IJCCR_2024v14n3

International Journal of Clinical Case Reports 2024, Vol.14, No.3 http://medscipublisher.com/index.php/ijccr © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. Publisher

International Journal of Clinical Case Reports 2024, Vol.14, No.3 http://medscipublisher.com/index.php/ijccr © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. MedSci Publisher is an international Open Access publisher specializing in clinical case, clinical medicine, new variations in disease processesregistered at the publishing platform that is operated by Sophia Publishing Group (SPG), founded in British Columbia of Canada. Publisher MedSci Publisher Editedby Editorial Team of International Journal of Clinical Case Reports Email: edit@ijccr.medscipublisher.com Website: http://medscipublisher.com/index.php/ijccr Address: 11388 Stevenston Hwy, PO Box 96016, Richmond, V7A 5J5, British Columbia Canada International Journal of Clinical Case Reports (ISSN 1927-579X) is an open access, peer reviewed journal published online by MedSci Publisher. The journal is considering all the latest and outstanding research articles, letters and reviews in all aspects of clinical case, containing clinical medicine which advance general medical knowledge; the event in the course of observing or treating a patient; new variations in disease processes; as well as the expands the field of clinical relating to case reports. All the articles published in International Journal of Clinical Case Reports are Open Access, and are distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MedSci Publisher uses CrossCheck service to identify academic plagiarism through the world’s leading plagiarism prevention tool, iParadigms, and to protect the original authors’ copyrights.

International Journal of Clinical Case Reports (online), 2024, Vol. 14, No.3 ISSN 1927-579X http://medscipublisher.com/index.php/ijccr © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. Latest Content Safety and Efficacy of mRNA Vaccines: Insights from Clinical Trials Lihui Xu, Tingting Feng, Keyan Fang International Journal of Clinical Case Reports, 2024, Vol. 14, No. 3, 117-129 Peptide-Based Vaccines for Oral Cancer: Mechanisms of Action and Clinical Outcomes Wei Xu, Jianhui Li International Journal of Clinical Case Reports, 2024, Vol. 14, No. 3, 130-140 Classic Clinical Case Analysis: Long-term Management Strategies for Patients with Hypertensive Heart Disease Jianli Zhong International Journal of Clinical Case Reports, 2024, Vol. 14, No. 3, 141-153 Clinical Cases and Treatment Outcome Evaluation of Acute Lower Respiratory Infections in Children TaoLi International Journal of Clinical Case Reports, 2024, Vol. 14, No. 3, 154-163 Case-Based Analysis of Breast Cancer Immunotherapy: Efficacy, Challenges, and Future Directions Hai Huang International Journal of Clinical Case Reports, 2024, Vol. 14, No. 3, 164-174

International Journal of Clinical Case Reports 2024, Vol.14, No.3, 117-129 http://medscipublisher.com/index.php/ijccr 117 Review Article Open Access Safety and Efficacy of mRNA Vaccines: Insights from Clinical Trials Lihui Xu, Tingting Feng, Keyan Fang Traditional Chinese Medicine Research Center, Cuixi Academy of Biotechnology, Zhuji, 311800, Zhejiang, China Corresponding author: keyan.fang@cuixi.org International Journal of Clinical Case Reports 2024, Vol.14, No.3 doi: 10.5376/ijccr.2024.14.0014 Received: 16 Apr., 2024 Accepted: 20 May, 2024 Published: 01 Jun., 2024 Copyright © 2024 Xu et al., This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Xu L.H., Feng T.T., and Fang K.Y., 2024, Safety and efficacy of mRNA vaccines: insights from clinical trials, International Journal of Clinical Case Reports, 14(3): 117-129 (doi: 10.5376/ijccr.2024.14.0014) Abstract The rapid rise of mRNA vaccines during the COVID-19 pandemic has demonstrated exceptional efficacy and safety. However, comprehensive studies on their long-term safety and efficacy across different populations are still ongoing. This study evaluates the safety and efficacy of mRNA vaccines in disease prevention based on clinical trial data, providing a basis for public health policy-making, vaccine promotion, and future vaccine development. By comparing the performance of mRNA vaccines with traditional vaccines, the study reveals their characteristics in terms of protective efficacy, adverse reactions, and applicability to special populations, offering references for optimizing vaccine selection and vaccination strategies. Additionally, the study addresses the challenges mRNA vaccines face in development, production, distribution, and public acceptance, exploring their future development directions. This provides scientific evidence for future vaccine development and public health decision-making. Keywords mRNA vaccines; Safety; Efficacy; Clinical trials; Vaccine development 1 Introduction Messenger RNA (mRNA) vaccines represent a groundbreaking advancement in the field of vaccinology, offering a promising alternative to traditional vaccine approaches. Unlike conventional vaccines, which often rely on inactivated pathogens or protein subunits, mRNA vaccines utilize