Combination therapy with oncolytic virus and T cells or mRNA vaccine amplifies antitumor effects.

Antitumor therapies based on adoptively transferred T cells or oncolytic viruses have made significant progress in recent years, but the limited efficiency of their infiltration into solid tumors makes it difficult to achieve desired antitumor effects when used alone. In this study, an oncolytic virus (rVSV-LCMVG) that is not prone to induce virus-neutralizing antibodies was designed and combined with adoptively transferred T cells. By transforming the immunosuppressive tumor microenvironment into an immunosensitive one, in B16 tumor-bearing mice, combination therapy showed superior antitumor effects than monotherapy. This occurred whether the OV was administered intratumorally or intravenously. Combination therapy significantly increased cytokine and chemokine levels within tumors and recruited CD8+ T cells to the TME to trigger antitumor immune responses. Pretreatment with adoptively transferred T cells and subsequent oncolytic virotherapy sensitizes refractory tumors by boosting T-cell recruitment, down-regulating the expression of PD-1, and restoring effector T-cell function. To offer a combination therapy with greater translational value, mRNA vaccines were introduced to induce tumor-specific T cells instead of adoptively transferred T cells. The combination of OVs and mRNA vaccine also displays a significant reduction in tumor burden and prolonged survival. This study proposed a rational combination therapy of OVs with adoptive T-cell transfer or mRNA vaccines encoding tumor-associated antigens, in terms of synergistic efficacy and mechanism.

Review: N1-methyl-pseudouridine (m1Ψ): Friend or foe of cancer?

Due to the health emergency created by SARS-CoV-2, the virus that causes the COVID-19 disease, the rapid implementation of a new vaccine technology was necessary. mRNA vaccines, being one of the cutting-edge new technologies, attracted significant interest and offered a lot of hope. The potential of these vaccines in preventing admission to hospitals and serious illness in people with comorbidities has recently been called into question due to the vaccines' rapidly waning immunity. Mounting evidence indicates that these vaccines, like many others, do not generate sterilizing immunity, leaving people vulnerable to recurrent infections. Additionally, it has been discovered that the mRNA vaccines inhibit essential immunological pathways, thus impairing early interferon signaling. Within the framework of COVID-19 vaccination, this inhibition ensures an appropriate spike protein synthesis and a reduced immune activation. Evidence is provided that adding 100 % of N1-methyl-pseudouridine (m1Ψ) to the mRNA vaccine in a melanoma model stimulated cancer growth and metastasis, while non-modified mRNA vaccines induced opposite results, thus suggesting that COVID-19 mRNA vaccines could aid cancer development. Based on this compelling evidence, we suggest that future clinical trials for cancers or infectious diseases should not use mRNA vaccines with a 100 % m1Ψ modification, but rather ones with the lower percentage of m1Ψ modification to avoid immune suppression.

Global burden of vaccine-associated multiple sclerosis, 1967-2022: A comprehensive analysis of the international pharmacovigilance database.

Vaccine-associated multiple sclerosis (MS) is rare, with insufficient evidence from case reports. Given the scarcity of large-scale data investigating the association between vaccine administration and adverse events, we investigated the global burden of vaccine-associated MS and potential related vaccines from 1967 to 2022. Reports on vaccine-associated MS between 1967 and 2022 were obtained from the World Health Organization International Pharmacovigilance Database (total number of reports = 120 715 116). We evaluated global reports, reporting odds ratio (ROR), and information components (IC) to investigate associations between 19 vaccines and vaccine-associated MS across 156 countries and territories. We identified 8288 reports of vaccine-associated MS among 132 980 cases of all-cause MS. The cumulative number of reports on vaccine-associated MS gradually increased over time, with a substantial increase after 2020, owing to COVID-19 mRNA vaccine-associated MS. Vaccine-associated MS develops more frequently in males and adolescents. Nine vaccines were significantly associated with higher MS reporting, and the highest disproportional associations were observed for hepatitis B vaccines (ROR 19.82; IC025 4.18), followed by encephalitis (ROR 7.42; IC025 2.59), hepatitis A (ROR 4.46; IC025 1.95), and papillomavirus vaccines (ROR 4.45; IC025 2.01). Additionally, MS showed a significantly disproportionate signal for COVID-19 mRNA vaccines (ROR 1.55; IC025 0.52). Fatal clinical outcomes were reported in only 0.3% (21/8288) of all cases of vaccine-associated MS. Although various vaccines are potentially associated with increased risk of MS, we should be cautious about the increased risk of MS following vaccination, particularly hepatitis B and COVID-19 mRNA vaccines, and should consider the risk factors associated with vaccine-associated MS.

