Immunogenicity and Efficacy of Personalized Adjuvant mRNA Cancer Vaccines.

In this issue, Gainor and colleagues report on the immunogenicity of personalized neoantigen-encoding mRNA vaccines that elicit measurable polyfunctional CD8+ and CD4+ T-cell responses in patients whose tumors have been resected. Reactivity is substantiated to 20% to 30% of the predicted MHC-I and MHC-II epitopes in four patients with NSCLC postsurgically treated with the vaccine alone and in 12 patients with melanoma treated with their individualized vaccines plus pembrolizumab in the context of a phase 1 clinical trial (NCT03313778). See related article by Gainor et al., p. 2209.

Advances and applications of RNA vaccines in tumor treatment.

Compared to other types of tumor vaccines, RNA vaccines have emerged as promising alternatives to conventional vaccine therapy due to their high efficiency, rapid development capability, and potential for low-cost manufacturing and safe drug delivery. RNA vaccines mainly include mRNA, circular RNA (circRNA), and Self-amplifying mRNA(SAM). Different RNA vaccine platforms for different tumors have shown encouraging results in animal and human models. This review comprehensively describes the advances and applications of RNA vaccines in antitumor therapy. Future directions for extending this promising vaccine platform to a wide range of therapeutic uses are also discussed.

SARS-CoV2 mRNA vaccine intravenous administration induces myocarditis in chronic inflammation.

The current COVID-19 mRNA vaccines were developed and applied for pandemic-emergent conditions. These vaccines use a small piece of the virus's genetic material (mRNA) to stimulate an immune response against COVID-19. However, their potential effects on individuals with chronic inflammatory conditions and vaccination routes remain questionable. Therefore, we investigated the effects of mRNA vaccines in a mouse model of chronic inflammation, focusing on their cardiac toxicity and immunogenicity dependent on the injection route. mRNA vaccine intravenous administration with or without chronic inflammation exacerbated cardiac pericarditis and myocarditis; immunization induced mild inflammation and inflammatory cytokine IL-1beta and IL-6 production in the heart. Further, IV mRNA vaccination induced cardiac damage in LPS chronic inflammation, particularly serum troponin I (TnI), which dramatically increased. IV vaccine administration may induce more cardiotoxicity in chronic inflammation. These findings highlight the need for further research to understand the underlying mechanisms of mRNA vaccines with chronic inflammatory conditions dependent on injection routes.

Repeated COVID-19 mRNA-based vaccination contributes to SARS-CoV-2 neutralizing antibody responses in the mucosa.

To prevent infection by respiratory viruses and consequently limit virus circulation, vaccines need to promote mucosal immunity. The extent to which the currently used messenger RNA (mRNA)-based COVID-19 vaccines induce mucosal immunity remains poorly characterized. We evaluated mucosal neutralizing antibody responses in a cohort of 183 individuals. Participants were sampled at several time points after primary adenovirus vector-based or mRNA-based COVID-19 vaccination and after mRNA-based booster vaccinations. Our findings revealed that repeated vaccination with mRNA boosters promoted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies in nasal secretions. Nasal and serum neutralizing antibody titers of both IgG and IgA isotypes correlated to one another. We investigated the source of these mucosal antibodies in a mouse model wherein mice received repeated mRNA vaccines for SARS-CoV-2. These experiments indicated that neutralizing antibody-producing cells reside in the spleen and bone marrow, whereas no proof of tissue homing to the respiratory mucosa was observed, despite the detection of mucosal antibodies. Serum transfer experiments confirmed that circulating antibodies were able to migrate to the respiratory mucosa. Collectively, these results demonstrate that, especially upon repeated vaccination, the currently used COVID-19 mRNA vaccines can elicit mucosal neutralizing antibodies and that vaccination might also stimulate mucosal immunity induced by previous SARS-CoV-2 infection. Moreover, migration of circulating antibodies to the respiratory mucosa might be a main mechanism. These findings advance our understanding of mRNA vaccine-induced immunity and have implications for the design of vaccine strategies to combat respiratory infections.

Personalized mRNA vaccines in glioblastoma therapy: from rational design to clinical trials.

