The Potential of mRNA Vaccines to Fight Against Viruses

Abstract

Vaccines have always been a critical tool in preventing infectious diseases. However, the development of traditional vaccines often takes a long time and may struggle to address the challenge of rapidly mutating viruses. The emergence of mRNA technology has brought revolutionary changes to vaccine development, particularly in rapidly responding to the threat of emerging viruses. The global promotion of mRNA vaccines against severe acute respiratory syndrome coronavirus 2 has demonstrated the importance of mRNA technology. Also, mRNA vaccines targeting viruses such as influenza, respiratory syncytial virus, and Ebola are under development. These vaccines have shown promising preventive effects and safety profiles in clinical trials, although the duration of immune protection is still under evaluation. However, the development of mRNA vaccines also faces many challenges, such as stability, efficacy, and individual differences in immune response. Researchers adopt various strategies to address these challenges. Anyway, mRNA vaccines have shown enormous potential in combating viral diseases. With further development and technological maturity, mRNA vaccines are expected to have a profound impact on public health and vaccine equity. This review discussed the potential of mRNA vaccines to fight against viruses, current progress in clinical trials, challenges faced, and future prospects, providing a comprehensive scientific basis and reference for future research.

Introduction

In the past few decades, the development and application of vaccines have saved millions of lives. At present, vaccines have already become powerful weapons for humanity to combat infectious diseases (Chen et al., 2021; Urbano and Ferreira, 2022). Since Edward Jenner successfully demonstrated in 1796 that the smallpox vaccine could prevent smallpox, vaccine development technology has been continuously advancing. From the initial development of live-attenuated and inactivated vaccines to the exploration of subunit and recombinant vaccines, each innovation has greatly improved the safety, efficacy, and accessibility of vaccines (Meyer and Zepp, 2022; Mobed, 2020; Shukla and Shah, 2018). However, despite the tremendous success of vaccines in epidemic prevention and control, traditional vaccine development still has limitations. For example, the development of vaccines often involves a long cycle, requires a significant amount of time and resources for pathogen culture and antigen screening, and needs to optimize the production process. Additionally, some vaccines require strict storage conditions to ensure stability. Moreover, many virus strains continuously mutate, affecting the efficacy of vaccines (Clegg et al., 2021; Luo et al., 2022; Zhou et al., 2020). Therefore, in recent years, researchers have been committed to finding more flexible and rapidly responsive vaccine platforms to address emerging infectious diseases and virus variants.

The rise of mRNA technology has brought a revolution to vaccine development. As a novel vaccine platform, mRNA vaccines deliver mRNA molecules encoding pathogen antigen proteins, thereby directly utilizing the protein synthesis mechanism of host cells to produce antigens and stimulate immune responses (Lin et al., 2022). The preparation process of mRNA vaccines does not require the cultivation of live viruses and can be efficiently produced once the design is complete. Particularly when facing rapidly spreading viruses and continuously expanding epidemics, the high efficiency of mRNA vaccines becomes crucial (Jain et al., 2021). The design of mRNA vaccines is highly adjustable and flexible, allowing them to quickly adapt to genetic variations in viruses. Furthermore, mRNA vaccines encode the mRNA of virus-specific antigens rather than using any form of virus as a vector, greatly reducing the risk of infection and ensuring vaccine safety (Arevalo et al., 2022; Pardi et al., 2022).

In this review, an investigation was performed primarily based on the potential of mRNA vaccines in combating viruses, including reviewing their technological advancements, assessing the effectiveness of clinical trials and clinical applications, and discussing the challenges faced and future directions. Also, we delved into analyzing the main reasons for mRNA vaccines becoming a crucial immunization strategy in a short period, particularly the enormous potential demonstrated during the global fight against the coronavirus disease 2019 (COVID-19) pandemic. Additionally, we would explore the prospects of mRNA vaccines in fighting against other viral diseases and discuss the possible approaches they address emerging and re-emerging infectious diseases in the future. Through this review, we expect to provide a comprehensive perspective to help better understand the contribution of mRNA vaccine technology to global public health security and provide scientific evidence for future research and policymaking.

