease”. Immunization is a major component of global and public health. Use of vaccines has resulted in the prevention of millions of deaths and cases of morbidity annually caused by infectious diseases around the world. Because vaccines are so widely used globally, it is imperative that these products be as safe and effective as current technology will permit⁴⁴. National regulatory authorities (NRAs) face a growing number of unique products, complex quality concerns, and new technical issues stemming from rapid scientific advancements when it comes to vaccine assessment, licensure, control, and surveillance. There is high need for a strong national regulatory authority, especially for the regulation of biological products such as vaccines, is recognized worldwide. Developed countries have established governmental regulatory agencies to review as well as determine the safety and effectiveness of vaccines; however, even today, many developing countries do not have established NRAs. WHO also communicates to national authorities and manufacturers through guidance documents addressing both general issues and specific products⁴⁵. NRAs are informed of the scientific background required to examine significant concerns through this mechanism, as well as which regulatory techniques and methodologies have been found to be most effective in maintaining a global supply of universally safe and efficacious vaccines of the highest quality. The Center for Biologics Evaluation and Research (CBER) of the US Food and Drug Administration (FDA) is the national regulatory authority in the United States charged with ensuring the safety, purity, as well as effectiveness of vaccines in the United States⁴⁶. CBER is regulatory body incharge of ensuring safety, quality and efficacy of vaccines in US. In UK, licence for vaccines and medicines are issued by medicines and healthcare products regulatory agency ⁴⁷.

7. CONCLUSION AND OUTCOMES:

Vaccines are one of the most important medical interventions since they have the power to eradicate a disease completely. Current vaccination research is primarily focused on two areas: first, the critical antigen that induces the desired immune response, and second, a needle-free delivery mechanism capable of inducing innate and adaptive immunity. Preclinical research has shown that mRNA vaccines are safe and effective against infectious diseases and cancer, which has prompted multiple clinical trials. Because of their shorter manufacturing periods and higher efficiency, RNA-based vaccines may have an influence in these areas. mRNA vaccines have the potential to be novel therapeutic alternatives for significant diseases such as cancer, in addition to infectious disorders. mRNA vaccines are not only faster to produce but also their production cost cheaper than traditional vaccines. A RNA based vaccines is also safer to patients, as they are not produced using infectious elements. mRNA vaccine have an self adjuvanting activity so there is no need to add any other adjuvant for enhancing efficacy. mRNA vaccines stimulate innate immune response. mRNA vaccines vary from other approaches such as they instruct our cells to become self-sufficient vaccine factory, as well as offering benefits including increased production speed and also the potential to keep up with new varieties.

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Received on 26.12.2021 Modified on 02.04.2022

Asian J. Pharm. Tech. 2022; 12(3):257-265.

DOI: 10.52711/2231-5713.2022.00042