Neutralizing antibody and CD8+ T cell responses following BA.4/5 bivalent COVID-19 booster vaccination in adults with and without prior exposure to SARS-CoV-2.

As severe acute respiratory coronavirus 2 (SARS-CoV-2) variants continue to emerge, it is important to characterize immune responses against variants which can inform on protection efficacies following booster vaccination. In this study, neutralizing breadth and antigen-specific CD8+ T cell responses were analyzed in both infection-naïve and infection-experienced individuals following administration of a booster bivalent Wuhan-Hu-1+BA.4/5 Comirnaty® mRNA vaccine. Significantly higher neutralizing titers were found after this vaccination compared to the pre-third booster vaccination time point. Further, neutralizing breadth to omicron variants, including BA.1, BA.2, BA.5, BQ.1 and XBB.1, was found to be boosted following bivalent vaccination. SARS-CoV-2-specific CD8+ T cells were identified, but with no evidence that frequencies were increased following booster vaccinations. Spike protein-specific CD8+ T cells were the only responses detected after vaccination and non-spike-specific CD8+ T cells were only detected after infection. Both spike-specific and non-spike-specific CD8+ T cells were found at much lower frequencies than CD8+ T cells specific to cytomegalovirus (CMV), Epstein-Barr virus (EBV) and influenza (Flu). Taken together, these results show that the bivalent Wuhan-Hu-1+BA.4/5 Comirnaty® mRNA vaccine boosted the breadth of neutralization to newer SARS-CoV-2 variants and that vaccination is able to induce spike protein-specific CD8+ T cell responses, which are maintained longitudinally.

The mRNA Vaccine Expressing Single and Fused Structural Proteins of Porcine Reproductive and Respiratory Syndrome Induces Strong Cellular and Humoral Immune Responses in BalB/C Mice.

PRRS is a viral disease that profoundly impacts the global swine industry, causing significant economic losses. The development of a novel and effective vaccine is crucial to halt the rapid transmission of this virus. There have been several vaccination attempts against PRRSV using both traditional and alternative vaccine design development approaches. Unfortunately, there is no currently available vaccine that can completely control this disease. Thus, our study aimed to develop an mRNA vaccine using the antigens expressed by single or fused PRRSV structural proteins. In this study, the nucleotide sequence of the immunogenic mRNA was determined by considering the antigenicity of structural proteins and the stability of spatial structure. Purified GP5 protein served as the detection antigen in the immunological evaluation. Furthermore, cellular mRNA expression was detected by immunofluorescence and western blotting. In a mice experiment, the Ab titer in serum and the activation of spleen lymphocytes triggered by the antigen were detected by ELISA and ICS, respectively. Our findings demonstrated that both mRNA vaccines can significantly stimulate cellular and humoral immune responses. More specifically, the GP5-mRNA exhibited an immunological response that was similar to that of the commercially available vaccine when administered in high doses. To conclude, our vaccine may show promising results against the wild-type virus in a natural host.

The dawn of a new Era: mRNA vaccines in colorectal cancer immunotherapy.

