Nobel Prize in Physiology or Medicine 2023

Katalin Karikó describes the discovery that replacing uridine with pseudouridine renders RNA non-immunogenic. This paved the way for developing mRNA for protein replacement therapy and, surprisingly, also for mRNA-based vaccine development.

Proactive efforts towards the development of new vaccines and antivirals, and the elimination of bottlenecks in vaccine development, will be essential to containing and eradicating future pandemics.

The COVID-19 pandemic has established mRNA vaccines as a rapid, effective and safe approach for the protection of individuals from infectious disease. Here, Whitehead and colleagues review the principles of mRNA vaccine design, synthesis and delivery, assessing recent progress and key issues in the development of mRNA vaccines for a range of infectious diseases.

The therapeutic potential ofin vitro-transcribed mRNA (IVT mRNA) extends from prophylactic and therapeutic vaccines to applications such as protein replacement and genome engineering. In this Review, the authors describe the recent developments in the IVT mRNA field, discuss the class-specific challenges with regards to translating IVT mRNA into a biopharmaceutical, and provide an overview of IVT mRNA drugs in development for different indications.

mRNA vaccines represent a promising alternative to conventional vaccine approaches, but their application has been hampered by instability and delivery issues. Here, Pardi and colleagues discuss recent advances in mRNA vaccine technology, assess mRNA vaccines currently in development for cancer and infectious diseases and consider future directions and challenges.

A lipid nanoparticle (LNP) component—an adjuvant lipidoid—is developed to enhance the adjuvanticity of LNPs, which significantly increases the innate and adaptive responses of the COVID-19 mRNA vaccines with good tolerability in mice.

In this study, the authors provide pre-clinical evaluation of immunogenicity of the “ChulaCov19” mRNA vaccine encoding the ectodomain of the SARS-CoV-2 S protein. The vaccine induced potent immune response when applied as homologous prime/boost immunization or as heterologous booster and protected mice from disease.

Gene delivery to fibroblasts for liver fibrosis treatment remains challenging. Here the authors develop a combinatorial library of ligand-tethered lipidoids via a modular synthetic method and adopt a 2-round screening strategy to identify lipidoids for potent and selective gene delivery to fibroblasts.

The role of empty lipid nanoparticles in eliciting dendritic cell maturation and innate immune signaling is shown to be impaired in older adults, potentially contributing to lower immune responses to SARS-CoV-2 mRNA-based vaccines.

A phase 1 clinical trial evaluates the safety, tolerability and immunogenicity of the ChulaCov19 mRNA vaccine in healthy adults.

Dysfunction of the lymphatic system leads to secondary lymphedema and results in degradation of quality of life. Here, the authors show that delivery of nucleoside-modified Vascular Endothelial Growth Factor C (VEGFC) mRNA, encapsulated in lipid nanoparticles, induces organ-specific lymphatic growth and reverses experimental lymphedema.

Base editors are effective and safe for cholesterol reduction in non-human primates.

When severely or chronically injured, the liver loses ability to regenerate. Here, the authors utilize transient lipid nanoparticle-enclosed HGF and EGF-encoding mRNA delivery to induce hepatocyte proliferation and harness recovery of liver function in murine acute and chronic liver injury models.

Carrasco et al. report a method that can predict the lipid nanoparticles (LNP) pKa from the structure of the ionizable lipid. They investigate the delivery efficiency for intramuscular and intravascular administration and propose design principles to limit off-target systemic distribution and expression for mRNA LNP vaccines.

The highly conserved influenza virus hemagglutinin (HA) stalk represents a potential target for a broadly protective vaccine. Here, the authors show that immunization with nucleoside-modified mRNA encoding full-length HA formulated in lipid nanoparticles elicits HA stalk-specific antibodies and protects from heterosubtypic virus infection.

A single, low-dose intradermal immunization with lipid-nanoparticle-encapsulated nucleoside-modified mRNA encoding the pre-membrane and envelope glycoproteins of Zika virus protects both mice and rhesus macaques against infection and elicits rapid and long-lasting neutralizing antibody responses.

Bispecific antibodies that connect T cells with tumor cells can be delivered in the form of in vitro–transcribed pharmacologically optimized mRNA; when injected into mice, these mRNA-encoded antibodies reject large established tumors as efficiently as the corresponding recombinant antibody protein.

Monoclonal antibodies are highly effective therapeutics that can be delivered as proteins or encoded DNA or mRNA. Here the authors develop lipid nanoparticle-formulated nucleoside-modified mRNA encoding an HIV-1 neutralizing antibody and see sustained and protective antibody levels in treated mice.

