RU2446824C2 - Influenza vaccine and method for preparing it - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine and concerns an influenza vaccine and method for preparing it. Substance of the invention involves the influenza vaccine containing the coupling of purified influenza virus antigens and a polymeric carrier representing 2-methyl-5-vinylpyridine and N-vinylpyrrolidone copolymer in proportions 1: 5-30, and a method for preparing the influenza vaccine involving the cultivation of influenza virus strain in chicken embryos to produce a purified viral concentrate that is followed by inactivating, splitting the viral concentrate to produce the purified influenza virus antigens and coupling with the polymer carrier representing 2-methyl-5-vinylpyridine and N-vinylpyrrolidone copolymer in proportions 1: 5-30.

EFFECT: preparation of the vaccine.

2 cl, 5 ex, 3 tbl

Description

The invention relates to medical biotechnology, in particular to a method for producing influenza vaccine.

Every year, the influenza epidemic is a serious problem for human health, and pharmaceutical companies are working in a number of areas of research projects to create new influenza vaccines (1).

The main types of flu vaccines licensed for clinical use are live or inactivated.

Live influenza vaccines are very effective, but for the prevention of influenza, it is still not possible to obtain attenuated strains that would provide not only high immunogenic activity, but at the same time be completely safe, especially for vaccinating children.

Currently, for the prevention of influenza in the vast majority of countries, the following inactivated influenza vaccines are used: whole virion, split and subunit.

Whole vaccines contain killed corpuscular (whole) influenza viruses.

Split vaccines are a mixture of the structural components of the virion (surface and internal), separated by various detergents.

Subunit vaccines contain hemagglutinin (GA) and neuraminidase (HA) antigens - purified glycoproteins of the outer shell of the influenza virus. These vaccines are the safest.

However, the effectiveness of influenza vaccines containing purified protein fragments of the virus is usually reduced due to insufficient immunogenicity, which cannot be said for vaccines based on whole virions that contain many immune-stimulating components and do not need help with penetration into the body.

In this regard, there is a need to use so-called adjuvants in the composition of purified vaccines - substances that act nonspecifically and increase the specific immune response. In addition, the use of adjuvant can reduce the antigen content in the vaccine.

Reducing the antigenic load in the vaccinating dose ensures the safety of the drug. Antigens with adjuvant form a complex that stimulates the humoral and cellular parts of the immune system. This leads to the formation of protective protein-specific antibodies responsible for protection against influenza.

There are two main modes of action of adjuvants, one of them is aimed at changing the properties of antigen, the other at stimulation of body functions.

The complex interaction of immunocompetent cells with adjuvants is under partial or complete genetic control of the body, but the complexity and heterogeneity of the structure of antigens and adjuvants makes it difficult to elucidate the mechanism of the immune response (2).

According to previously existing concepts, the role of adjuvants was limited only to the retention of antigen at the injection site, due to which its subsequent release led to a secondary immune response after primary stimulation (3). It has now been found that adjuvants interact with the most important antigen-presenting cells (macrophages, Langerhans cells, dendritic cells) and effector cells (plasma cells and natural killer cells), T-helper cells and inflammatory cells (polymorphic nuclear basophils, eosinophils).

Depending on the adjuvant, each type of cell can behave differently: proliferate, differentiate, change cell receptors, etc. Various adjuvants affect the induction and regulation of the synthesis of different classes of antibodies, the formation of memory B cells and the development of cellular immunity. There are no universal adjuvants, each of them has its own characteristics. The same adjuvant with different antigens stimulates immunity to varying degrees (4) and for each type of antigen the adjuvant is selected individually: after studying its immunostimulating properties.

Adjuvants used in vaccines can be classified by origin:

1. mineral - the most commonly used alumina hydrate and aluminum phosphate;

2. vegetable - saponin;

3. microbial, the most famous are sodium nucleonate (yeast RNA hydrolyzate), muramyl dipeptide (peptidoglycan component of the bacterial cell wall);

4. "water-in-oil" or "oil-in-water" - tocopherol;

5. complex artificial adjuvant systems - liposomes, microcapsules;

6. synthesized polymers and copolymers - polyoxidonium, etc.