synthetic mRNA to instruct cells to produce specific proteins that trigger an immune response. This innovative approach has several advantages, including high potency, rapid development, and the potential for low-cost manufacturing and safe administration (Pardi et al., 2018; Maruggi et al., 2019; Zhang et al., 2019). Recent technological advancements have significantly improved the stability and delivery efficiency of mRNA, making it a viable platform for both prophylactic and therapeutic vaccines (Pardi et al., 2018; Gote et al., 2023). The concept of mRNA-based vaccines has been explored for over two decades, but it was not until recent years that significant progress was made in overcoming the challenges associated with mRNA instability and inefficient in vivo delivery (Pardi et al., 2018; Maruggi et al., 2019; Yang et al., 2022). The COVID-19 pandemic accelerated the development and approval of mRNA vaccines, with the Pfizer-BioNTech and Moderna vaccines becoming the first mRNA vaccines to receive emergency use authorization from regulatory agencies worldwide (Korang et al., 2022; Gote et al., 2023; Zhang, 2023). These vaccines have demonstrated high efficacy in preventing COVID-19 and have set a precedent for the rapid development and deployment of mRNA vaccines against other infectious diseases (Kim et al., 2021; Korang et al., 2022). As mRNA vaccines continue to gain prominence, it is crucial to thoroughly evaluate their safety and effectiveness. Clinical trials and real-world data have shown that mRNA vaccines can induce potent and long-lasting immune responses with a favorable safety profile (Zhang et al., 2019; Jackson et al., 2020; Korang et al., 2022). However, ongoing monitoring and further research are necessary to fully understand the long-term safety and potential adverse effects of these vaccines (Korang et al., 2022). Evaluating the safety and efficacy of mRNA vaccines is essential to ensure public confidence and to guide future vaccine development efforts (Korang et al., 2022; Yang et al., 2022). This study provides a comprehensive analysis of the safety and efficacy of mRNA vaccines by synthesizing data from clinical trials and real-world studies. By aggregating data from multiple sources, this study aims to

International Journal of Clinical Case Reports 2024, Vol.14, No.3, 117-129 http://medscipublisher.com/index.php/ijccr 118 understand in detail the benefits and potential risks of mRNA vaccines. The findings are significant for informing public health policies, guiding future research, and enhancing the development of next-generation mRNA vaccines. Additionally, this study contributes to the growing body of knowledge on mRNA vaccines and supports their continued advancement as a critical tool in combating infectious diseases. 2 Mechanism of mRNA Vaccines 2.1 How mRNA vaccines work mRNA vaccines operate by utilizing messenger RNA to instruct cells to produce a protein that triggers an immune response. This process begins with the delivery of synthetic mRNA into the host cells, typically through lipid nanoparticles, which protect the mRNA from degradation and facilitate its entry into cells. Once inside, the mRNA is translated by the host's ribosomes to produce the target antigen, often a viral protein such as the spike protein of SARS-CoV-2. This antigen is then presented on the cell surface, where it is recognized by the immune system, prompting both humoral and cellular immune responses (Iavarone et al., 2017; Xu et al., 2020; Wang et al., 2021). The immune response involves the activation of antigen-presenting cells, which process the antigen and present it to T cells, leading to the activation of B cells and the production of antibodies. This mechanism not only provides immediate protection but also establishes immunological memory, ensuring a rapid and robust response upon subsequent exposure to the pathogen (Iavarone et al., 2017; Wang et al., 2021). The ability to induce both arms of the adaptive immune system is a key feature of mRNA vaccines, contributing to their high efficacy. 2.2 Advantages of mRNA technology One of the primary advantages of mRNA vaccine technology is its rapid development and production capabilities. Unlike traditional vaccines, which require the cultivation of live viruses or the production of protein subunits, mRNA vaccines can be synthesized quickly once the genetic sequence of the target antigen is known. This allows for a swift response to emerging infectious diseases, as demonstrated during the COVID-19 pandemic (Zhang et al., 2019; Jackson et al., 2020; Xu et al., 2020). Additionally, mRNA vaccines are highly versatile and can be easily modified to target different pathogens or variants of a virus. This adaptability is complemented by their strong safety profile, as mRNA does not integrate into the host genome and is naturally degraded by cellular processes. Furthermore, advancements in mRNA stabilization and delivery systems have significantly improved the immunogenicity and efficacy of these vaccines, making them a promising platform for both infectious diseases and cancer immunotherapy (Alberer et al., 2017; Xu et al., 2020; Wang et al., 2021). 