Colorectal cancer (CRC) is a typical cancer that accounts for 10% of all new cancer cases annually and nearly 10% of all cancer deaths. Despite significant progress in current classical interventions for CRC, these traditional strategies could be invasive and with numerous adverse effects. The poor prognosis of CRC patients highlights the evident and pressing need for more efficient and targeted treatment. Novel strategies regarding mRNA vaccines for anti-tumor therapy have also been well-developed since the successful application for the prevention of COVID-19. mRNA vaccine technology won the 2023 Nobel Prize in Physiology or Medicine, signaling a new direction in human anti-cancer treatment: mRNA medicine. As a promising new immunotherapy in CRC and other multiple cancer treatments, the mRNA vaccine has higher specificity, better efficacy, and fewer side effects than traditional strategies. The present review outlines the basics of mRNA vaccines and their advantages over other vaccines and informs an available strategy for developing efficient mRNA vaccines for CRC precise treatment. In the future, more exploration of mRNA vaccines for CRC shall be attached, fostering innovation to address existing limitations.

Initial Efficacy of the COVID-19 mRNA Vaccine Booster and Subsequent Breakthrough Omicron Variant Infection in Patients with B-Cell Non-Hodgkin's Lymphoma: A Single-Center Cohort Study.

It has been suggested that the effect of coronavirus disease 2019 (COVID-19) booster vaccination in patients with B-cell non-Hodgkin's lymphoma (B-NHL) is inferior to that in healthy individuals. However, differences according to histological subtype or treatment status are unclear. In addition, there has been less research on patients who subsequently develop breakthrough infections. We investigated the effects of the first COVID-19 booster vaccination for patients with B-NHL and the clinical features of breakthrough infections in the Omicron variant era. In this study, B-NHL was classified into two histological subtypes: aggressive lymphoma and indolent lymphoma. Next, patients were subdivided according to treatment with anticancer drugs at the start of the first vaccination. We also examined the clinical characteristics and outcomes of patients who had breakthrough infections after a booster vaccination. The booster effect of the COVID-19 mRNA vaccine in patients with B-NHL varied considerably depending on treatment status at the initial vaccination. In the patient group at more than 1 year after the last anticancer drug treatment, regardless of the histological subtype, the booster effect was comparable to that in the healthy control group. In contrast, the booster effect was significantly poorer in the other patient groups. However, of the 213 patients who received the booster vaccine, 22 patients (10.3%) were infected with COVID-19, and 18 patients (81.8%) had mild disease; these cases included the patients who remained seronegative. Thus, we believe that booster vaccinations may help in reducing the severity of Omicron variant COVID-19 infection in patients with B-NHL.

Humoral and cellular response of two different vaccines against SARS-CoV-2 in a group of healthcare workers: An observational study.

On March 13, 2021, Tunisia started a widespread immunization program against SARS-CoV-2 utilizing different vaccinations that had been given emergency approval. Herein, we followed prospectively a cohort of participant who received COVID-19 vaccine (Pfizer BioNTech and Sputnik-Gameleya V). The goal of this follow-up was to define the humoral and cellular immunological profile after immunization by assessing neutralizing antibodies and IFN- γ release. 26 vaccinated health care workers by Pfizer BioNTech (n=12) and Sputnik-Gameleya V (n=14) were enrolled from June to December 2021 in Military hospital of Tunis. All consenting participants were sampled for peripheral blood after three weeks of vaccination. The humoral response was investigated by the titer of anti-SARS-CoV-2 immunoglobulin G (IgG) antibodies to S1 protein. The CD4 and CD8 T cell responses were evaluated by the QuantiFERON® SARS-CoV-2 (Qiagen® Basel, Switzerland). Regardless the type of vaccine, the assessment of humoral and cellular response following vaccination showed a strong involvement of the later with expression of IFN-γ as compared to antibodies secretion. Moreover, we showed that people with past SARS-CoV-2 infection developed high levels of antibodies than those who are not previously infected. However, no significant difference was detected concerning interferon gamma (IFN-γ) expression by CD4 and CD8 T cells in health care worker (HCW) previously infection or not with COVID-19 infection. Analysis of immune response according to the type of vaccine, we found that Pfizer BioNTech induced high level of humoral response (91.66%) followed by Sputnik-Gameleya V (64.28%). However, adenovirus vaccine gave a better cellular response (57.14%) than mRNA vaccine (41.66%). Regarding the immune response following vaccine doses, we revealed a significant increase of neutralizing antibodies and IFN-γ release by T cells in patients fully vaccinated as compared to those who have received just one vaccine. Collectively, our data revealed a similar immune response between Pfizer BioNTech and Sputnik-Gameleya V vaccine with a slight increase of humoral response by mRNA vaccine and cellular response by adenovirus vaccine. It's evident that past SARS-CoV-2 infection was a factor that contributed to the vaccination's increased immunogenicity. However, the administration of full doses of vaccines (Pfizer BioNTech or Sputnik-Gameleya V) induces better humoral and cellular responses detectable even more than three months following vaccination.

Advancements in mRNA Vaccines: A Promising Approach for Combating Human Papillomavirus-Related Cancers.

The human papillomavirus (HPV) is a typical sexually transmitted disease that affects different epithelial cells and can cause a number of health problems. HPV is mainly spread through sexual contact and is extremely contagious, even in the absence of obvious symptoms. It is linked to a number of malignancies, such as oropharyngeal, cervical, anal, vulvar, vaginal, and cutaneous as well as anogenital and cutaneous warts. Different vaccines targeting various HPV virus strains have been produced to prevent HPV infections. Vaccines can help prevent HPV-related illnesses, but they cannot cure malignancies that have already been caused by HPV. But new developments in mRNA vaccines have shown potential in combating malignancies linked to HPV. mRNA vaccines stimulate the immune system to identify and attack particular proteins present in viruses or tumour cells. The efficacy of mRNA vaccines in preventing HPV-related malignancies has been shown in preliminary experiments in mice. Additionally, in clinical trials aimed at individuals with HPV-related head and neck malignancies, personalised mRNA vaccines in combination with immune checkpoint drugs have demonstrated encouraging results. Even though mRNA vaccines have drawbacks and restrictions such as immunogenicity and instability, further research and development in this area has a great deal of promise for developing effective therapies for HPV-related malignancies.

mRNA vaccine designs for optimal adjuvanticity and delivery.

Adjuvanticity and delivery are crucial facets of mRNA vaccine design. In modern mRNA vaccines, adjuvant functions are integrated into mRNA vaccine nanoparticles, allowing the co-delivery of antigen mRNA and adjuvants in a unified, all-in-one formulation. In this formulation, many mRNA vaccines utilize the immunostimulating properties of mRNA and vaccine carrier components, including lipids and polymers, as adjuvants. However, careful design is necessary, as excessive adjuvanticity and activation of improper innate immune signalling can conversely hinder vaccination efficacy and trigger adverse effects. mRNA vaccines also require delivery systems to achieve antigen expression in antigen-presenting cells (APCs) within lymphoid organs. Some vaccines directly target APCs in the lymphoid organs, while others rely on APCs migration to the draining lymph nodes after taking up mRNA vaccines. This review explores the current mechanistic understanding of these processes and the ongoing efforts to improve vaccine safety and efficacy based on this understanding.

Immunogenicity and effectiveness of an mRNA therapeutic vaccine for HPV-related malignancies.

Human papillomavirus (HPV) infections account for several human cancers. There is an urgent need to develop therapeutic vaccines for targeting preexisting high-risk HPV (such as HPV 16 and 18) infections and lesions, which are insensitive to preventative vaccines. In this study, we developed a lipid nanoparticle-formulated mRNA-based HPV therapeutic vaccine (mHTV), mHTV-02, targeting the E6/E7 of HPV16 and HPV-18. mHTV-02 dramatically induced antigen-specific cellular immune response and robust memory T-cell immunity in mice, besides significant CD8+ T-cell infiltration and cytotoxicity in TC-1 tumors expressing HPV E6/E7, resulting in tumor regression and prolonged survival in mice. Moreover, evaluation of routes of administration found that intramuscular or intratumoral injection of mHTV-02 displayed significant therapeutic effects. In contrast, intravenous delivery of the vaccine barely showed any benefit in reducing tumor size or improving animal survival. These data together support mHTV-02 as a candidate therapeutic mRNA vaccine via specific administration routes for treating malignancies caused by HPV16 or HPV18 infections.

