Featured Publications

An mRNA Vaccine against SARS-CoV-2 — Preliminary Report

New England Journal of Medicine
July 2020

This Phase 1 interim analysis showed that an mRNA vaccine against COVID-19 induced rapid and strong immune responses against SARS-CoV-2, supporting further clinical development and the potential of mRNA as a vaccine platform.

Prophylactic Vaccines
Title Journal Description
Nature SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness

This pre-clinical study showed that an mRNA vaccine against COVID-19 induced potent neutralizing antibody responses and CD8 T cell responses and protected against SARS-CoV-2 infection in the lungs and nose of mice without evidence of vaccine-associated enhanced respiratory disease (VAERD) when given at sub-protective doses.

New England Journal of Medicine Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates

This pre-clinical study showed a two-dose vaccination schedule of mRNA-1273 led to a robust immune response and protection against SARS-CoV-2 infection in the upper and lower airways in non-human primates, without evidence of vaccine-associated enhanced respiratory disease (VAERD).

Vaccine Immunogenicity generated by mRNA vaccine encoding VZV gE antigen is comparable to adjuvanted subunit vaccine and better than live attenuated vaccine in nonhuman primates

This pre-clinical study found that an mRNA vaccine against varicella-zoster virus (VZV), the cause of shingles, was highly immunogenic in non-human primates and generated comparably robust responses to an approved protein vaccine and markedly higher responses compared to an approved live attenuated vaccine.

An mRNA Vaccine against SARS-CoV-2 — Preliminary Report

This Phase 1 interim analysis showed that an mRNA vaccine against COVID-19 induced rapid and strong immune responses against SARS-CoV-2, supporting further clinical development and the potential of mRNA as a vaccine platform.

Vaccines Tetravalent Immunogen Assembled from Conserved Regions of HIV-1 and Delivered as mRNA Demonstrates Potent Preclinical T-Cell Immunogenicity and Breadth

This pre-clinical study shows that an mRNA vaccine against HIV induced potent and broad T cell responses, supporting the ability of mRNA technology to accelerate HIV vaccine discovery.

npj Vaccines Modified mRNA/lipid nanoparticle-based vaccines expressing respiratory syncytial virus F protein variants are immunogenic and protective in rodent models of RSV infection

This pre-clinical study shows that an mRNA RSV vaccine elicited both neutralizing antibodies and robust cellular immune response in rodent models of RSV infection and suggests mRNA vaccines may improve immune responses through presentation of antigens that better mimics what is observed during natural infection.

Journal of infection diseases figure 1 Protective efficacy of nucleic acid vaccines against transmission of Zika virus during pregnancy in mice

This pre-clinical study demonstrates the ability of mRNA vaccines to protect against congenital viral infection in mice.

Frontiers in Immunology figure 1 A modified mRNA vaccine targeting immunodominant NS epitopes protects against Dengue virus infection in HLA class I transgenic mice

This pre-clinical study shows that an mRNA vaccine protects against viral infection in transgenic mice modeling human antigen presentation to T cells.

prophylactic efficacy of CHKV-24 mRNA A lipid-encapsulated mRNA encoding a potently neutralizing human monoclonal antibody protects against chikungunya infection

Pre-clinical study of mRNA encoding an antibody against chikungunya virus protected against infection, showed dose-dependent protein expression and no dose-limiting toxicities in vivo.

HAI seroprotective rates mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials

Phase 1 clinical studies of the first mRNA vaccines against H10N8 and H7N9 influenza viruses elicited robust immune responses, further supporting the potential of mRNA as a vaccine platform.

 Lipid Nanoparticles Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines

Modified mRNA vaccines delivered with a proprietary Moderna LNP show enhanced tolerability and comparable immunogenicity relative to legacy LNP.

Multi-antigenic, pentamer-based, human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity

Animal studies demonstrate that a challenging viral antigen, such as a multimeric, membrane-bound protein complex, encoded by mRNA, can elicit a robust, protective immune response.

A modified mRNA-based Ebola vaccine elicits a robust immune response and protects guinea pigs from a lethal challenge

This preclinical study with a LNP-formulated, modified mRNA vaccine demonstrates 100% survival and higher protective antibody titers than previously observed with viral vector vaccines.

