Vaccine Preparations

Abstract

A vaccine preparation administered intramuscularly that has no or at least minimal adverse effects includes, in addition to the mRNA vaccine, at least one vasoconstrictor, such as epinephrine, levonordefrin, and norepinephrine.

Description

[Technical field]

[0001] The present invention relates to a vaccine preparation containing at least one vaccine. [Background technology]

[0002] Since the first mRNA vaccines against COVID-19 (Chaudhary, N., Weissman, D. & Whitehead, K.A. mRNA vaccines for infectious diseases: principles, delivery and clinical translation. Nat. Rev. Drug Discov. 20, 817-838 (2021)) were introduced by Pfizer-BioNTech (Benjamini, O. et al., Safety and efficacy of the BNT162b mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. Haematologica 107, 625-634 (2021)) and Moderna (Baden, L. R. et al., Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N. Engl. J. Med. 384, 403-416 (2021)), this new vaccine technology has attracted widespread public attention. These vaccines showed high protection rates and were well tolerated, but some rare complications, such as cases of myocarditis, were reported (Mevorach, D. et al., Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel. N. Engl. J. Med. 385, pp. 2140-2149 (2021) and Koizumi, T. et al., Myocarditis after COVID-19 mRNA vaccines. QJM Int. J. Med. 114, pp. 741-743 (2021)). Experiments conducted in mice showed that the entry of an mRNA vaccine into the bloodstream is associated with a significantly increased risk of myocardial inflammation (Li, C. et al., Intravenous Injection of Coronavirus Disease 2019 (COVID-19) mRNA Vaccine Can Induce Acute Myopericarditis in Mouse Model. Clin. Infect. Dis. 74, pp. 1933-1950 (2022)).The application of mRNA vaccines is carried out by intramuscular injection, but there is always the possibility that blood vessels may be damaged during injection, allowing easy entry into the bloodstream (Li, C. et al., Intravenous Injection of Coronavirus Disease 2019 (COVID-19) mRNA Vaccine Can Induce Acute Myopericarditis in Mouse Model. Clin. Infect. Dis. 74, pp. 1933-1950 (2022) and Arin, Kim. Is injection technique responsible for vaccine side effects? Korean Her. (2021)).

[0003] Combining a local anesthetic with a vasoconstrictor such as adrenaline prior to injection is an established technique (Sisk, A.L. Vasoconstrictors in local anesthesia for dentistry. Anesth. Prog. 39, 187-193 (1992)). This significantly reduces migration of the anesthetic through the tissue, with the benefit of enhancing and prolonging the anesthetic effect (Sisk, A.L. Vasoconstrictors in local anesthesia for dentistry. Anesth. Prog. 39, 187-193 (1992) and Aberg, G., Dhuner, K.-G. & Sydnes, G. Studies on the Duration of Local Anaesthesia: Structure / Activity Relationships in a Series of Homologous Local Anaesthetics. Acta Pharmacol. Toxicol. (Copenh.) 41, 432-443 (2009)).

[0004] Vasoconstrictors are added to local anesthetics in the following exemplary concentrations (Sisk, A.L. Vasoconstrictors in local anesthesia for dentistry. Anesth. Prog. 39, pp. 187-193 (1992)): Adrenaline / epinephrine: 1:50,000 (0.02 mg / mL) 1:100,000 (0.01 mg / mL) 1:200,000 (0.005 mg / mL) Levonordefrin: 1:20,000 (0.05mg / mL) Norepinephrine 1:30,000 (0.033 mg / mL) Local anesthetics contain, for example, the drug lidocaine 20-500 mg (specialized information lidocaine https: / / s3.eu-central-1.amazonaws.com / prod-cerebro-ifap / media_all / 78264.pdf) and are applied by injection in volumes of 0.5-1.5 mL. These are combined, for example, with epinephrine in concentrations ranging from 1:200,000 to 1:100,000. This vasoconstrictor is therefore applied in doses between 0.0025 and 0.015 mg.

[0005] mRNA vaccines: The CoViD-19 vaccines of Moderna (Spikevax Patent Number: US10933127) and Pfizer / Biontech (Comirnaty Patent Number: GB2594364A) are used in the examples provided in this document. The individual compositions of these vaccines are not described in the respective patents; they essentially only list possible ingredients. Instead, the complete ingredient list can be found in the respective data sheets (Product Information Comirnaty https: / / www.ema.europa.eu / en / documents / product-information / comirnaty-epar-product-information_en.pdf and Product Information Spikevax https: / / www.ema.europa.eu / en / documents / product-information / spikevax-previously-covid-19-vaccine-moderna-epar-product-information_en.pdf), which can be downloaded from the homepage of the European Medicines Agency (EMA). These are designated as follows: Comirnaty: The vaccine is supplied in multidose vials, the contents of which (0.45 mL) are specified to contain six doses of 0.3 mL of vaccine each and therefore must be diluted before use.