Overview of the mRNA vaccine technology

The development of mRNA vaccines can be traced back to 1993 when Martinon et al. demonstrated the potential of mRNA technology for influenza virus vaccines through in vivo experiments in mice (Martinon et al., 1993). However, technological limitations caused the development of mRNA vaccines to stagnate until recent advancements in nucleoside modification propelled the technology forward (Delaunay et al., 2024; Gao et al., 2021). Key milestones included the incorporation of modified nucleosides (such as pseudouridine and N1-methylpseudouridine), which helped to reduce the innate immune response and improve stability and translational efficiency. Additionally, the development of lipid nanoparticles (LNPs) as delivery vehicles was another significant breakthrough, protecting mRNA molecules from degradation and facilitating their delivery into cells. These advancements have made mRNA vaccines a feasible and highly effective platform for rapid vaccine development.

mRNA vaccines guide cells to produce pathogen-specific antigen proteins, thereby eliciting an immune response. Compared to traditional vaccine technologies, mRNA vaccines are characterized with significant advantages such as rapid development speed, high adjustability, relatively low production costs, and rapid response to new variant strains (Duan et al., 2022; Yu et al., 2023; Zhang et al., 2023). These advantages have quickly made mRNA vaccines a powerful tool in combating emerging or continuously mutating viral infectious diseases globally. Based on the genetic characteristics, mRNA vaccines can be classified into three types: nonreplicating mRNA, self-amplifying RNA (saRNA), and circular RNA (circRNA). However, the working principle of these three mRNA vaccines is based on a simple concept. Briefly speaking, mRNA sequences encoding target pathogen antigen proteins are designed and synthesized first. Then, these mRNA molecules are introduced into cells through appropriate delivery systems. Next, the cellular translation system is identified and utilized to translate the corresponding antigen proteins with the newly imported mRNA molecules as templates. These proteins are subsequently displayed on the cell surface and recognized by the immune system, thereby activating T cells and B cells to produce an immune response, including the production of antibodies against the antigen proteins and activation of cytotoxic T cells (Buhre et al., 2022; Pan et al., 2024). It is evident that mRNA vaccines share the same ultimate goal as traditional vaccines. In other words, both mRNA vaccines and traditional vaccines are committed to enhancing the ability to clear infections and provide long-term immune memory.

When designing a sequence of mRNA vaccines, the selection of target antigens needs to give priority to the protein or protein fragment in the pathogen that can induce the strongest immune response. For example, in mRNA vaccines targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the spike protein of SARS-CoV-2 is a primary target antigen due to its role in viral entry into host cells (Chen et al., 2022; Goel et al., 2021). Furthermore, the immunostimulatory ability, stability, and translatability of mRNA are major key issues that need to be optimized in mRNA vaccine development. Therefore, synthesized mRNA usually undergoes regional optimization or modification and the optimized regions mainly include a 5′ cap structure and the polyadenylation of the 3′ end (Salleh et al., 2022). For example, traditional reverse cap structure reduces the translation efficiency of mRNA, while adding antireverse cap analogs significantly improve the translation efficiency of mRNA (Grudzien-Nogalska et al., 2007). In addition, incorporating naturally modified nucleosides (such as m5C, m6A, m5U, s2U, or pseudouridine and N1-methylpseudouridine) into mRNA can prevent the activation of intracellular pathogen sensors such as Toll-like receptor 3 (TLR-3), TLR-7, and TLR-8, thereby reducing the host’s innate immune response to RNA (Nance and Meier, 2021).

The production process of mRNA vaccines can achieve standardization. Once an mRNA synthesis platform is established, sequences can be quickly adjusted to target different pathogens. The flexibility of mRNA vaccines is particularly important in combating rapidly mutating viruses such as influenza and coronaviruses. Additionally, for enhancing the delivery efficiency in vivo and stability within cells, mRNA molecules are commonly encapsulated by LNP delivery systems. LNPs typically consist of a lipid bilayer shell with a circular aqueous core, mainly relying on ionizable cationic lipids whose positive charges can effectively bind to RNA with negative charges (Cui et al., 2008). Moreover, some anionic and neutral agents carried by LNPs, such as phospholipids and cholesterol, disrupt the phospholipid bilayer of cells, carry mRNA to the cells, and then release the carried mRNA into the cytoplasm(Reichmuth et al., 2016). In a nutshell, selecting an appropriate carrier is crucial. LNPs not only protect mRNA from degradation by intracellular enzymes but also facilitate mRNA crossing the cell membrane and entering the cells.

Safety is another advantage of mRNA vaccines. Since mRNA vaccines do not contain live viruses or the complete form of viruses, they do not pose a risk of infection to vaccine recipients. This makes them particularly suitable for individuals with weakened immune systems (Linares-Fernandez et al., 2020). Additionally, mRNA molecules have a relatively short lifespan in the body; they are naturally degraded by cells after completing the production of antigen proteins. This reduces the risk of prolonged negative effects in the body after vaccination (Qin et al., 2022).

Overall, mRNA vaccine technology represents a significant breakthrough in the field of vaccinology, which provides a powerful tool for rapid responses to emerging infectious diseases. With the continuous progress of technology and the accumulation of clinical data, mRNA vaccines are expected to play an increasingly important role in future vaccine development and disease prevention.

Application of mRNA Vaccine in Fighting Against Viruses

Currently, mRNA vaccines targeting different viruses are in various stages of development (Table 1). It is well known that rapidly mutating influenza viruses pose a significant challenge to public health. The production methods of traditional vaccines struggle to keep up with the mutations of viruses and the emergence of new strains. In contrast, mRNA vaccine technology has clear advantages in this regard. In fact, vaccines targeting new influenza strains can be quickly designed and produced by encoding the mRNA of influenza virus surface antigen protein (Kelvin and Falzarano, 2022). For instance, Bahl et al. used the hemagglutinin (HA) sequence of avian influenza A (H7N9) as the antigen sequence for mRNA vaccines and found that these vaccines significantly protected mice from lethal attacks by H10N8 and H7N9 viruses and reduced lung virus titers (Bahl et al., 2017). Interestingly, Freyn and his colleagues injected mice with a mixture of modified mRNA vaccines expressing conserved influenza virus antigens (HA, neuraminidase, matrix 2 ion channel, and nucleoprotein [NP]) simultaneously. They observed that this combined injection method enhanced the immune potency of mice compared to single antigen injection (Freyn et al., 2020). Additionally, some research has suggested that optimizing the sequences of conserved influenza virus antigens can enhance the immunogenicity and protective efficacy of mRNA-based influenza vaccines. For example, altering the catalytic site of neuraminidase can reduce enzyme activity and maintain protective immunity; besides, disrupting the activity of the M2 ion channel can increase the immunogenicity and protective efficacy of the vaccine and reduce reactogenicity (Freyn et al., 2021). Moreover, Pardi et al. developed a pentavalent mRNA vaccine targeting influenza B viruses and demonstrated its effectiveness in defending against attacks from ancestral and recent influenza B viruses from two antigenic lineages; this vaccine could protect mice at a very low dose of 50 ng (Pardi et al., 2022). The above findings indicated that mRNA vaccines can be continuously optimized to achieve better results. Such characteristic enables mRNA vaccines to be flexibly adjusted according to the variation of the influenza virus to cope with the changes in seasonal influenza.