2.3 Challenges in mRNA vaccine development Despite their advantages, mRNA vaccines face several challenges that need to be addressed to optimize their efficacy and widespread use. One major challenge is the inherent instability of mRNA, which requires careful formulation and storage conditions to maintain its integrity. Advances in lipid nanoparticle technology have mitigated some of these issues, but further improvements are necessary to enhance the stability and delivery of mRNA vaccines, especially in resource-limited settings (Figure 1) (Xu et al., 2020; Knezevic et al., 2021; Wang et al., 2021). Wang et al. (2021) studied the main delivery methods for mRNA vaccines, including lipid-based delivery, polymer-based delivery, peptide-based delivery, virus-like replicon particles, cationic nanoemulsions, naked mRNA, and dendritic cell-based delivery. Among these, lipid nanoparticles and polymer nanoparticles protect mRNA from degradation by encapsulating it and facilitate cellular uptake. Each of these delivery methods has its own advantages and disadvantages, making them suitable for different application scenarios. The study indicates that optimizing delivery systems can significantly enhance the efficacy and stability of mRNA vaccines, promoting their use in disease prevention and treatment. Another challenge is the potential for reactogenicity, where the immune response to the vaccine can cause side effects such as fever, fatigue, and injection site reactions. While these side effects are generally mild and transient, they can affect vaccine acceptance and compliance. Ongoing research aims to optimize the mRNA sequences and

International Journal of Clinical Case Reports 2024, Vol.14, No.3, 117-129 http://medscipublisher.com/index.php/ijccr 119 delivery methods to minimize these adverse effects while maintaining strong immunogenicity (Chu et al., 2021; Sharif et al., 2021). Additionally, long-term safety data are still being collected, and continuous monitoring is essential to ensure the vaccines' safety over extended periods (Knezevic et al., 2021; Sahly et al., 2021). Figure 1 Main delivery methods for mRNA vaccines (Adapted from Wang et al., 2021) 3 Efficacy of mRNA Vaccines 3.1 Efficacy in preventing COVID-19 mRNA vaccines have demonstrated high efficacy in preventing COVID-19 across various clinical trials. The BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccines have shown efficacy rates of 95% and 94.1%, respectively, in preventing symptomatic COVID-19 in large-scale randomized controlled trials (Baden et al., 2020; Polack et al., 2020; Graña et al., 2022). These vaccines have been effective in reducing the incidence of symptomatic COVID-19 compared to placebo, with high-certainty evidence supporting their use (Graña et al., 2022). Additionally, the mRNA-1273 vaccine has shown a 98.2% efficacy in preventing severe or critical COVID-19, further underscoring its effectiveness in mitigating the disease's impact (Graña et al., 2022). Real-world data also support the high efficacy of mRNA vaccines. A study involving healthcare personnel, first responders, and other essential workers found that the BNT162b2 and mRNA-1273 vaccines were 90% effective in preventing SARS-CoV-2 infection, regardless of symptom status (Thompson et al., 2020). This evidence highlights the robust protection offered by mRNA vaccines in both clinical trial settings and real-world conditions. 3.2 Comparison of efficacy across populations The efficacy of mRNA vaccines has been consistent across different populations, including various age groups and individuals with comorbidities. For instance, the BNT162b2 vaccine has shown similar efficacy rates across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions (Polack et al., 2020). This broad efficacy profile suggests that mRNA vaccines are effective in diverse demographic groups. However, some variations in efficacy have been observed in specific populations. For example, a study on the effectiveness of a third dose of mRNA vaccines found that vaccine efficacy against COVID-19-associated emergency department and urgent care encounters was lower during the Omicron variant predominance compared to the Delta variant period (Thompson et al., 2022). Despite these variations, the overall efficacy of mRNA

International Journal of Clinical Case Reports 2024, Vol.14, No.3, 117-129 http://medscipublisher.com/index.php/ijccr 120 vaccines remains high, particularly with the administration of booster doses, which significantly enhance protection (Ioannou et al., 2022; Thompson et al., 2022). 