WO2022055375A1 - Vaccin vivant recombinant pour le sars-cov-2 à base de salmonella enteritidis recombinante - Google Patents

Vaccin vivant recombinant pour le sars-cov-2 à base de salmonella enteritidis recombinante Download PDF

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WO2022055375A1
WO2022055375A1 PCT/PE2021/000006 PE2021000006W WO2022055375A1 WO 2022055375 A1 WO2022055375 A1 WO 2022055375A1 PE 2021000006 W PE2021000006 W PE 2021000006W WO 2022055375 A1 WO2022055375 A1 WO 2022055375A1
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recombinant
sars
cov
vaccine
salmonella enteritidis
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Manolo Clemente FERNANDEZ DÍAZ
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Farmacológicos Veterinarios Sac
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    • 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
    • A61K39/215—Coronaviridae, e.g. avian infectious bronchitis virus
    • 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
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/74—Vectors or expression systems specially adapted for prokaryotic hosts other than E. coli, e.g. Lactobacillus, Micromonospora
    • 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
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/42—Salmonella

Definitions

  • the present invention is framed in the health sector, mainly in human health. Especially in the development of alternative live vaccines to counteract the pandemic caused by the SARS CoV-2 virus.
  • the present invention refers to a live recombinant vaccine based on a strain of SE, Salmonella enteritidis 3934 XXII XrpoS waaL (3934VacR) attenuated and rough which has been modified for the expression of a protein of the Sars-Cov-2 virus caused by the COVID-19 pandemic.
  • This strain of Salmonella enterica (3934VacR) is capable of expressing the heterologous protein xenoantigen RBD (receptor binding domain) external to protein S of the Sars-Cov-2 COV-19 virus.
  • the present invention also includes the use of this strain as a vaccine vector against the Sars-Cov-2 virus, via a process of insertion and integration of the genes that encode the RBD surface protein antigen of the Sars-Cov-2 virus.
  • Covid-19 The SE vector used has been genetically modified to function as a vehicle for the expression of the immunodominant genes of the RBD protein antigen of the Sars-Cov-2 virus, with the ultimate goal of stimulating an effective and lasting immune response against the virus.
  • Sars-Cov-2 virus The generated strain is totally safe because it is free of the twelve genes that encode the proteins of the GMP-di-cyclic secondary messenger signaling pathway, the RpoS sigma factor and the WaaL protein.
  • this strain is proposed as a new effective and safe recombinant live vaccine against the SArs-Cov-2 virus, suitable for vaccinating populations of mammals, especially humans, where all the components of this vaccine have been specifically designed. and developed with the three successive priority factors: efficacy, safety and cost.
  • Coronaviruses are enveloped RNA viruses distributed widely in humans, some mammals and birds causing respiratory, enteric, hepatic and neurological diseases (Weiss SR, Leibowitz JL.) (Masters PS, Perlman S.).
  • Weiss SR Leibowitz JL.
  • Six species of coronavirus are now known to cause human illness, and four of them — 229E, OC43, NL63 and HKU1 — are the most prevalent and typical cause of these viral infections.
  • Sa S, Wong G, Shi W, et al. The most outstanding clinical characteristics of the patients are shown in the article entitled "Clinical Characteristics of Coronavirus Disease 2019 in China" (Guan, Wei-jie et.aL).
  • document CN101838627 refers to a recombinant structure of salmonella choleraesuis, a bivalent genetic engineering vaccine and a method of preparation and application of the recombination of salmonella choleraesuis, where the Salmonella choleraesuis recombination does not comprise a resistance marker and expresses the major Cap proteins of porcine circovirus II antigen.
  • Salmonella choleraesuis recombination conservation number C501 pYA-delta 410RF2 which does not comprise the resistance marker, expresses the major antigenic sites of porcine circovirus II and is prepared by the invention of CCTCC M209314.
  • Salmonella choleraesuis recombination deletes asd genes that are necessary for salmonella choleraesuis growth and comprises a plasmid that can express asd genes and porcine circovirus II Cap protein antigenic site genes in salmonella choleraesuis recombination .
  • patent WO205/035556 refers to systems such as recombinant plasmids, viruses and prokaryotes that express the M, E and S proteins associated with the SARS-CoV membrane in cells, such as human cells, both in in vitro and in vivo where SARS-CoV M, E and S proteins spontaneously form SARS-CoV virus-like particles (SARS-CoV-VLP).