Table 1.

mRNA Vaccines Targeting Different Viruses

Vaccine	Target virus	Developer	Stage of development
BNT162b2	SARS-CoV-2	BioNTech/Pfizer	Approved
mRNA-1273.222	SARS-CoV-2	Moderna	Approved
CVnCoV	SARS-CoV-2	CureVac	Phase 2/3
mRNA-1010	Influenza	Moderna	Phase 2/3
mRNA-1345	RSV	Moderna	Phase 3
mRNA-1944	CHIKV	Moderna	Phase 1
CV7202	Rabies	CureVac	Phase 3
ZIKV mRNA	Zika Virus	Moderna	Phase 1
HIV mRNA	HIV	Fortner & Bucur	Phase 1
HBV mRNA	Hepatitis B Virus	Ely et al.	Preclinical

Respiratory syncytial virus (RSV) is one of the leading causes of severe respiratory infections in infants and the elderly (Li et al., 2022). Developing an effective RSV vaccine is a long-standing challenge as there is currently no vaccine available to effectively prevent RSV infection. Fortunately, mRNA vaccine technology offers new possibilities to address this issue (Hajiaghapour Asr et al., 2023). Nearly 20 years ago, research on the mRNA vaccine targeting RSV successfully designed an RNA vaccine targeting the RSV F protein that could activate the body’s T-cell immune response. Nevertheless, the overall immune effect was not ideal due to the inability to maintain RNA activity in the body at that time (Fleeton et al., 2001). Encouragingly, with advances in delivery vehicle research, significant breakthroughs have been made in the development of mRNA-based RSV vaccines. Espeseth et al. evaluated the immunogenicity and safety of chemically modified mRNA vaccines encapsulated with LNPs encoding various forms of RSV F proteins in rodent models; these vaccines exhibited protective effects against RSV in mice and rats. Additionally, they compared the immune effects of mRNA vaccines with RSV F trimer protein vaccine (DS-Cav1) and discovered that mRNA vaccines induced the production of more CD4 and CD8+ T-cell subtypes, demonstrating the potential advantages of mRNA vaccines in activating cell-mediated immune responses (Espeseth et al., 2020). Austin et al. confirmed that staggered injections of mRNA vaccines encoding RSV F protein could enhance the immune response to RSV (Austin et al., 2023). Li et al. evaluated the potency of mRNA-based RSV vaccines at the cellular level to support Phase II development of these vaccines (Li et al., 2023). Although the research on mRNA-based RSV vaccines is ongoing, the use of mRNA technology can accelerate the development and progression of vaccines and provide more effective prevention measures.

Ebola is a highly lethal virus capable of rapidly triggering large-scale outbreaks, posing a significant threat to global public health security (Jacob et al., 2020). As a mRNA virus, Ebola contains seven major structural proteins as follows: NP, glycoprotein (GP), polymerase protein (L), viral protein (VP) 24, VP35, VP30, and VP40. Specifically, the polymerase protein (L) forms the nucleocapsid of the Ebola virus, VP40 forms the matrix layer around the nucleocapsid, and the surface GP inserts into the envelope, being the only surface protein of the Ebola virus (Marcinkiewicz et al., 2014). Researchers prepared vaccines using mRNAs encoding the GP or NP of Ebola virus and observed that mRNA vaccines based on the GP sequence could induce strong humoral and cellular immune responses in mice, thereby protecting them from Ebola virus infection. In their study, the administration of mRNA vaccines based on the NP sequence alone did not affect the survival rate of mice infected with the Ebola virus, while simultaneous administration of mRNA vaccines targeting both GP and NP provided better protection to mice than administration of mRNA vaccines targeting GP alone (Krahling et al., 2023). However, in recombinant protein vaccines, the impact of adding NP on the injection of recombinant GP protein is negligible (Sullivan et al., 2006; Sullivan et al., 2003). Previous studies have shown that the generation of NP-specific CD8+ T cells in the body is a key factor in combating Ebola virus infection (Sullivan et al., 2011). It is evident that mRNA vaccines encoding Ebola virus-related proteins can elicit more effective immune responses in the host. Although the development of mRNA vaccines against the Ebola virus is still in the early stages and related research is also limited, mRNA vaccines still demonstrate significant potential in combating this deadly virus.