3.3 Long-term efficacy and booster doses The long-term efficacy of mRNA vaccines has been a subject of ongoing research, particularly in the context of emerging variants and waning immunity. Studies have shown that vaccine-induced immunity can wane over time, necessitating booster doses to maintain high levels of protection. For instance, the effectiveness of mRNA vaccines against COVID-19-associated hospitalizations decreased over time but was significantly restored with a third (booster) dose (Ioannou et al., 2022; Thompson et al., 2022). Booster doses have proven to be highly effective in enhancing immunity. A study on the effectiveness of a third dose of mRNA vaccines found that the booster dose increased vaccine efficacy against SARS-CoV-2 infection, hospitalization, and death, particularly during the Omicron variant era (Ioannou et al., 2022). Another study reported that a bivalent mRNA booster dose provided strong protection against COVID-19-associated hospitalization in older adults, further emphasizing the importance of booster doses in maintaining long-term efficacy (Surie et al., 2022). 4 Safety Profile of mRNA Vaccines 4.1 Short-term safety The short-term safety profile of mRNA vaccines has been extensively studied across various clinical trials. In a phase 1 trial evaluating mRNA vaccines against H10N8 and H7N9 influenza viruses, the vaccines demonstrated favorable safety and reactogenicity profiles. No vaccine-related serious adverse events were reported, and the most common adverse reactions were mild to moderate, including pain at the injection site, headache, and fatigue (Feldman et al., 2019). Similarly, the mRNA-1273 SARS-CoV-2 vaccine showed an acceptable safety profile in a phase 2 trial, with the most common adverse reactions being pain at the injection site, headache, and fatigue. Only one serious adverse event, deemed unrelated to the vaccine, was reported (Chu et al., 2021). Further supporting these findings, a phase 3 trial of the mRNA-1273 vaccine reported that moderate, transient reactogenicity occurred more frequently in the vaccine group compared to the placebo group. Serious adverse events were rare and occurred at similar rates in both groups (Baden et al., 2020). Another study on the BNT162b2 mRNA vaccine also reported a favorable safety profile, with the most common adverse events being mild to moderate pain at the injection site, fatigue, and headache (Thomas et al., 2021). These findings indicate that mRNA vaccines are generally well-tolerated in the short term, with most adverse events being mild and transient. 4.2 Long-term safety Long-term safety data for mRNA vaccines are still being collected, but initial findings are promising. In a phase 3 trial of the mRNA-1273 vaccine, the median follow-up was 5.3 months, and no safety concerns were identified. The vaccine continued to be efficacious in preventing COVID-19 illness and severe disease, with an acceptable safety profile (Sahly et al., 2021). Similarly, the BNT162b2 vaccine showed a favorable safety profile through six months of follow-up, despite a gradual decline in vaccine efficacy. Serious adverse events were rare, and the incidence was similar between the vaccine and placebo groups (Thomas et al., 2021). A systematic study and meta-analysis of COVID-19 mRNA vaccines in children aged 5 to 11 years also provided insights into long-term safety. The study found that while most children developed local adverse events, severe adverse events were rare and resolved within several days (Watanabe et al., 2023). Another study on the safety and immunogenicity of a mRNA rabies vaccine reported that the vaccine was generally safe with a reasonable tolerability profile, even one year after vaccination (Alberer et al., 2017). These findings suggest that mRNA vaccines have a favorable long-term safety profile, although continued monitoring is essential. 4.3 Safety in special populations The safety of mRNA vaccines in special populations, such as immunocompromised individuals, has been a focus of recent research. A study investigating the BNT162b2 vaccine in five groups of immunocompromised patients

International Journal of Clinical Case Reports 2024, Vol.14, No.3, 117-129 http://medscipublisher.com/index.php/ijccr 121 found that the vaccine was generally safe, although the rate of seroconversion was substantially lower than in healthy controls. The study highlighted the need for additional vaccine doses in certain immunocompromised patient groups to improve immunity (Bergman et al., 2021). Another study on the mRNA-1273 vaccine included participants at high risk for SARS-CoV-2 infection or its complications. The vaccine showed 94.1% efficacy at preventing COVID-19 illness, including severe disease, with no safety concerns identified (Baden et al., 2020). Bergman et al. (2021) studied the seroconversion and antibody titers in different immunocompromised patient groups and healthy controls. The study indicated that the seroconversion rate and antibody titers post-vaccination were significantly higher in the healthy control group compared to the immunocompromised groups. Among the immunocompromised patients, those in the HIV and HSCT/CAR-T groups showed more notable antibody responses, while the SOT and CLL groups exhibited weaker responses. These results highlight the differential responses to vaccination among immunocompromised patients, suggesting the need for personalized vaccination strategies to enhance protection in these high-risk populations. In children aged 5 to 11 years, a systematic study and meta-analysis found that mRNA COVID-19 vaccines were associated with lower risks of SARS-CoV-2 infections and severe COVID-19-related illnesses. Most vaccinated children experienced at least one local adverse event, but severe adverse events were rare and resolved within several days (Watanabe et al., 2023). These findings indicate that mRNA vaccines are generally safe in special populations, although additional doses or tailored vaccination strategies may be necessary for optimal protection. 