Aug 2026· Asian Journal of Biology· Vol 22, pp. 23-44· 0 citations
TL;DR
Analysis of the reported discrepancies indicates that heterogeneity in neoantigen prediction pipelines, assay thresholds for defining an immune response, and tumour microenvironmental context explain much of the apparent inconsistency between trials.
Abstract
Messenger RNA (mRNA) vaccines entered oncology on the strength of a technology validated at population scale for infectious disease prophylaxis, and the therapeutic cancer vaccine field has been reshaped accordingly. The platform permits rapid design-to-dose intervals, encoding of many epitopes within a single product, cell-free manufacture and a dosing schedule compatible with combination immunotherapy. Enthusiasm has nevertheless outpaced the maturity of the clinical evidence. This critical narrative review evaluates the strength, internal consistency and methodological quality of the literature on mRNA cancer vaccines, and distinguishes conclusions that are reasonably secure from those that remain provisional. Literature published between January 2005 and 13 June 2026 was identified through structured searching of biomedical and multidisciplinary scholarly indexes, supplemented by backward and forward citation tracing. Evidence was appraised for design adequacy, endpoint validity, sample size, control structure and consistency across independent groups, then organised thematically rather than study by study.
Four conclusions are well supported. RNA constructs can reliably prime de novo, poly-epitopic CD4-positive and CD8-positive T cell responses against both shared and mutation-derived antigens in humans; vaccine-induced clones can persist for years; formulation and administration route govern the anatomical site of antigen presentation and the character of innate activation; and toxicity in the reported oncology cohorts has been predominantly low grade. Four conclusions remain insecure. Randomised evidence of clinical benefit rests on a single phase 2b melanoma trial whose primary comparison did not reach conventional significance; immunogenicity has been treated as an efficacy surrogate without formal validation; comparative data on antigen-selection strategies, delivery chemistries and dosing schedules are almost entirely absent; and the durability, cardiac and excipient-related safety questions raised by mass prophylactic use have not been examined in repeatedly dosed patients with cancer. Analysis of the reported discrepancies indicates that heterogeneity in neoantigen prediction pipelines, assay thresholds for defining an immune response, and tumour microenvironmental context explain much of the apparent inconsistency between trials. Priorities include randomised platform trials with harmonised immunological endpoints, head-to-head comparison of antigen and delivery strategies, and prospective surrogate-endpoint validation.
Messenger RNA (mRNA) cancer vaccines have progressed rapidly, with personalized platforms such as mRNA-4157 and BNT122 demonstrating feasibility, safety, and durable immune activity but limited scalability. Off-the-shelf constructs, including BNT111 and BNT113, enable faster, broader deployment, yet they risk reduced precision or immune tolerance. These complementary approaches reveal key translational dualities: personalization versus shared antigen (off-the-shelf), potency versus safety, and speed versus durability. This mini-review synthesizes emerging clinical evidence and outlines strategies such as modular vaccine design, prime-boost vaccination regimens, and adaptive trial frameworks to reconcile these trade-offs and advance scalable, durable mRNA vaccines for broad oncologic impact.
SIGNIFICANCE
By dissecting the competing design pressures that shape mRNA vaccine performance, this mini-review proposes integrative strategies, spanning modular architectures, prime-boost regimens, and adaptive trials, to reconcile immunologic potency with manufacturability and safety, charting a roadmap toward next-generation cancer vaccines.
Seongdong Jeong, Benjamin R. Schrank, James J. Mancuso et al.· Cancer Discovery· 0 citations
Available seasonal influenza vaccines, most of which are still produced in eggs, have several limitations. Messenger RNA (mRNA) technology has emerged as a transformative approach capable of overcoming some of these shortcomings. This overview synthesizes clinical trials evaluating the immunogenicity, efficacy, and safety of standalone and combination mRNA influenza vaccines. Moderna’s mRNA-1010 (now approved in the United States) and Pfizer’s modified-nucleoside RNA candidate (modRNA) represent the most advanced standalone platforms, while Moderna’s combination influenza and COVID-19 vaccine, mRNA-1083, was recently granted European authorization. Following iterative platform optimization, these vaccines induce robust humoral and cell-mediated responses, especially against influenza A strains, characterized by extended germinal center reactions, continuous somatic hypermutation, enhanced Fc-mediated effector functions, and strong T helper 1 engagement. In phase III relative efficacy trials, an optimized mRNA-1010 formulation achieved superiority over standard-dose vaccines with a relative efficacy of 26.6% (95% CI: 16.7%, 35.4%) in adults aged ≥50 years. Pfizer’s first-generation quadrivalent modRNA candidate showed 34.5% (95% CI: 7.4%, 53.9%) relative efficacy against a standard-dose comparator in younger adults aged 18–64 years, but failed to demonstrate non-inferiority in older adults (≥65 years), showing a relative efficacy of −5.8% (95% CI: −47.2%, 23.8%). However, whether mRNA platforms offer incremental benefits over enhanced formulations (such as high-dose, adjuvanted, or recombinant vaccines), which are the preferred options in some countries for older adults, remains to be established. The safety profile aligns with licensed COVID-19 mRNA vaccines; although reactogenicity is higher than with conventional vaccines, adverse reactions are predominantly mild-to-moderate and transient. Operationally, transitioning to single-dose pre-filled syringes alongside expanding refrigerated stability data significantly mitigates historical cold-chain bottlenecks. However, while standalone and combination mRNA platforms represent a major technological advance, real-world implementation challenges may affect their broader global health impact.