Induction of robust B cell responses after Influenza mRNA vaccination is accompanied by circulating hemagglutinin-specific ICOS+PD-1+CXCR3+ T follicular helper cells

This non-human primate study of mRNA vaccines characterizes the cellular immune response that accompanies robust production of neutralizing antibodies, furthering our understanding of the immune signature associated with effective protection.

Rhesus macaque myeloid-derived suppressor cells demonstrate T cell inhibitory functions and are transiently increased after vaccination

Results in non-human primates characterize the response of immune-suppressive cells to vaccination, expanding our understanding of the mechanisms underlying vaccine immunogenicity versus reactogenicity.

Efficient targeting and activation of antigen-presenting cells in vivo after modified mRNA vaccine administration in rhesus macaques

This non-human primate study with mRNA vaccines characterizes the immune cells activated – and their subsequent priming of T cells – supporting our fundamental understanding of vaccine efficacy.

Vaccine Mediated Protection Against Zika Virus-Induced Congenital Disease

This research demonstrates that LNP-formulated mRNA vaccines can induce protection against viral placental and fetal damage in mouse models, critical for vaccines against viruses that exhibit vertical transmission.

Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 Influenza viruses

Two clinical studies demonstrate that an LNP-formulated, modified mRNA vaccine can elicit a protective immune response with an acceptable safety profile.

Modified mRNA vaccines protect against Zika virus infection

This in vivo research demonstrates that a mRNA vaccine encoding components of a subviral particle can prevent disease.

Overview of vaccine adjuvants: introduction, history, and current status (Review)

This review summarizes the current use and future prospects of adjuvants, which enhance the body's immune response to vaccines.

Localized Regenerative Therapeutics
Title Journal Description
VEGF-A day 14 Intradermal Delivery of Modified mRNA Encoding VEGF-A in Patients with Type 2 Diabetes

Data from a Phase 1a/b study of mRNA encoding for vascular endothelial growth factor A (VEGF-A) shows tolerability, protein expression and protein pharmacology in human subjects and its potential for use as a regenerative therapeutic.

Concentrations of human VEGF-A Rapid Production of Human VEGF-A following Intradermal Injection of Modified VEGF-A mRNA Demonstrated by Cutaneous Microdialysis in the Rabbit and Pig In Vivo

In vivo studies show that intradermal injection of mRNA encoding the VEGF-A protein results in rapid and local dose-dependent protein production, suggesting therapeutic potential in vascular conditions.

(This publication is the work of a Moderna strategic collaborator and Moderna assumes no responsibility for the information or statements therein).

AZD8601 Modified VEGF-A mRNA induces sustained multifaceted microvascular response and accelerates diabetic wound healing

In mouse models, the intradermal administration of mRNA encoding for VEGF-A can induce a localized, sustained, and reproducible biological response, including blood vessel formation and oxygenation to accelerate diabetic wound healing.

(This publication is the work of a Moderna strategic collaborator and Moderna assumes no responsibility for the information or statements therein).

Biocompatible, Purified VEGF-A mRNA Improves Cardiac Function after Intracardiac Injection 1 Week Post-myocardial Infarction in Swine

Large animal studies demonstrate that direct injection of modified mRNA can produce local protein expression while maintaining immune silence, and can induce physiological effects at an organ level.

Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction

This foundational paper establishes that direct injection of modified mRNA in mice can induce local physiological changes and could be an effective approach for regenerative therapeutics.

Systemic Therapeutics
Title Journal Description
Scientific Reports Systemic modified messenger RNA for replacement therapy in alpha 1-antitrypsin deficiency

This pre-clinical study shows mRNA encoding the alpha 1-antitrypsin (AAT) protein led to functional protein expression in human AAT deficient patient hepatocytes and mouse models of AAT deficiency, supporting the translation of mRNA in hepatocytes and secretion of AAT protein into systemic circulation as a potential replacement therapy.

Molecular Therapy Nucleic Acids Treatment of Hemophilia A Using Factor VIII Messenger RNA Lipid Nanoparticles

This pre-clinical study shows administration of mRNA encoding the factor VIII protein led to rapid and prolonged therapeutic levels of factor VIII expression in mouse models of Hemophilia A, supporting an mRNA therapy approach that may also offer advantages over current protein replacement therapies.

Disease pharmacokinetic‐pharmacodynamic modelling in acute intermittent porphyria to support the development of mRNA‐based therapies

This publication outlines a translational modeling framework that can be used to describe the effects of mRNA therapy for acute intermittent porphyria (AIP) in preclinical models and support development in humans.

Galactose Novel mRNA-based therapy reduces toxic galactose metabolites and overcomes galactose sensitivity in a mouse model of Classic Galactosemia

This pre-clinical study shows that systemic administration of mRNA encoding the enzyme GALT reduced toxic metabolites in mouse models of the rare genetic disease, Classic Galactosemia. This study supports the potential of mRNA therapy to target proteins that cannot be treated by traditional enzyme replacement therapy.

Days Post-AAV8-TBG-Cre injection Lipid nanoparticle-targeted mRNA therapy as a treatment for the inherited metabolic liver disorder arginase deficiency

This pre-clinical study shows that repeat dosing of mRNA encoding ARG1 delivered via lipid nanoparticles was able to treat mouse models of arginase deficiency and supports the potential of mRNA therapeutics to treat rare metabolic disorders.

hMUT mRNA tratement ameliorates disease biomarkers Long-term efficacy and safety of mRNA therapy in two murine models of methylmalonic acidemia

This pre-clinical study demonstrates that repeat dose mRNA therapy substantially improved survival and growth and ameliorated biochemical abnormalities with no adverse effects in multiple MMA mouse models, supporting long-term treatment with mRNA therapeutics.

VK-positive crystalline material Generation of a mouse model of primary hyperoxaluria type 1 via CRISPR/Cas9 mediated gene editing

Creation of a genetic mouse model that resembles much of the clinical phenotype of rare disease patients demonstrates the value of translational research in developing novel therapies for rare diseases.

mRNA-based therapies mRNA therapy improves metabolic and behavioral abnormalities in a murine model of citrin deficiency

Preclinical data in a mouse model of citrin deficiency reinforces the potential of mRNA-based therapies to treat rare metabolic disorders.

MMA caused by methylmalonyl-CoA mutase (mut) deficiency Systematic literature review and meta-analysis on the epidemiology of methylmalonic acidemia (MMA) with a focus on MMA caused by methylmalonyl-CoA mutase (mut) deficiency

A systematic review of the global epidemiology literature on MMA confirms that MMA and its subtypes are ultra-rare with similar detection rates across geographic regions with the exception of the Middle East, where the disease is more frequent.

Lyso-GB3 Systemic mRNA Therapy for the Treatment of Fabry Disease: Preclinical Studies in Wild-Type Mice, Fabry Mouse Model and Wild-Type Non-human Primates

Administration of mRNA encoding human α-Gal demonstrate pre-clinical proof-of-concept, across species, of a potential systemic mRNA therapy for the treatment of Fabry disease.

epidemiology of propionic acidemia Systematic literature review and meta-analysis on the epidemiology of propionic acidemia

A systematic review of the global epidemiology literature on PA confirms that PA is an ultra-rare disorder with similar detection rates across geographic regions with the exception of the Middle East, where the disease is more frequent.

Messenger RNA as an etiological treatment for acute intermittent porphyria

Rapid onset of effect with mRNA therapeutics is demonstrated in the acute setting, imparting hepatic enzymatic activity with repeat dosing in small and large animals.

Systemic messenger RNA therapy as a treatment for methylmalonic acidemia

Results in a mouse disease model suggest that repeat systemic administration of LNP-formulated mRNA can elicit intracellular protein expression in hepatocytes for rapid and sustained amelioration of disease.

Cancer Vaccines
Title Journal Description
An RNA toolbox for cancer immunotherapy

This review highlights the potential for RNA cancer immunotherapies, including mRNA applications in cancer vaccines and immune modulation.