  • SARS-CoV-VLP SARS-CoV virus-like particles
  • the intracellular expression of the SARS-CoV M, E and S proteins and their association to form virus-like particles that present the viral proteins in their "natural" context causes the induction of an immune system response.
  • It also relates to methods for eliciting an immune response in animals, such as humans and other mammals, by identifying a subject at risk of developing SARS and administering to the subject one or more genetic constructs capable of expressing SARS-CoV M, E and Polypeptides. /o S.
  • the invention teaches that live attenuated prokaryotic strains must maintain a balance between attenuation and immunogenicity and that do not cause any disease or alter the normal physiology of the host.
  • WO201 1/126976 is also known which provides a modified reovirus S1 protein comprising a first antigenic epitope of a non-reovirus antigen located in the helical region of the protein.
  • the first epitope may insert into the alpha-helical region of the protein, or may replace one or more heptad repeats in the alpha-helical region of the protein.
  • the first epitope can be a viral epitope, among which the SARS-associated coronavirus is found, and a bacterial epitope of a bacterium, among which Salmonella spp.
  • US2018/296663 teaches a combination of a first component and a second component, wherein the first component is typically an immunogenic component and wherein the second component is typically an adjuvant component, wherein the first component (immunogenic ) comprises at least one nucleic acid molecule encoding at least one antigen, or a fragment or variant thereof.
  • the second (adjuvant) component of the combination comprises at least one adjuvant compound, wherein at least one adjuvant compound is preferably an immunopotentiating compound.
  • the second component (adjuvant) of the combination comprises at least one immune-enhancing compound, and/or at least one compound of the delivery system.
  • Pathogenic antigens are peptide or protein antigens preferably derived from a pathogen associated with an infectious disease, among which the SARS coronavirus is considered.
  • RNA vaccines that are based on the knowledge that RNA (for example, messenger RNA (mRNA)) can safely direct the cellular machinery of the body to produce almost any protein of interest, from native proteins to antibodies and other entirely new proteins.
  • mRNA messenger RNA
  • the constructs may have therapeutic activity inside and outside cells.
  • RNA (eg mRNA) vaccines can be used to induce a balanced immune response against hMPV, PrV, RSV, MeV and/or BetaCoV (eg MERS-CoV, SARS-CoV, HCoV-OC43 , HCoV-229E, HCoV-NL63, HCoV-NL, HCoV-NH and/or HCoV-HKU1), or any combination of two or more of the above viruses, comprising cellular and humoral immunity, without risk of insertional mutagenesis, eg hMPV, PIV, RSV, MeV, BetaCoV (eg MERS-CoV, SARS-CoV, HCoV -OC43, HCoV-229E, HCoV-NL63, HCoV-NL, HCoV-NH and HCoV-HKUl) and combinations thereof.
  • BetaCoV eg MERS-CoV, SARS-CoV, HCoV-OC43,
  • flagellin is a monomeric protein of approximately 500 amino acids that polymerizes to form the flagella associated with bacterial movement. Flagellin is expressed by a variety of flagellated bacteria (Salmonella typhimurium for example) as well as by non-flagellated bacteria (such as Escherichia coli) for detection of flagellin by cells of the innate immune system.
  • US2016/339097 teaches the preparation and isolation of coronavirus proteins and antigens, particularly porcine coronaviruses, and further provides viral proteins and antigens obtained from coronavirus-infected cells and compositions comprising the proteins and antigens. Describes a method for preparing coronavirus proteins and/or antigens, such as PEDV or PDCoV proteins and/or antigens, from cells infected with a coronavirus, such as PEDV or PDCoV. The proteins and/or antigens are harvested at an early time point after infection when most, or all, of the viral proteins and/or antigens remain associated with the infected cells.
  • coronavirus proteins and/or antigens such as PEDV or PDCoV proteins and/or antigens
  • the vaccine composition may comprise proteins and/or antigens from at least one additional pathogen which may be any pathogen that causes disease and/or infection in a porcine subject.
  • the recombinant vector was introduced into Salmonella Typhimurium SL3261 vaccine strain, and stable soluble expression of the chimeric protein was assessed and confirmed by Western blotting with polyclonal antisera. from C. parvum.
  • the present invention provides the development of a live and recombinant vaccine against Sars-Cov-2 that has a very high probability of success based on the stability of the recombinant protein, simplicity and ease of application that is would offer national and international public health using an attenuated SE strain as a vector.