A. Domnich, Andrea Orsi· Frontiers in Immunology· 0 citations
The strongest current signal supports use in adjuvant, perioperative, and minimal residual disease settings, usually in combination with checkpoint blockade or other immune-modifying strategies, usually in combination with checkpoint blockade or other immune-modifying strategies.
Minglu Ge, Ning Wu· Cancer Treatment and Researc...· 0 citations
mRNA drives the production of functional proteins to achieve therapeutic intervention, rendering it an attractive molecular platform for biomedical applications. In the 1990s, researchers established in vitro transcription (IVT) systems to produce linear mRNA encoding target proteins. Neverthe-less, unmodified mRNA exhibits potent immunogenicity and elicits robust innate immune responses in vivo , which brought early translational research of mRNA to a prolonged standstill. In 2005, the Karikó and Weissman team demonstrated that re-placing native uridine (U) with chemically modified pseudouridine ( ψ ) during IVT could drastically reduce mRNA immunogenicity and evade innate immune sensing. 1,2 This breakthrough resolved the safety bottleneck of mRNA and fueled the rapid advancement of mRNA vaccines. During the COVID-19 pandemic, mRNA vaccines received regulatory approval and were widely administered owing to their short development timelines, high production efficiency, and potent protective immunity. Linear mRNA suffers from poor stability and a short in vivo half-life. In 2022, a research team from Peking University pio-neered a circular RNA (circRNA) vaccine platform worldwide. The covalently closed circular conformation of circRNA markedly improves its in vivo stability and substantially extends its half-life. 3 Since then, circRNA-based cancer vaccines and in vivo chimeric antigen receptor T (CAR-T) cell immunotherapies have been documented successively. 4 However, the issue of circRNA immunogenicity remains unresolved. Analogous to linear mRNA, IVT produced circRNA triggers vigorous innate immune reactions in mammalian cells. Unlike mRNA, circRNA cannot attenuate immunogenicity
Xin-Yue Wang, Sheng-Nan She, Chi Zhang et al.· Molecular Therapy: Nucleic A...· 0 citations
Background Human papillomavirus (HPV) infection represents a substantial global health burden, being the primary etiological agent of cervical cancer, anogenital and oropharyngeal malignancies. Although prophylactic virus-like particle (VLP) vaccines have been successfully implemented, they lack therapeutic efficacy against established infections and lesions in the host. The messenger RNA (mRNA) vaccine platform has emerged as a promising alternative, offering rapid manufacturing and the ability to induce potent cellular immune responses required for effective therapeutic outcomes. Objective This systematic review aimed to synthesize and evaluate preclinical evidence regarding the immunogenicity and protective efficacy of mRNA-based HPV vaccines in animal models, focusing on their ability to prevent oncogenic infections and induce regression of established tumors. Methods The study is registered in Prospero (CRD420261362037, 14 July 2026). A systematic search of PubMed, Scopus, Europe PMC, and ScienceDirect databases was conducted according to the PRISMA 2020 guidelines. Eligible studies included in vivo preclinical experimental research evaluating mRNA vaccines targeting high-risk HPV types (HPV-16 and HPV-18) in animal models. Immunogenicity (CD8+ T-cell responses and IgG titers) and oncogenic outcome (tumor volume and survival rate) data were extracted. The risk of bias was assessed using the SYRCLE’s risk-of-bias tool. The meta-analysis utilized a random-effects model to calculate standardized mean differences (SMD) and evaluate heterogeneity via the I
2
statistic. Result and Conclusion Ten studies met the inclusion criteria and provided detailed data for the analysis. mRNA vaccines have demonstrated high immunogenicity, significantly expanding antigen-specific CD8+ T-cell populations and inducing robust IFN gamma secretion. The pooled results indicated a significant reduction in tumor volume (SMD -2.305; 95% CI: −2.64 to −1.97) and near-complete viral load reduction in the challenge models. High-risk HPV mRNA vaccines delivered via lipid nanoparticles (LNPs) or lipopolyplexes (LPPs) have a promising therapeutic potential as both prophylactic and therapeutic agents, supporting their advancement to clinical trials.
Seasonal influenza remains a major global public health challenge despite decades of vaccine development, underscoring the need for more effective and adaptable immunization strategies. The recently approved mRNA-1010 vaccine represents a promising advance by applying messenger RNA technology to a pathogen characterized by continuous antigenic drift. Recent Phase 3 clinical trials conducted in support of regulatory review have demonstrated robust immunogenicity and superior protective efficacy against seasonal influenza compared with standard influenza vaccines in adults aged 50 years and older. However, increased reactogenicity, particularly among younger adults, together with the need for continued post-marketing safety surveillance, highlights the balance between enhanced immune responses and tolerability. Beyond seasonal influenza, mRNA-1010 provides a foundation for next-generation respiratory vaccines, including combination formulations targeting influenza, SARS-CoV-2, and respiratory syncytial virus (RSV), while illustrating the broader potential of mRNA vaccine technology. At the same time, challenges related to manufacturing scalability, cost, cold-chain requirements, and global accessibility remain important considerations for widespread implementation. This perspective examines whether mRNA-1010 represents an incremental advance in influenza vaccination or a potential transformative milestone in respiratory immunization, while considering the continuing roles of alternative vaccine platforms in achieving optimal effectiveness, safety, and equitable global access.
Antonios-Periklis Panagiotopoulos, D. Tsakri, K. Ranellou et al.· Vaccines· 0 citations
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