WO2023002492A1 - Optimisation de codon d'acides nucléiques - Google Patents
Optimisation de codon d'acides nucléiques Download PDFInfo
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- WO2023002492A1 WO2023002492A1 PCT/IL2022/050794 IL2022050794W WO2023002492A1 WO 2023002492 A1 WO2023002492 A1 WO 2023002492A1 IL 2022050794 W IL2022050794 W IL 2022050794W WO 2023002492 A1 WO2023002492 A1 WO 2023002492A1
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- codon
- amino acid
- sequence
- encodes
- protein
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2800/00—Nucleic acids vectors
- C12N2800/22—Vectors comprising a coding region that has been codon optimised for expression in a respective host
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention in some embodiments thereof, relates to a method of codon optimizing nucleic acids of proteins and, more particularly, but not exclusively, to antigenic proteins which are used in vaccines.
- mRNA vaccines transfects molecules of synthetic RNA into immune cells. Once inside the immune cells, the vaccine's RNA functions as mRNA, causing the cells to build the foreign protein that would normally be produced by a pathogen (such as a virus) or by a cancer cell. These protein molecules stimulate an adaptive immune response which teaches the body how to identify and destroy the corresponding pathogen or cancer cells.
- the delivery of mRNA is achieved by a co-formulation of the molecule into lipid nanoparticles which protect the RNA strands and helps their absorption into the cells.
- RNA vaccines over traditional protein vaccines are superior design and production speed, lower cost of production, and the induction of both cellular as well as humoral immunity.
- Vaccination of the human population against SARS-Cov2 using mRNA vaccines has yielded promising results in reducing infection, severe disease, mortality and transmission.
- mRNA-1273 Moderna COVID-19 vaccine
- BNT162b2 Pfizer-BioNTech COVID-19 vaccine
- a method of codon optimizing the sequence of a nucleic acid encoding a protein of a vaccine comprising:
- a method of generating a nucleic acid based vaccine for the treatment or prevention of a disease comprising:
- a vaccine comprising a nucleic acid encoding an antigenic protein or peptide of a pathogen, wherein the nucleic acid is codon optimized at at least one mutation site of a variant of the antigenic protein, wherein the codon optimization increases the likelihood of mis-incorporating the mutated amino acid at the predetermined position.
- the prevalence of the variant is above a predetermined level in a human population.
- the protein is of a pathogen.
- the nucleic acid is DNA.
- the nucleic acid is RNA.
- the protein is an antigenic protein.
- the protein is a neoantigen.
- the selecting further takes into consideration the expression potential of the synonymous codon.
- the pathogen is a virus.
- the pathogen is a bacteria.
- the virus is selected from the group consisting of a coronavirus, an influenza virus, cytomegalovirus (CMV), human immunodeficiency virus (HIV-1), rabies virus, measles virus, chickenpox virus, Respiratory syncytial virus (RSV), Epstein- Barr virus (EBV) and a Zika virus.
- the pathogen causes a respiratory disease.
- the pathogen causes cancer.
- the virus is a coronavirus.
- the coronavirus is SARS-CoV2.
- the protein is a spike protein.
- the protein is a spike protein
- the predetermined position is selected from the group consisting of position 18, 111, 222, 239, 314, 446, 477, 483, 484, 614, 982, 1202 and 1223, wherein the numbering of the position is according to the spike protein as set forth in SEQ ID NO: 1.
- the sequence of the codon which encodes the amino acid at position 18 is TTG;
- the sequence of the codon which encodes the amino acid at position 111 is GAT;
- the sequence of the codon which encodes the amino acid at position 222 is GCC;
- the sequence of the codon which encodes the amino acid at position 239 is CAA;
- the sequence of the codon which encodes the amino acid at position 314 is CAA;
- the sequence of the codon which encodes the amino acid at position 446 is GGT;
- the sequence of the codon which encodes the amino acid at position 477 is AGC;
- the sequence of the codon which encodes the amino acid at position 483 is GTA;
- the sequence of the codon which encodes the amino acid at position 484 is GAA;
- the sequence of the codon which encodes the amino acid at position 614 is GGT;
- the sequence of the codon which encodes the amino acid at position 222 is GCC;
- the nucleic acid is DNA.
- the nucleic acid is RNA.
- the RNA comprises a chemically modified nucleotide.
- the RNA comprises a non-natural cap.
- the RNA is encapsulated in a particle.
- the particle comprises lipids.
- the pathogen is a virus.
- the pathogen is a bacteria.
- the virus is selected from the group consisting of a coronavirus, an influenza virus, cytomegalovirus (CMV), human immunodeficiency virus (HIV-1), rabies virus, measles virus, chickenpox virus, Respiratory syncytial virus (RSV), Epstein- Barr virus (EBV) and a Zika virus.
- CMV cytomegalovirus
- HAV-1 human immunodeficiency virus
- rabies virus measles virus
- chickenpox virus chickenpox virus
- RSV Respiratory syncytial virus
- EBV Epstein- Barr virus
- Zika virus Zika virus
- the pathogen causes a respiratory disease.
- the pathogen causes cancer.
- the virus is a coronavirus.
- the coronavirus is SARS-CoV2.
- the antigenic protein is a spike protein.
- the antigenic protein is a spike protein
- the predetermined position is selected from the group consisting of position 18, 111, 222, 239, 314, 446, 477, 483, 484, 614, 982, 1202 and 1223, wherein the numbering of the position is according to the spike protein as set forth in SEQ ID NO: 1.
- FIGs. 1A-C Amino acid mistranslation patterns at codon resolution in E. coli and S. cerevisiae and human
- A the substitutions identifications matrices of S. cerevisiae (green channel, left) and E. coli (red channel, right) are compared and overlaid (middle).
- the intensity of the color is proportional to the logarithm of the number of independent identification, with one pseudo-count. Values are normalised by the highest entry in the matrix for each of the two organisms.
- the blue box highlights the recently described property of eukaryotic AlaRS to mischarge tRNA Cys Grey boxes are either correct base-pairings, or mismatches to which no substitutions could be unambiguously mapped.
- FIG. 2 Same error-bearing peptides are detected repeatedly on melanoma cancerous MHC-I.
- MHC-I presented peptide with translation errors.
- Each dot represents a pair of correct and error-bearing peptide counterparts, detected on MHC-I, marked with original amino acid, positions of error, and destination amino acid upon error.
- Peptides are positioned on x- and y-axis according to their mass-spec intensity (naturally, typically higher for the correct peptide).
- the color code for each peptide signifies the number of samples, out of 8 examined, in which the error-bearing peptide in the pair has been identified.
- FIGs. 3A-F Retrospective analysis (all spike positions) & prospective analysis - Pfizer vaccine, the Modema vaccine. Mutations along the Spike protein for which we could suggest a beneficial codon swap. Number of mutation is given for a certain cutoff of replacement fraction or higher. Colored lines represent repeated analysis based on replacement fraction derived from the error data derived from the e. coli, yeast, or human data. Mutations with 0 frequency were excluded. A and B are for the retrospective and C and D are for the prospective compilations. (E, F) Number of proposed codon replacement mutations (left), of positions within the sequence (right) as a function of the frequency of the mutation in the human population in the retrospective compilation. E - Pfizer vaccine, F -Moderna.
- the present invention in some embodiments thereof, relates to a method of codon optimizing nucleic acids of proteins and, more particularly, but not exclusively, to antigenic proteins which are used in vaccines.
- Vaccination is the most effective method of preventing infectious diseases; widespread immunity due to vaccination is largely responsible for the worldwide eradication of smallpox and the restriction of diseases such as polio, measles, and tetanus from much of the world.