Glioblastomas (GBMs) are the most common and aggressive malignant brain tumors, presenting significant challenges for treatment due to their invasive nature and localization in critical brain regions. Standard treatment includes surgical resection followed by radiation and adjuvant chemotherapy with temozolomide (TMZ). Recent advances in immunotherapy, including the use of mRNA vaccines, offer promising alternatives. This review focuses on the emerging use of mRNA vaccines for GBM treatment. We summarize recent advancements, evaluate current obstacles, and discuss notable successes in this field. Our analysis highlights that while mRNA vaccines have shown potential, their use in GBM treatment is still experimental. Ongoing research and clinical trials are essential to fully understand their therapeutic potential. Future developments in mRNA vaccine technology and insights into GBM-specific immune responses may lead to more targeted and effective treatments. Despite the promise, further research is crucial to validate and optimize the effectiveness of mRNA vaccines in combating GBM.

Lipopolyplex-formulated mRNA cancer vaccine elicits strong neoantigen-specific T cell responses and antitumor activity.

mRNA neoantigen cancer vaccine inducing neoantigen-specific T cell responses holds great promise for cancer immunotherapy; however, its clinical translation remains challenging because of suboptimal neoantigen prediction accuracy and low delivery efficiency, which compromise the in vivo therapeutic efficacy. We present a lipopolyplex (LPP)-formulated mRNA cancer vaccine encoding tandem neoantigens as a cancer therapeutic regimen. The LPP-formulated mRNA vaccines elicited robust neoantigen-specific CD8+ T cell responses in three syngeneic murine tumor models (CT26, MC38, and B16F10) to suppress tumor growth. Prophylactic cancer vaccine treatment completely prevented tumor development, and long-lasting memory T cells protected mice from tumor cell rechallenge. Combining the vaccine with immune checkpoint inhibitor further boosted the antitumor activity. Of note, LPP-based personalized cancer vaccine was administered in two cancer patients and induced meaningful neoantigen-specific T cell and clinical responses. In conclusion, we demonstrated that the LPP-based mRNA vaccine can elicit strong antitumor immune responses, and the results support further clinical evaluation of the therapeutic mRNA cancer vaccine.

Immunogenicity of Comirnaty Omicron XBB.1.5 booster COVID-19 mRNA vaccine in long-term survivors after allogeneic hematopoietic stem cell transplantation.

Primary mRNA vaccination against COVID-19 typically involves three doses for immunocompromised individuals, including hematopoietic stem cell transplantation (allo-HSCT) recipients. However, optimal subsequent boosting strategies remain unclear. This study aimed to assess the immunogenicity of a booster dose using the most recently updated vaccine (Comirnaty Omicron XBB.1.5) among long-term allo-HSCT survivors having previously received multiple mRNA vaccine doses, in median 4 (2-6). Thirty-four allo-HSCT recipients were enrolled at Sahlgrenska University Hospital, and peripheral blood samples were collected immediately before and four weeks after booster. Antibodies against the receptor-binding domain (anti-RBD) of spike 1 (S1) and nucleocapsid, as well as S1-specific ex vivo T-cell responses, were evaluated. Adverse events were monitored. Despite a median of 13 months since the prior vaccine dose, both humoral and T-cell responses against S1 were present in the pre-booster samples in all but two participants, who suffered from severe chronic Graft-versus-host disease. Notably, 62% of participants had a previously confirmed COVID-19 infection. Significantly higher pre-booster antibody levels were observed in women than men (p = 0.003). Booster dosing strengthened specific antibody and T cell responses and equalized pre-booster gender differences, although responses remained significantly lower among those receiving immunosuppressive treatment (p = 0.041). In a population of long-term allo-HSCT survivors, the majority of whom had a prior confirmed COVID-19 infection, both pre- and post-booster immune responses were robust. However, patients undergoing immunosuppressive treatment for GvHD exhibited significantly weaker responses.

Replacing poly(ethylene glycol) with RAFT lipopolymers in mRNA lipid nanoparticle systems for effective gene delivery.