  • (3) can be administered by intradermal, oral, and intranasal inoculation routes;
  • Figure 1 illustrates SDS-PAGE electrophoresis with coomassie staining performed with anti-HIS of the total extracts obtained.
  • Figure 2 illustrates SDS-PAGE electrophoresis with coomassie staining and anti-SARS-CoV-2 immunodetection of total protein extracts (Western Blot).
  • Figure 3 shows the results of the agglutination test that detects antibodies against the particulate antigen.
  • Figure 4 shows photographs of Peth dishes with stool samples from individuals immunized with the vaccine according to the present invention.
  • Figure 5 shows the results of the response of individuals immunized with the Salmonella enteritidis antigen expressing RBD of SARs_CoV-2 (Covid-19).
  • Figure 6 shows the results of immune cells from the spleen of mice immunized with the oral vaccine, according to the present invention, where it shows a great immunological activity of T cells that produce functional cytokines such as IFN-y (interferon gamma ) among other.
  • the present invention relates to a live recombinant vaccine based on a strain of Salmonella enteritidis that expresses the S protein of the Sars-2019-Cov-2 virus where the best expression has been achieved when the insert is in the plasmid instead of the chromosome. Likewise, it refers to a vaccine that requires said strain.
  • the present invention refers to the use of a strain of Salmonella enteritidis 3934 (deposited in the Spanish Collection of Type Cultures (CECT) with the access number CECT9332) for the treatment of SARS-Cov-2 and to the method to control SARS-CoV-2 infection by administering a live recombinant vaccine to mammals
  • the present invention relates to the development of a vaccine against SARS-Cov-2-2019 causing the COVID-19 pandemic, for which the ⁇ PR-LppOmpA-RBD-6XHis-TTterminator> cassette was constructed by PCR overlapping of two fragments of 670 and 671 base pairs. A linker (GGGSGGGS) was included between the LppOmpA fragment and the RBD fragment. Finally, the 1348 bp fragment obtained was subcloned into an expression plasmid specifically designed for the insertion of sequences in the attTn7 locus, which was used to transform the rough strain of Salmonella enteritidis 3934 AXII ArpoS Awaal (3934VacR) by electroporation. Transformant colonies were selected in the presence of ampicillin.
  • an expression "cassette” has been designed and built, which is characterized in that it includes:
  • the plasmid contains, apart from the recombination framework regions, an expression cassette that is integrated into the chromosome.
  • the resulting strain to which this invention refers is a modified mutant strain of Salmonella enteritidis that carries a deletion of the waaL gene, and therefore presents a rough phenotype, and expresses a gene that encodes the RBD protein domain of the S protein of Sars-Cov-2-2019, causing the Covid-19 pandemic.
  • Salmonella enteritidis is an abbreviation for Salmonella enterica serovar Enteritidis and the strain SE3934-Cap has been deposited under the name SALVAC CIRCO in the international depositary in accordance with the guidelines of the BUDAPEST treaty. Therefore, throughout the technical document, these names may be interchangeable.
  • a live vaccine or vaccine vector must be safe and effective, with fully controlled genotype and phenotype, avoiding the risk of reversion to virulence.
  • the strain must maintain a balance between the degree of attenuation and immunogenicity, remaining in the host organism long enough to give rise to a protective immune response against homologous and/or heterologous antigens.
  • the live recombinant vaccine comprises the strain of Salmonella enteritidis 3934 generated, which has as its main characteristics a drastic attenuation of the disease, where it is a registered and accepted strain for the present invention.
  • the Salmonella enteritidis 3934 strain is unable to form biofilms and has a very low survival rate in the environment, avoiding any risk associated with the period in which mammals, such as vaccinated animals, can excrete this strain. So it is also estimated that it may have a potential use in humans.
  • its genotype and phenotype are fully controlled and it does not have antibiotic resistance genes. The safety of live and attenuated bacteria has been verified in other models such as the 9R vaccine, whose reports scientifically rule out a potential reversion to the original virulent form (Okamoto., et al 2010 Brazilian Journal of Poultry Science).
  • the present invention also involves the use of a strain of Salmonella enteritidis 3934 (deposited in the Spanish Collection of Type Cultures (CECT) with the access number CECT9332) to which, by genetic engineering techniques, The twelve genes encoding diguanylate cyclase enzymes, the rpoS gene and the waaL gene have been deleted. This last mutation was made with the aim of obtaining a vaccine strain with a rough phenotype (Salmonella enteritidis 3934vac DwaaL) that confers protection to mammalian animals, including humans.
  • CECT Collection of Type Cultures
  • another aspect of the present invention comprises a vaccine strain with a rough phenotype that carries an expression cassette for the heterologous antigen RBD of the protein S of the Sars-Cov2-2019 virus that causes the 2019 coronavirus pandemic, which it confers immunity against viral infection caused by viruses in certain animals. That is, the CECT-9932 strain has been modified to express a protein of the heterologous RBD antigen of the protein S of the SARS-Cov-2-2019 virus.
  • the methodology used to generate the rough mutants generally uses the following steps: a) Construction of the integrative vector pKO:waaL b) Integration of the suicide vector pKO:waaL (first recombination) c) Exclusion of the integrative vector pKO :waaL (second recombination) d) Verification of the mutants by PCR Transformation of the expression cassette ⁇ PR-LppOmoA-RBD-6XHis-TT> in strain 3934:
  • the immunodetection experiment showed the presence of a specific band of approximately 35-38 KDa (which corresponds to the expected protein size) both in the strains in which the expression came from the plasmid (lines 2, 3 and 4) and in those strains with the expression cassette integrated in the chromosome (lanes 5, 6, 7 and 8).
  • Protein extracts from the wild type 3934Vac strain (WT) were used as negative control, in which no expression of the antigen was detected (line 9). Extracts from a clone of E. coi! containing the expression vector (line 1). The band is recognized by both the Anti-His and the Anti-SARS-CoV-2 antibodies (Fig. 2).
  • Vaccine compositions according to the present invention may be administered by any conventional route, including injection, oral, inhalation intranasal aerosol, eg, a nasal spray or drops, or by gradual infusion over time. Administration can be, for example, oral, intravenous, intraperitoneal, intramuscular, intracavitary, subcutaneous, or transdermal. In a preferred embodiment of the invention, the live recombinant vaccine is administered orally.
  • the vaccine compositions of the present invention may be administered in effective amounts.
  • An "effective amount" is that amount of a vaccine composition which, alone or in conjunction with additional doses, produces the desired immune response.
  • the presentation of the doses and/or packaging for the recombinant live vaccine for SARS-CoV 2 based on recombinant salmonella enteritidis can be any known form, for example, that is, the primary packaging, that is, the packaging that is in direct contact with the vaccine, it can be, but is not limited to, sterile glass or plastic ampoules, shachets (envelopes), either in single-dose or multi-dose vials.
  • the vaccine may be in one vial and the adjuvant or diluent in a separate vial, wherein the volume of vaccine and diluent in each vial is determined in accordance with normal practice.
  • the manufacturer and may be in secondary packaging, that is, a box containing several primary containers of the vaccine and/or the adjuvant or diluent.
  • These packages can be at a temperature between -5°C and 10°C, preferably between 5°C and 8°C; Therefore, it is an additional advantage of the recombinant live vaccine of the present invention, since it does not require special storage and/or transport devices to maintain extreme low temperatures.
  • the vaccine compositions comprise an adjuvant and/or excipient, wherein pharmaceutically acceptable adjuvants are defined as substances that increase antigen-specific immune responses by modulating immune cell activity.
  • adjuvants that can be used in the present invention for the recombinant live vaccine include, but are not limited to saponins, agonist antibodies to co-stimulatory molecules, Freund's adjuvant, muramyl dipeptide (MPD), bacterial DNA (oligo CpG), lipo- polysaccharides (LPS), MPL (Mozilla Public license) and synthetic derivatives, ipopeptides and liposomes, among others.
  • the adjuvant is an immunomodulator.
  • other preferred adjuvants may be squalene, Quillaja saponaria, and surfactants.
  • the vaccine according to the present invention comprises a strain of Salmonella Enteritidis modified according to the present invention which expresses proteins of the RBD region of the S1 domain of SARS CoV-2, sterile water and optionally, adjuvants such as squalene, quillaja saponaria and surfactants, [040]
  • the vaccine doses or concentrations thereof according to the present invention are formulated and administered in doses between a range of 10 5 CFU and 10 15 CFU; preferably, in a range between 10 8 CFU and 10 12 CFU according to any standard procedure in the art.
  • the administration can be carried out in one, two, three or more doses in recommended periods.