- the effectiveness of vaccination has been widely studied and verified; for example, vaccines that have proven effective include the influenza vaccine, the HPV vaccine, and the chicken pox vaccine.
- Vaccination of the human population against SARS-Cov2 has also yielded promising results in reducing infection, severe disease, mortality and transmission. Yet, emergence of Variants of Concern (VoC), viral mutants with enhanced infectivity, or with ability to evade immunity, is a major public-health concern. As the amount of variants increases rapidly, it may become impractical to design, assay, pass through clinical trials, approve, deliver and administer multiple tailored-made vaccines, one against each VoC. Thus, the present inventors have now tackled the challenge of redesigning a single mRNA sequence of a vaccine that may collaterally target several VoCs.
- VoC Variants of Concern
- Codon optimization of vaccine sequence is a common practice in which among all the synonymous codons of each amino acid along the antigen protein sequence, an optimal codon is chosen. So-far codon optimization has mainly been used for the enhancement of protein expression level. The present inventors now propose to optimize codon choice of vaccines to allow collateral targeting of multiple VoCs.
- amino acid mis-incorporation events tend to recur in multiple proteins, and their prevalence may be as high as 1% or even higher;
- errors tend to predictably occur depending on choice of synonymous codon used to encode the original amino acid, and they often dictate the identity of the amino acid destination of a mis-translation event.
- the present inventors thus examined bioinformatically if codon re-design of current mRNA vaccines of SARS-Cov2 could control the rate and patterns of translation errors and if it has a potential to create translation errors that will mimic genetic mutations that appear in VoCs. Investigations of the Pfizer and Modema vaccines suggest a potential for codon substitutions that through translation errors might collaterally targets multiple VoCs.
- a method of codon optimizing the sequence of a nucleic acid encoding a protein of a vaccine comprising:
- vacun refers to a composition which comprises a protein or peptide for administration to a subject (e.g. human), against which an immune response is elicited.
- a vaccine is a therapeutic.
- a vaccine is prophylactic. Further details on vaccines are provided herein below.
- codon-optimizing refers to adapting a nucleic acid sequence (e.g., a nucleic acid coding region) by replacing one, or more than one, or a significant number, of codons with one or more codons that although encode for the wild-type amino acid, have a higher likelihood (compared to all other codons which encode the wild-type amino acid) to incorporate an incorrect amino acid.
- the codon which is selected has the highest likelihood out of all synonymous codons to incorporate an incorrect amino acid.
- the codon which is selected has the highest likelihood out of all synonymous codons to incorporate a particular incorrect amino acid.
- the nucleic acid which is codon optimized encodes proteins or fragments thereof which are antigenic - i.e. capable of eliciting an immune response in the subject being immunized.
- the nucleic acid may encode a full length protein or a fragment of the protein. Any length of the fragment is contemplated as long as it is able to elicit the immune response in the subject being vaccinated.
- the protein of the vaccine is derived from (naturally found in) an organism (e.g. virus, bacteria, parasite, fungus) which is pathogenic to a mammal.
- an organism e.g. virus, bacteria, parasite, fungus
- the pathogenic organism is one that brings about an infectious disease in a mammal.
- infectious disease refers to a transmissible disease caused by a pathogenic organism.
- infectious disease is a respiratory disease - e.g. COVID, influenza.
- the infectious disease may be transmitted in any way including droplet contact, fecal-oral transmission, sexual transmission, oral transmission, direct contact and vehicle transmission.
- the protein of the vaccine is a cancer-specific protein or peptide.
- the protein of the vaccine may originate from, but is not limited to any of the following families of virus: Adenovirus, arenaviridae, astroviridae, bunyaviridae, caliciviridae, coronaviridae, flaviviridae, herpesviridae, orthomyxoviridae, paramyxoviridae, picornaviridae, poxviridae, reoviridae, retroviridae, rhabdoviridae and togaviridae.
- Adenovirus arenaviridae, astroviridae, bunyaviridae, caliciviridae, coronaviridae, flaviviridae, herpesviridae, orthomyxoviridae, paramyxoviridae, picornaviridae, poxviridae, reoviridae, retroviridae, rhabdoviridae and togaviridae.
- At least one antigen or antigenic sequence may be derived from any of the following virus: Influenza A such as H1N1, H1N2, H3N2 and H5N1 (bird flu), Influenza B, Influenza C virus, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis D virus, Hepatitis E virus, Rotavirus, any virus of the Norwalk virus group, enteric adenoviruses, parvovirus, Dengue fever virus, Monkey pox, Mononegavirales, Lyssavirus such as rabies virus, Lagos bat virus, Mokola virus, Duvenhage virus, European bat virus 1 & 2 and Australian bat virus, Ephemerovirus, Vesiculovirus, Vesicular Stomatitis Virus (VSV), Herpesviruses such as Herpes simplex virus types 1 and 2, varicella zoster, cytomegalovirus, Epstein-Bar virus (EBV), human herpesvirusses (HHV), human herpes
- the protein of the vaccine is derived from a coronavirus, such as SARS-CoV-2.
- SARS-CoV-2 contains four major structural proteins, namely spike (S), membrane (M) and envelope (E) proteins, all of which are embedded in the viral surface envelope, and nucleocapsid (N) protein, which is in the ribonucleoprotein core.
- S proteins are responsible for recognition of the host cellular receptor to initiate virus entry.
- M proteins are embedded in the envelope and shape the virion envelope.
- E proteins are small polypeptides that are crucial for CoV infectivity.
- N proteins make up the helical nucleocapsid and bind along the viral RNA genome.
- SARS-CoV-2 encodes 16 non- structural proteins (nspl-16) and 9 accessory proteins.
- SARS-CoV-2 antigenic proteins include the spike protein (having the amino acid sequence at least 85 %, 86 %, 87 %, 88 %, 89 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 %, 99 % identical or homologous to the sequence as set forth in SEQ ID NO: 1).
- the spike protein consists of a membrane-distal SI subunit and a membrane-proximal
- the S2 subunit and exists in the virus envelope as a homotrimer.
- the SI subunit determines receptor recognition via its receptor-binding domain (RBD), whereas the S2 subunit is responsible for membrane fusion, which is required for virus entry.
- RBD receptor-binding domain
- the RBD is located in the C-terminal domain of the SI subunit.
- the N-terminal domain (NTD) of the S 1 subunit can be used for receptor binding (such as in mouse hepatitis virus) or might also be involved in virus attachment to host cells by recognizing specific sugar molecules (such as in TGEV, BCoV and IBV) or has an important role in the pre-fusion to post-fusion transition of the S protein.
- the S2 subunit contains the fusion peptide (FP), connecting region (CR), heptad repeat 1 (HR1) and HR2 around a central helix as a helix-tum-helix structure.
- the protein of the vaccine is the full-length Spike protein of SARS-CoV-2 with two proline substitutions (K986P and V987P).
- the protein of the vaccine is the receptor binding domain (RBD) of SARS-CoV-2 (or fragments thereof).
- An embodiment of the present invention includes at least one antigenic protein or peptide or fragment of an antigenic protein or peptide from a microorganism (e.g. bacteria). More specifically, the protein of the vaccine may be derived from one of the following bacteria: Anthrax (Bacillus anthracis), Mycobacterium tuberculosis, Salmonella (Salmonella gallinarum, S. pullorum, S. typhi, S. enteridtidis, S. paratyphi, S. dublin, S.