SARS-CoV-2 has spurred rapid development and application of mRNA vaccine technology (Hu et al., 2021). SARS-CoV-2 currently poses an unprecedented impact on human health and global public health security. To control the spread of the epidemic, governments around the world have invested substantial manpower and resources in the development of SARS-CoV-2 vaccines (V’Kovski et al., 2021). As of 2022, 47 mRNA vaccines had been developed, with BioNTech and Moderna being the main developers of mRNA vaccines for SARS-CoV-2 (Barda et al., 2021). SARS-CoV-2, a positive-sense, single-stranded RNA (ssRNA) virus consisting of 9,860 amino acids, encodes 16 nonstructural proteins, 9 accessory proteins, and 4 structural proteins. Among them, the four structural proteins include spike protein, envelope protein, membrane protein, and nucleocapsid protein (Yadav et al., 2021). The spike protein plays a crucial role in mediating the invasion of host cells by the virus and is therefore considered the primary antigen for vaccine design (Fang et al., 2022). However, the spike protein is a trimer with a relatively complex structure. During infection, the spike protein is cleaved into two subunits, the S1 subunit (including signal peptide, receptor-binding domain [RBD], N-terminal domain, C-terminal domain 1 [CTD1], and CTD2) and the S2 subunit (fusion peptide, heptad repeat sequences, central helix [CH], connector domain [CD], transmembrane domain, and cytoplasmic tail). Subsequently, structural rearrangement of the S protein occurs after the binding of RBD and angiotensin-converting enzyme 2 receptor on the host cell membrane, leading to postfusion conformation (Xia, 2021). Therefore, the key to preparing mRNA vaccines is to prepare stable prefusion conformations of the S protein. For example, two amino acids at the top of the CH position in the S2 subunit are replaced by proline (K986P and V987P) and such a mutation has been proven to effectively increase the stability of the S protein in prefusion conformation (Wrapp et al., 2020). Based on this, mRNA vaccines for SARS-CoV-2 can quickly and efficiently modify the structure of the S protein during the development process. Such modification can help optimize the efficacy, safety, and stability of the vaccine, thereby enhancing the ability of the immune system to protect against SARS-CoV-2.

In addition to the viruses mentioned above, mRNA vaccine technology has also been applied in research against various other viral diseases, including Zika virus (Zhou et al., 2021), human immunodeficiency virus (HIV) (Fortner and Bucur, 2022), and hepatitis B virus (Ely et al., 2021). With further research and technological advancements, more mRNA vaccines are expected to be developed to address a broader range of viral diseases in the future.

Clinical Trials and Efficacy Evaluation of mRNA Vaccines

The development and application of mRNA vaccines mark a significant advancement in vaccine technology. It is worth noting that mRNA vaccines demonstrate clear advantages not only in early-stage research but also in clinical trials, particularly in the fight against SARS-CoV-2. Current clinical trial data, such as those from the collaboration between BioNTech and Pfizer in developing mRNA candidate vaccines against SARS-CoV-2 during the COVID-19 pandemic, have shown that the nucleoside-modified mRNA candidate vaccines elicit broad cross-protective neutralizing antibody responses against different variants of SARS-CoV-2 (Branche et al., 2023; Hannawi et al., 2023). The ongoing mutations of SARS-CoV-2 have also accelerated the development process of many corresponding mRNA vaccines. One relevant clinical study worth noting is that the bivalent mRNA-1273.222 vaccine based on the Omicron BA.4/BA.5 variant shows neutralizing antibody responses against the Omicron variant and does not present new safety concerns (Chalkias et al., 2023). Overall, mRNA candidate vaccines against SARS-CoV-2 have demonstrated excellent preventive efficacy in phase 1 and phase 2 clinical trials (such as CVnCoV), effectively reducing the incidence of symptomatic COVID-19 cases.