Intratumoral Immuno-Oncology
Title Journal Description
Clinical Cancer Research Intratumoral interleukin-12 mRNA therapy promotes TH1 transformation of the tumor microenvironment

This pre-clinical study showed mRNA encoding for IL-12 administered intratumorally promoted a Th1 tumor microenvironment and robust systemic anti-tumor immune response in mouse models, suggesting the potential of local IL-12 mRNA therapy to drive tumor regression while mitigating systemic tolerability challenges.

IL-23_IL-36γ_OX40L Durable anticancer immunity from intratumoral administration of IL-23, IL-36γ and OX40L mRNAs

Local delivery of mRNA encoding the secreted cytokines IL-23 and IL-36γ and the membrane-bound T-cell co-stimulator OX40L induced a broad immune response promoting tumor regression in both injected lesions and distant un-injected tumors in mice.

Platform
Title Journal Description
Science Advances Impact of mRNA chemistry and manufacturing process on innate immune activation

This study shows that both modifying nucleotide chemistry as well as engineering the mRNA production process to reduce double-stranded RNA are important for controlling innate immune activation, providing important insights for mRNA therapies.

Inclusion of modified nucleotides in mRNA alters Luc expression mRNA structure regulates protein expression through changes in functional half-life

This study shows that the structure of the mRNA coding sequence regulates protein expression through changes in functional mRNA half-life, highlighting an important role of mRNA secondary structure in regulating mRNA stability and potentially enabling enhanced control of protein expression levels for mRNA therapeutics.

nature biotech figure 1 Human 5′ UTR design and variant effect prediction from a massively parallel translation assay

This study describes a deep learning model of 5’ UTR impact on protein expression, demonstrating the ability to optimize expression levels with mRNA therapeutics.

ImmunoHorizons figure 1 Accelerated blood clearance of lipid nanoparticles entails a biphasic humoral response of B-1 followed by B-2 lymphocyte to distinct antigenic moieties

This study elucidates the fundamental mechanism of accelerated blood clearance of LNPs, informing improved designs for nanoparticle delivery systems.

Analytical Chemistry figure Oligonucleotide sequence mapping of large therapeutic mRNAs via parallel ribonuclease digestions and LC-MS/MS

This study describes a novel analytical method to characterize mRNA sequences with great specificity and to detect minor sequence impurities to inform technical development of mRNA therapeutics.

MicroRNAs Enable mRNA Therapeutics to Selectively Program Cancer Cells to Self-Destruct

Non-human primate and rodent studies demonstrate tissue-targeted mRNA translation and mitigation of potential off-target effects through the use of microRNA binding sites.

A Novel Amino Lipid Series for mRNA Delivery: Improved Endosomal Escape and Sustained Pharmacology and Safety in Non-human Primates

Non-human primate and rodent studies demonstrate the potential for repeat dosing of mRNA safely and at therapeutically relevant levels with proprietary Moderna lipids.

Lipid nanoparticle packaging is an effective and non-toxic mRNA delivery platform in embryonic zebrafish

This study suggests that direct injection of LNP-formulated mRNA may be a valuable tool in the study of developmental biology given transfection of distinct tissues in a developing vertebrate embryo.

Safety evaluation of lipid nanoparticle-formulated modified mRNA in the Sprague-Dawley rat and cynomolgus monkey

In vivo studies with systemic delivery of modified mRNA in an industry standard LNP demonstrate therapeutic levels of protein expression and predictable pharmacology and toxicology.

Boosting intracellular delivery of lipid nanoparticle-encapsulated mRNA

This research focuses on the mechanism of LNP endosomal escape, highlighting opportunities to increase LNP potency by improving the efficiency of escape.

Messenger RNA as a Novel Therapeutic Approach (Chapter)

This chapter highlights recent advances in the delivery of nucleotide therapeutics and their application to mRNA therapeutics.

A sensitivity analysis of RNA folding nearest neighbor parameters identifies a subset of free energy parameters with the greatest impact on RNA secondary structure prediction

This study explores the impact of folding energetics on mRNA secondary structure, contributing toward structure prediction and design of mRNA therapeutics.

N1-methyl-pseudouridine in mRNA enhances translation through eIF2α-dependent and independent mechanisms by increasing ribosome density

This paper explores the molecular mechanisms through which modified nucleosides can promote translation efficiency, which is critical to designing potent mRNA therapeutics.