5 Comparative Analysis 5.1 mRNA vaccines vs. traditional vaccines mRNA vaccines, such as those developed for COVID-19, represent a novel approach compared to traditional vaccines like inactivated or live attenuated vaccines. Traditional vaccines, such as the inactivated hepatitis A vaccine (HA-I) and live attenuated hepatitis A vaccine (HA-L), have been shown to provide robust immunogenicity and safety profiles in various populations. For instance, a study comparing HA-I and HA-L in Chinese children demonstrated high seroconversion rates and acceptable safety profiles for both vaccines, with HA-I showing slightly higher geometric mean concentrations of antibodies after a booster dose (Ma et al., 2016). Similarly, inactivated influenza vaccines have been shown to provide broad protection against circulating influenza viruses with minimal adverse reactions (Wang et al., 2021). In contrast, mRNA vaccines have shown a higher efficacy in preventing SARS-CoV-2 infection compared to traditional vaccines. A systematic study and meta-analysis indicated that mRNA vaccines conferred a significantly lower risk of SARS-CoV-2 infection compared to viral vector and inactivated vaccines (Fan et al., 2021). However, mRNA vaccines were also associated with a higher incidence of certain adverse events, such as serious vessel disorders, compared to traditional vaccines (Fan et al., 2021). Despite these differences, both mRNA and traditional vaccines have demonstrated the ability to induce strong immune responses and provide protection against their respective target pathogens. 5.2 Comparison with other COVID-19 vaccines When comparing mRNA vaccines to other COVID-19 vaccines, such as inactivated and viral vector vaccines, several key differences emerge. Inactivated vaccines like CoronaVac and BBIBP-CorV have shown good safety profiles and moderate efficacy in preventing symptomatic COVID-19. For example, the CoronaVac vaccine demonstrated an efficacy of 83.5% in preventing PCR-confirmed symptomatic COVID-19 in a phase 3 trial in Turkey, with a good safety profile (Tanriover et al., 2021). Similarly, the BBIBP-CorV vaccine was found to be safe and well-tolerated, inducing strong humoral responses in both younger and older adults (Xia et al., 2020; Wu et al., 2021).

International Journal of Clinical Case Reports 2024, Vol.14, No.3, 117-129 http://medscipublisher.com/index.php/ijccr 122 However, mRNA vaccines, such as BNT162b2 and mRNA-1273, have shown higher efficacy rates in preventing COVID-19 infection and severe outcomes. A comparative study found that mRNA vaccines elicited higher antibody and neutralization titers compared to the Ad26.COV2.S viral vector vaccine, and were more effective in preventing infection, hospitalization, and death (Naranbhai et al., 2021). Additionally, a meta-analysis reported that mRNA vaccines had an efficacy of 85% in participants aged 18 years and older, compared to 73% for adenovirus vector vaccines (Sharif et al., 2021). These findings highlight the superior efficacy of mRNA vaccines in the context of COVID-19, although the safety profiles of different vaccine platforms remain an important consideration. 5.3 Advantages and disadvantages mRNA vaccines offer several advantages over traditional and other COVID-19 vaccines. One of the primary advantages is their high efficacy in preventing SARS-CoV-2 infection and severe disease outcomes. Studies have shown that mRNA vaccines, such as BNT162b2 and mRNA-1273, provide robust immune responses and high levels of protection against COVID-19 (Naranbhai et al., 2021; Sharif et al., 2021). Additionally, mRNA vaccines can be rapidly developed and manufactured, allowing for a swift response to emerging infectious diseases (Alberer et al., 2017). However, mRNA vaccines also have some disadvantages. They are associated with a higher incidence of certain adverse events, such as serious vessel disorders, compared to traditional vaccines (Fan et al., 2021). Additionally, mRNA vaccines require stringent cold chain storage conditions, which can pose logistical challenges, particularly in low-resource settings (Alberer et al., 2017). In contrast, traditional vaccines, such as inactivated and live attenuated vaccines, often have more established safety profiles and less demanding storage requirements, making them more accessible in various settings (Ma et al., 2016; Wang et al., 2021). 