The mRNA-1010 vaccine is a quadrivalent seasonal influenza vaccine targeting the HA membrane GP of four influenza strains (A/H1N1, A/H3N2, B/Victoria, and B/Yamagata). In a mid-term report of a phase 1/2 clinical trial for mRNA-1010, the immune activity was detected in both young and elderly participants. Furthermore, compared to the quadrivalent influenza vaccine (Afluria), mRNA-1010 vaccine triggered a more robust immune response (Lee et al., 2023). Additionally, clinical studies have stated that mRNA vaccines targeting H10N8 and H7N9 exhibit good safety and reactogenicity. Of them, the serum conversion rates for 100 µg of H10N8 mRNA vaccine were 78.3% (hemagglutination inhibition) and 87.0% (microneutralization), while those for 50 µg of H7N9 mRNA vaccine were 96.3% (hemagglutination inhibition) and 100% (microneutralization), without cell-mediated immunity observed (Feldman et al., 2019). Relative to nonreplicating RNA influenza virus vaccines, saRNA vaccines function with much lower dosages (Vogel et al., 2018), which highlights the potential application of mRNA vaccines in combating influenza.

With the advancement of mRNA vaccine technology, many mRNA vaccines targeting other viral diseases are also in the stage of clinical trial evaluation, including mRNA vaccines against RSV, chikungunya virus (CHIKV), and pseudorabies virus. Aliprantis et al. conducted a clinical trial of the experimental mRNA vaccine mRNA-1777 targeting RSV. By the way, mRNA-1777 is an RSV mRNA vaccine that encodes the full-length RSV F protein in the prefusion conformation. Their study results indicated that mRNA-1777 not only could increase RSV F-specific humoral and cellular immune responses in both young and elderly healthy adults but also exhibited good tolerability (Aliprantis et al., 2021). Additionally, mRNA-1345 is an mRNA vaccine that encodes the stabilized RSV prefusion F GP. In a clinical study involving approximately 35,000 participants, mRNA-1345 exhibited a protective efficacy of 83.7% against RSV-related lower respiratory tract diseases with at least two symptoms or signs, a protective efficacy of 82.4% against diseases with at least three symptoms or signs, and the similar efficacy against two subtypes of RSV (Wilson et al., 2023). These results support the research on mRNA vaccines based on the RSV prefusion F protein. However, further optimization of the vaccine is still needed to enhance its immunogenicity for preventing susceptible populations from RSV infection. Additionally, mRNA-1944 is a lipid-encapsulated mRNA vaccine encoding CHIKV-specific monoclonal neutralizing antibody CHKV-24. Clinical trials have verified the expression and antibody activity of mRNA-1944 vaccine in vivo, offering new therapeutic options for CHIKV infection (August et al., 2022). CV7202 is a mRNA vaccine targeting the rabies virus GP. According to clinical trial results, only 1 µg or 2 µg of CV7202 can induce neutralizing antibody responses against rabies meeting the standards of the World Health Organization (Aldrich et al., 2021). These clinical trials evaluated the protective effects of mRNA vaccines against different viruses and the immune responses they triggered in various populations. The preliminary results are promising, indicating that mRNA technology may change the way people prevent and combat various infectious diseases.

The safety assessment of mRNA vaccines is also an important step that cannot be ignored in the vaccine development process. Clinical trial data indicate that mRNA vaccines not only effectively prevent viral infections but also demonstrate good safety during mass vaccination campaigns. In a clinical trial of an HIV mRNA vaccine, no severe adverse events or deaths were observed among participants receiving different doses of the vaccine (Anonymous, 2019). After receiving SARS-CoV-2 mRNA vaccines, common side effects include pain at the injection site, as well as fatigue, headache, muscle pain, chills, fever, and joint pain, but these symptoms are typically mild to moderate and resolve within a few days, almost without serious side effects (Munro et al., 2022, Munro et al., 2021). Wilson et al. evaluated the safety of the mRNA-1345 vaccine targeting RSV prefusion F protein in elderly individuals. Among 17,000 participants aged 60 years and above, 16.2% suffered local adverse reactions and 32.9% suffered systemic adverse reactions, most of which were mild to moderate and of short duration (Wilson et al., 2023). The current clinical trials and large-scale postvaccination monitoring data have revealed that the benefits of mRNA vaccines in preventing diseases far outweigh their potential risks.