Lipid nanoparticles (LNPs) have emerged as promising carriers to efficiently transport mRNA into cells for protein translation, as seen with the mRNA vaccines used against COVID-19. However, they contain a widely used polymer - poly(ethylene glycol) (PEG) - which lacks the functionality to be easily modified (which could effectively control the physicochemical properties of the LNPs such as its charge), and is also known to be immunogenic. Thus, it is desirable to explore alternative polymers which can replace the PEG component in mRNA LNP vaccines and therapeutics, while still maintaining their efficacy. Herein, we employed reversible addition-fragmentation chain transfer (RAFT) polymerisation to synthesise five PEG-lipid alternatives that could stabilise LNPs encapsulating mRNA or pDNA molecules. Importantly, the resultant RAFT lipopolymer LNPs exhibit analogous or higher in vivo gene expression and antigen-specific antibody production compared to traditional PEG-based formulations. Our synthesis strategy which allows the introduction of positive charges along the lipopolymer backbone also significantly improved the in vivo gene expression. This work expands the potential of RAFT polymer-conjugated LNPs as promising mRNA carriers and offers an innovative strategy for the development of PEG-free mRNA vaccines and therapeutics.

Vaccination and Therapeutics.

In the wake of the novel Coronavirus, it has become imperative to develop vaccines that can alert our immune system to the virus, hence reducing the severity of disease if exposed to it. Different types of vaccines have been studied in this respect, such as nucleic acid vaccines (mRNA and DNA vaccines), vector-based vaccines, whole-virus vaccines (inactivated virus and live-attenuated vaccine), as well as protein subunits vaccines. The results have demonstrated that these vaccines are efficient against both the original strain and emerging variants. Furthermore, they also proved their safety with no grave adverse events. Despite this, hesitancy toward taking these vaccines is still present among certain groups in society due to various factors. Special emphasis has been placed on studies concerning pregnant women, children, elderly people, and immunocompromised individuals where efficacy and safety were proven.

Deciphering the HLA-E immunopeptidome with mass spectrometry: an opportunity for universal mRNA vaccines and T-cell-directed immunotherapies.

Advances in immunotherapy rely on targeting novel cell surface antigens, including therapeutically relevant peptide fragments presented by HLA molecules, collectively known as the actionable immunopeptidome. Although the immunopeptidome of classical HLA molecules is extensively studied, exploration of the peptide repertoire presented by non-classical HLA-E remains limited. Growing evidence suggests that HLA-E molecules present pathogen-derived and tumor-associated peptides to CD8+ T cells, positioning them as promising targets for universal immunotherapies due to their minimal polymorphism. This mini-review highlights recent developments in mass spectrometry (MS) technologies for profiling the HLA-E immunopeptidome in various diseases. We discuss the unique features of HLA-E, its expression patterns, stability, and the potential for identifying new therapeutic targets. Understanding the broad repertoire of actionable peptides presented by HLA-E can lead to innovative treatments for viral and pathogen infections and cancer, leveraging its monomorphic nature for broad therapeutic efficacy.

Current landscape of mRNA technologies and delivery systems for new modality therapeutics.

Realizing the immense clinical potential of mRNA-based drugs will require continued development of methods to safely deliver the bioactive agents with high efficiency and without triggering side effects. In this regard, lipid nanoparticles have been successfully utilized to improve mRNA delivery and protect the cargo from extracellular degradation. Encapsulation in lipid nanoparticles was an essential factor in the successful clinical application of mRNA vaccines, which conclusively demonstrated the technology's potential to yield approved medicines. In this review, we begin by describing current advances in mRNA modifications, design of novel lipids and development of lipid nanoparticle components for mRNA-based drugs. Then, we summarize key points pertaining to preclinical and clinical development of mRNA therapeutics. Finally, we cover topics related to targeted delivery systems, including endosomal escape and targeting of immune cells, tumors and organs for use with mRNA vaccines and new treatment modalities for human diseases.

mRNA vaccines: a new era in vaccine development.

