The disclosure features lipid nanoparticle (LNP) compositions comprising metabolic reprogramming molecules and uses thereof. The LNP compositions of the present disclosure comprise mRNA therapeutics encoding metabolic reprogramming polypeptides, e.g., IDO, TDO, AMPK, AhR, ALDH1A2, HMOX1, CD73 or CD39. The LNP compositions of the present disclosure can reprogram myeloid and/or dendritic cells, suppress T cells and/or induce immune tolerance in vivo.

Provided herein are methods of treating brain cancer in a subject, comprising evaluating one or more biological samples from a subject who has brain cancer for the presence of a miRNAs and administering interleukin-12 (IL-12); an immunogenic composition of human telomerase reverse transcriptase (hTERT), Wilms Tumor-1 (WT-1), and prostate specific membrane antigen (PSMA); and an anti-programmed cell death receptor 1 (PD-1) antibody to said subject if the subject has an increased expression level of the mIR-331-3p miRNA or isomiRs thereof and the miR-1537-3p miRNA or isomiRs thereof relative to a control population of subjects. Also provided herein are methods of treating brain cancer in a subject, comprising measuring an expression level of at least one mRNA biomarker selected from SYNGR3, OTX1, GABBR2, LHX1, CADM3, MLLT11, MNX1, GRB14, SLC34A2, PHYHIP, WNT10B, SLC17A6, CRLF1, HOXD13, TGFβR3, UBA7, SFRP4, or any combination thereof, in a tumor sample from a subject and administering IL-12; an immunogenic composition hTERT, WT-1, and PSMA; and an anti-PD-1 antibody to said subject if the expression level of SYNGR3, OTX1, GABBR2, LHX1, CADM3, MLLT11, MNX1, GRB14, SLC34A2, PHYHIP, WNT10B, SLC17A6, CRLF1 and HOXD13 is decreased or if the expression level of TGFβR3, UBA7, SFRP4 is increased.

The disclosure relates to compositions and methods for the preparation, manufacture and therapeutic use of combinations of immunomodulatory polynucleotides (e.g., mRNAs) encoding an immune response primer polypeptide (e.g., an interleukin 23 (IL-23) polypeptide or an interleukin 36γ (IL-36-gamma) polypeptide), and an immune response co-stimulatory signal polypeptide (e.g., an OX40L polypeptide).

The present invention is directed to a nucleic acid suitable for use in treatment or prophylaxis of an infection with a coronavirus, preferably with a Coronavirus SARS-CoV-2, or a disorder related to such an infection, preferably COVID-19. The present invention is also directed to compositions, polypeptides, and vaccines. The compositions and vaccines preferably comprise at least one of said nucleic acid sequences, preferably nucleic acid sequences in association a lipid nanoparticle (LNP). The invention is also directed to first and second medical uses of the nucleic acid, the composition, the polypeptide, the combination, the vaccine, and the kit, and to methods of treating or preventing a coronavirus infection, preferably a Coronavirus infection.

The present disclosure relates to the use of nucleic acid (e.g., mRNA) combination therapies for the treatment of cancer. The disclosure provides compositions, and methods for their preparation, manufacture, and therapeutic use, wherein those compositions comprise at least two polynucleotides (e.g., mRNAs) in combination wherein the at least two polynucleotides are selected from the group consisting of (i) a polynucleotide encoding an immune response primer (e.g., IL23), (ii) a polynucleotide encoding an immune response co-stimulatory signal (e.g., OX40L), (iii) a polynucleotide encoding a checkpoint inhibitor (e.g., an anti CTLA-4 antibody), and, (iv) a combination thereof. The therapeutic methods disclosed herein comprise, e.g., the administration of a combination therapy disclosed herein for the treatment of cancer, e.g., by reducing the size of a tumor or inhibiting the growth of a tumor, in a subject in need thereof. In some aspects, the combination therapies disclosed herein disclosed are administered intratumorally.

The present disclosure relates to immunogenic compositions comprising a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen, and a toll-like receptor 9 (TLR9) agonist, such as an oligonucleotide comprising an unmethylated cytidine-phospho-guanosine (CpG) motif. The immunogenic compositions are suitable for stimulating an immune response against a SARS-CoV-2 in an individual in need thereof.

The invention relates to the field of RNA stabilisation, and more particularly to the use of deuterium oxide (D.sub.2O) during storage and/or synthesis of RNA molecules. Described herein are deuterium-stabilised ribonucleic acid (RNA) molecules that display an increased resistance to thermal and enzymatic hydrolysis. Also described are aqueous compositions comprising stabilized RNA molecules and methods for making same. The invention is particularly useful for in the manufacture of RNA-based therapeutics, such as mRNA vaccines, to render them less sensitive to temperature fluctuations.

Compositions and methods for the prevention and/or treatment of a viral infection, in particular of the Coronaviridae family.

Modified HCMV gB proteins in a non-post-fusogenic conformation, compositions comprising such proteins, and uses thereof.

Disclosed herein are embodiments of a compound useful for treating or preventing betacoronavirus infections such as SARS-Cov-2 infections. Also disclosed is a method for administering the compound to a subject, particularly a human subject, to treat or prevent a betacoronavirus infection in the subject. The compound can comprise an oligomer comprising a nucleic acid base sequence that is antisense to at least a portion of a SARS-CoV-2 genomic RNA, and can comprise a sequence present in the 5′ UTR and first 20 nt of coding sequence of the SARS-CoV-2 genomic RNA. The compound also can contain a peptide sequence. In some embodiments, the compound is a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO).