Enhancing Vaccine Efficacy and Stability: A Review of the Utilization of Nanoparticles in mRNA Vaccines.

The development of vaccines has entered a new era with the advent of nanotechnology, particularly through the utilization of nanoparticles. This review focuses on the role of nanoparticles in enhancing the efficacy and stability of mRNA vaccines. Nanoparticles, owing to their unique properties such as high surface area, tunable size, and their ability to be functionalized, have emerged as powerful tools in vaccine development. Specifically, lipid nanoparticles (LNPs) have revolutionized the delivery of mRNA vaccines by protecting the fragile mRNA molecules and facilitating their efficient uptake by cells. This review discusses the various types of nanoparticles employed in mRNA vaccine formulations, including lipid-based, polymer-based, and inorganic nanoparticles, highlighting their advantages and limitations. Moreover, it explores the mechanisms by which nanoparticles improve immune responses, such as enhanced antigen presentation and the prolonged release of mRNA. This review also addresses the challenges and future directions in nanoparticle-based vaccine development, emphasizing the need for further research to optimize formulations for broader applications. By providing an in-depth analysis of the current advancements in and potential of nanoparticles in mRNA vaccines, this review aims to shed light on their critical role in combating infectious diseases and improving public health outcomes.

Persistent longitudinal T cell responses after SARS-CoV-2 mRNA vaccines in MS patients on different disease modifying treatments.

Few data are available regarding vaccine induced SARS-CoV-2 specific T cell responses over time and after booster doses in multiple sclerosis (MS) patients on different disease modifying treatments. We measured SARS-CoV-2 specific CD4+ T cell responses in 72 samples collected from 36 MS patients. The percentage of CD4+ CTVlow CD25+ ICOS+ T cells after stimulation with Spike Recombinant Protein was 29.9 (17.0-43.6) on teriflunomide, 32.4 (11.9-42.5) on ocrelizumab, but much lower (0.6 [0.3-5.9]) on sphingosine-1-phospate receptor modulators (ß = -26.35, p = 0.003). SARS-CoV-2 specific T cells were mainly of Th1 type and stable over time and after booster vaccine doses. mRNA vaccines elicit strong and persistent CD4+ T cell responses against SARS-CoV-2 in MS patients on anti-CD20 and teriflunomide, but not in those on sphingosine-1-phospate receptor modulators.

Opportunities and challenges to implementing mRNA-based vaccines and medicines: lessons from COVID-19.

The messenger RNA (mRNA) platform emerged at the forefront of vaccine development during the COVID-19 pandemic, with two mRNA COVID-19 vaccines being among the first authorized globally. These vaccines were developed rapidly. Informed by decades of laboratory research, and proved to be safe and efficacious tools for mitigating the global impact of the COVID-19 pandemic. The mRNA platform holds promise for a broader medical application beyond COVID-19. Herein, we provide an overview of this platform and describe lessons learned from the COVID-19 pandemic to help formulate strategies toward enhancing uptake of future mRNA-based interventions. We identify several strategies as vital for acceptance of an expanding array of mRNA-based vaccines and therapeutics, including education, accurate and transparent information sharing, targeted engagement campaigns, continued investment in vaccine safety surveillance, inclusion of diverse participant pools in clinical trials, and addressing deep-rooted inequalities in access to healthcare. We present findings from the Global Listening Project (GLP) initiative, which draws on quantitative and qualitative approaches to capture perceptions and experiences during the COVID-19 pandemic to help design concrete action plans for improving societal preparedness for future emergencies. The GLP survey (>70,000 respondents in 70 countries) revealed tremendous disparities across countries and sociodemographic groups regarding willingness to accept novel mRNA vaccines and medicines. The comfort in innovations in mRNA medicines was generally low (35%) and was marginally lower among women (33%). The GLP survey and lessons learnt from the COVID-19 pandemic provide actionable insights into designing effective strategies to enhance uptake of future mRNA-based medicines.

Lipid nanoparticle-based mRNA vaccines: a new frontier in precision oncology.

The delivery of lipid nanoparticle (LNP)-based mRNA therapeutics has captured the attention of the vaccine research community as an innovative and versatile tool for treating a variety of human malignancies. mRNA vaccines are now in the limelight as an alternative to conventional vaccines owing to their high precision, low-cost, rapid manufacture, and superior safety profile. Multiple mRNA vaccine platforms have been developed to target several types of cancer, and many have demonstrated encouraging results in animal models and human trials. The effectiveness of these new mRNA vaccines depends on the efficacy and stability of the antigen(s) of interest generated and the reliability of their delivery to antigen-presenting cells (APCs), especially dendritic cells (DCs). In this review, we provide a detailed overview of mRNA vaccines and their delivery strategies and consider future directions and challenges in advancing and expanding this promising vaccine platform to widespread therapeutic use against cancer.

A Comprehensive Review on the Intricate Interplay between COVID-19 Immunization and the New Onset of Pemphigus Foliaceus.

Autoimmune bullous diseases (AIBDs) are characterized by the formation of vesicles, bullous lesions, and mucosal erosions. The autoantibodies target the cellular anchoring structures from the surface of epidermal keratinocyte named desmosomes, leading to a loss of cellular cohesion named acantholysis. AIBDs are classified into intraepidermal or subepidermal types based on clinical features, histological characteristics, and immunofluorescence patterns. Pemphigus foliaceus (PF) is an acquired, rare, autoimmune skin condition associated with autoantibodies that specifically target desmoglein-1, leading to a clinical presentation characterized by delicate cutaneous blisters, typically sparing the mucous membranes. Several factors, including genetic predisposition, environmental triggers, malignancies, medication use, and vaccination (for influenza, hepatitis B, rabies, tetanus, and more recently, severe acute respiratory syndrome Coronavirus 2 known as SARS-CoV-2), can potentially trigger the onset of pemphigus. With the advent of vaccines playing a pivotal role in combatting the 2019 coronavirus disease (COVID-19), extensive research has been conducted globally to ascertain their efficacy and potential cutaneous adverse effects. While reports of AIBDs post-COVID-19 vaccination exist in the medical literature, instances of PF following vaccination have been less commonly reported worldwide. The disease's pathophysiology is likely attributed to the resemblance between the ribonucleic acid (RNA) antigen present in these vaccines and cellular nuclear matter. The protein produced by the BNT-162b2 messenger ribonucleic acid (mRNA) vaccine includes immunogenic epitopes that could potentially trigger autoimmune phenomena in predisposed individuals through several mechanisms, including molecular mimicry, the activation of pattern recognition receptors, the polyclonal stimulation of B cells, type I interferon production, and autoinflammation. In this review, we present a comprehensive examination of the existing literature regarding the relationship between COVID-19 and PF, delving into their intricate interactions. This exploration improves the understanding of both pemphigus and mRNA vaccine mechanisms, highlighting the importance of close monitoring for PF post-immunization.

Optimization of the 5' untranslated region of mRNA vaccines.

To investigate the impact of different 5' untranslated regions (UTRs) on mRNA vaccine translation efficiency, five dual-reporter gene expression plasmids with different 5'UTRs were constructed. The corresponding mRNA transcripts were transcribed and capped in vitro. By comparing the expression levels of reporter genes with different 5'UTRs, we identified the 5'UTR associated with the highest expression level. Subsequently, HIVgp145 mRNA vaccines containing various 5'UTRs were constructed and verified. The results demonstrated that mRNA 3 (ß-globin 5'UTR) displayed the greatest number of green fluorescence-positive cells and the highest luciferase fluorescence intensity in the reporter gene expression system. Further, among the HIVgp145 mRNA vaccines with different 5'UTRs, mRNA 7 (ß-globin 5'UTR) exhibited the highest level of expression. These findings indicate that it is feasible to use the 5'UTR of ß-globin in an mRNA vaccine, laying the foundation for animal immunogenicity testing.

Advances in Melanoma: From Genetic Insights to Therapeutic Innovations.

Advances in melanoma research have unveiled critical insights into its genetic and molecular landscape, leading to significant therapeutic innovations. This review explores the intricate interplay between genetic alterations, such as mutations in BRAF, NRAS, and KIT, and melanoma pathogenesis. The MAPK and PI3K/Akt/mTOR signaling pathways are highlighted for their roles in tumor growth and resistance mechanisms. Additionally, this review delves into the impact of epigenetic modifications, including DNA methylation and histone changes, on melanoma progression. The tumor microenvironment, characterized by immune cells, stromal cells, and soluble factors, plays a pivotal role in modulating tumor behavior and treatment responses. Emerging technologies like single-cell sequencing, CRISPR-Cas9, and AI-driven diagnostics are transforming melanoma research, offering precise and personalized approaches to treatment. Immunotherapy, particularly immune checkpoint inhibitors and personalized mRNA vaccines, has revolutionized melanoma therapy by enhancing the body's immune response. Despite these advances, resistance mechanisms remain a challenge, underscoring the need for combined therapies and ongoing research to achieve durable therapeutic responses. This comprehensive overview aims to highlight the current state of melanoma research and the transformative impacts of these advancements on clinical practice.

mRNA vaccines in tumor targeted therapy: mechanism, clinical application, and development trends.

Malignant tumors remain a primary cause of human mortality. Among the various treatment modalities for neoplasms, tumor vaccines have consistently shown efficacy and promising potential. These vaccines offer advantages such as specificity, safety, and tolerability, with mRNA vaccines representing promising platforms. By introducing exogenous mRNAs encoding antigens into somatic cells and subsequently synthesizing antigens through gene expression systems, mRNA vaccines can effectively induce immune responses. Katalin Karikó and Drew Weissman were awarded the 2023 Nobel Prize in Physiology or Medicine for their great contributions to mRNA vaccine research. Compared with traditional tumor vaccines, mRNA vaccines have several advantages, including rapid preparation, reduced contamination, nonintegrability, and high biodegradability. Tumor-targeted therapy is an innovative treatment modality that enables precise targeting of tumor cells, minimizes damage to normal tissues, is safe at high doses, and demonstrates great efficacy. Currently, targeted therapy has become an important treatment option for malignant tumors. The application of mRNA vaccines in tumor-targeted therapy is expanding, with numerous clinical trials underway. We systematically outline the targeted delivery mechanism of mRNA vaccines and the mechanism by which mRNA vaccines induce anti-tumor immune responses, describe the current research and clinical applications of mRNA vaccines in tumor-targeted therapy, and forecast the future development trends of mRNA vaccine application in tumor-targeted therapy.

Advances in the study of LNPs for mRNA delivery and clinical applications.

Messenger ribonucleic acid (mRNA) was discovered in 1961 as an intermediary for transferring genetic information from DNA to ribosomes for protein synthesis. The COVID-19 pandemic brought worldwide attention to mRNA vaccines. The emergency use authorization of two COVID-19 mRNA vaccines, BNT162b2 and mRNA-1273, were major achievements in the history of vaccine development. Lipid nanoparticles (LNPs), one of the most superior non-viral delivery vectors available, have made many exciting advances in clinical translation as part of the COVID-19 vaccine and therefore has the potential to accelerate the clinical translation of many gene drugs. In addition, due to these small size, biocompatibility and excellent biodegradability, LNPs can efficiently deliver nucleic acids into cells, which is particularly important for current mRNA therapeutic regimens. LNPs are composed cationic or pH-dependent ionizable lipid bilayer, polyethylene glycol (PEG), phospholipids, and cholesterol, represents an advanced system for the delivery of mRNA vaccines. Furthermore, optimization of these four components constituting the LNPs have demonstrated enhanced vaccine efficacy and diminished adverse effects. The incorporation of biodegradable lipids enhance the biocompatibility of LNPs, thereby improving its potential as an efficacious therapeutic approach for a wide range of challenging and intricate diseases, encompassing infectious diseases, liver disorders, cancer, cardiovascular diseases, cerebrovascular conditions, among others. Consequently, this review aims to furnish the scientific community with the most up-to-date information regarding mRNA vaccines and LNP delivery systems.

Elucidating allergic reaction mechanisms in response to SARS-CoV-2 mRNA vaccination in adults.

BACKGROUND: During the COVID-19 pandemic, novel nanoparticle-based mRNA vaccines were developed. A small number of individuals developed allergic reactions to these vaccines although the mechanisms remain undefined. METHODS: To understand COVID-19 vaccine-mediated allergic reactions, we enrolled 19 participants who developed allergic events within 2 h of vaccination and 13 controls, nonreactors. Using standard hemolysis assays, we demonstrated that sera from allergic participants induced stronger complement activation compared to nonallergic subjects following ex vivo vaccine exposure. RESULTS: Vaccine-mediated complement activation correlated with anti-polyethelyne glycol (PEG) IgG (but not IgM) levels while anti-PEG IgE was undetectable in all subjects. Depletion of total IgG suppressed complement activation in select individuals. To investigate the effects of vaccine excipients on basophil function, we employed a validated indirect basophil activation test that stratified the allergic populations into high and low responders. Complement C3a and C5a receptor blockade in this system suppressed basophil response, providing strong evidence for complement involvement in vaccine-mediated basophil activation. Single-cell multiome analysis revealed differential expression of genes encoding the cytokine response and Toll-like receptor (TLR) pathways within the monocyte compartment. Differential chromatin accessibility for IL-13 and IL-1B genes was found in allergic and nonallergic participants, suggesting that in vivo, epigenetic modulation of mononuclear phagocyte immunophenotypes determines their subsequent functional responsiveness, contributing to the overall physiologic manifestation of vaccine reactions. CONCLUSION: These findings provide insights into the mechanisms underlying allergic reactions to COVID-19 mRNA vaccines, which may be used for future vaccine strategies in individuals with prior history of allergies or reactions and reduce vaccine hesitancy.

Reflections on the Advisory Committee on Immunization Practices During the COVID-19 Pandemic.

Pediatricians and primary care providers serve an important role in building trust with families and communities. To support the critical role of front-line providers, this perspective seeks to reflect on the work of the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices to support COVID-19 pandemic response efforts. Although Advisory Committee on Immunization Practice (ACIP) recommends vaccines for all age groups, this perspective focuses on the pediatric lens and is tailored to Academic Pediatrics. ACIP adapted from in-person meetings 3 times yearly to virtual meetings on an emergency basis to ensure a thorough review and presentation of all the components of the evidence to recommendation framework, including explicit consideration of equity in the decision-making process. The need for diverse enrollment in clinical trials was highlighted as critical for supporting recommendations and enhancing trust. Near real-time vaccine safety surveillance was implemented at scale and emphasized the importance of collaboration between federal partners engaged in vaccine safety in the United States and extended to other countries with similar safety surveillance systems to enable early recognition and response to safety concerns. A key equity opportunity for future pandemics is to shorten the time between vaccines being available for adults and young children.

mRNA-based HIV-1 vaccines.

SUMMARYThe success of the Severe Acute Respiratory Syndrome Coronavirus 2 mRNA vaccines to lessen/prevent severe COVID-19 opened new opportunities to develop RNA vaccines to fight other infectious agents. HIV-1 is a lentivirus that integrates into the host cell genome and persists for the lifetime of infected cells. Multiple mechanisms of immune evasion have posed significant obstacles to the development of an effective HIV-1 vaccine over the last four decades since the identification of HIV-1. Recently, attempts to address some of these challenges have led to multiple studies that manufactured, optimized, and tested, in different animal models, mRNA-based HIV-1 vaccines. Several clinical trials have also been initiated or are planned to start soon. Here, we review the current strategies applied to HIV-1 mRNA vaccines, discuss different targeting approaches, summarize the latest findings, and offer insights into the challenges and future of HIV-1 mRNA vaccines.

Comparative safety of monovalent and bivalent mRNA COVID-19 booster vaccines in adolescents aged 12 to 17 years in the Republic of Korea.

