CN114887050A - Application of lentinan in preparation of novel coronavirus respiratory mucosa vaccine - Google Patents
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Abstract
The invention relates to the technical field of medicines, and relates to application of lentinan in preparation of a novel coronavirus respiratory mucosa vaccine. The novel coronavirus respiratory mucosa vaccine is a vaccine which is inoculated by taking lentinan as a unique immunological adjuvant or a composite adjuvant containing lentinan in the vaccine through a nasal drip or nasal spray way to prevent the novel coronavirus infection.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of lentinan in preparation of a novel coronavirus respiratory mucosa vaccine.
Background
The new type of Coronavirus (SARS-CoV-2), hereinafter referred to as new Coronavirus for short, has extremely high infectivity and rapid interpopular transmission ability, and can cause viral pneumonia in some infected patients (Coronavir Disease 2019, COVID-19).
Vaccines are the most effective way for humans to prevent infection and alleviate the lesions caused by pathogens, and current vaccines administered by intramuscular injection, including inactivated vaccines, adenoviral vector vaccines, recombinant antigen subunit vaccines, and mRNA vaccines, do not induce respiratory mucosal immunity, thus limiting their ability to prevent viral infection. Immunization with intramuscular vaccines requires a significant amount of dedicated human resources to support. The vaccine inoculated by respiratory tract mucosa route, such as nasal drop inoculation and nasal spray inoculation, not only is convenient for inoculation, but also can efficiently induce upper respiratory tract mucosa immunity, and is a first barrier for resisting virus invasion into human body, so that the vaccine is a better vaccine selection
The spike protein on the surface of the new corona virus envelope mediates the binding of the receptor on the surface of the viral and host cell membranes and triggers the fusion of the viral envelope with the host endosomal membranes, and thus is the target antigen for the induction of virus neutralizing antibodies, and is also the target antigen for most of the current new corona vaccines. mRNA vaccines, adenoviral vector vaccines and recombinant subunit vaccines based on the target antigen are on the market and are promoted globally.
Lentinan (LNT) is an effective active ingredient extracted from fruiting body of high-quality Lentinus edodes, is an immunomodulator, and especially can effectively enhance T cell activity. Clinical and pharmacological research shows that lentinan has the functions of resisting virus, resisting tumor, regulating immunity, stimulating the formation of interferon, etc. The active component is beta- (1-3) -D-glucan with branches, the main chain is composed of beta- (1-3) -linked glucosyl, and the glucosyl linked by the beta- (1-6) is randomly distributed along the main chain and is in a comb-shaped structure. Lentinan injection and oral lentinan tablets are clinically used for the adjuvant treatment of chronic hepatitis and tumors in a plurality of countries including China, can effectively enhance the antiviral and antitumor immune response of patients, and have good safety. The lentinan can be used as a vaccine adjuvant and can effectively induce protective immune response against trichina and influenza viruses by intramuscular injection and subcutaneous injection inoculation of mice. Reference documents: 1. lentinan improved the efficacy of vaccine against Trichinella spiralis in an NLRP3 dependent manner.jin X, Liu X, Ding J, Zhang L, Yang Y, Wang X, Yang Y, Liu M.PLoS Negl Trop Dis.2020 Sep 25; 14(9) e 0008632; 2. immune-adjuvant activity of lentinan-modified calcium carbonate microparticles on a H5N1 vacine. He J, Liu Z, Jiang W, Zhu T, Wusimann A, GuP, Liu J, Wang D.int J Biol Macromol.2020 Nov 15; 163:1384-1392.
Disclosure of Invention
The invention aims to provide a new coronavirus recombinant subunit vaccine which takes lentinan as an adjuvant and is inoculated through respiratory mucosa and is used for preventing new coronavirus infection.
The invention provides an application of lentinan in preparing a novel coronavirus respiratory mucosa vaccine.
Further, the invention provides an application, which is characterized in that: lentinan is used as an effective upper respiratory mucosa immunoadjuvant, is used as an immunoadjuvant for novel coronavirus recombinant antigens or inactivated viruses, and is used for preventing novel coronavirus infection through nasal drip or nasal spray inoculation.