Reactive axillary lymph nodes after COVID-19 mRNA vaccination: comparison of mRNA vs. attenuated whole-virus vaccines.

OBJECTIVE: To compare the incidence and natural course of reactive axillary lymph nodes (RAL) between mRNA and attenuated whole-virus vaccines using Deauville criteria. METHODS: In this multi-institutional PET-CT study comprising multiple vaccine types (Pfizer-BioNTech/Comirnaty, Moderna/Spikevax, Sinovac/CoronaVac and Janssen vaccines), we evaluated the incidence and natural course of RAL in a large cohort of oncological patients utilizing a standardized Deauville scaling system (n=522; 293 Female, Deauville 3-5 positive for RAL). Univariate and multivariate analyses were conducted to evaluate the predictive value of clinical parameters (absolute neutrophil count [ANC], platelets, age, sex, tumor type, and vaccine-to-PET interval) for PET positivity. RESULTS: Pfizer-BioNTech/Comirnaty and Moderna vaccines revealed similar RAL incidences for the first 20 days after the second dose of vaccine administration (44% for the first 10 days for both groups, 26% vs. 20% for 10-20 days, respectively for Moderna and Pfizer). However, Moderna recipients revealed significantly higher incidences of RAL after 20 days compared to Pfizer-BioNTech/Comirnaty, with nodal reactivity spanning up to the 9th week post-vaccination (15% vs. 4%, respectively P  < 0.001). No RAL was observed in patients who received either a single dose of J&J vaccine or two doses of CroronaVac. Younger patients showed increased likelihood of RAL, otherwise, clinical/demographic parameters were not predictive of RAL ( P  = 0.014 for age, P  > 0.05 for additional clinical/demographic parameters). CONCLUSION: RAL based on strict PET criteria was observed with mRNA but not with attenuated whole-virus vaccines, in line with higher immunogenicity and stronger protection offered by mRNA vaccines.

In silico designed novel multi-epitope mRNA vaccines against Brucella by targeting extracellular protein BtuB and LptD.

Brucella, a gram-negative intracellular bacterium, causing Brucellosis, a zoonotic disease with a range of clinical manifestations, from asymptomatic to fever, fatigue, loss of appetite, joint and muscle pain, and back pain, severe patients have developed serious diseases affecting various organs. The mRNA vaccine is an innovative type of vaccine that is anticipated to supplant traditional vaccines. It is widely utilized for preventing viral infections and for tumor immunotherapy. However, research regarding its effectiveness in preventing bacterial infections is limited. In this study, we analyzed the epitopes of two proteins of brucella, the TonB-dependent outer membrane receptor BtuB and the LPS assembly protein LptD, which is involved in nutrient transport and LPS synthesis in Brucella. In order to effectively stimulate cellular and humoral immunity, we utilize a range of immunoinformatics tools such as VaxiJen, AllergenFPv.1.0 and SignalP 5.0 to design proteins. Finally, five cytotoxic T lymphocyte (CTL) cell epitopes, ten helper T lymphocyte (HTL) cell epitopes, and eight B cell epitopes were selected to construct the vaccine. Computer simulations are also used to verify the immune response of the vaccine. The codon optimization, in silico cloning showed that the vaccine can efficiently transcript and translate in E. coli. The secondary structure of mRNA vaccines and the secondary and tertiary structures of vaccine peptides were predicted and then docked with TLR-4. Finally, the stability of the developed vaccine was confirmed through molecular dynamics simulation. These analyses showed that the design the multi-epitope mRNA vaccine could potentially target extracellular protein of prevalent Brucella, which provided novel strategies for developing the vaccine.

A potential bivalent mRNA vaccine candidate protects against both RSV and SARS-CoV-2 infections.