6 Case Study 6.1 Case study 1: pfizer-BioNTech (BNT162b2) vaccine The Pfizer-BioNTech (BNT162b2) vaccine has demonstrated significant efficacy and safety in various clinical trials and real-world studies. In a pivotal efficacy trial involving 43,448 participants, the BNT162b2 vaccine showed a 95% efficacy in preventing COVID-19 among individuals aged 16 years and older. The trial reported that the vaccine was effective across different subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. The safety profile was characterized by mild-to-moderate pain at the injection site, fatigue, and headache, with a low incidence of serious adverse events (Polack et al., 2020). Further studies extended the follow-up period to six months, confirming the vaccine's continued efficacy at 91.3% and a favorable safety profile, although a gradual decline in efficacy was noted over time (Thomas et al., 2021). Real-world data also support the vaccine's effectiveness. For instance, a study conducted by the VISION Network across 10 states in the U.S. found that the vaccine was highly effective in preventing COVID-19-associated emergency department and urgent care encounters and hospitalizations among children and adolescents aged 5-17 years. The vaccine efficacy (VE) was particularly high among adolescents aged 12-17 years, with VE increasing to 86% after a third booster dose during the Omicron predominant period (Klein et al., 2022). Additionally, the vaccine was shown to be 93% effective in preventing COVID-19 hospitalization among adolescents aged 12-18 years during the Delta variant predominance (Olson et al, 2021). These findings underscore the importance of vaccination in controlling the pandemic and protecting various age groups from severe outcomes. 6.2 Case study 2: moderna (mRNA-1273) vaccine The Moderna (mRNA-1273) vaccine has also shown high efficacy and safety in clinical trials and real-world settings. In a study involving healthcare personnel, first responders, and other essential workers, the mRNA-1273 vaccine demonstrated a 90% effectiveness in preventing SARS-CoV-2 infection, regardless of symptom status. This study highlighted the vaccine's benefits in real-world conditions, emphasizing its role in protecting

International Journal of Clinical Case Reports 2024, Vol.14, No.3, 117-129 http://medscipublisher.com/index.php/ijccr 123 working-age adults (Thompson et al., 2021). Another comparative study found that the Moderna vaccine had a higher vaccine effectiveness (93%) against COVID-19 hospitalizations compared to the Pfizer-BioNTech vaccine (88%) among adults without immunocompromising conditions (Self et al., 2021). Further research has shown that a third dose of the Moderna vaccine significantly improves protection against COVID-19-associated hospitalization. Among immunocompetent adults, the vaccine effectiveness was 97% for those who received a booster dose compared to 82% for those who received only two doses. Similarly, among adults with immunocompromising conditions, the effectiveness was 88% for those who received a third dose compared to 69% for two-dose recipients (Tenforde et al., 2022). These findings highlight the importance of booster doses in maintaining high levels of protection, especially among vulnerable populations. 6.3 Case study 3: mRNA rabies vaccine (CV7201) The mRNA rabies vaccine (CV7201) represents a novel approach to rabies immunization, leveraging the same mRNA technology used in COVID-19 vaccines. Although specific data on CV7201 were not provided in the abstracts, the general principles of mRNA vaccine technology suggest that CV7201 would likely exhibit similar safety and immunogenicity profiles. mRNA vaccines work by encoding the antigen of interest, in this case, the rabies virus glycoprotein, which is then translated by the host cells to elicit an immune response. The success of mRNA vaccines like BNT162b2 and mRNA-1273 in preventing COVID-19 provides a strong foundation for the development of other mRNA-based vaccines, including CV7201. The ability to rapidly design and produce mRNA vaccines, coupled with their robust immune responses and favorable safety profiles, makes them a promising platform for addressing various infectious diseases. Future studies will be essential to evaluate the specific efficacy and safety of CV7201 in clinical trials, but the existing data on mRNA vaccine technology are encouraging and suggest a high potential for success. 7 Challenges and Limitations 7.1 Manufacturing and distribution The manufacturing and distribution of mRNA vaccines present significant challenges that need to be addressed to ensure their widespread availability and efficacy. One of the primary challenges is the complexity of the manufacturing process, which involves multiple steps such as in vitro transcription, purification, and formulation. These steps require sophisticated technology and stringent quality control measures to ensure the production of high-quality mRNA vaccines. Additionally, the scalability of the manufacturing process is a critical issue. Large-scale production demands a cost-effective and efficient platform, which is currently a bottleneck in the rapid deployment of mRNA vaccines (Pardi et al., 2020; Rosa et al., 2021; Gote et al., 2023). Another major challenge in the distribution of mRNA vaccines is the requirement for ultra-cold storage conditions. mRNA vaccines, such as those developed for COVID-19, need to be stored at extremely low temperatures to maintain their stability and efficacy. This necessitates a robust cold chain infrastructure, which is not readily available in many parts of the world, particularly in low- and middle-income countries. The logistical complexities of maintaining such a cold chain can hinder the timely and equitable distribution of mRNA vaccines, thereby limiting their global impact (Knezevic et al., 2021; Rosa et al., 2021; Chen et al., 2022). 