A Multi-Targeting, Nucleoside-Modified mRNA Influenza Virus Vaccine Provides Broad Protection in Mice

Freyn, Alec W.; Silva, Jamile Ramos da; Rosado, Victoria; Bliss, Carly M.; Pine, Matthew K.; Mui, Barbara L.; Tam, Ying K.; Madden, Thomas D.; Ferreira, Luís Carlos de Souza; Weissman, Drew; Krammer, Florian; Coughlan, Lynda; Palese, Peter; Pardi, Norbert; Nachbagauer, Raffael

doi:10.1016/j.ymthe.2020.04.018

Cited by 201 publications

(182 citation statements)

References 56 publications

Supporting

Mentioning

170

Contrasting

Unclassified

Order By: Relevance

“…mRNA vaccines were designed based on the SARS-CoV-2 spike (S) protein sequence (Wuhan-Hu-1, GenBank: MN908947.3). Coding sequences of full length WT S protein, full length Δfurin S protein (RRAR furin cleavage site abolished between amino acids 682-685), RBD (amino acids 1-14 fused with amino acids 319-541) and firefly luciferase (Luc) were codon-optimized, synthesized and cloned into the mRNA production plasmid as described ( Freyn et al., 2020 ). mRNA production and LNP encapsulation was performed as described ( Freyn et al., 2020 ).…”

Section: Methodsmentioning

confidence: 99%

“…One of the most widely studied of these vaccine platforms uses antigen-encoding nucleoside-modified mRNA encapsulated into lipid nanoparticles (mRNA-LNP) ( Pardi et al., 2015 ). Nucleoside-modified mRNA-LNP vaccines have induced protective immune responses against various pathogens in preclinical studies ( Awasthi et al., 2019 ; Espeseth et al., 2020 ; Freyn et al., 2020 ; Meyer et al., 2018 ; Pardi et al., 2017 , 2018a , 2018c ; Richner et al., 2017 ; Roth et al., 2019 ), in many cases, after administration of a single dose ( Freyn et al., 2020 ; Pardi et al., 2017 , 2018a , 2018c ). This vaccine type has been shown to elicit particularly strong CD4 + T cell, germinal center B cell and long-lived plasma cell responses associated with durable, protective neutralizing antibody responses ( Lindgren et al., 2017 ; Pardi et al., 2018a ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Single Immunization with Nucleoside-Modified mRNA Vaccines Elicits Strong Cellular and Humoral Immune Responses against SARS-CoV-2 in Mice

et al. 2020

Self Cite

View full text Add to dashboard Cite

Summary SARS-CoV-2 infection has emerged as a serious global pandemic. Because of the high transmissibility of the virus and the high rate of morbidity and mortality associated with COVID-19, developing effective and safe vaccines is a top research priority. Here, we provide a detailed evaluation of the immunogenicity of lipid nanoparticle-encapsulated, nucleoside-modified mRNA (mRNA-LNP) vaccines encoding the full-length SARS-CoV-2 spike protein or the spike receptor binding domain in mice. We demonstrate that a single dose of these vaccines induces strong type 1 CD4 + and CD8 + T cell responses, as well as long-lived plasma and memory B cell responses. Additionally, we detect robust and sustained neutralizing antibody responses and the antibodies elicited by nucleoside-modified mRNA vaccines do not show antibody-dependent enhancement of infection in vitro . Our findings suggest that the nucleoside-modified mRNA-LNP vaccine platform can induce robust immune responses and is a promising candidate to combat COVID-19.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Single Immunization with Nucleoside-Modified mRNA Vaccines Elicits Strong Cellular and Humoral Immune Responses against SARS-CoV-2 in Mice

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…The multiple possibilities of the modification and functionalization, as well as the diversity of NPs types, making them very attractive potential transfection reagents (Figure 3). targeting mRNA-LNPs vaccine has been confirmed to induce broad immune responses in mice using single and low dosage [68].…”

Section: Nanotechnology In Gene Silencing Strategiesmentioning

confidence: 98%

“…The very recent study allowed the authors to select the perfect candidate for the universal, multi-targeting anti-influenza vaccine construction. The multi-targeting mRNA-LNPs vaccine has been confirmed to induce broad immune responses in mice using single and low dosage [68].…”

Section: Mrna Vaccines Strategy Based On Nps Deliverymentioning

confidence: 99%

Anti-Influenza Strategies Based on Nanoparticle Applications

2020

View full text Add to dashboard Cite

Influenza virus has the potential for being one of the deadliest viruses, as we know from the pandemic’s history. The influenza virus, with a constantly mutating genome, is becoming resistant to existing antiviral drugs and vaccines. For that reason, there is an urgent need for developing new therapeutics and therapies. Despite the fact that a new generation of universal vaccines or anti-influenza drugs are being developed, the perfect remedy has still not been found. In this review, various strategies for using nanoparticles (NPs) to defeat influenza virus infections are presented. Several categories of NP applications are highlighted: NPs as immuno-inducing vaccines, NPs used in gene silencing approaches, bare NPs influencing influenza virus life cycle and the use of NPs for drug delivery. This rapidly growing field of anti-influenza methods based on nanotechnology is very promising. Although profound research must be conducted to fully understand and control the potential side effects of the new generation of antivirals, the presented and discussed studies show that nanotechnology methods can effectively induce the immune responses or inhibit influenza virus activity both in vitro and in vivo. Moreover, with its variety of modification possibilities, nanotechnology has great potential for applications and may be helpful not only in anti-influenza but also in the general antiviral approaches.

show abstract

“…86 Pseudouridine modifications are now commonplace and have been used instead of UTP to make mRNAs for vaccination against Zika virus and influenza. 87,88 More recently, it has been found that chemically modifying mRNA can influence the activation of protein kinase R (PKR) in cells. Incorporation of pseudouridine into mRNA reduced activation of PKR, which was not previously known to be activated by mRNA.…”

Section: Chemically Modifying Mrna Drugs Improves Their Safety and Efmentioning

confidence: 99%

Treating Cystic Fibrosis with mRNA and CRISPR

et al. 2020

View full text Add to dashboard Cite

Less than 20% of the protein coding genome is thought to be targetable using small molecules. mRNA therapies are not limited in the same way since in theory, they can silence or edit any gene by encoding CRISPR nucleases, or alternatively, produce any missing protein. Yet not all mRNA therapies are equally likely to succeed. Over the past several years, an increasing number of clinical trials with siRNA-and antisense oligonucleotide-based drugs have revealed three key concepts that will likely extend to mRNA therapies delivered by nonviral systems. First, scientists have come to understand that some genes make better targets for RNA therapies than others. Second, scientists have learned that the type and position of chemical modifications made to an RNA drug can alter its therapeutic window, toxicity, and bioavailability. Third, scientists have found that safe and targeted drug delivery vehicles are required to ferry mRNA therapies into diseased cells. In this study, we apply these learnings to cystic fibrosis (CF). We also describe lessons learned from a subset of CF gene therapies that have already been tested in patients. Finally, we highlight the scientific advances that are still required for nonviral mRNA-or CRISPR-based drugs to treat CF successfully in patients.

show abstract

A Multi-Targeting, Nucleoside-Modified mRNA Influenza Virus Vaccine Provides Broad Protection in Mice

Cited by 201 publications

References 56 publications

A Single Immunization with Nucleoside-Modified mRNA Vaccines Elicits Strong Cellular and Humoral Immune Responses against SARS-CoV-2 in Mice

A Single Immunization with Nucleoside-Modified mRNA Vaccines Elicits Strong Cellular and Humoral Immune Responses against SARS-CoV-2 in Mice

Anti-Influenza Strategies Based on Nanoparticle Applications

Treating Cystic Fibrosis with mRNA and CRISPR

Contact Info

Product

Resources

About