[0006] Each dose (0.3 mL) contains 30 micrograms of Tojinamelan, a 5'-capped single-stranded messenger RNA (mRNA) embedded in lipid-nanoparticles.

[0007] Other ingredients include: ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoic acid) (ALC-0315) 2-[(Polyethylene glycol)-2000]-N,N-ditetradecylacetamide (ALC-0159) 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) cholesterol Potassium chloride Potassium dihydrogen phosphate Sodium chloride Disodium Phosphate Dihydrate sucrose water for injection Sodium hydroxide (for pH adjustment) Hydrochloric acid (for pH adjustment) Spikebacks: The vaccine is supplied in multi-dose vials, but may also be in single doses.

[0008] The following table from the product information sheet sets forth the dosages and delivery forms:

[0009] [Table 1] Ellasomeran is a 5'-capped single-stranded mRNA embedded in a lipid-nanoparticle.

[0010] Other ingredients include: SM-102 (Heptadecan-9-yl 8-{(2-hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino}octanoic acid) cholesterol 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) 1,2-Dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (PEG2000-DMG) Trometamol Trometamol hydrochloride Acetic acid Sodium Acetate Trihydrate sucrose water for injection US2003 / 0147899A1 discloses a vaccine containing endogenous epinephrine and glucocorticoids. The vaccine is said to enhance antigen-specific cellular immune responses and defense against infectious agents, such as viruses. Epinephrine and glucocorticoids, such as cortisol, are disclosed as endogenous stress hormones. The combination of these hormones is used as an adjuvant or immunomodulator and is said to activate the immune system, while glucocorticoids themselves are widely used to efficiently suppress immune responses.

[0011] WO2020 / 248010A1 discloses a local drug delivery formulation applied to an open wound but not subcutaneously. The formulation aims to avoid a rapid peak of systemic effects. Among the drugs, no vaccines are mentioned. Rather, the drug may be a vasoconstrictor such as adrenaline (epinephrine). Among the delivery formulations, no vaccines are disclosed.

[0012] US2004 / 0062778A1 relates to a controlled release system that targets and controls the release of an active ingredient. The composition includes a substrate but does not include a vaccine.

[0013] Management of COVID-19 vaccine-induced anaphylaxis: This document describes treating an elderly patient with an anaphylactic reaction with intramuscular administration of adrenaline. There is no disclosure in the vaccine itself that indicates the use of adrenaline. Summary of the Invention [Problem to be solved by the invention]

[0014] It is an object of the present invention to provide a vaccine preparation which, upon administration, has no or few side effects (serious complications). [Means for solving the problem]

[0015] This object is achieved by a vaccine preparation with the features of claim 1.

[0016] Preferred and advantageous embodiments of the vaccine preparation according to the invention are the subject matter of the dependent claims.

[0017] It was unexpected that the addition of a vasoconstrictor to a vaccine, particularly an mRNA vaccine, would improve tolerability and reduce adverse reactions, an effect that could be achieved by sustained persistence of the vaccine in muscle tissue.

[0018] The present invention is based on the hypothesis that the distribution of a vaccine within the body determines the amount and type of cells that ultimately take up the vaccine. By adding a vasoconstrictor to the vaccine, it is hoped that it will persist in muscle tissue and reduce transport to surrounding tissues and blood vessels.

[0019] In contrast to the prior art, the combination of vaccines, particularly mRNA vaccines, with vasoconstrictors such as adrenaline / epinephrine does not include an adjuvant, but rather a therapeutic combination to control the effect of vaccines, particularly mRNA-based therapeutics. In contrast to conventional vaccines that contain one or more antigens of a pathogenic microorganism as the main component, mRNA therapeutics contain lipid-nanoparticles that contain modified synthetic mRNA cargo. Their mode of action is significantly different, as these mRNAs, once taken up into cells, self-amplify and initiate the intracellular production of proteins, e.g., parts of the viral spike protein. Although the idea of ​​using mRNA as a therapeutic agent was already discussed in the 1990s (Gaviria, M. & Kilic, BA network analysis of COVID-19 mRNA vaccine patents. Nat. Biotechnol. 39, 546-548 (2021) and Wolff, JA et al., Direct Gene Transfer into Mouse Muscle in Vivo, Science 247, 1465-1468 (1990)), the basic technologies making this possible were not developed before 2005 (Gaviria, M. & Kilic, BA network analysis of COVID-19 mRNA vaccine patents. Nat. Biotechnol. 39, 546-548 (2021) and Karik6, K. Buckstein, M., Ni, H. & Weissmann, D. Suppression of RNA Recognition by Toll-like Receptors: The Impact of Nucleoside Modification and the Evolutionary Origin of RNA. Immunity 23, pp. 165-175 (2005)), also long before the first mRNA-based vaccines were developed by Pfizer-Biontech and Moderna (Baden, LR et al., Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N. Engl. J. Med.384, pp. 403-416 (2021) and Benjamini, 0. et al., Safety and efficacy of the BNT162b mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. Haematologica 107, pp. 625-634 (2021) and Chaudhary, N., Weissmann, D. & Whitehead, K.A. mRNA vaccines for infectious diseases: principles, delivery and clinical translation. Nat. Rev. Drug Discov. 20, pp. 817-838 (2021)).