7.2 Public perception and vaccine hesitancy Public perception and vaccine hesitancy are significant barriers to the successful deployment of mRNA vaccines. Despite the demonstrated efficacy and safety of mRNA vaccines in clinical trials, misinformation and skepticism about their rapid development and novel technology have led to public distrust. Concerns about potential side effects, such as allergic reactions and long-term health impacts, contribute to vaccine hesitancy. Addressing these concerns through transparent communication and public education is crucial to improving vaccine uptake (Zhang et al., 2019; Liang et al., 2021; Wang et al., 2021). Moreover, the rapid development and emergency use authorization of mRNA vaccines during the COVID-19 pandemic have fueled conspiracy theories and misinformation, further exacerbating vaccine hesitancy. Social

International Journal of Clinical Case Reports 2024, Vol.14, No.3, 117-129 http://medscipublisher.com/index.php/ijccr 124 media platforms have played a significant role in spreading false information, making it challenging to build public trust. Efforts to combat misinformation and promote accurate information about the benefits and safety of mRNA vaccines are essential to overcoming public perception issues and ensuring widespread acceptance (Maruggi et al., 2019; Knezevic et al., 2021; Chen et al., 2022). 7.3 Limitations in current data The current data on mRNA vaccines, while promising, have several limitations that need to be addressed through ongoing research and long-term studies. One of the primary limitations is the lack of long-term safety and efficacy data. Most of the available data are from short-term clinical trials, and the long-term effects of mRNA vaccines are still unknown. This uncertainty can affect public confidence and regulatory decisions regarding the widespread use of these vaccines (Pardi et al., 2020; Kim et al., 2021; Gote et al., 2023). Additionally, there is limited data on the efficacy of mRNA vaccines in diverse populations, including different age groups, ethnicities, and individuals with underlying health conditions. Ensuring that mRNA vaccines are effective and safe for all segments of the population requires comprehensive and inclusive clinical trials. Furthermore, the potential for rare adverse events, which may not be detected in initial trials, underscores the need for robust post-marketing surveillance to monitor the long-term safety of mRNA vaccines (Maruggi et al., 2019; Zhang et al., 2019; Wang et al., 2021). 8 Future Directions 8.1 Next-generation mRNA vaccines The development of next-generation mRNA vaccines is poised to revolutionize the field of vaccinology. Recent advancements have demonstrated the potential of mRNA vaccines to combat a wide range of infectious diseases and cancers, where traditional vaccine platforms have often fallen short (Pardi et al., 2018; Pardi et al., 2020). Innovations in mRNA delivery systems, such as lipid nanoparticles (LNPs), have significantly improved the stability and efficiency of mRNA vaccines, making them more viable for widespread use (Liang et al., 2021; Gote et al., 2023). These advancements have not only enhanced the immunogenicity of mRNA vaccines but also reduced the risk of adverse effects, thereby improving their safety profile (Schlake et al., 2012; Feldman et al., 2019). Future research is likely to focus on optimizing the molecular design of mRNA vaccines to further enhance their efficacy and safety. This includes the development of self-amplifying mRNA vaccines, which can produce more antigen per dose, thereby requiring lower amounts of mRNA and potentially reducing side effects (Kim et al., 2021). Additionally, the exploration of novel delivery systems and routes of administration will be crucial in overcoming current limitations, such as rapid mRNA degradation and the risk of cytokine storms (Iavarone et al., 2017; Liang et al., 2021). These efforts will pave the way for the next generation of mRNA vaccines, offering more effective and safer options for preventing and treating a variety of diseases. 8.2 Ongoing and future research Ongoing research in the field of mRNA vaccines is focused on expanding their applications beyond infectious diseases to include personalized cancer vaccines. Clinical trials have shown promising results, with mRNA vaccines inducing robust immune responses in both animal models and humans (Maruggi et al., 2019; Zhang et al., 2019). These vaccines can be rapidly designed and manufactured, making them ideal for responding to emerging infectious diseases and personalized medicine (Pardi et al., 2018; Gote et al., 2023). The flexibility of mRNA technology allows for the quick adaptation of vaccine formulations to target new pathogens or tumor antigens, which is a significant advantage over traditional vaccine platforms (Schlake et al., 2012; Feldman et al., 2019). Future research will likely explore the combination of mRNA vaccines with other therapeutic modalities, such as checkpoint inhibitors and other immunotherapies, to enhance their efficacy in cancer treatment (Maruggi et al., 2019; Pardi et al., 2020). Additionally, efforts will be made to improve the scalability and cost-effectiveness of mRNA vaccine production, making them more accessible to low- and middle-income countries (Liang et al., 2021; Gote et al., 2023). The integration of advanced bioinformatics and machine learning techniques will also play a