In geographic atrophy, a type of macular degeneration, retinal pigmented epithelium (RPE) cells die. This paper finds that DICER1, which processes miRNA precursors, is reduced in RPE from individuals with geographic atrophy. Cell death is not due to loss of miRNA processing, however; rather, the absence of DICER1 allows accumulation of pathological Alu repeat sequence RNAs. This work reveals a novel function of Dicer in degrading Alu RNAs.

The antiangiogenic effect of siRNAs does not depend on the target of the siRNA, or on intraocular administration. Rather, the siRNAs activate TLR3, a cell surface receptor for long viral dsRNAs, and innate immunity.

Nobel laureate Katalin Karikó retraces her origins and funds mRNA research at her alma mater.

Katalin Karikó and Drew Weissman laid the groundwork for immunizations that were rolled out during the pandemic at record-breaking speed.

Hundreds of scientists had worked on mRNA vaccines for decades before the coronavirus pandemic brought a breakthrough.

Pioneers of mRNA vaccines and next-generation sequencing techniques are among the winners of science’s most lucrative awards.

This Progress article provides an update on the COVID-19 vaccine effort in the light of ongoing vaccine efficacy studies and real-world data on vaccine effectiveness, including the impact of virus variants of concern and challenges for global deployment.

This Progress article summarizes our current understanding of the immune mechanisms of protection induced by the available COVID-19 vaccines. The authors compare vaccine-induced antibody responses following one or two doses of different vaccines and consider the relative importance of neutralizing antibodies for vaccine-mediated protection against SARS-CoV-2.

The development of vaccines against SARS-CoV-2 is reviewed, including an overview of the development process, the different types of vaccine candidate, and data from animal studies as well as phase I and II clinical trials in humans.

An Omicron BA.4/BA.5 mRNA booster vaccine elicits high neutralizing responses to the BA.4/BA.5 variant and to ancestral SARS-CoV-2, supporting tailoring booster vaccines to the predominant Omicron variant.

Analysis of antibody responses to COVID-19 vaccines encoding variant-specific spike, with or without ancestral spike, suggests no loss of neutralization of the ancestral virus with variant-only vaccines, which may simplify future vaccine updates.

Satija and colleagues use multimodal sequencing technologies and cross-modality integration tools to define distinct subpopulations of CD8⁺ T cells that are predictive of COVID-19 severity.

Pace and colleagues assessed the antibody titers, B cell and T cell memory response against SARS-COV-2 in mRNA-vaccinated individuals to show that reduced antibody titers combined with a distinctive memory T cell profile in low vaccine responders correlated with breakthrough infection.

Head-to-head comparison of third doses of mRNA COVID-19 vaccines in US Veterans finds that both are effective against documented SARS-CoV-2 infection and severe COVID-19 outcomes.

Current vaccines induce broadly cross-reactive cellular immunity against SARS-CoV-2 variants, including Omicron, and provide protection against severe disease despite a substantially reduced neutralizing antibody response.

Sequencing of B cell receptors and expression of the corresponding monoclonal antibodies is used to characterize the evolution of the long-term B cell response to SARS-CoV-2 mRNA vaccination.

A third dose of an mRNA vaccine against SARS-CoV-2 results in an expanded B cell repertoire that produces antibodies with increased potency and breadth.

Neutralization of the SARS-CoV-2 Omicron variant is markedly impaired in sera from recipients of two doses of the COVID-19 vaccine BNT162b2 or from convalescent individuals, but is robustly increased in both groups following a booster vaccine dose.

BNT162b2 booster vaccination in individuals who had previously received two doses of CoronaVac elevates neutralizing antibodies against the Omicron variant, but titers remain reduced compared with those against the ancestral SARS-CoV-2 virus and the Delta variant.

The Moderna (mRNA-1273) and Pfizer–BioNTech (BNT162b2) vaccines elicit anti-RBD antibodies similar to those elicited through natural infection with SARS-CoV-2, but their potent neutralizing activity was reduced or abolished by new viral variants of concern.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

Individuals over eighty years of age are less likely to mount a good immune response against SARS-CoV-2 (measured by neutralization titres) after the first dose of the BNT162b2 mRNA vaccine, but achieve good neutralization after the second dose.

Profiling the immune responses of 56 volunteers vaccinated with BNT162b2 reveals how this mRNA vaccine primes the innate immune system to mount a potent response to SARS-CoV-2 after booster immunization.