The advent of RNA therapy, particularly through the development of mRNA cancer vaccines, has ushered in a new era in the field of oncology. This article provides a concise overview of the key principles, recent advancements, and potential implications of mRNA cancer vaccines as a groundbreaking modality in cancer treatment. mRNA cancer vaccines represent a revolutionary approach to combatting cancer by leveraging the body's innate immune system. These vaccines are designed to deliver specific mRNA sequences encoding cancer-associated antigens, prompting the immune system to recognize and mount a targeted response against malignant cells. This personalized and adaptive nature of mRNA vaccines holds immense potential for addressing the heterogeneity of cancer and tailoring treatments to individual patients. Recent breakthroughs in the development of mRNA vaccines, exemplified by the success of COVID-19 vaccines, have accelerated their application in oncology. The mRNA platform's versatility allows for the rapid adaptation of vaccine candidates to various cancer types, presenting an agile and promising avenue for therapeutic intervention. Clinical trials of mRNA cancer vaccines have demonstrated encouraging results in terms of safety, immunogenicity, and efficacy. Pioneering candidates, such as BioNTech's BNT111 and Moderna's mRNA-4157, have exhibited promising outcomes in targeting melanoma and solid tumors, respectively. These successes underscore the potential of mRNA vaccines to elicit robust and durable anti-cancer immune responses. While the field holds great promise, challenges such as manufacturing complexities and cost considerations need to be addressed for widespread adoption. The development of scalable and cost-effective manufacturing processes, along with ongoing clinical research, will be pivotal in realizing the full potential of mRNA cancer vaccines. Overall, mRNA cancer vaccines represent a cutting-edge therapeutic approach that holds the promise of transforming cancer treatment. As research progresses, addressing challenges and refining manufacturing processes will be crucial in advancing these vaccines from clinical trials to mainstream oncology practice, offering new hope for patients in the fight against cancer.

The immune response to Covid-19 mRNA vaccination among Lymphoma patients receiving anti-CD20 treatment.

The monoclonal antibody rituximab improves clinical outcome in the treatment of CD20-positive lymphomatous neoplasms, and it is an established drug for treatment of these cancers. Successful mRNA COVID-19 (SARS-CoV-2) vaccination is extremely important for lymphoma patients because they tend to be elderly with comorbidities which leaves them at increased risk of poor outcomes once infected by Coronavirus. Anti-CD20 therapies such as rituximab, deplete B-cell populations and can affect vaccine efficacy. Therefore, a knowledge of the effect of COVID-19 vaccination in this group is critical. We followed a cohort of 28 patients with CD20-positive lymphomatous malignancies treated with rituximab that started prior to their course of COVID-19 vaccination, including boosters. We assayed for vaccine "take" in the humoral (IgG and IgA) and cellular compartment. Here, we show that short-term and long-term development of IgG and IgA antibodies directed toward COVID-19 spike protein are reduced in these patients compared to healthy controls. Conversely, the robustness and breath of underlying T-cell response is equal to healthy controls. This response is not limited to specific parts of the spike protein but spans the spike region, including response to the conserved Receptor Binding Domain (RBD). Our data informs on rational vaccine design and bodes well for future vaccination strategies that require strong induction of T-cell responses in these patients.

COVID-19 vaccine adverse events: Evaluating the pathophysiology with an emphasis on sulfur metabolism and endotheliopathy.

In this narrative review, we assess the pathophysiology of severe adverse events that presented after vaccination with DNA and mRNA vaccines against COVID-19. The focus is on the perspective of an undersulfated and degraded glycocalyx, considering its impact on immunomodulation, inflammatory responses, coagulation and oxidative stress. The paper explores various factors that lead to glutathione and inorganic sulfate depletion and their subsequent effect on glycocalyx sulfation and other metabolites, including hormones. Components of COVID-19 vaccines, such as DNA and mRNA material, spike protein antigen and lipid nanoparticles, are involved in possible cytotoxic effects. The common thread connecting these adverse events is endotheliopathy or glycocalyx degradation, caused by depleted glutathione and inorganic sulfate levels, shear stress from circulating nanoparticles, aggregation and formation of protein coronas; leading to imbalanced immune responses and chronic release of pro-inflammatory cytokines, ultimately resulting in oxidative stress and systemic inflammatory response syndrome. By understanding the underlying pathophysiology of severe adverse events, better treatment options can be explored.