Objectives: This study analyzed the safety of coronavirus disease 2019 (COVID-19) bivalent and monovalent booster vaccines, including the frequency of adverse events (AEs) such as myocarditis and pericarditis, in adolescents aged 12 to 17 years in the Republic of Korea. We aimed to share the safety profile of the COVID-19 bivalent vaccine booster doses. Methods: We analyzed the frequencies of AEs reported to the COVID-19 vaccination management system (CVMS) or self-reported through the text message survey (TMS). Diagnostic eligibility and causality with vaccines were compared using odds ratios (ORs) by vaccine type, and incidence rates per 100,000 person-days were calculated for confirmed cases of myocarditis and pericarditis following monovalent and bivalent booster doses. Results: In the CVMS, the AE reporting rate (per 100,000 doses) was lower after the bivalent booster (66.5) than after the monovalent booster (264.6). Among the AEs reported for both monovalent and bivalent vaccines, 98.2% were non-serious and 1.8% were serious. According to the TMS, both local and systemic AEs were reported less frequently after the bivalent vaccination than after the monovalent vaccination in adolescents aged 12 to 17 years (p<0.001). The incidence rates per 100,000 person-days for confirmed myocarditis/pericarditis following monovalent and bivalent booster doses were 0.03 and 0.05, respectively; this difference was not statistically significant (OR, 1.797; 95% confidence interval, 0.210-15.386). Conclusion: AEs in 12- to 17-year-olds following the bivalent booster were less frequent than those following the monovalent booster in the Republic of Korea, and no major safety issues were identified. However, the reporting rates for AEs were low.

Potential of mRNA-based vaccines for the control of tick-borne pathogens in one health perspective.

The One Health approach, which integrates the health of humans, animals, plants, and ecosystems at various levels, is crucial for addressing interconnected health threats. This is complemented by the advent of mRNA vaccines, which have revolutionized disease prevention. They offer broad-spectrum effectiveness and can be rapidly customized to target specific pathogens. Their utility extends beyond human medicine, showing potential in veterinary practices to control diseases and reduce the risk of zoonotic transmissions. This review place mRNA vaccines and One Health in the context of tick-borne diseases. The potential of these vaccines to confer cross-species immunity is significant, potentially disrupting zoonotic disease transmission cycles and protecting the health of both humans and animals, while reducing tick populations, infestations and circulation of pathogens. The development and application of mRNA vaccines for tick and tick-borne pathogens represent a comprehensive strategy in global health, fostering a healthier ecosystem for all species in our interconnected world.

Acquired Hemophilia A after SARS-CoV-2 Immunization: A Narrative Review of a Rare Side Effect.

Acquired hemophilia A (AHA) is a rare bleeding disorder (1.4 per million inhabitants per year) caused by neutralizing antibodies against factor VIII. Although uncommon, these autoantibodies can cause a high rate of morbidity and mortality. Several conditions are linked with AHA; based on an EACH2 study, 3.8% of AHA could be connected to infection. In the last four years, most humans have contracted the SARS-CoV-2 infection or have been vaccinated against it. Whether or not COVID-19 immunization might induce AHA remains controversial. This review aims to evaluate the evidence about this possible association. Overall, 18 manuscripts (2 case series and 16 case reports) were included. The anti-SARS-CoV-2 vaccination, as also happens with other vaccines, may stimulate an autoimmune response. However, older individuals with various comorbidities are both at risk of developing AHA and of COVID-19-related morbidity and mortality. Therefore, the COVID-19 vaccine must always be administered because the benefits still outweigh the risks. Yet, we should consider the rare possibility that the activation of an immunological response through vaccination may result in AHA. Detailed registries and prospective studies would be necessary to analyze this post-vaccine acquired bleeding disorder, looking for possible markers and underlying risk factors for developing the disease in association with vaccination.

Multivalent mRNA Vaccine Elicits Broad Protection against SARS-CoV-2 Variants of Concern.

SARS-CoV-2 new waves are primarily caused by changes to the spike protein (S), which can substantially decrease the efficacy of vaccines. Therefore, we tested several multivalent mRNA-LNP vaccines, targeting the full-length S proteins of different variants, and identified an optimal combination for protection against VOCs in BALB/c mice. The tested formulations included trivalent (WT + BA.5 + XBB.1.5), pentavalent (WT + BA.5 + XBB.1.5 + BQ.1.1 + CH.1.1), and octavalent (WT + BA.5 + XBB.1.5 + BQ.1.1 + CH.1.1 + Alpha + Delta + BA.2) vaccines. Among these multivalent vaccines, the pentavalent vaccine showed superior protection for almost all tested variants. Despite this, each multivalent vaccine elicited greater broad-spectrum neutralizing antibodies than the previously evaluated bivalent vaccine (WT + BA.5). Subsequently, we redesigned the multivalent vaccine to efficiently generate neutralizing antibodies against recent VOCs, including EG.5.1. Immunization with the redesigned pentavalent vaccine (WT + EG.5.1 + XBB.1.16 + Delta + BA.5) showed moderate levels of protection against recent Omicron VOCs. Results suggest that the neutralization activity of multivalent vaccines is better than those of the tested bivalent vaccines against WT + BA.5 and WT + EG.5.1. Moreover, the pentavalent vaccine we developed may be highly useful for neutralizing new Omicron VOCs.

Systemic and Mucosal Immunogenicity of Monovalent XBB.1.5-Adapted COVID-19 mRNA Vaccines in Patients with Inflammatory Bowel Disease.

Recently updated COVID-19 mRNA vaccines encode the spike protein of the omicron subvariant XBB.1.5 and are recommended for patients with inflammatory bowel disease (IBD) on immunosuppressive treatment. Nonetheless, their immunogenicity in patients with IBD against rapidly expanding virus variants remains unknown. This prospective multicenter cohort study is the first study to investigate the immunogenicity of XBB.1.5-adapted vaccines in patients with IBD. Systemic and mucosal antibodies targeting the receptor-binding domains (RBDs) of the omicron subvariants XBB.1.5, EG.5.1, and BA.2.86, as well as their neutralization were quantified before and two to four weeks after vaccination with monovalent XBB.1.5-adapted mRNA vaccines. Vaccination increased levels of serum anti-RBD IgG targeting XBB.1.5, EG.5.1, and BA.2.86 (1.9-fold, 1.8-fold, and 2.6-fold, respectively) and enhanced corresponding neutralization responses (2.3-fold, 3.1-fold, and 3.5-fold, respectively). Following vaccination, anti-TNF-treated patients had reduced virus neutralization compared to patients on treatments with other cellular targets. 11.1% and 16.7% of patients lacked EG.5.1 and BA.2.86 neutralization, respectively; all these patients received anti-TNF treatment. At mucosal sites, vaccination induced variant-specific anti-RBD IgG but failed to induce RBD-targeting IgA. Our findings provide a basis for future vaccine recommendations while highlighting the importance of frequent booster vaccine adaptation and the need for mucosal vaccination strategies in patients with IBD.

The mRNA vaccine platform for veterinary species.

Vaccination has proven to be an effective means of controlling pathogens in animals. Since the introduction of veterinary vaccines in the 19th century, several generations of vaccines have been introduced. These vaccines have had a positive impact on global animal health and production. Despite, the success of veterinary vaccines, there are still some pathogens for which there are no effective vaccines available, such as African swine fever. Further, animal health is under the constant threat of emerging and re-emerging pathogens, some of which are zoonotic and can pose a threat to human health. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has highlighted the need for new vaccine platforms that are safe and efficacious, but also importantly, are adaptable and can be modified rapidly to match the circulating pathogens. mRNA vaccines have been shown to be an effective vaccine platform against various viral and bacterial pathogens. This review will cover some of the recent advances in the field of mRNA vaccines for veterinary species. Moreover, various mRNA vaccines and their delivery methods, as well as their reported efficacy, will be discussed. Current limitations and future prospects of this vaccine platform in veterinary medicine will also be discussed.

Development of mRNA rabies vaccines.

Rabies, primarily transmitted to humans by dogs (accounting for 99% of cases). Once rabies occurs, its mortality rate is approximately 100%. Post-exposure prophylaxis (PEP) is critical for preventing the onset of rabies after exposure to rabid animals, and vaccination is a pivotal element of PEP. However, high costs and complex immunization protocols have led to poor adherence to rabies vaccinations. Consequently, there is an urgent need to develop new rabies vaccines that are safe, highly immunogenic, and cost-effective to improve compliance and effectively prevent rabies. In recent years, mRNA vaccines have made significant progress in the structural modification and optimization of delivery systems. Various mRNA vaccines are currently undergoing clinical trials, positioning them as viable alternatives to the traditional rabies vaccines. In this article, we discuss a novel mRNA rabies vaccine currently undergoing clinical and preclinical testing, and evaluate its potential to replace existing vaccines.