Analysis of antigen-specific B cells in lymph nodes of individuals vaccinated with BNT162b2 reveals lasting germinal centre responses, explaining the robust humoral immunity induced by SARS-CoV-2 mRNA-based vaccines.

Phase 1 trial results of the messenger RNA vaccine candidate BNT162b1, which encodes the receptor-binding domain of the SARS-CoV-2 spike protein, show safety and elicitation of antibody and T cell responses in both younger and older Chinese adults.

In an observational cohort of pregnant women in Israel, the BNT162b2 COVID-19 vaccine was found to have effectiveness similar to that seen in the general population.

A self-controlled case series using individual-patient-level data from over 38 million people aged 16 years and over, reveals an increased risk of myocarditis within a week of receiving a first dose of ChAdOx1, BNT162b2 and mRNA-1273 vaccines, which was further increased after a second dose of either mRNA vaccine. SARS-CoV-2 infection was associated with even greater risk of myocarditis, as well as pericarditis and cardiac arrhythmia.

In a phase I/II dose-escalation clinical trial, the mRNA COVID-19 vaccine BNT162b1 elicits specific T cell and antibody responses that suggest it has protective potential.

Malaria is a vector-borne disease caused by Plasmodium parasites. In an exciting new study, Ganley et al. harness the power of mRNA vaccines to summon tissue-resident memory T cells to battle the parasite as it replicates in the liver.

Nature Medicine explores the latest translational and clinical research news, with Moderna’s clinical trial of a vaccine against respiratory syncytial virus in older adults.

Nature Medicine explores the latest translation and clinical research news, with a phase 3 trial from Merck and Moderna testing mRNA-4157 combined with pembrolizumab in melanoma.

Nature Medicine explores the latest translational and clinical research news

Flush with COVID-19 vaccine success, pharma and biotech companies are moving forward with mRNAs engineered to make therapeutic proteins.

mRNA vaccines are now in the limelight as a key tool for tackling COVID-19, but the technology was originally developed for other diseases, such as cancer, that researchers are now hoping to treat.

mRNA for therapeutics is growing in popularity owing to the relative ease of synthesis and nucleotide alteration for personalized medicine. In this Review, Liu et al. outline the characteristics of in vitro transcribed mRNA-based therapeutics for cancer treatment, highlighting the ongoing clinical studies, current challenges and future opportunities.

In oncology, mRNA–lipid nanoparticles (LNPs) have been used either to achieve intratumoural expression of immune-stimulating cytokine combinations or as cancer vaccines, and new strategies are in development to enable the selective delivery of payloads into cancer cells previously considered unreachable. The authors of this Review present various approaches for delivering mRNA–LNPs to tumours and discuss improvements that will improve the selective targeting of cancer cells with mRNA–LNPs.

mRNA vaccines have proven safe and effective in preventing serious illness and death during the COVID-19 pandemic. In this Comment, Morris and Kopetz argue that these technologies offer a novel approach towards personalizing immune-based treatments for patients with cancer with the potential for immune activation beyond commonly utilized immunotherapies.

As the Plasmodium species that cause malaria replicate in the liver, Heath and colleagues designed mRNA vaccines to limit infection by inducing liver-resident memory T cells. Efficacy was observed in mice, including in hosts with previous blood-stage infection.

Wherry and colleagues define the kinetics of vaccine-primed recall immune responses during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection, highlighting rapid activation of memory T cells and broadly enhanced immune responses in previously vaccinated individuals.

The authors report mRNA vaccines encoding a fusion protein of MPXV A35R extracellular domain and full-length M1R and observe improved anti-M1R antibody response. The vaccines show enhanced active and passive protection in female mice challenged with a lethal dose of vaccinia virus.

Lassa virus infections in humans can result in severe disease, including hemorrhagic fever. Here the authors describe an mRNA-based Lassa virus vaccine that shows protection without requirement for neutralizing antibody in a guinea pig model of infection.

Here the authors show that in non-human primates two doses of an mRNA-based rabies vaccine induce higher levels of vaccine-specific B cells and cross-neutralizing antibodies compared to two doses of a licensed whole inactivated virus vaccine.

Here the authors report initial findings of a phase 1 clinical trial, showing that an investigational, mRNA-based vaccine for seasonal influenza (mRNA-1010) has no safety concerns and produces immune responses in adults that are similar or higher than a licensed comparator vaccine.