Rational optimization of glycoprotein E (gE)-encoding mRNA for improved Varicella-zoster virus mRNA vaccine development.

mRNA platform holds promise for next-generation Varicella-zoster Virus (VZV) vaccine development due to its high potency at inducing strong T-cell response. Built upon the design of our 1st-generation VZV mRNA vaccine that encodes for full-length gE antigen, in this study we reported on a novel combinatorial strategy to further optimize the gE-encoding mRNA sequence through signal peptide replacement, C-terminal modification, and insertion of mRNA-stabilizing motif, which collectively contributed to significantly improved vaccine immunogenicity. In adult mice, aged mice, and immunocompromised mice, this optimized VZV mRNA vaccine showed strong superiority in multiple aspects including the induction of gE-specific antibodies, specific memory B-cell response, as well as Th1-type T-cell response.

Anti-MDA5 autoantibodies predict clinical dynamics of dermatomyositis following SARS-CoV-2 mRNA vaccination: a retrospective statistical analysis of case reports.

Since the introduction of mRNA vaccines against SARS-CoV-2, the induction of autoimmunity by mRNA vaccination has been discussed. Several cases of dermatomyositis (DM) associated with mRNA vaccination against SARS-CoV-2 infection have been reported. The question is whether there is a common pathomechanism for the induction of DM by this mRNA vaccination. The aim of this review is to analyse the sample of previously published case reports of DM following COVID-19 mRNA vaccination for common indicators of a possible immune pathomechanism.In this review, we summarised case reports of DM following mRNA vaccination against COVID-19. We considered this case report landscape as a cumulative sample (n = 32) and identified common clinical and molecular parameters in the intersection of case reports and statistically analysed the effect of these parameters on the development of DM.MDA-5 antibodies seem to play a role in the autoantibody signature after mRNA vaccination. MDA-5-positive DM is statistically more strongly associated with mRNA vaccination and interstitial lung disease/rapidly progressive interstitial lung disease (ILD/RP-ILD) than MDA-5-negative DM. MDA-5-positive DM seems not to be associated with an increased risk of malignancy, whereas MDA-5-negative DM is more strongly associated with malignancy.Our findings emphasize the potential role of innate antiviral signalling pathways in connecting DM to mRNA vaccination. MDA-5 autoantibodies appear to be predictive of a severe DM progression following mRNA vaccination. There seems to be an association between MDA-5 autoantibodies and paraneoplastic DM post-vaccination. Further studies are required to uncover the underlying mechanisms of autoimmunity triggered by mRNA vaccination.

Identification of immunity- and ferroptosis-related signature genes as potential design targets for mRNA vaccines in AML patients.

Immune-associated ferroptosis plays an important role in the progression of acute myeloid leukemia (AML); however, the targets that play key roles in this process are currently unknown. This limits the development of mRNA vaccines based on immune-associated ferroptosis for clinical therapeutic applications. In this study, based on the rich data resources of the TCGA-LAML cohort, we analyzed the tumor mutational burden (TMB), gene mutation status, and associations between immune and ferroptosis genes to reveal the disease characteristics of AML patients. To gain a deeper understanding of differentially expressed genes, we applied the Limma package for differential expression analysis and integrated data sources such as ImmPort Shared Data and FerrDb V2. Moreover, we established gene modules related to TMB according to weighted gene coexpression network analysis (WGCNA) and explored the functions of these modules in AML and their relationships with TMB. We focused on the top 30 most frequent genes through a detailed survey of missense mutations and single nucleotide polymorphisms (SNPs) and selected potentially critical gene targets for subsequent analysis. Based on the expression of these genes, we successfully subgrouped AML patients and found that the subgroups associated with TMB (C1 and C2) exhibited significant differences in survival. The differences in the tumor microenvironment and immune cells between C1 and C2 patients were investigated with the ESTIMATE and MCP-counter algorithms. A predictive model of TMB-related genes (TMBRGs) was constructed, and the validity of the model was demonstrated by categorizing patients into high-risk and low-risk groups. The differences in survival between the high-risk patients and high-TMB patients were further investigated, and potential vaccine targets were identified via immune cell-level analysis. The identification of immunity- and ferroptosis-associated signature genes is an independent predictor of survival in AML patients and provides new information on immunotherapy for AML.

Stealth mRNA nanovaccines to control lymph node trafficking.

mRNA-based vaccines symbolize a new paradigm shift in personalized medicine for the treatment of infectious and non-infectious diseases. However, the reactogenicity associated with the currently approved formulations limits their applicability in autoinflammatory disorders, such as tumour therapeutics. In this study, we present a delivery system showing controlled immunogenicity and minimal non-specific inflammation, allowing for selective delivery of mRNA to antigen presenting cells (APCs) within the medullary region of the lymph nodes. Our platform offers precise control over the trafficking of nanoparticles within the lymph nodes by optimizing stealth and targeting properties, as well as the subsequent opsonization process. By targeting specific cells, we observed a potent adaptive and humoral immune response, which holds promise for preventive and therapeutic anti-tumoral vaccines. Through spatial programming of nanoparticle distribution, we can promote robust immunization, thus improving and expanding the utilization of mRNA vaccines. This innovative approach signifies a remarkable step forward in the field of targeted nanomedicine.

Comparison of long-term anti-RBD SARS-CoV-2 antibody response following different vaccination schemes in Tunisia.

AIM: The study aimed to compare long-term vaccine-induced humoral immunity following different vaccines regimens. METHODS: Anti-S-RBD total antibody levels were measured in blood samples of 167 participants nearly 6 months post-vaccination. Participants had received one; two or four doses of Pfizer vaccine or who received a third dose of mRNA vaccine (Pfizer) and primed with mRNA (Pfizer/Moderna), adenoviral (AstraZeneca/Jonson & Jonson) or inactivated (CoronaVac/Sinopharm) vaccine. RESULTS: Among all vaccination regimens, fourth dose of Pfizer achieved the highest S-RBD antibody titers. Nevertheless, the third dose of mRNA vaccine primed with adenoviral vaccine achieved the lowest titers of S-RBD antibody. Notably, the group that received a third dose of mRNA primed with two doses of mRNA vaccine exhibited higher S-RBD antibody compared to groups inoculated with a third dose of mRNA and primed with inactivated or adenovirus vaccine. CONCLUSION: Our data showed the superiority of three mRNA vaccinations compared to third heterologous vaccine (inactivated of adenoviral) including mRNA as booster in terms of humoral immunogenicity. Our findings supporting the use of additional booster shot from a more potent vaccine type such as mRNA vaccines. Nevertheless, due to the limited number of subjects, it is difficult to extrapolate the results of our study to the whole of Tunisian population. Future studies should investigate a larger cohort and other potential correlates of protection, such as cellular immunity and how it is affected by different vaccination schemes after long-term post-vaccination.

Screening of tumor antigens and immunogenic cell death landscapes of prostate adenocarcinoma for exploration of mRNA vaccine.

BACKGROUND: In this study, effective antigens of mRNA vaccine were excavated from the perspective of ICD, and ICD subtypes of PRAD were further distinguished to establish an ICD landscape, thereby determining suitable vaccine recipients. RESEARCH DESIGN AND METHODS: TCGA and MSKCC databases were applied to acquire RNA-seq data and corresponding clinical data of 554 and 131 patients, respectively. GEPIA was employed to measure prognostic indices. Then, a comparison of genetic alterations was performed utilizing cBioPortal, and correlation of identified ICD antigens with immune infiltrating cells was analyzed employing TIMER. Moreover, ICD subtypes were identified by means of consensus cluster, and ICD landscape of PRAD was depicted utilizing graph learning-based dimensional reduction. RESULTS: In total, 4 PRAD antigens were identified in PRAD, including FUS, LMNB2, RNPC3, and ZNF700, which had association with adverse prognosis and infiltration of APCs. PRAD patients were classified as two ICD subtypes based on their differences in molecular, cellular, and clinical features. Furthermore, ICD modulators and immune checkpoints were also differentially expressed between two ICD subtype tumors. Finally, the ICD landscape of PRAD showed substantial heterogeneity among individual patients. CONCLUSIONS: In summary, the research may provide a theoretical foundation for developing mRNA vaccine against PRAD as well as determining appropriate vaccine recipients.