  • a subject is a mammal, preferably a human, and includes primate, bovine, equine, porcine, ovine, feline, and rodent.
  • Vaccine compositions according to the present invention may also optionally contain suitable preservatives, such as: benzalkonium chloride; chlorobutanol, parabens and thiomerosal, among others; inactivating agents such as formaldehyde, glutaraldehyde, propiolactone and beta-propiolactone are used in a trace level amount.
  • suitable preservatives such as: benzalkonium chloride; chlorobutanol, parabens and thiomerosal, among others; inactivating agents such as formaldehyde, glutaraldehyde, propiolactone and beta-propiolactone are used in a trace level amount.
  • Vaccine compositions suitable for parenteral administration conveniently comprise a sterile aqueous or nonaqueous vaccine preparation, which is preferably isotonic with the blood of the recipient.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanedioL
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed as a solvent or suspending medium.
  • fatty acids such as oleic acid can be used in the preparation of injectables.
  • a suitable carrier formulation can be found for subcutaneous, intravenous, intramuscular, oral administrations.
  • sterile water, yeasts, starches, gelatin, albumin, sucrose, lactose, sodium glutamate and glycine in pharmaceutically acceptable amounts can be used as adjuvants, vehicles and/or diluents.
  • Balb/c mice were divided into 7 groups of 6 mice each. A pre-immune blood sample was collected through a cut in the tail vein. Subsequently, each group was administered orally, 60 mL of culture medium with ampicillin, medium with Salmonella "wild type", medium with Salmonella modified with the PL-1 insert, as well as a treatment with the modification of PL-1 1, PL-12, PL-13 and one additional with a combination of all inserts. All groups received a concentration of 10 8 CFU/mL. Then 2 additional reinforcements were administered every 15 days, after taking a blood sample.
  • Figure 5 shows results where the response of individuals immunized with the Salmonella enteritidis antigen expressing RBD is observed. Note that the response increases with days and the chromosome 30 antigenic sample stands out at 35 days, while the response of the chromosome 23 microorganism is lower.
  • Slide or plate agglutination is a serological test used to detect antibodies against a particulate antigen. It is a quick and simple test, where the particulate antigen is deposited on a slide, in this case the modified Salmonella enteritidis, on whose surface the recombinant viral molecule RBD is expressed. An amount of immune serum from the antigen is deposited on the antigen. antigen-stimulated individual. For 2-3 minutes, the slide is rotated and/or shaken to promote binding between the antigen and the antibody to form antigen-antibody complexes. In a positive sample, the immunoglobulin molecules bound with the bacterial particles will be visible to the naked eye as they have a clumpy appearance as shown in Figure 3(B).
  • Salmonella Cellular immune response Interferon Gamma 5 week old female mice received the oral vaccine according to the present invention at 0 and 15 days with 10 8 CFU/ml. After vaccinating them at 15 and 30 DPV with Salmonella, they were euthanized and their spleens were aseptically removed. The organs were disaggregated, the cell suspension filtered and placed in a centrifuge tube containing 2 mL of Histopaque 1077 (Sigma), obtaining mononuclear cells.
  • the present invention is not limited to the scope of the microorganisms deposited in the patent since these represent a specific illustration of an aspect of the invention. Any microorganism or plasmid that is functionally equivalent to those described in the invention are included within the invention.

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Abstract

La présente invention se rapporte à un vaccin vivant recombinant élaboré à partir d'une souche de Salmonella enteritidis qui exprime la protéine S du virus Sars-2019-Cov-2, et pour lequel la meilleure expression a été obtenue quand l'insertion se produit dans le plasmide plutôt que dans le chromosome. Ainsi, il s'agit d'un vaccin qui a besoin de cette souche. L'invention se rapporte également à l'utilisation d'une souche de Salmonella enteritidis 3934 (déposée dans la Collection espagnole de cultures types (CECT) sous le numéro d'accès CECT9332) pour le traitement du SARS-Cov-2 et à la méthode pour contrôler l'infection par le SARS-CoV-2 par l'administration à des mammifères d'un vaccin vivant recombinant.
PCT/PE2021/000006 2020-09-09 2021-04-09 Vaccin vivant recombinant pour le sars-cov-2 à base de salmonella enteritidis recombinante WO2022055375A1 (fr)

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PE2020001382A PE20201405A1 (es) 2020-09-09 2020-09-09 Vacuna viva recombinante para sars-cov-2 basada en salmonella enteritidis recombinante
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