- Anthrax Bacillus anthracis
- Mycobacterium tuberculosis derived from one of the following bacteria: Anthrax (Bacillus anthracis), Mycobacterium tuberculosis, Salmonella (Salmonella gallinarum, S. pullorum, S. typhi, S. enteridtidis, S. paratyphi, S. dublin, S.
- Clostridium botulinum Clostridium perfringens, Cory neb acterium diphtheriae, Bordetella pertussis, Campylobacter such as Campylobacter jejuni, Crytococcus neoformans, Yersinia pestis, Yersinia enterocolitica, Yersinia pseudotuberculosis, Listeria monocytogenes, Leptospira species, Legionella pneumophila, Borrelia burgdorferi, Streptococcus species such as Streptococcus pneumoniae, Neisseria meningitides, Haemophilus influenzae, Vibrio species such as Vibrio cholerae 01, V.
- EEC Enterovirulent Escherichia coli EEC
- ETEC Escherichia coli- enterotoxigenic
- EPEC Escherichia coli-enteropathogenic
- EHEC Escherichia coli 0157:H7 enter ohemorrhagic
- EIEC Escherichia coli-enteroinvasive
- Staphylococcus species such as S. aureus and especially the vancomycin intermediate/resistant species (VISA/VRSA) or the multidrug resistant species (MRSA)
- Shigella species such as S. flexneri, S. sonnei, S. dysenteriae, Cryptosporidium parvum, Brucella species such as B. abortus, B.
- B. ovis B. suis
- B. canis Burkholderia mallei and Burkholderia pseudomallei
- Chlamydia psittaci Coxiella burnetii
- Francisella tularensis Francisella tularensis
- Rickettsia prowazekii Histoplasma capsulatum
- Coccidioides immitis
- An embodiment of the present invention includes at least one antigenic protein or peptide or fragment of an antigenic protein or peptide from a parasite, examples of which include, but are not limited to: Plasmodium species such as Plasmodium malariae, Plasmodium ovale, Plasmodium vivax, Plasmodium falciparum, Endolimax nana, Giardia lamblia, Entamoeba histolytica, Cryptosporidium parvum, Blastocystis hominis, Trichomonas vaginalis, Toxoplasma gondii, Cyclospora cayetanensis, Cryptosporidium muris, Pneumocystis carinii, Leishmania donovani, Leishmania tropica, Leishmania braziliensis, Leishmania mexicana, Acanthamoeba species such as Acanthamoeba castellanii, and A.
- Plasmodium species such as Plasmodium malariae
- the protein of the vaccine may be derived from pathogens that infect and cause disease in domestic animals, especially commercially relevant animals such as pigs, cows, horses, sheep, goats, llamas, rabbits, mink, mice, rats, dogs, cats, ferrets, poultry such as chicken, turkeys, pheasants and others, fish such as trout, salmon, cod and other farmed species.
- diseases or agents here of from which at least one antigen or antigenic sequence may be derived include, but are not limited to: Multiple species diseases such as: Anthrax, Aujeszky's disease, Bluetongue, Brucellosis such as: Brucella abortus, Brucella melitensis or Brucella suis; Crimean Congo haemorrhagic fever, Echinococcosis/hydatidosis, virus of the family Picornaviridae, genus Aphthovirus causing Foot and Mouth disease especially any of the seven immunologically distinct serotypes: A, O, C, SAT1, SAT2, SAT3, Asial, or Heartwater, Japanese encephalitis, Leptospirosis, Newworld screwworm (Cochliomyia hominivorax), Old world screwworm (Chrysomya bezziana), Paratuberculosis, Q fever, Rabies, Rift Valley fever, Rinderpest, Trichinellosis, Tularemia, Ves
- Equine diseases such as: African horse sickness, Contagious equine metritis, Dourine, Equine encephalomyelitis (Eastern), Equine encephalomyelitis (Western), Equine infectious anaemia, Equine influenza, Equine piroplasmosis, Equine rhinopneumonitis, Equine viral arteritis, Glanders, Surra (Trypanosoma evansi) or Venezuelan equine encephalomyelitis; Swine diseases such as: African swine fever, Classical swine fever, Nipah virus encephalitis, Porcine cysticercosis, Porcine reproductive and respiratory syndrome, Swine vesicular disease or Transmissible gastroenteritis; Avian diseases such as: Avian chlamydiosis, Avian infectious bronchitis, Avian infectious laryngotracheitis, Avian mycoplasmosis
- the protein is derived from a cancer- causing pathogen including, but not limited to H. pylori, human papillomavims (HPV), hepatitis B vims (HBV), hepatitis C vims (HCV), and Epstein-Barr vims (EBV).
- a cancer- causing pathogen including, but not limited to H. pylori, human papillomavims (HPV), hepatitis B vims (HBV), hepatitis C vims (HCV), and Epstein-Barr vims (EBV).
- the first step in optimizing the sequence of the nucleic acid encoding the protein of the vaccine is identification of known mutation sites in the variant protein which are present in the variant pathogens.
- variant protein refers to a protein whose amino acid sequence has a mutation e.g. substitution of one or several (e.g. 1, 2, 3, 4, 5, 6, 7, 8 or 9) amino acids as compared to the wild-type or unmodified protein.
- the mutation in the variant protein serves to increase the pathogenicity of the pathogen - e.g. increases the spread and/or vimlence of the pathogen.
- the protein variant has an amino acid sequence which is at least 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 %, 99 % identical to the wild-type or unmodified protein.
- the protein variant causes the pathogen to be more infectious, immune evasive and/or vimlent.
- the invention described herein is particularly useful for generating vaccines against highly contagious diseases and ones which are very prevalent (e.g. COVID19).
- the invention described herein is particularly useful for generating vaccines against infectious diseases caused by microorganisms that have a high rate of spontaneous mutation. Rates of spontaneous mutation vary amply among viruses. RNA viruses mutate faster than DNA viruses, single-stranded viruses mutate faster than double-strand virus, and genome size appears to correlate negatively with mutation rate.
- the protein variant comprises a conservative substitution.
- conservative substitution refers to amino acid substitutions which would not disadvantageously affect or change the essential properties of a protein/polypeptide comprising the amino acid sequence.
- a conservative substitution may be introduced by standard techniques known in the art such as site-directed mutagenesis and PCR-mediated mutagenesis.
- Conservative amino acid substitutions include substitutions wherein an amino acid residue is substituted with another amino acid residue having a similar side chain, for example, a residue physically, chemically, or functionally similar (such as, having similar size, shape, charge, chemical property including the capability of forming covalent bond or hydrogen bond, etc.) to the corresponding amino acid residue.
- the families of amino acid residues having similar side chains have been defined in the art.
- amino acids having basic side chains for example, lysine, arginine and histidine
- amino acids having acidic side chains for example, aspartic acid and glutamic acid
- amino acids having uncharged polar side chains for example, glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan
- amino acids having nonpolar side chains for example, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine
- amino acids having branched side chains such as threonine, valine, isoleucine
- amino acids having aromatic side chains for example, tyrosine, phenylalanine, tryptophan, histidine.
- a conservative substitution refers to a substitution of a corresponding amino acid residue with another amino acid residue from the same side-chain family.
- Methods for identifying amino acid conservative substitutions are well known in the art (see, for example, Brummell et ak, Biochem. 32: 1180-1187 (1993); Kobayashi et al., Protein Eng. 12(10): 879-884 (1999); and Burks et al., Proc. Natl. Acad. Sci. USA 94: 412-417 (1997), which are incorporated herein by reference).
- the protein variant comprises a non-conservative substitution.
- non-conservative substitutions refers to replacement of the amino acid as present in the parent sequence by another naturally occurring amino acid, having different electrochemical and/or steric properties.
- the side chain of the substituting amino acid can be significantly larger (or smaller) than the side chain of the native amino acid being substituted and/or can have functional groups with significantly different electronic properties than the amino acid being substituted.
- non-conservative substitutions of this type include the substitution of phenylalanine for alanine, isoleucine for glycine
- substitution mutations which are present in the variant protein of the pathogen may be carried out using methods known in the art.
- the substitution mutation may be identified on the protein level, on the RNA level and/or on the genomic level.
- Exemplary methods that can be used for detecting sequence alteration are well known in the art and include, but not limited to, DNA sequencing (e.g. whole genome sequencing), electrophoresis, an enzyme-based mismatch detection assay and a hybridization assay such as PCR, RT-PCR, RNase protection, in- situ hybridization, primer extension, Southern blot, Northern Blot and dot blot analysis.
- Sequence alterations in a specific gene can also be determined at the protein level using e.g. chromatography, electrophoretic methods, immunodetection assays such as ELISA and Western blot analysis and immunohistochemistry.
- the method of this aspect of the present invention may also be carried out on sites of predicted mutation.
- Methods of predicting sites of potential mutation are known in the art - see for example Starr, Tyler N., Allison J. Greaney, Amin Addetia, William W. Hannon, Manish C. Choudhary, Adam S. Dingens, Jonathan Z. Li, and Jesse D. Bloom. 2021. “Prospective Mapping of Viral Mutations That Escape Antibodies Used to Treat COVID-19 ” Science 371 (6531): 850-54; Starr, Tyler N., Allison J. Greaney, Sarah K. Hilton, Daniel Ellis, Katharine H. D. Crawford, Adam S. 1973ns, and Mary Jane Navarro al. 2020.
- SARS-CoV-2 RBD in Vitro Evolution followss Contagious Mutation Spread, yet Generates an Able Infection Inhibitor.” /?/o//. ’ .www(dot)doi(dot)org/l 0(dot) 1 101/2021 (dot)O l (dot)06(dot)425392, the contents of each are incorporated herein by reference.
- Exemplary substitution positions on the spike protein of SARS-CoV-2 include, but are not limited position 18, 111, 222, 239, 314, 446, 477, 483, 484, 614, 982, 1202 and 1223, wherein the numbering of said position is according to the spike protein as set forth in SEQ ID NO: 1.
- the present invention contemplates selecting a synonymous codon for the mutated amino acid wherein the synonymous codon has a likelihood above a predetermined level to mis-incorporate the mutated amino acid at the substitution site.
- the mis-incorporated amino acid is the amino acid which is present at the substitution site in the variant protein. In this way, the probability of both the wild-type protein and the variant protein being expressed is increased.
- the mis- incorporated amino acid is the amino acid which has the highest likelihood of encoding the amino acid which is present at the substitution site in the variant protein.
- the selection of the mis- incorporated amino acid is based on yeast data. In one embodiment, the selection of the mis- incorporated amino acid is based on E. coli data. In one embodiment, the selection of the mis- incorporated amino acid is based on human data. In one embodiment, the selection of the mis- incorporated amino acid is based on yeast, E. coli and human data.
- sequence of the wild-type protein refers to the original sequence when first identified. In other cases, the sequence of the wild-type protein refers to the most prevalent sequence of the protein at the time of designing the vaccine.
- the sequence of the wild-type protein refers to the most prevalent sequence of the protein at the time of designing the vaccine.
- a codon may be selected which encodes E. The codon could then be optimized such that a codon that encodes E, but mistakenly is translated to Q is selected.
- Table 1 herein below provides a summary of exemplary synonymous codons that can be used to increase the likelihood of expressing the variant amino acid instead of the wild-type amino acid upon immunization of the vaccine.
- the codons in Table 1 are represented by RNA codons, the present invention also contemplates the corresponding DNA codon, wherein the U is replaced by T.
- UGG may also be TGG which is the DNA codon which encodes W (and also misincorporates D) etc.
- the bases (ribonucleotides) described in Table 1 may refer to a modified base.
- Table 1 refers to the base U (uridine) which incorporates all modifications of uridine such as pseudouridine.
- Pseudouridine is an isomer of the nucleoside uridine in which the uracil is attached via a carbon-carbon instead of a nitrogen-carbon glycosidic bond. (In this configuration, uracil is sometimes referred to as “pseudouracil”.
- Table 1 can be expanded by adding additional synonymous codons as they are discovered in different organisms or by studying additional expression data in mammals (such as humans, cows, pigs, horses, cats, dogs), yeast, and/or E. coli. These may be uncovered by mapping additional translation errors made by ribosomes and other translation factors within cells. Care should be taken that the selected codon does not introduce unwanted secondary sequence functions that impede expression of the resulting open reading frames.
- codons can be selected for generating vaccines to cover particular variants.
- a COVID vaccine which encodes for the SARS-CoV-2 spike protein (having the amino acid sequence as set forth in SEQ ID NO: 1)
- at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten of the following codons are suggested.
- the codon which is selected can be translated, due to errors (i.e. mistakenly translated) into more than one variant protein.
- the codon which is selected may cover two variant proteins.
- An example for that may arise at position 484 of the spike protein of SARS-CoV-2 (SEQ ID NO: 1). This position has an original glutamic acid (E) - see SEQ ID NO: 1. That may be erroneously translated to glutamine (Q) and lysine (K), both of which are mutations of interest, appearing in the Beta and Delta strains, respectively of SARS-CO-V2.
- one codon is translated into three different amino-acids: the original one, and two destinations (via translation errors).
- selection of the codon may also take into account other parameters such as matching codon frequencies in target and host organisms to ensure proper folding; bias GC content to increase mRNA stability or reduce secondary structures; minimize tandem repeat codons or base runs that may impair gene construction or expression; customize transcriptional and translational control regions; insert or remove protein trafficking sequences; remove/add post translation modification sites in encoded protein (e.g. glycosylation sites); add, remove or shuffle protein domains; insert or delete restriction sites; modify ribosome binding sites and mRNA degradation sites; adjust translational rates to allow the various domains of the protein to fold properly; or to reduce or eliminate problem secondary structures within the polynucleotide.
- Traditional codon optimization tools, algorithms and services are known in the art. Non-limiting examples include services from GeneArt (Life Technologies), DNA2.0 (Menlo Park Calif.) and/or proprietary methods.
- the nucleic acid sequence may then be synthesized (in order to prepare the vaccine).
- a method of generating a nucleic acid based vaccine for the treatment or prevention of a disease comprising:
- the codon optimized nucleic acid sequence obtained by the method described herein above may then be used as a template for e.g. chemical RNA synthesis or in vitro transcription to generate an RNA based vaccine.
- a codon optimized mRNA as described herein in the 3 '->5' direction is well established in prior art.
- the technology utilizes a ribonucleoside with suitable N- protecting group: generally 5T-Protecting group, the most popular being dimethoxytriphenyl, i.e. the DMT group; T-protecting group, out of which most popular is t-Butyldimethylsilyl ether; and, a 3'-phosphoramidite, the most popular of which is cyanoethyl diisopropyl (component 1).
- N- protecting group generally 5T-Protecting group, the most popular being dimethoxytriphenyl, i.e. the DMT group
- T-protecting group out of which most popular is t-Butyldimethylsilyl ether
- a 3'-phosphoramidite the most popular of which is cyanoethyl diisopropyl (component 1).
- This component is then coupled with a nucleoside with a suitable N-protecting group, 2' or 3' succinate of a ribonucleoside attached to a solid support (component 2).
- component 1 and 5'-OH-n-protected -2',3'-protected-nucleoside (component 3) are also achieved in solution phase in presence of an activator leading to dimers and oligoribonucleotides, followed by oxidation (3'- >5' direction synthesis), also leads to a protected dinucleotide having a 3'-5'-intemucleotide linkage (Ogilvie, K. K., Can. J. Chem., 58, 2686, 1980).
- Other technologies for chemical RNA synthesis i.e. for the synthesis of the modified RNA according to the invention are known in prior art, such as, e.g. the method disclosed in US 20110275793 Al.
- the codon-optimized mRNA of the present invention may be obtained by in vitro transcription, preferably by bacteriophage-mediated in vitro transcription, preferably by Sp6 polymerase in vitro transcription and/or T3 polymerase-mediated in vitro transcription, more preferably by T7 polymerase-mediated in vitro transcription.
- RNA-dependent phage T7, T3, and SP6 RNA polymerases are widely used to synthesize a large quantity of RNAs. These enzymes are highly processive and are thus capable of generating long RNA molecules of up to thousands of nucleotides in length with low probability of falling off DNA templates during transcription and may thus be used for in vitro transcription in the present invention.
- Phage RNA polymerases specifically recognize their 18-bp promoter sequences (T7, 5'-TAATACGACTCACTATAG (SEQ ID NO: 2); T3, 5'-AATTAACCCTCACTAAAG (SEQ ID NO: 3); and SP6, 5'- ATTTAGGTGACACTATAG (SEQ ID NO: 4)) and initiate transcription precisely at the 18th nucleotide guanosine.
- T7, T3, or SP6 promoter fused to the 5' end of a DNA template, the transcription reaction is expected to generate an RNA molecule with the predicted sequence.
- a DNA molecule corresponding to the codon-modified mRNA of the present invention is transcribed in vitro for the production of the mRNA.
- This DNA matrix has a suitable promoter, for example a T7 and/or SP6 and/or T3 promoter, for the in vitro transcription, followed by the desired nucleotide sequence for the mRNA to be produced and a termination signal for the in vitro transcription.
- the DNA molecule that forms the matrix of the RNA construct to be produced such as e.g. the codon optimized mRNA according to the present invention is prepared by fermentative replication and subsequent isolation as part of a plasmid replicable in bacteria.
- Suitable plasmids for in vitro transcription of the modified mRNA according to the present invention are known in the art and are commercially available.
- the following plasmids may be mentioned as examples pT7Ts (GeneBank Accession No. U26404), the pGEM® series, for example pGEM®-l (GeneBank Accession No. X65300) and pSP64 (GeneBank-Accession No. X65327); see also Mezei and Storts, Purification of PCR Products, in: Griffin and Griffin (Eds.), PCR Technology: Current Innovation, CRC Press, Boca Raton, Fla., 2001.
- the in vitro transcription of the modified mRNA according to the present invention may also include ribonucleoside triphosphates (rNTPs) analogues, such as those, e.g. required for 5' capping of the in vitro transcribed modified mRNA according to the invention.
- rNTP analogues other than those naturally present in mRNAs, in particular mammalian mRNAs, such as e.g. human mRNAs, should not be used for in vitro transcription, since the mRNA of the inventive mRNA may be disadvantageously affected and, more importantly, if the in vitro transcribed inventive mRNA is to be used in protein replacement therapy, this may not be in accordance with national regulatory affairs.
- the codon-optimized mRNA that is obtainable by the method according to the present invention may be synthesized by in vitro transcription including naturally occurring rNTP analogues, for example 5-methyl-cytidine triphosphate and/or pseudouridine triphosphate.
- the codon-optimized mRNA obtainable by the inventive method may be synthesized by in vitro transcription, including other than naturally occurring rNTP analogues.
- ribonucleoside triphosphate analogues refers to ribonucleoside triphosphate compounds comprising a chemical modification, wherein the chemical modification may comprise a backbone modification, a sugar modification, or a base modification. These ribonucleoside triphosphate analogues are also termed herein as modified nucleoside triphosphates, modified ribonucleosides or modified nucleosides.
- the modified nucleoside triphosphates as defined herein are nucleotide analogs/modifications, e.g. backbone modifications, sugar modifications or base modifications.
- a backbone modification in the context of the present invention is a modification, in which phosphates of the backbone of the nucleotides are chemically modified.
- a sugar modification in the context of the present invention is a chemical modification of the sugar of the nucleotides.
- a base modification in in the context of the present invention is a chemical modification of the base moiety of the nucleotides.
- nucleotide analogs or modifications are preferably selected from nucleotide analogs, which are applicable for transcription and/or translation. 5' Capping
- the 5' cap structure of an mRNA is involved in nuclear export, increasing mRNA stability and binds the mRNA Cap Binding Protein (CBP), which is responsible for mRNA stability in the cell and translation competency through the association of CBP with poly(A) binding protein to form the mature cyclic mRNA species.
- CBP mRNA Cap Binding Protein
- the cap further assists the removal of 5' proximal introns removal during mRNA splicing.
- mRNA molecules which have been codon-optimized according to embodiments described herein may be 5 '-end capped generating a 5 '-ppp-5 '-triphosphate linkage between a terminal guanosine cap residue and the 5 '-terminal transcribed sense nucleotide of the mRNA molecule.
- This 5'-guanylate cap may then be methylated to generate an N7-methyl-guanylate residue.
- the ribose sugars of the terminal and/or anteterminal transcribed nucleotides of the 5' end of the mRNA may optionally also be 2'-0-methylated.
- 5 '-decapping through hydrolysis and cleavage of the guanylate cap structure may target a nucleic acid molecule, such as an mRNA molecule, for degradation.
- Modifications to mRNAs of the present invention may generate a non-hydrolyzable cap structure preventing decapping and thus increasing mRNA half-life. Because cap structure hydrolysis requires cleavage of 5 '-ppp-5' phosphorodiester linkages, modified nucleotides may be used during the capping reaction. For example, a Vaccinia Capping Enzyme from New England Biolabs (Ipswich, Mass.) may be used with a-thio-guanosine nucleotides according to the manufacturer's instructions to create a phosphorothioate linkage in the 5 '-ppp-5' cap. Additional modified guanosine nucleotides may be used such as a-methyl-phosphonate and seleno-phosphate nucleotides.
- Additional modifications include, but are not limited to, 2'-0-methylation of the ribose sugars of 5 '-terminal and/or 5 '-anteterminal nucleotides of the mRNA (as mentioned above) on the 2'-hydroxyl group of the sugar ring.
- Multiple distinct 5 '-cap structures can be used to generate the 5 '-cap of a nucleic acid molecule, such as an mRNA molecule.
- Cap analogs which herein are also referred to as synthetic cap analogs, chemical caps, chemical cap analogs, or structural or functional cap analogs, differ from natural (i.e. endogenous, wild-type or physiological) 5 '-caps in their chemical structure, while retaining cap function. Cap analogs may be chemically (i.e. non-enzymatically) or enzymatically synthesized and/or linked to a nucleic acid molecule.
- 5' terminal caps may include endogenous caps or cap analogs.
- a 5' terminal cap may comprise a guanine analog.
- Useful guanine analogs include, but are not limited to, inosine, Nl-methyl-guanosine, 2'fluoro- guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2- azido-guanosine.
- the mRNA which has been codon optimized according to embodiments of the present invention may also undergo capping and/or tailing reactions.
- a capping reaction may be performed by methods known in the art to add a 5' cap to the 5' end of the primary construct. Methods for capping include, but are not limited to, using a Vaccinia Capping enzyme (New England Biolabs, Ipswich, Mass.).
- RNA nucleic acid molecules Additional examples of ribonucleoside triphosphate analogues and other modifications that can be made to the RNA nucleic acid molecules are disclosed in 11,034,729, 10,064,959, 9868692, 10,577,403 and 10,703,789, the contents of which are incorporated herein by reference.
- the mRNA molecules may also be synthesized such that they contain an internal ribosome entry site (IRES).
- IRES internal ribosome entry site
- An IRES plays an important role in initiating protein synthesis in absence of the 5' cap structure.
- An IRES may act as the sole ribosome binding site, or may serve as one of multiple ribosome binding sites of an mRNA.
- Polynucleotides, primary constructs or mmRNA containing more than one functional ribosome binding site may encode several peptides or polypeptides that are translated independently by the ribosomes (“ multi cistronic nucleic acid molecules”). Examples of IRES sequences that can be used according to the invention include without limitation, those from picornaviruses (e.g.
- FMDV pest viruses
- CFFV pest viruses
- PV polio viruses
- ECMV encephalomyocarditis viruses
- FMDV foot-and-mouth disease viruses
- HCV hepatitis C viruses
- CSFV classical swine fever viruses
- MLV murine leukemia virus
- SIV simian immune deficiency viruses
- CrPV cricket paralysis viruses
- a long chain of adenine nucleotides may be added to a polynucleotide such as an mRNA molecules in order to increase stability.
- a polynucleotide such as an mRNA molecules
- the 3' end of the transcript may be cleaved to free a 3' hydroxyl.
- poly-A polymerase adds a chain of adenine nucleotides to the RNA.
- the process called polyadenylation, adds a poly-A tail that can be between, for example, approximately 100 and 250 residues long.
- the length of a poly-A tail of mRNAs which have been codon optimized according to embodiments described herein is greater than 30 nucleotides in length.
- the poly-A tail is greater than 35 nucleotides in length (e.g., at least or greater than about 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000,
- the nucleic acid molecules include from about 30 to about 3,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 750, from 30 to 1,000, from 30 to 1,500, from 30 to 2,000, from 30 to 2,500, from 50 to 100, from 50 to 250, from 50 to 500, from 50 to 750, from 50 to 1,000, from 50 to 1,500, from 50 to 2,000, from 50 to 2,500, from 50 to 3,000, from 100 to 500, from 100 to 750, from 100 to 1,000, from 100 to 1,500, from 100 to 2,000, from 100 to 2,500, from 100 to 3,000, from 500 to 750, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 2,500, from 500 to 3,000, from 1,000 to 1,500, from 1,000 to 2,000, from 1,000 to 2,500, from 1,000 to 3,000, from 1,500 to 2,000, from 1,500 to 2,500, from 1,500 to 2,500, from from
- the poly-A tail is designed relative to the length of the overall mRNA. This design may be based on the length of the coding region, the length of a particular feature or region (such as the first or flanking regions), or based on the length of the ultimate product expressed from the mRNA.
- a poly-A tailing reaction may be performed by methods known in the art, such as, but not limited to, 2' O-methyltransferase and by methods as described herein. If the primary construct generated from cDNA does not include a poly-T, it may be beneficial to perform the poly-A-tailing reaction before the primary construct is cleaned.
- the nucleic acid may be purified.
- mRNA purification may include, but is not limited to, mRNA clean-up, quality assurance and quality control.
- mRNA clean-up may be performed by methods known in the arts such as, but not limited to, AGENCOURT® beads (Beckman Coulter Genomics, Danvers, Mass.), poly-T beads, LNATM oligo-T capture probes (EXIQON® Inc, Vedbaek, Denmark) or HPLC based purification methods such as, but not limited to, strong anion exchange HPLC, weak anion exchange HPLC, reverse phase HPLC (RP-HPLC), and hydrophobic interaction HPLC (HIC- HPLC).
- purified when used in relation to a nucleic acid such as a “purified mRNA” refers to one that is separated from at least one contaminant.
- a “contaminant” is any substance which makes another unfit, impure or inferior.
- a purified polynucleotide e.g., DNA and RNA
- a quality assurance and/or quality control check may be conducted using methods such as, but not limited to, gel electrophoresis, UV absorbance, or analytical HPLC.
- the mRNA may be sequenced by methods including, but not limited to reverse-transcriptase-PCR.
- the mRNA may be quantified using methods such as, but not limited to, ultraviolet visible spectroscopy (UV/Vis).
- UV/Vis ultraviolet visible spectroscopy
- a non-limiting example of a UV/Vis spectrometer is a NANODROP® spectrometer (ThermoFisher, Waltham, Mass.).
- the quantified mRNA may be analyzed in order to determine if the mRNA may be of proper size, check that no degradation of the mRNA has occurred.
- Degradation of the mRNA may be checked by methods such as, but not limited to, agarose gel electrophoresis, HPLC based purification methods such as, but not limited to, strong anion exchange HPLC, weak anion exchange HPLC, reverse phase HPLC (RP-HPLC), and hydrophobic interaction HPLC (HIC-HPLC), liquid chromatography-mass spectrometry (LCMS), capillary electrophoresis (CE) and capillary gel electrophoresis (CGE).
- HPLC based purification methods such as, but not limited to, strong anion exchange HPLC, weak anion exchange HPLC, reverse phase HPLC (RP-HPLC), and hydrophobic interaction HPLC (HIC-HPLC), liquid chromatography-mass spectrometry (LCMS), capillary electrophoresis (CE) and capillary gel electrophoresis (CGE).
- the codon optimized nucleic acid sequence obtained by the method described herein above may then be used as a DNA based vaccine.
- the DNA encoding the antigenic protein is comprised in an expression vector together with suitable regulatory sequences (such as a promoter) to allow for expression of the antigenic protein in vivo.
- promoter refers to a DNA sequence capable of controlling the expression of a coding sequence or functional RNA.
- a coding sequence is located 3' to a promoter sequence. Promoters may be derived in their entirety from a native gene, or be composed of different elements derived from different promoters found in nature, or even comprise synthetic DNA segments. A promoter may be selected to promote expression of a coding sequence in a particular cell type or at different stages of development, or in response to different environmental conditions.
- promoter sequences are known in the art and selection of an appropriate promoter sequence for a specific context is within the ability of those of skill in the art.
- operably linked refers to the association of nucleic acid sequences on a single nucleic acid fragment so that the function of one is affected by the other.
- a promoter is operably linked with a coding sequence when it is capable of affecting the expression of that coding sequence (i.e., the coding sequence is under the transcriptional control of the promoter).
- Expression vector refers to a nucleic acid in which a coding sequence is operably linked to a promoter sequence to permit expression of the coding sequence under the control of the promoter.
- Expression vectors include, but are not limited to, viral vectors or plasmid vectors. Methods for delivery of expression vectors into cells are known in the art.
- Expression can be transient (on the order of days to weeks) or sustained (weeks to months, or longer), depending upon the specific construct used and the target tissue or cell type.
- transgenes can be introduced as a linear construct, a circular plasmid, or a viral vector, which can be an integrating or non-integrating vector. In one embodiment, a non-integrating vector is used.
- the protein or the vaccine (or peptide fragment) can be transcribed from a promoter on an expression vector.
- the expression vectors are generally DNA plasmids or viral vectors. Eukaryotic cell expression vectors are well known in the art and are available from a number of commercial sources. Typically, such vectors are provided containing convenient restriction sites for insertion of the desired nucleic acid segment. Delivery of protein expressing vectors can be systemic, such as by subcutaneous, intravenous, or intramuscular administration.
- Viral vector systems which can be utilized with the methods and compositions described herein include, but are not limited to, (a) adenovirus vectors; (b) retrovirus vectors, including but not limited to lentiviral vectors, moloney murine leukemia virus, etc.; (c) adeno-associated virus vectors; (d) herpes simplex virus vectors; (e) SV 40 vectors; (f) polyoma virus vectors; (g) papilloma virus vectors; (h) picomavirus vectors; (i) pox virus vectors such as an orthopox, e.g., vaccinia virus vectors including modified vaccinia virus Ankara vector or avipox, e.g.
- the constructs can include viral sequences for transfection, if desired.
- the construct can be incorporated into vectors capable of episomal replication, e.g. EPV and EBV vectors.
- a vaccine comprising a nucleic acid (RNA or DNA) encoding an antigenic protein or peptide of a pathogen, wherein the nucleic acid is codon optimized at at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20 mutation site (or potential mutation site) of a variant of said antigenic protein, wherein the codon optimization increases the likelihood of mis-incorporating the mutated amino acid at said predetermined position.
- RNA or DNA nucleic acid
- At least 1 %, 2 %, 3 %, 4 %, 5 %, 6 %, 7%, 8 %, 9 %, 10 %, 11 %, 12 %, 13 %, 14 %, 15 %, 16 %, 17 %, 18 %, 19 %, 20 %, 21 %, 22 %, 23 %, 24 %, 25 %, 26 %, 27 %, 28 %, 29 %, 30 %, 31 %, 32 %, 33 %, 34%, 35%, 36 %, 37 %, 38 %, 39 %, 40 %, 41 %, 42 %, 43 %, 44 %, 45 %, 46 %, 47%, 48 %, 49 %, 50 %, of the codons of the nucleic acid of the vaccine have been selected so as to increase the probability of expression of a variant as compared to its commercially available counterpart.
- the nucleic acid of the vaccine comprises codons that cover (i.e. increase the probability to express) at least 2, 3, 4, 5, 6, 7, 8, 9, 10 or more known substitutions in known variants of concern.
- a vaccine for treating COVID10 which comprises a nucleic acid sequence encoding a protein as set forth in SEQ ID NO: 1
- at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19 20 or more codons are substituted relative to the codons selected by Moderna or Pfizer (as set forth in Tables 2 or 3) according to the methods of the present invention.
- the selected codon suggestion for one commercially available vaccine e.g. Pfizer
- the selected codon suggestion for one commercially available vaccine is one which is already in use in a different commercially available vaccine (e.g. Moderna).
- the nucleic acid in the vaccine can be formulated using one or more excipients to: (1) increase stability; (2) increase cell transfection; (3) permit the sustained or delayed release (e.g., from a depot formulation of the nucleic acid; (4) alter the biodistribution to specific tissues or cell types); (5) increase the translation of encoded protein in vivo; and/or (6) alter the release profile of encoded protein in vivo.
- excipients of the present invention can include, without limitation, lipidoids, liposomes, lipid nanoparticles, polymers, lipoplexes, core-shell nanoparticles, peptides, proteins, cells transfected with the nucleic acid, hyaluronidase, nanoparticle mimics and combinations thereof.
- the formulations of the invention can include one or more excipients, each in an amount that together increases the stability of the nucleic acid, increases cell transfection by the polynucleotide, increases the expression of polynucleotide, or mRNA encoded protein, and/or alters the release profile of polynucleotide, mRNA encoded proteins.
- Formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of associating the active ingredient with an excipient and/or one or more other accessory ingredients.
- a pharmaceutical composition in accordance with the present disclosure may be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
- a “unit dose” refers to a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
- the amount of the active ingredient may generally be equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage including, but not limited to, one-half or one-third of such a dosage.
- Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition in accordance with the present disclosure may vary, depending upon the identity, size, and/or condition of the subject being treated and further depending upon the route by which the composition is to be administered.
- the composition may comprise between 0.1% and 99% (w/w) of the active ingredient.
- the formulations described herein may contain at least one mRNA.
- the formulations may contain 1, 2, 3, 4 or 5 mRNA.
- the formulation may contain modified mRNA encoding proteins selected from categories such as, but not limited to, human proteins, veterinary proteins, bacterial proteins, biological proteins, antibodies, immunogenic proteins, therapeutic peptides and proteins, secreted proteins, plasma membrane proteins, cytoplasmic and cytoskeletal proteins, intracellular membrane bound proteins, nuclear proteins, proteins associated with human disease and/or proteins associated with non human diseases.
- the formulation contains at least three modified mRNA encoding proteins.
- the formulation contains at least five modified mRNA encoding proteins.
- compositions may additionally comprise a pharmaceutically acceptable excipient, which, as used herein, includes, but is not limited to, any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, and the like, as suited to the particular dosage form desired.
- a pharmaceutically acceptable excipient includes, but is not limited to, any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, and the like, as suited to the particular dosage form desired.
- excipients for formulating pharmaceutical compositions and techniques for preparing the composition are known in the art (see Remington: The Science and Practice of Pharmacy, 21 st Edition, A. R. Gennaro, Lippincott, Williams & Wilkins, Baltimore, Md
- any conventional excipient medium may be contemplated within the scope of the present disclosure, except insofar as any conventional excipient medium may be incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition.
- the particle size of the lipid nanoparticle may be increased and/or decreased.
- the change in particle size may be able to help counter biological reaction such as, but not limited to, inflammation or may increase the biological effect of the modified mRNA delivered to mammals.
- compositions include, but are not limited to, inert diluents, surface active agents and/or emulsifiers, preservatives, buffering agents, lubricating agents, and/or oils. Such excipients may optionally be included in the pharmaceutical formulations of the invention.
- the codon-optimized nucleic acids of the invention can be formulated using one or more lipidoids, liposomes, lipoplexes, or lipid nanoparticles. Further details on these formulations are provided in 11,034,729, 10,064,959, 9868692, 10,577,403 and 10,703,789, the contents of which are incorporated herein by reference.
- the vaccine comprises an excipient, which, as used herein, includes any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
- Remington's The Science and Practice of Pharmacy, 21 st Edition, A. R. Gennaro discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof.
- a pharmaceutically acceptable excipient is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% pure.
- an excipient is approved for use in humans and for veterinary use.
- an excipient is approved by United States Food and Drug Administration.
- an excipient is pharmaceutical grade.
- an excipient meets the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and/or the International Pharmacopoeia.
- compositions include, but are not limited to, inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Such excipients may optionally be included in pharmaceutical compositions.
- Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and/or combinations thereof.
- Exemplary granulating and/or dispersing agents include, but are not limited to, potato starch, com starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (VEEGEIM®), sodium lauryl sulfate, quaternary ammonium compounds, etc., and/or combinations thereof.
- VEEGEIM® magnesium aluminum silicate
- Exemplary surface active agents and/or emulsifiers include, but are not limited to, natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and VEEGEIM® [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g.
- natural emulsifiers e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin
- colloidal clays e.g. bentonite [aluminum silicate
- stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
- polyoxyethylene monostearate [MYRJ®45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and SOLUTOL®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. CREMOPHOR®), polyoxyethylene ethers, (e.g.
- polyoxyethylene lauryl ether [BRIJ®30]), poly(vinyl-pyrrolidone), di ethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, PLUORINC® F 68, POLOXAMER®188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
- Exemplary binding agents include, but are not limited to, starch (e.g. cornstarch and starch paste); gelatin; sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol); natural and synthetic gums (e.g.
- acacia sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan); alginates; polyethylene oxide; polyethylene glycol; inorganic calcium salts; silicic acid; polymethacrylates; waxes; water; alcohol; etc.; and combinations thereof.
- Exemplary preservatives may include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and/or other preservatives.
- Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabi sulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabi sulfite, and/or sodium sulfite.
- Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and/or trisodium edetate.
- EDTA ethylenediaminetetraacetic acid
- citric acid monohydrate disodium edetate
- dipotassium edetate dipotassium edetate
- edetic acid fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and/or trisodium edetate.
- antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chi oroxy lend, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and/or thimerosal.
- Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and/or sorbic acid.
- Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and/or phenylethyl alcohol.
- Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and/or phytic acid.
- preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabi sulfite, potassium sulfite, potassium metabi sulfite, GLYDANT PLUS®, PHENONIP®, methylparaben, GERM ALL® 115, GERMABEN® II, NEOLONETM, KATHONTM, and/or EUXYL®.
- Exemplary buffering agents include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic
- Exemplary lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.
- oils include, but are not limited to, almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury
- oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and/or combinations thereof.
- Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and/or perfuming agents can be present in the composition, according to the judgment of the formulator.
- the vaccine of the present invention may be administered by any route which results in a therapeutically effective outcome.
- routes include, but are not limited to enteral, gastroenterol, epidural, oral, transdermal, epidural (peridural), intracerebral (into the cerebrum), intracerebroventricular (into the cerebral ventricles), epicutaneous (application onto the skin), intradermal, (into the skin itself), subcutaneous (under the skin), nasal administration (through the nose), intravenous (into a vein), intraarterial (into an artery), intramuscular (into a muscle), intracardiac (into the heart), intraosseous infusion (into the bone marrow), intrathecal (into the spinal canal), intraperitoneal, (infusion or injection into the peritoneum), intravesical infusion, intravitreal, (through the eye), intracavernous injection, (into the base of the penis), intravaginal administration, intrauterine, extra-amniotic administration, transdermal (d
- compositions, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
- a compound or “at least one compound” may include a plurality of compounds, including mixtures thereof.
- various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range.
- a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range.
- the phrases “ranging/ranges between” a first indicate number and a second indicate number and “ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.
- method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
- treating includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.
- sequences that substantially correspond to its complementary sequence as including minor sequence variations, resulting from, e.g., sequencing errors, cloning errors, or other alterations resulting in base substitution, base deletion or base addition, provided that the frequency of such variations is less than 1 in 50 nucleotides, alternatively, less than 1 in 100 nucleotides, alternatively, less than 1 in 200 nucleotides, alternatively, less than 1 in 500 nucleotides, alternatively, less than 1 in 1000 nucleotides, alternatively, less than 1 in 5,000 nucleotides, alternatively, less than 1 in 10,000 nucleotides.
- Translation error matrices in the form of 64 codons by 19 amino acids were obtained for E. Coli and S. Cerevisiae from previously published data (Mordret et al. 2019). Matching proteomic data for H. Sapiens was collected using the protocol described by (Mordret et al. 2019), from A375 and SKMEL30 cell lines. Data collected from untreated SKMEL30 was summed with both untreated and PUNCH-P treated A375 cells to create a single, joined table for H. Sapiens. All tables were normalized by the sum of the table (all error types detected) to obtain the codon to amino acid replacement fraction.
- SARS-CoV-2 genomic sequencing data was downloaded in fasta file format from GISAID (www(dot)(dot)gisaid(dot)org/) via the website’s ‘Downloads’ tab, selecting the ‘unmasked MSA’ option. This data included all the sequences available at the time of downloading (2021-02-07).
- VoCs potential variants of concern
- SARS-Cov2 Spike protein of SARS-Cov2
- the “retrospective” set consisted of variants of the virus that already appeared in the human population
- the “prospective” sub-set consists of variants that were found by in-vitro molecular screens and due to their properties that are predicted to have a potential to invade the population and/or evade immunity.
- the Spike protein nucleic acid sequence from -366,000 infected human individuals from GISAID (Elbe and Buckland-Merrett 2017) was downloaded and aligned. In each sequence position along the Spike gene, the most frequent amino acid substitutions were identified relative to the consensus amino acid at that position.
- the prospective sub-set of VoCs was constructed from experimental molecular screens of mutated versions of the Spike protein. In particular the selected mutations were those that were either found (i) when yeast cells expressing Spike were evolved to increase affinity to the ACE2 receptor (Zahradnik et al. 2021); (ii) when a library of Spike mutations derived from deep mutagenesis scan (Starr et al.
- the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) nucleotide sequence of Spike vaccine sequence (NAalytics n.d.)
- the computational screen consists of three components. The first is the data translation error propensities of codons in the genetic table, the second is and the above lists of SARS-Cov2 VoCs, and the third are the nucleotide sequences of the two current SARS-Cov2 mRNA vaccines.
- the present inventors computed the “mis-incorporation fraction” of each of the synonymous codons of the original amino acid at a position.
- the mis-incorporation fraction is the normalized number of translation error events from a particular codon to a desired amino acid destination that can replace the original one by a translation error event.
- the present inventors propose to use the synonymous codon with a maximal mis-incorporation fraction as it might maximize the tendency to mis-incorporate the original amino acid by that of the VoC at the position.
- Figures 3 A-F shows a summary statistics of the number of amino acid positions along the vaccine in which it is possible to suggest a potentially useful synonymous codon replacement.
- the minimal cut-off score of the mis-incorporation fraction is gradually increased along the x-axis, using data derived from each of the three species ( Figures 1 A-C), on each of the two vaccines, done each, on the retrospective and prospective data ( Figure 3A-D).
- the data shows that it is possible to propose 52 and 54 codon substitutions for the Pfizer and Modema vaccines respectively that will allow improved collateral targeting of VoCs.
- Table 4 provides a summary of suggested codons which can be used in the Pfizer/Moderna vaccine for treating COVID, based on human data.
- Table 5 provides a summary of suggested codons which can be used in the Pfizer/Moderna vaccine for treating COVID, based on yeast data.
- Tables 4 and 5 show a summary of highlighted proposed codon swaps. Each line is a proposed re-design of one vaccine mRNA position. It shows our proposed selected codon among the synonymous codons of the amino acid, i.e, the codon that upon predicted translation errors will, at the maximal probability, be translated within cells into an amino acid not specified by the vaccine nucleotide sequence.
- the two parts of the Table refer to the retrospective (upper) and prospective compilations.
- the first row in the upper table report that on position 222 of the Spike, the original amino acid is Ala, while a desired destination is a mutant that has Val at that position. This mutant currently segregates at 22.5% of the human population.
- the Pfizer codon for the original Ala is GCT
- Moderna’s is GCC
- our proposed codon (based on the human data of translation error propensities in Figures 1 A-C) is GCC - like the Moderna, not the Pfizer version.
- the error propensity of the suggested codon is 0.0212.
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Abstract
L'invention concerne un procédé d'optimisation de codon de la séquence d'un acide nucléique codant pour une protéine d'un vaccin, comprenant : (a) l'identification de codons synonymes pour un acide aminé à une position prédéterminée de la protéine, ladite position prédéterminée étant un site de mutation d'un variant de la protéine ; et (b) la sélection du codon synonyme qui a une probabilité au-dessus d'un niveau prédéterminé pour mal incorporer l'acide aminé muté à la position prédéterminée.
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