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The idea of mRNA therapy had been conceived for decades before it came into reality during the Covid-19 pandemic. The mRNA vaccine emerges as a powerful and general tool against new viral infections, largely due to its versatility and rapid development. In addition to prophylactic vaccines, mRNA technology also offers great promise for new applications as a versatile drug modality. However, realizing the conceptual potential faces considerable challenges, such as minimal immune stimulation, high and long-term expression, and efficient delivery to target cells and tissues. Here we review the applications of mRNA-based therapeutics, with emphasis on the innovative design and future challenges/solutions. In addition, we also discuss the next generation of mRNA therapy, including circular mRNA and self-amplifying RNAs. We aim to provide a conceptual overview and outlook on mRNA therapeutics beyond prophylactic vaccines.

Messenger RNA (mRNA) vaccines, while demonstrating great successes in the fight against COVID-19, have been extensively studied in other areas such as personalized cancer immunotherapy based on tumor neoantigens. In addition to the design of mRNA sequences and modifications, the delivery carriers are also critical in the development of mRNA vaccines. In this work, we synthesized fluoroalkane-grafted polyethylenimine (F-PEI) for mRNA delivery. Such F-PEI could promote intracellular delivery of mRNA and activate the Toll-like receptor 4 (TLR4)-mediated signaling pathway. The nanovaccine formed by self-assembly of F-PEI and the tumor antigen-encoding mRNA, without additional adjuvants, could induce the maturation of dendritic cells (DCs) and trigger efficient antigen presentation, thereby eliciting anti-tumor immune responses. Using the mRNA encoding the model antigen ovalbumin (mRNA<SUP>OVA</SUP>), our F-PEI-based mRNA<SUP>OVA</SUP> cancer vaccine could delay the growth of established B16-OVA melanoma. When combined with immune checkpoint blockade therapy, the F-PEI-based MC38 neoantigen mRNA cancer vaccine was able to suppress established MC38 colon cancer and prevent tumor reoccurrence. Our work presents a new tool for mRNA delivery, promising not only for personalized cancer vaccines but also for other mRNA-based immunotherapies.

On March 11, 2020, the World Health Organization (WHO) declared the coronavirus disease 2019 (COVID-19) outbreak a pandemic. Simultaneously, in Italy, in which the first case had occurred on February 18, the rigid phase of the lockdown began. The country has attracted worldwide attention, becoming at the same time a field of study both concerning the spread of the pandemic and advanced assessments of the effectiveness of political, public health, and therapeutic measures. The protagonists of the Italian crisis were the healthcare workers (HCWs) who were exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) without having any perception of what they were facing, courageously contributing to the containment of the epidemic to be defined by the media as "heroes." However, in the first phase of the pandemic (March─May 2020), the price that the Italian Public Health System had to pay both in terms of the number of positive virus cases and deaths among the HCWs was beyond and represented a peculiarity compared to what happened in other countries. In the current study, after a summary of the evolution of the pandemic in Italy, we offer an analysis of the statistical data concerning contagions and deaths among healthcare workers (physicians in particular). In conclusion, we describe the critical issues that still need to be resolved and the future challenges facing healthcare workers and the general population.

Current messenger RNA (mRNA) vaccines in the clinic were reported to induce side effects in the liver, such as reversible hepatic damages and T cell-dominant immune-mediated hepatitis, which might be caused by the undesired expression of antigens in the liver. Therefore, exploring a lymphoid-organ-specific mRNA vaccine could be a promising strategy for developing next-generation mRNA vaccines. Herein, we reported a lymph-node-targeting mRNA vaccine based on lipid nanoparticles named 113-O12B for cancer immunotherapy. The targeted delivery of the mRNA vaccine elicits robust CD8<SUP>+</SUP> T cell responses, exhibiting excellent protective and therapeutic effects on B16F10 melanoma. Notably, 113-O12B can efficiently deliver both a full-length protein and a short-peptide-based, antigens-encoded mRNA, thus providing a universal platform for mRNA vaccines.

Until now, design of the annual influenza vaccine has relied on phylogenetic or whole-sequence comparisons of the viral coat proteins hemagglutinin and neuraminidase, with vaccine effectiveness assumed to correlate monotonically to the vaccine-influenza sequence difference. We use a theory from statistical mechanics to quantify the non-monotonic immune response that results from antigenic drift in the epitopes of the hemagglutinin and neuraminidase proteins. The results explain the ineffectiveness of the 2003--2004 influenza vaccine in the United States and provide an accurate measure by which to optimize the effectiveness of future annual influenza vaccines.

mRNA therapy is gaining worldwide attention as an emerging therapeutic approach. The widespread use of mRNA vaccines during the COVID-19 outbreak has demonstrated the potential of mRNA therapy. As mRNA-based drugs have expanded and their indications have broadened, more patents for mRNA innovations have emerged. The global patent landscape for mRNA therapy has not yet been analyzed, indicating a research gap in need of filling, from new technology to productization. This study uses social network analysis with the patent quality assessment to investigate the temporal trends, citation relationship, and significant litigation for 16,101 mRNA therapy patents and summarizes the hot topics and potential future directions for this industry. The information obtained in this study not only may be utilized as a tool of knowledge for researchers in a comprehensive and integrated way but can also provide inspiration for efficient production methods for mRNA drugs. This study shows that infectious diseases and cancer are currently the primary applications for mRNA drugs. Emerging patent activity and lawsuits in this field are demonstrating that delivery technology remains one of the key challenges in the field and that drug-targeting research in combination with vector technology will be one of the major directions for the industry going forward. With significant funding, new organizations have developed novel delivery technologies in an attempt to break into the patent thicket established by companies such as Arbutus. The global mRNA therapeutic landscape is undergoing a multifaceted development pattern, and the monopoly of giant companies is being challenged.

Optimizing the mRNA codon has an essential impact on gene expression for a specific target protein. It is an NP-hard problem; thus, exact solutions to such optimization problems become computationally intractable for realistic problem sizes on both classical and quantum computers. However, approximate solutions via heuristics can substantially impact the application they enable. Quantum approximate optimization is an alternative computation paradigm promising for tackling such problems. Recently, there has been some research in quantum algorithms for bioinformatics, specifically for mRNA codon optimization. This research presents a denser way to encode codons for implementing mRNA codon optimization via the variational quantum eigensolver algorithms on a gate-based quantum computer. This reduces the qubit requirement by half compared to the existing quantum approach, thus allowing longer sequences to be executed on existing quantum processors. The performance of the proposed algorithm is evaluated by comparing its results to exact solutions, showing well-matching results.

This study examines the roles of public and private sector actors in the development of mRNA vaccines, a breakthrough innovation in modern medicine. Using a dataset of 151 core patent families and 2,416 antecedent (cited) patents, we analyze the structure and dynamics of the mRNA vaccine knowledge network through network theory. Our findings highlight the central role of biotechnology firms, such as Moderna and BioNTech, alongside the crucial contributions of universities and public research organizations (PROs) in providing foundational knowledge.We develop a novel credit allocation framework, showing that universities, PROs, government and research centers account for at least 27% of the external technological knowledge base behind mRNA vaccine breakthroughs - representing a minimum threshold of their overall contribution. Our study offers new insights into pharmaceutical and biotechnology innovation dynamics, emphasizing how Moderna and BioNTech's mRNA technologies have benefited from academic institutions, with notable differences in their institutional knowledge sources.

INTRODUCTION: In light of the SARS-CoV-2 pandemic, protecting vulnerable groups has become a high priority. Persons at risk of severe disease, for example, those receiving immunosuppressive therapies for chronic inflammatory cdiseases (CIDs), are prioritised for vaccination. However, data concerning generation of protective antibody titres in immunosuppressed patients are scarce. Additionally, mRNA vaccines represent a new vaccine technology leading to increased insecurity especially in patients with CID. OBJECTIVE: Here we present for the first time, data on the efficacy and safety of anti-SARS-CoV-2 mRNA vaccines in a cohort of immunosuppressed patients as compared with healthy controls. METHODS: 42 healthy controls and 26 patients with CID were included in this study (mean age 37.5 vs 50.5 years). Immunisations were performed according to national guidelines with mRNA vaccines. Antibody titres were assessed by ELISA before initial vaccination and 7 days after secondary vaccination. Disease activity and side effects were assessed prior to and 7 days after both vaccinations. RESULTS: Anti-SARS-CoV-2 antibodies as well as neutralising activity could be detected in all study participants. IgG titres were significantly lower in patients as compared with controls (2053 binding antibody units (BAU)/mL ±1218 vs 2685±1102). Side effects were comparable in both groups. No severe adverse effects were observed, and no patients experienced a disease flare. CONCLUSION: We show that SARS-CoV-2 mRNA vaccines lead to development of antibodies in immunosuppressed patients without considerable side effects or induction of disease flares. Despite the small size of this cohort, we were able to demonstrate the efficiency and safety of mRNA vaccines in our cohort.

BACKGROUND AND AIMS: The National Multiple Sclerosis Society and other expert organizations recommended that all patients with multiple sclerosis (MS) should be vaccinated against COVID-19. However, the effect of disease-modifying therapies (DMTs) on the efficacy to mount an appropriate immune response is unknown. We aimed to characterize humoral immunity in mRNA-COVID-19 MS vaccinees treated with high-efficacy DMTs. METHODS: We measured SARS-CoV-2 IgG response using anti-spike protein-based serology (EUROIMMUN) in 125 MS patients vaccinated with BNT162b2-COVID-19 vaccine 1 month after the second dose. Patients were either untreated or under treatment with fingolimod, cladribine, or ocrelizumab. A group of healthy subjects similarly vaccinated served as control. The percent of subjects that developed protective antibodies, the titer, and the time from the last dosing were evaluated. RESULTS: = 26), respectively. SARS-CoV-2 IgG antibody titer was high in healthy subjects, untreated MS patients, and MS patients under cladribine treatment, within 29.5-55 days after the second vaccine dose. Only 22.7% of patients treated with ocrelizumab developed humoral IgG response irrespective to normal absolute lymphocyte count. Most fingolimod-treated MS patients had very low lymphocyte count and failed to develop SARS-COV-2 antibodies. Age, disease duration, and time from the last dosing did not affect humoral response to COVID-19 vaccination. CONCLUSIONS: Cladribine treatment does not impair humoral response to COVID-19 vaccination. We recommend postponing ocrelizumab treatment in MS patients willing to be vaccinated as a protective humoral response can be expected only in some. We do not recommend vaccinating MS patients treated with fingolimod as a protective humoral response is not expected.