At present, long-term data on the duration of immune protection and immunological memory provided by mRNA vaccines are still being collected. Preliminary studies suggest that the immune response generated after receiving mRNA vaccine can persist for several months or even longer, but the specific duration of protection requires further observation (Chen et al., 2023; Liu et al., 2023). Overall, mRNA vaccines have demonstrated efficient preventive effects and good safety in clinical trials, making them powerful tools in combating the COVID-19 pandemic and other viral diseases. With the development of more vaccines and the accumulation of long-term data, we will fully understand the importance of these vaccines in global health protection.

Challenges and Solutions for mRNA Vaccines

Due to the relative instability of mRNA molecules themselves and their susceptibility to degradation by enzymes in the external environment, one of the main challenges for mRNA vaccines is their stability and storage conditions. Currently, the primary method to ensure vaccine stability is to store and transport them under low-temperature conditions to maintain the integrity and activity of their structure (Reichmuth et al., 2016). For example, COVID-19 mRNA vaccines require storage in ultra-low temperatures below −70°C, posing significant logistical challenges for global vaccine distribution and administration (Crommelin et al., 2021). Solutions of the above challenges include improving the design and modification of mRNA molecules, such as enhancing stability through chemical modifications. Structural features of mRNA, such as the 5′ cap, poly (A) tail, and untranslated regions, directly affect mRNA stability and translation efficiency (Orlandini von Niessen et al., 2019). Besides, both the 5′ and 3′-end cap and poly (A) tail of mRNA are crucial for the stability of mRNA (Kim et al., 2022). Also, research has uncovered that increasing the content of C and G in the mRNA coding region can enhance the stability of mRNA (Homma et al., 2016). Furthermore, circRNA is a special type of RNA molecule with a closed circular structure. Up to now, circRNA vaccines are still in the early stages of development and their optimization, delivery, and application require further development and evaluation (Niu et al., 2023). There are numerous challenges in the development process of circRNA vaccines, including the inability of circRNA to spontaneously process into monomeric functional proteins after translation into multimeric polyproteins. Although this issue can be addressed by methods such as inserting self-cleaving peptides to facilitate the production of various independent functional active proteins (Costello et al., 2019; Liu et al., 2022), the efficiency of circRNA vaccines still needs to be improved.

Apart from optimizing mRNA, developing novel LNPs to more effectively encapsulate and protect mRNA molecules is also an effective pathway to improve the delivery efficiency and stability of vaccines (Kon et al., 2022). LNPs typically consist of four components, including ionizable cationic lipids, phospholipids, cholesterol, and PEGylated lipids. Researchers tend to adjust the tail structure of ionizable cationic lipids. In other words, they expect to enhance efficacy or confer specific functions by altering tail number, designing linear or branched structures, and introducing unsaturated or biodegradable bonds (Han et al., 2021). Besides, scientists have been searching for suitable forms of phospholipids to enhance the physical and biological functions of phospholipids. Liu et al. developed hundreds of ionizable phospholipids, among which phospholipids named 9A1P9 exhibited more efficient functions to deliver and release mRNA (Liu et al., 2021). Cholesterol helps to increase the stability of LNPs and facilitate membrane fusion and optimizing the structure of cholesterol can also enhance the delivery efficiency of LNPs (Paunovska et al., 2018). The choice of polyethylene glycol (PEG) is also crucial. Some studies believed that PEG2000 lipids are the optimal choice for forming stable LNPs as they do not compromise RNA delivery efficiency (Mui et al., 2013). Additionally, selecting components and balancing their internal ratios are of great importance for LNP-mediated mRNA delivery. By the way, LNP-mediated mRNA delivery can even achieve targeted delivery of vaccines (Swingle et al., 2021). In addition to optimizing LNPs, research is ongoing into alternative delivery systems, such as polymeric nanoparticles and electroporation, to improve mRNA vaccine delivery and efficacy.