Dysfunction of the lymphatic system leads to secondary lymphedema and results in degradation of quality of life. Here, the authors show that delivery of nucleoside-modified Vascular Endothelial Growth Factor C (VEGFC) mRNA, encapsulated in lipid nanoparticles, induces organ-specific lymphatic growth and reverses experimental lymphedema.

Results of an exploratory interim analysis from a phase I trial show that an RNA vaccine targeted towards four melanoma-associated antigens produces durable objective responses in patients with melanoma that are accompanied by strong CD4⁺ and CD8⁺ T-cell immunity.

In a dose-escalation study of the COVID-19 RNA vaccine BNT162b1 in 45 healthy adults, RBD-binding IgG concentrations and SARS-CoV-2 neutralizing titres in sera increased with dose level and after a second vaccine dose.

The authors report the first-in-human application of personalized neo-antigen RNA vaccines in patients with melanoma.

Bispecific antibodies that connect T cells with tumor cells can be delivered in the form of in vitro–transcribed pharmacologically optimized mRNA; when injected into mice, these mRNA-encoded antibodies reject large established tumors as efficiently as the corresponding recombinant antibody protein.

The COVID-19 mRNA vaccines have transformed the field of mRNA nanomedicine, but this new class of therapeutics has the potential to treat many other diseases. This Review profiles the latest advances and challenges.

RNA therapies can be used to manipulate gene expression or produce therapeutic proteins. Here, the authors describe the growing number of RNA therapies and their molecular mechanisms of action. They also discuss the path from preclinical drug delivery research to clinical approval of these drugs.

Native nucleotide modifications regulate RNA function and metabolism, the study of which has revealed disease mechanisms, offers therapeutic potential and enables innovative clinical strategies. Chemical modifications in RNA are harnessed for clinical use in stable artificial RNAs such as mRNA vaccines and synthetic small RNA molecules.

Lipid nanoparticle–mRNA formulations have entered the clinic as coronavirus disease 2019 (COVID-19) vaccines, marking an important milestone for mRNA therapeutics. This Review discusses lipid nanoparticle design for mRNA delivery, highlighting key points for clinical translation and preclinical studies of lipid nanoparticle–mRNA therapeutics for various diseases.

Lipid nanoparticles are essential to mRNA vaccines. The groundwork for lipid-based drug delivery systems was laid more than 40 years ago in the lab of Pieter Cullis, Professor at the University of British Columbia. Nature Reviews Materials talks to Pieter Cullis about the history and future of lipid nanoparticle–nucleic acid drugs.

This Review summarizes recent advances in the field of mRNA therapeutics. The synthetic materials that encapsulate and deliver mRNA payloads are described, alongside an overview of commercial development of mRNA drugs.

mRNA vaccines produce rapid and precise immune responses against infectious diseases and cancers. Chen et al. discuss the development of biomaterials and nanotechnology for mRNA vaccines, how these are designed and evaluated and the underlying mechanisms of cellular uptake and immune stimulation.

This PrimeView highlights the production of nanotechnology-based mRNA vaccines, with a focus on their use to prevent infectious disease and in targeting tumours.

In this Primer, Conde and colleagues explain how to design smart nucleic acid delivery methods, which provide functionality and efficacy in the layout of molecular diagnostics and therapeutic systems.

This PrimeView highlights the design of nanoparticles as smart nucleic acid delivery methods.

An algorithm based on concepts established in computational linguistics enables rapid principled design of mRNA vaccines optimizing both structural stability and codon usage, resulting in improved half-life, protein expression and immune responses.

mRNA vaccines must be rigorously analysed to measure their integrity and detect contaminants, which can be time-consuming and costly. Here, authors describe a method to analyse mRNA vaccine quality using long-read sequencing and a custom bioinformatic pipeline.

Carrasco et al. report a method that can predict the lipid nanoparticles (LNP) pKa from the structure of the ionizable lipid. They investigate the delivery efficiency for intramuscular and intravascular administration and propose design principles to limit off-target systemic distribution and expression for mRNA LNP vaccines.

CV2CoV, a second-generation mRNA COVID-19 vaccine with non-modified nucleosides but optimized non-coding regions, is demonstrated to be effective against SARS-CoV-2 challenge when tested in non-human primates.

mRNA vaccines such as those used to prevent COVID-19 owe part of their success to methylation that masks immunostimulatory properties of the mRNA, but the immunological mechanisms of adjuvanticity are unclear. Two new studies reveal distinct mechanisms for innate sensing of this hidden adjuvant.