As the world continues to confront severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respiratory syncytial virus (RSV) is also causing severe respiratory illness in millions of infants, elderly individuals, and immunocompromised people globally. Exacerbating the situation is the fact that co-infection with multiple viruses is occurring, something which has greatly increased the clinical severity of the infections. Thus, our team developed a bivalent vaccine that delivered mRNAs encoding SARS-CoV-2 Omicron spike (S) and RSV fusion (F) proteins simultaneously, SF-LNP, which induced S and F protein-specific binding antibodies and cellular immune responses in BALB/c mice. Moreover, SF-LNP immunization effectively protected BALB/c mice from RSV infection and hamsters from SARS-CoV-2 Omicron infection. Notably, our study pointed out the antigenic competition problem of bivalent vaccines and provided a solution. Overall, our results demonstrated the potential of preventing two infectious diseases with a single vaccine and provided a paradigm for the subsequent design of multivalent vaccines.

COVID-19 vaccines and adverse events of special interest: A multinational Global Vaccine Data Network (GVDN) cohort study of 99 million vaccinated individuals.

BACKGROUND: The Global COVID Vaccine Safety (GCoVS) Project, established in 2021 under the multinational Global Vaccine Data Network™ (GVDN®), facilitates comprehensive assessment of vaccine safety. This study aimed to evaluate the risk of adverse events of special interest (AESI) following COVID-19 vaccination from 10 sites across eight countries. METHODS: Using a common protocol, this observational cohort study compared observed with expected rates of 13 selected AESI across neurological, haematological, and cardiac outcomes. Expected rates were obtained by participating sites using pre-COVID-19 vaccination healthcare data stratified by age and sex. Observed rates were reported from the same healthcare datasets since COVID-19 vaccination program rollout. AESI occurring up to 42 days following vaccination with mRNA (BNT162b2 and mRNA-1273) and adenovirus-vector (ChAdOx1) vaccines were included in the primary analysis. Risks were assessed using observed versus expected (OE) ratios with 95 % confidence intervals. Prioritised potential safety signals were those with lower bound of the 95 % confidence interval (LBCI) greater than 1.5. RESULTS: Participants included 99,068,901 vaccinated individuals. In total, 183,559,462 doses of BNT162b2, 36,178,442 doses of mRNA-1273, and 23,093,399 doses of ChAdOx1 were administered across participating sites in the study period. Risk periods following homologous vaccination schedules contributed 23,168,335 person-years of follow-up. OE ratios with LBCI > 1.5 were observed for Guillain-Barré syndrome (2.49, 95 % CI: 2.15, 2.87) and cerebral venous sinus thrombosis (3.23, 95 % CI: 2.51, 4.09) following the first dose of ChAdOx1 vaccine. Acute disseminated encephalomyelitis showed an OE ratio of 3.78 (95 % CI: 1.52, 7.78) following the first dose of mRNA-1273 vaccine. The OE ratios for myocarditis and pericarditis following BNT162b2, mRNA-1273, and ChAdOx1 were significantly increased with LBCIs > 1.5. CONCLUSION: This multi-country analysis confirmed pre-established safety signals for myocarditis, pericarditis, Guillain-Barré syndrome, and cerebral venous sinus thrombosis. Other potential safety signals that require further investigation were identified.

Audiovestibular adverse events following COVID-19 vaccinations.

INTRODUCTION: Evidence regarding audiovestibular adverse events post COVID-19 vaccination to date has been inconclusive regarding a potential association. This study aimed to determine if there was an increase in audiovestibular events following COVID-19 vaccination in South-eastern Australia during January 2021-March 2023. METHODS: A multi-data source approach was applied. First, a retrospective observational analysis of spontaneous reports of audiovestibular events to a statewide vaccine safety surveillance service, SAEFVIC. Second, a self-controlled case series analysis using general practice data collected via the POpulation Level Analysis and Reporting (POLAR) tool. RESULTS AND CONCLUSIONS: This study is the first to demonstrate an increase in general practice presentations of vertigo following mRNA vaccines (RI = 1.40, P <.001), and tinnitus following both the Vaxzevria® adenovirus vector and mRNA vaccines (RI = 2.25, P <.001 and 1.53, P <.001 respectively). There was no increase in hearing loss following any COVID-19 vaccinations. Our study, however, was unable to account for the potential of concurrent COVID-19 infections, which literature has indicated to be associated with audiovestibular events. Healthcare providers and vaccinees should be alert to potential audiovestibular complaints after COVID-19 vaccination. Our analysis highlights the importance of using large real-world datasets to gather reliable evidence for public health decision making.