Actively addressing individual differences in mRNA vaccine immune responses is another important challenge in the development of vaccination schedules and immunization strategies. Variations in immune status among different individuals may affect the effectiveness of vaccine (Boretti, 2024). Additionally, precise control of mRNA vaccine dosage is necessary to ensure adequate immune protection and minimize adverse effects (Polack et al., 2020). To tackle this issue, researchers are conducting a comprehensive dose-response assessment to determine the optimal vaccine dosage. Furthermore, personalized medical approaches can be implemented to adjust vaccine dosages or vaccination schedules according to individual needs (Lee et al., 2022). Moreover, monitoring immune responses and adjusting immunization strategies as needed can enhance the overall effectiveness of vaccines.

Finally, the understanding and acceptance of the public to novel vaccines may also impact the efficiency of vaccination and have a certain influence on achieving herd immunity. To improve public acceptance, it is essential to provide accurate vaccine information through active and effective communication strategies as well as transparent public information channels. The relevant measures include publicity and education of relevant knowledge and explanation of the safety, efficacy, and importance of vaccines. Moreover, cooperating with trusted healthcare institutions and utilizing social media and other platforms for scientific dissemination are also key strategies for enhancing public acceptance. Through these efforts, public willingness to receive vaccinations can be increased, thereby facilitating the smooth progress of vaccination.

Future and Prospects

Currently, there is a need not only to improve the efficacy of mRNA vaccines in preventing viral infections but also to enhance their stability, safety, and production efficiency. In terms of increasing vaccine efficacy, continuous optimization of mRNA sequence design and identification of suitable sequences are required to enhance the immunogenicity of the encoded antigen proteins. Concerning improving vaccine stability, optimizing mRNA modification methods or designing more efficient encapsulation vehicles can protect mRNA from rapid degradation and ensure its effective delivery to target cells. As for addressing safety issues, reducing nonspecific immune responses and inflammatory responses triggered by mRNA vaccines is a key focus of research. Additionally, multivalent and combined mRNA vaccines have tremendous potential. By encoding antigen proteins of different pathogens, multivalent vaccines can provide protection against multiple virus infections with a single vaccination (Arevalo et al., 2022). However, research in this area is still in the preliminary stages. In summary, mRNA vaccines present broad prospects for public health security construction.

Conclusion

Although mRNA vaccine technology is still in the development stage, the application of mRNA vaccines has achieved significant success. During the COVID-19 pandemic, fast and precise mRNA technology contributed to the rapid design and production of vaccines targeting different virus strain variations, thereby enabling people to address the changes and challenges of the epidemic. Compared to traditional vaccines, mRNA vaccines have several advantages. First, the production process of mRNA vaccines is simpler and more flexible, allowing for rapid responses to epidemic needs. Second, mRNA vaccines do not contain live virus components, so they have no risk of inducing infection and present higher safety. Additionally, mRNA vaccines can be designed through targeting different pathogens, providing broader applicability. With continuous technological advancements and innovations, we anticipate the development and application of more mRNA vaccines targeting various viruses and diseases. In the future, through global collaboration and technological innovation, mRNA vaccines may become a core component of public health defense systems, thereby making greater contributions to human health and social stability.

Footnotes

Authors’ Contributions

Conception and writing, X.W.; Charting and writing, X.W.; data analysis, X.W.; reference acquisition, X.W.; comments and suggestions, X.W.; article revision, X.W.; visualization, X.W.; funding acquisition, X.W. All the authors approved the final article.

Author Disclosure Statement

No competing financial interests exist.

Availability of Data and Materials

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

Funding Information

No funding was received for this article.

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