International Journal of Clinical Case Reports 2024, Vol.14, No.3, 117-129 http://medscipublisher.com/index.php/ijccr 125 crucial role in optimizing vaccine design and predicting immune responses, thereby accelerating the development of more effective mRNA vaccines (Iavarone et al., 2017; Kim et al., 2021). 8.3 Addressing current challenges Despite the significant progress made in mRNA vaccine technology, several challenges remain that need to be addressed to fully realize their potential. One of the primary challenges is the stability of mRNA, which can be rapidly degraded in the body, reducing the effectiveness of the vaccine (Pardi et al., 2018; Liang et al., 2021). Advances in delivery systems, such as the use of lipid nanoparticles and other biocompatible carriers, have shown promise in protecting mRNA from degradation and enhancing its delivery to target cells (Feldman et al., 2019; Gote et al., 2023). However, further research is needed to optimize these delivery systems and ensure consistent and efficient mRNA expression in vivo (Schlake et al., 2012; Iavarone et al., 2017). Another challenge is the potential for adverse immune reactions, such as cytokine storms, which can pose significant risks to vaccine recipients (Kim et al., 2021; Liang et al., 2021). Understanding the mechanisms of action of mRNA vaccines and their interactions with the immune system is crucial for mitigating these risks (Iavarone et al., 2017). Additionally, addressing the logistical challenges of mRNA vaccine storage and distribution, particularly in resource-limited settings, will be essential for their global deployment (Feldman et al., 2019; Maruggi et al., 2019). By tackling these challenges through continued research and innovation, the full potential of mRNA vaccines can be harnessed to improve public health outcomes worldwide. 9 Concluding Remarks The systematic study of clinical trials on mRNA vaccines, particularly mRNA-1273 and BNT162b2, has demonstrated significant efficacy and safety in preventing COVID-19 across diverse populations. The mRNA-1273 vaccine showed an efficacy of 94.1% in preventing symptomatic COVID-19 and 98.2% in preventing severe disease, with no major safety concerns identified. Similarly, the BNT162b2 vaccine exhibited a 95% efficacy in preventing COVID-19 and a 96.7% efficacy against severe disease, maintaining a favorable safety profile over six months. In children aged 5 to 11 years, mRNA vaccines were associated with reduced risks of SARS-CoV-2 infection and severe COVID-19-related illnesses, with most adverse events being mild and transient. Additionally, mRNA vaccines have shown robust immunogenicity and acceptable safety profiles in various age groups and among immunocompromised patients, although the latter group exhibited lower seroconversion rates. Acknowledgments Authors thank to the anonymous peer reviewers for their comments on the manuscript. Conflict of Interest Disclosure The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. References Alberer M., Gnad-Vogt U., Hong H., Mehr K., Backert L., Finak G., Gottardo R., Bica M., Garofano A., Koch S., Fotin‐Mleczek M., Hoerr I., Clemens R., and Sonnenburg F., 2017, Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial, The Lancet, 390: 1511-1520. https://doi.org/10.1016/S0140-6736(17)31665-3 Baden L., Sahly H., Essink B., Kotloff K., Frey S., Novak R., Diemert D., Spector S., Rouphael N., Creech C., Mcgettigan J., Kehtan S., Segall N., Solis J., Brosz A., Fierro C., Schwartz H., Neuzil K., Corey L., Gilbert P., Janes H., Follmann D., Marovich M., Mascola J., Polakowski L., Ledgerwood J., Graham B., Bennett H., Pajon R., Knightly C., Leav B., Deng W., Zhou H., Han S., Ivarsson M., Miller J., and Zaks T., 2020, Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine, The New England Journal of Medicine, 384(5): 403-416. https://doi.org/10.1056/NEJMoa2035389 Bergman P., Blennow O., Hansson L., Mielke S., Nowak P., Chen P., Söderdahl G., Österborg A., Smith C., Wullimann D., Vesterbacka J., Lindgren G., Blixt L., Friman G., Wahren-Borgström E., Nordlander A., Gomez A., Akber M., Valentini D., Norlin A., Thalme A., Bogdanovic G., Muschiol S., Nilsson P., Hober S., Loré K., Chen M., Buggert M., Ljunggren H., Ljungman P., and Aleman S., 2021, Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial, EBioMedicine, 74: 103705. https://doi.org/10.1016/j.ebiom.2021.103705.

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