[0020] In conclusion, the conventional vaccine adjuvants disclosed in US2003 / 0147899A1 were not intended for use with mRNA vaccines, as these not only involve an entirely different technology, but also did not yet exist at the time.

[0021] Although the present invention is essentially suitable for all vaccines applied by intramuscular injection, it is particularly advantageous for mRNA vaccines.

[0022] Vasoconstrictors contemplated for use in the present invention are adrenaline / epinephrine, angiotensin I and II, serotonin, thromboxane A2, endothelin, phenylephrine, alpha-methylnorepinephrine, felypressin, and noradrenaline / norepinephrine. Combinations of at least two of the aforementioned agents are also contemplated. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] EXAMPLES

[0024] The examples are formulated to fit into containers supplied by the manufacturer.

[0025] Example 1 6 doses of epinephrine and Cominaty combination (0.45 mL) vial. Each dose of this combination contains 0.01 mg of epinephrine (0.3 mL after dilution).

[0026] Cominaty 0.45ml (stock) Epinephrine 0.06 mg Example 2 Six doses of the combination of Levonordefrin and Cominaty (0.45 mL) vial. Each dose of this combination contains 0.05 mg of Levonordefrin (0.3 mL after dilution).

[0027] Cominaty 0.45ml (stock) Levonordefrin 0.3mg Example 3 6 doses of Norepinephrine and Cominaty combination (0.45 mL) vial. Each dose of this combination contains 0.033 mg of norepinephrine (0.3 mL after dilution).

[0028] Cominaty 0.45ml (stock) Norepinephrine 0.2 mg Example 4 A combination of epiphrine and Spikebax dispersion in a ready-to-inject syringe. This combination contains a single dose (50 micrograms) of 0.01 mg epiphrine in 0.5 mL of Spikebax dispersion.

[0029] Spikebacks 0.5mL (dispersion liquid) Epinephrine 0.01mg Example 5 A combination of levonordefrin and Spikevax dispersion in a ready-to-inject syringe. This combination contains a single dose (50 micrograms) of 0.05 mg levonordefrin in 0.5 mL of Spikevax dispersion.

[0030] Spikebacks 0.5mL (dispersion liquid) Levonordefrin 0.05mg Example 6 A combination of norepinephrine and Spikebax dispersion in a ready-to-inject syringe. This combination contains a single dose (50 micrograms) of 0.033 mg norepinephrine in 0.5 mL of Spikebax dispersion.

[0031] Spikebacks 0.5mL (dispersion liquid) Norepinephrine 0.033mg In conclusion, an embodiment of the present invention can be described as follows.

[0032] The vaccine preparation, which improves the tolerability of vaccines, such as mRNA vaccines, with few or no adverse side effects, further contains at least one vasoconstrictor, such as adrenaline.

Claims

1. A vaccine preparation comprising at least one vaccine, the preparation comprising in addition to said vaccine at least one vasoconstrictor.

2. The preparation of claim 1 , wherein the vaccine is an mRNA vaccine.

3. 3. The preparation of claim 2, wherein the vaccine is an mRNA vaccine against COVID-19.

4. 4. The preparation of any one of claims 1 to 3, wherein the vasoconstrictor is at least one selected from the group comprising adrenaline / epinephrine, norepinephrine, angiotensin I and II, serotonin, thromboxane A2, endothelin, phenylephrine, levonordefrin, and alpha-noradrenaline / norepinephrine.

5. The preparation according to any one of claims 1 to 3, wherein the vaccine preparation is adapted for intramuscular administration.

6. 4. The vaccine preparation according to claim 1, wherein the vaccine preparation contains, in addition to the vaccine, 0.005 to 0.1 mg, in particular 0.01 to 0.05 mg, of a vasoconstrictor per administered dose of vaccine preparation.