mRNA delivery systems for cancer immunotherapy: Lipid nanoparticles and beyond.

mRNA-based vaccines are emerging as a promising alternative to standard cancer treatments and the conventional vaccines. Moreover, the FDA-approval of three nucleic acid based therapeutics (Onpattro, BNT162b2 and mRNA-1273) has further increased the interest and trust on this type of therapeutics. In order to achieve a significant therapeutic efficacy, the mRNA needs from a drug delivery system. In the last years, several delivery platforms have been explored, being the lipid nanoparticles (LNPs) the most well characterized and studied. A better understanding on how mRNA-based therapeutics operate (both the mRNA itself and the drug delivery system) will help to further improve their efficacy and safety. In this review, we will provide an overview of what mRNA cancer vaccines are and their mode of action and we will highlight the advantages and challenges of the different delivery platforms that are under investigation.

Discovery of lung adenocarcinoma tumor antigens and ferroptosis subtypes for developing mRNA vaccines.

mRNA vaccines are becoming a feasible alternative for treating cancer. To develop mRNA vaccines against LUAD, potential antigens were identified and LUAD ferroptosis subtypes distinguished for selecting appropriate patients. The genome expression omnibus, cancer genome atlas (TCGA) and FerrDB were used to collect gene expression profiles, clinical information, and the genes involved in ferroptosis, respectively. cBioPortal was used to visualize and compare genetic alterations, GEPIA2 to calculate prognostic factors of the selected antigens, and TIMER to visualize the relationship between potential antigens and tumor immune cell infiltration. Consensus clustering analysis was utilized to identify ferroptosis subtypes and their prognostic value assessed by Log-rank and cox regression tests. The modules of ferroptosis-related gene screening were conducted by weight gene co-expression network analysis. The LUAD ferroptosis landscape was visualized through dimensionality reduction and graph learning. Six tumor antigens had obvious LUAD-mutations, positively correlated with different antigen-presenting cells, and might induce tumor cell ferroptosis. LUAD patients were stratified into three ferroptosis subtypes (FS1, FS2, and FS3) according to diverse molecular, cellular, and clinical characteristics. FS3 showed the highest tumor mutation burden and the most somatic mutations, deemed potential indicators of mRNA vaccine effectiveness. Moreover, different ferroptosis subtypes expressed distinct immune checkpoints and immunogenic cell death modulators. AGPS, NRAS, MTDH, PANX1, NOX4, and PPARD are potentially suitable for mRNA vaccinations against LUAD, specifically in patients with FS3 tumors. This study defines vaccination candidates and establishes a theoretical basis for LUAD mRNA vaccinations.

Novel Lipid Nanoparticles Stable and Efficient for mRNA Transfection to Antigen-Presenting Cells.

mRNA vaccines have emerged as a pivotal tool in combating COVID-19, offering an advanced approach to immunization. A key challenge with these vaccines is their need for extremely-low-temperature storage, which affects their stability and shelf life. Our research addresses this issue by enhancing the stability of mRNA vaccines through a novel cationic lipid, O,O'-dimyristyl-N-lysyl aspartate (DMKD). DMKD effectively binds with mRNA, improving vaccine stability. We also integrated phosphatidylserine (PS) into the formulation to boost immune response by promoting the uptake of these nanoparticles by immune cells. Our findings reveal that DMKD-PS nanoparticles maintain structural integrity under long-term refrigeration and effectively protect mRNA. When tested, these nanoparticles containing green fluorescent protein (GFP) mRNA outperformed other commercial lipid nanoparticles in protein expression, both in immune cells (RAW 264.7 mouse macrophage) and non-immune cells (CT26 mouse colorectal carcinoma cells). Importantly, in vivo studies show that DMKD-PS nanoparticles are safely eliminated from the body within 48 h. The results suggest that DMKD-PS nanoparticles present a promising alternative for mRNA vaccine delivery, enhancing both the stability and effectiveness of these vaccines.