Further, the invention provides an application, which is characterized in that: the new crown vaccine taking lentinan as an adjuvant adopts the inoculation route comprising nasal drip and nasal spray.
The invention uses new coronavirus envelope spike protein as antigen, mixes the antigen protein solution and lentinan solution, inoculates syrian golden hamster by nasal drip, then detects the antibody in the serum of the hamster, and infects the syrian golden hamster by live virus, detects that the nasal drip vaccine can effectively induce the hamster to generate IgG antibody of anti-new coronavirus spike protein receptor binding functional zone, and effectively protects the hamster against new coronavirus infection, reduces the virus load in the upper respiratory tract of the hamster and lightens the disease of the hamster, and has application prospect.
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FIG. 1 vaccine immunization of Syrian golden yellow hamster induced Receptor Binding Domain (RBD) IgG antibodies in serum anti-neocoronavirus spike protein
anti-RBD specific IgG antibodies were detected in mouse sera after the 1 st and 2 nd immunizations using ELISA, i.e., day 14 and day 28 in the figure. Str is a trimer of the extracellular segment of the envelope spike protein of the new coronavirus.
FIG. 2 relative content of N gene nucleic acid of neocoronavirus in turbinate of guinea pigs on day 4 after challenge with neocoronavirus
On day 4 after virus challenge, 3 mice from each group were sacrificed, turbinates were removed, ground, histiocyte RNA was extracted, and the relative expression level of the new coronavirus N gene was detected by reverse transcription-quantitative PCR.
FIG. 3 weight change of mice after infection with New coronavirus
Daily body weight changes in 5 mice per group following virus challenge, with no virus challenge in the placebo group.
Detailed Description
In order to more clearly illustrate the invention, the invention is further described below in connection with preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.
The ixazofamid used in the embodiments of the present invention can be purchased commercially.
One, virus, medicine, reagent and other materials
1. Virus: SARS-CoV-2 virus was isolated and cultured from a sample of a nasopharyngeal swab from a patient having COVID-19 by the university of military medical science and education laboratory, and its gene sequence is shown in GenBank Accession No. MZ664555, and virus was cultured using Vero E6 cells. The cultured virus infected Vero E6 cells, 18 hours later, the titer of the virus (FFU), i.e., the number of infectious virus particles per ml of virus fluid, was determined by immunofluorescence staining. The experimental procedures involving viral infection were all performed at the naval military medical university P3 laboratory.
2. The vaccine antigen is a full-length extracellular segment of a new coronavirus spike envelope protein, wherein the furin site amino acid residue PRRARS between S1/S2 subunits is replaced by GSAS, both leucine at the 986 th position and valine at the 987 th position are mutated into proline, and a T4 bacteriophage fibrin trimer motif is fused at the carboxyl terminal. The expression product formed a homotrimer (Str), expressed by secretion from CHO cells used in the biomedical protection research laboratory of the university of naval military medical science.
3. Lentinan (LNT), available from mce (medchemexpress), catalogue number: HY-N6653 dissolved in DMSO.
4. Aluminum hydroxide adjuvant (Al adjuvant), available from InvivoGen, catalog No.: vac-alu-250.
5. The fluorescent quantitative PCR detection reagent for the new coronavirus nucleic acid is purchased from Shanghai Berjie Biotech, Inc.
6. Syrian golden hamster, male, 8 week old, beijing vitamin deli laboratory animal technology ltd.
7. Other reagents: 293 cell-expressed prototype strain, New coronavirus Receptor Binding Domain (RBD) protein, purchased from Shanghai, offshore Biotechnology Ltd; high adsorption enzyme-labeled microwell plates, purchased from Nunc corporation; horseradish peroxidase (HRP) labeled anti-mouse IgG was purchased from Thermo Fisher, catalog No.: 31430; enzyme-linked immunosorbent assay (ELISA) TMB chromogenic reagents were purchased from Thermo Fisher, catalog No.: 34024; RNA extraction reagent Trizol LS was purchased from Thermo Fisher, catalog No.: 10296010.
II, an experimental method:
(one) Syrian golden hamster immunization
Syrian golden yellow mice were divided into four groups, and animals were first anesthetized with isoflurane inhalation, followed by vaccination.
Negative control group, when challenged with virus, was subdivided into blank control group (5) and infection control group (8), 13 in total: nasal drip PBS, nasal drip to both nostrils, 25 microliters per nostril;
single antigen (Str) nasal drops, 8: nasal drops are applied to the nostrils at both sides, 25 microliter per nostril at each side, and 10 micrograms of Str protein is contained;
str + LNT nasal drop group, 8: nasal drops in both nostrils, 25 microliters per nostril, containing 10 micrograms Str protein and 200 micrograms LNT;
str + Al adjuvant intramuscular injection group, 8: the thigh was injected bilaterally intramuscularly, 100 microliters on each side, containing 10 micrograms of Str protein and 80 micrograms of aluminum hydroxide.
The immunization was performed twice, with an interval of 14 days, and the second immunization was performed on the day after blood collection.
(II) detection of hamster serum antibodies
At 14, 28 th after the first immunization, blood is collected from the orbit of the hamster by a capillary tube, serum is separated by high-speed centrifugation and is frozen in a refrigerator at the temperature of 80 ℃ below zero.
The antibody detection is carried out according to an ELISA conventional technology, RBD protein is coated on a high-adsorption enzyme-labeled microporous plate, each hole of protein is 0.1 microgram, and the plate is placed in a refrigerator at 4 ℃ for overnight; the next day, the protein solution was aspirated off, the wells were washed once with phosphate buffered saline (PBS, pH 7.0), then blocked with 3% bovine serum albumin in PBS (3% BSA-PBS) at room temperature for 2 hours, then the blocking solution was aspirated off, and the wells were washed 3 times with PBS; adding two times of continuously diluted hamster serum into each well, wherein the diluent is 3% BSA-PBS with the volume of 100 microliter/well, and placing in a refrigerator at 4 ℃ overnight; the next day, serum dilutions were aspirated off, wells were washed 5 times with PBS containing 0.05% Tween 20 (0.05% Tween 20-PBS), and then HRP-labeled anti-mouse IgG was added at 1000-fold dilution in 3% BSA-PBS at a volume of 100. mu.l/well for 40 min at room temperature; removing HRP antibody diluent by suction, and washing the wells with 0.05% Tween 20-PBS for 5 times; adding TMB developing solution with 100 microliter per hole, developing for 10 min, adding stop solution, and measuring light absorption values at 450nm and 630nm by using an enzyme-labeling instrument; antibody titers were calculated for each serum sample using Graphpadprism 5 software based on light absorbance values.
RBD is the main target of neutralizing antibodies of the new coronavirus, and the level of RBD antibodies in serum represents the virus neutralizing capacity. The RBD IgG antibody titer of each group of hamster serum is shown in figure 1, single Str nasal drip immunity, namely, new coronavirus envelope spike protein extracellular segment tripolymer nasal drip immunity induces the RBD IgG antibody level to be extremely low, and Str combined lentinan nasal drip immunity can induce the high-level RBD IgG antibody, and the level of the antibody induced by Str combined human adjuvant aluminum hydroxide intramuscular injection immunization is similar to that of the antibody induced by Str combined human adjuvant aluminum hydroxide intramuscular injection. After boosting, the antibody levels of both adjuvant groups were moderately increased. Since there is no commercially available anti-hamster IgA reagent, the sensitivity of detecting hamster IgA with anti-mouse IgA was extremely low, and therefore the upper respiratory mucosal RBD IgA antibody of hamster was not detected.
(III) Virus challenge protection experiment
8 weeks after the first immunization, each group of mice was challenged with new coronavirus nasally at a dose of 1.8 x 10 8 And (4) FFU. Of 13 mice in the negative control group, 8 mice were used as infection control group, and the remaining 5 mice were not infected with virus and used as blank control group. The body weight of the rats was weighed from the day of virus challenge (before dropping rhinovirus), and thereafter daily. 3 mice are taken from each group on the 4 th day after the virus attack and killed after isoflurane anesthesia, nasal turbinates are cut and taken, a homogenizer is used for grinding, a Trizol LS reagent is used for extracting the RNA of tissue cells, the reverse transcription real-time fluorescence quantitative technology is used for detecting the content of the N gene nucleic acid of the new coronavirus nucleocapsid, and the relative level of each group of mice is calculated. The remaining 5 mice in each group continued to observe weight changes by day 15.
The relative level amounts of the neocoronavirus N gene nucleic acid in the turbinates at day 4 post virus challenge for each group of mice are shown in figure 2: setting the average level of N genes of 4 days of 3 mice infected with a control group as 1, wherein the relative level of a single Str nasal drop group is 0.81; the Str + aluminum hydroxide intramuscular injection group relative level was 0.79; the Str + LNT nasal drop group relative level was 0.14. The relative level of N gene in Str + LNT nasal drop group was significantly lower than that in other groups (p < 0.001, p < 0.01; t-test). Although no upper respiratory mucosal RBD IgA antibodies were detected in the rats, comparison of nucleic acid levels of the N gene of the neocoronavirus in the hamster turbinates of the various groups showed that Str + LNT nasal drops were effective in inducing a local immune response against the neocoronavirus in the upper respiratory mucosa.
The weight change of the hamster is shown in fig. 3: the weight of the mice in the blank control group is continuously increased; the weight of the infected control group mice continuously decreases after virus challenge, the maximum decrease amplitude reaches 14.6 percent, and the mice begin to rise again after the 6 th day; the weight of the single Str nasal drip group is similar to the weight change of the infected control group; the weight change of the Str + aluminum hydroxide intramuscular injection group is shown as mild increase, and the Str + aluminum hydroxide intramuscular injection group has a better immune protection effect; compared with the Str + aluminum hydroxide intramuscular injection group, the Str + LNT nasal drop group has larger body weight increase amplitude and shows better immune protection effect.
The experimental results show that the new coronavirus spike protein is used as an antigen, and combined with lentinan adjuvant, nose-dropping immunization is performed on the syrian golden hamster, so that a high-level protective antibody (an RBD antibody is a protective antibody) can be induced, and the hamster can be effectively protected against the attack of the new coronavirus (after the virus attack, virus replication in the nasal concha of the hamster is remarkably inhibited, the weight of the hamster is not reduced, and the weight of the hamster quickly begins to be improved).
The new coronavirus spike protein is combined with an adjuvant aluminum hydroxide for human use to carry out intramuscular injection immunization, and the weight change of the hamster shows that the immunization method also has an obvious protection effect. However, compared with the nasal drop immunization group combined with the lentinan adjuvant, the replication level of the new coronavirus in the nasal concha of the rats in the combination with the aluminum hydroxide intramuscular injection group is higher, and the weight gain amplitude is lower.
The results show that: lentinan can be used as effective immunologic adjuvant for upper respiratory mucosa, and can be used for preventing new coronavirus infection by combining envelope spike protein of new coronavirus with lentinan for nasal drip inoculation.
Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (3)
1. Application of lentinan in preparing novel coronavirus respiratory tract mucosa vaccine is provided.
2. Use according to claim 1, characterized in that: lentinan is used as an effective upper respiratory mucosa immunoadjuvant, is used as an immunoadjuvant for novel coronavirus recombinant antigens or inactivated viruses, and is used for preventing novel coronavirus infection through nasal drip or nasal spray inoculation.
3. Use according to any one of claims 1-2, characterized in that: the new crown vaccine taking lentinan as an adjuvant adopts the inoculation route comprising nasal drip and nasal spray.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210419481.4A CN114887050A (en) | 2022-04-20 | 2022-04-20 | Application of lentinan in preparation of novel coronavirus respiratory mucosa vaccine |
| PCT/CN2022/101512 WO2023201881A1 (en) | 2022-04-20 | 2022-06-27 | Use of lentinan in preparing sars-cov-2 respiratory mucosal vaccine |
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| CN202210419481.4A CN114887050A (en) | 2022-04-20 | 2022-04-20 | Application of lentinan in preparation of novel coronavirus respiratory mucosa vaccine |
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| WO2021256470A1 (en) * | 2020-06-16 | 2021-12-23 | Sophy Inc. | Beta-glucan for immuno-enhancement and/or immuno-balancing, and for adjuvant use |
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