The most used adjuvants in the production of inactivated vaccines are mineral oils (5, 6, 7) and aluminum salts (8, 9).

An influenza vaccine is known where muramyl peptide derivatives are used as an immunostimulating agent (10).

Vaccines are known that contain, as adjuvant, a mixture of chitosonium glutamate (11) and deacetylated chitosan (12).

An immunogenic composition is known, where it is proposed to use live bacterial cells of microorganisms belonging to the genus Bifidobacterium - bifidobacteria as a carrier and adjuvant (13).

Recently, new synthetic adjuvants - polymers and copolymers have been developed and used to obtain vaccines. Synthetic polymer adjuvants are new and more effective immunomodulators and immunostimulants.

A known composition that stimulates the immune response containing nanoparticles based on malevic anhydride methyl vinyl ether copolymer (14).

A viral vaccine is known where a composition selected from acrylic and methacrylic polymers and maleic anhydride is used as an auxiliary immunostimulating agent (15).

One vaccine against influenza with a polymer immunostimulating carrier (adjuvant) is known in the domestic market - it is the trivalent polymer subunit vaccine Grippol (16) containing, as an adjuvant and carrier, a poly-1,4-ethylene piperazine derivative - Polyoxidonium® (17). This vaccine is the closest analogue of the present invention.

The method of obtaining includes:

1. The cultivation of influenza virus in developing chicken embryos.

2. Obtaining a viral concentrate.

3. Purification of the viral concentrate by ultracentrifugation in a sucrose density gradient.

4. Inactivation of viral material.

5. Cleavage of the viral concentrate with a detergent.

6. Isolation of influenza virus antigens.

7. The reduction of monovaccines into the vaccine.

8. Addition of the immunostimulant "Polyoxidonium".

Synthetic polymer Polyoxidonium is a sparingly soluble synthetic polymer with an immunostimulating effect. The drug Polyoxidonium increases the body's immune resistance to local and generalized infections and has a detoxifying effect (18). In an influenza vaccine, the Polyoxidonium adjuvant-carrier provides high immunogenicity and stability of antigens in the finished preparation, and allows a significant (three-fold increase in comparison with the world standard for influenza vaccines) vaccination dose of antigens (17).

Today, there is a large selection of new adjuvants at the development and testing stage, aimed at initiating various types of immune responses that combine different levels of efficacy and safety indicators. Therefore, studies on the inclusion of various types of adjuvants in the composition of inactivated vaccines are very relevant, they are conducted by most pharmaceutical companies involved in the production of vaccines (19).

The problem to which the present invention is directed, is to expand the arsenal of influenza vaccines that increase the overall resistance of the body to the influenza virus, which are highly effective and safe.

The technical result of the invention consists in the development of an industrial method and the preparation of a multivalent influenza vaccine in combination with an immunostimulating agent, a copolymer of 2-methyl-5-vinylpyridine and N-vinylpyrrolidone, which has high antigenic activity, safety and storage stability.

The essence of the invention is to obtain purified influenza antigens in combination with an immunostimulating carrier-adjuvant copolymer of 2-methyl-5-vinylpyridine and N-vinylpyrrolidone.

The inventive method involves the cultivation of influenza virus in developing chicken embryos, followed by separation of the virus-containing allantoic fluid, concentration, purification, inactivation and cleavage of the virus. Concentration and purification is carried out by sorption of the virus on chicken red blood cells, followed by ultracentrifugation in a sucrose density gradient. Inactivation and cleavage of the virus is carried out by any means authorized for use. The digested virus concentrate is centrifuged and ultrafiltered. The resulting concentrate of purified antigens of each strain of influenza virus is considered as a monovaccine. After reducing monovaccines, a copolymer of 2-methyl-5-vinylpyridine and N-vinylpyrrolidone is added to the multivaccine at a carrier antigen ratio of 1: 5-30.

The proposed polymer multivalent vaccine contains strains of influenza virus type A, B and a copolymer of 2-methyl-5-vinylpyridine and N-vinylpyrrolidone, where the ratio of antigen-carrier is 1: 5-30.

Unlike the prototype, the claimed method for producing influenza vaccine uses a new synthetic polymer carrier and adjuvant - a copolymer of 2-methyl-5-vinylpyridine and N-vinylpyrrolidone.

The copolymer of 2-methyl-5-vinylpyridine and N-vinylpyrrolidone is a water-soluble polymer with a medium viscosity molecular weight M _η = 30000 ÷ 55000 daltons, non-toxic, with an immunostimulating effect (20).

Studies of immunostimulating activity were carried out on animals: calves and sheep with anthrax and gilts with classical swine fever.

A summary of the method of obtaining

For the preparation of the vaccine, influenza virus strains are used, according to WHO recommendations.

To obtain a virus-containing allantoic fluid (IMPORTANT), the infection of chicken embryos with the influenza virus is carried out on automatic machines. Infection with different types of influenza virus is carried out at different times and with different infection systems.

After infection, chicken embryos are incubated for 48-72 hours at a temperature of (34 ± 2) ° C.

At the end of the incubation period, the eggs are ovoscopic. The collection of virus-containing allantoic fluid is carried out on an automatic production line in the bottle. The hemagglutinating titer should be at least 1:80 for all types of virus.

After determining the hemagglutinating activity (GA), formalized chicken red blood cells are added to the bottle.

The completeness of sorption of the influenza virus is controlled by determining the titer of HA in the supernatant.

A phosphate buffered saline (PBS) is added to the erythrocyte sediment. A suspension of red blood cells is centrifuged at a rotational speed (1800 ± 200) rpm. The resulting eluate is fed to a continuous flow ultracentrifuge. The virus is distributed in a sucrose density gradient. Phosphate buffer solution displaces the gradient fractions from the rotor and collect in sterile bottles.

A virus concentrate diluted for inactivation is passed through an ultraviolet unit or inactivated with a formalin solution.

The estimated amount of a 1% solution of tetradecyltrimethylammonium bromide (TDTAB) is added to a bottle with a diluted inactivated concentrate. At the end of the process of obtaining a split concentrate, the separation of the viral antigen from the detergent is carried out in an ultrafiltration unit.

After sterilizing filtration, semi-finished products of type A and B mono-vaccines are mixed into a multivaccine.

The resulting multivaccine is monitored for total protein, specific activity, and pyrogenicity. Then, a concentrate of a copolymer of 2-methyl-5-vinylpyridine and N-vinylpyrrolidone in an antigen-carrier ratio of 1: 5-30 is added to the bottle with the multivaccine through a siphon. The resulting preparation is filtered and poured into ampoules or syringes.

The resulting influenza polymer vaccine meets the highest criteria of immunogenicity and safety.

The proposed method is as follows.

Example 1

To obtain the influenza vaccine, influenza virus strains of type A (H ₁ N ₁ ), A (H ₃ H ₂ ) and B are used.

Chicken embryos of 10-12 days old are infected in the allantoic cavity. Trays with infected embryos are placed in a thermal room at a temperature of (34 ± 2) ° C and humidity from 70 to 80% for 48-72 hours, depending on the strain used. At the end of the incubation, the embryos are checked using ovoscopes. Viable embryos are placed in a refrigerator at a temperature of (1 ± 1) ° C for (18 ± 2) h for cooling.

The collection of virus-containing allantoic fluid (hereinafter referred to as IMPORTANT) is carried out on the production line. After filling the vessel, 1 bottle with 45 ml of kanamycin solution is added to 9 l of the collected IMPORTANT.

A 50% suspension of formalin erythrocytes (4-11% of the volume of the IMPORTANT) is added to the bottle with IMPORTANT. Maintain a mixture of IMPORTANT with red blood cells for 24-72 hours at a temperature of (4 ± 2) ° C. Then the supernatant is drained. The sediment of red blood cells with adsorbed virus is washed twice with phosphate-buffered solution, and then placed in a water bath at a temperature of (37 ± 2) ° C to elute the virus. A suspension of red blood cells is centrifuged. The resulting eluate is concentrated and purified in a 50-60% sucrose density gradient at a rotor speed of (30,000 ± 2000) rpm on a Hitachi ultracentrifuge.

A phosphate buffer solution is added to the viral concentrate and the viral protein content is adjusted to at least 1 mg / ml.

To inactivate the virus, an apparatus containing a source of ultraviolet rays with a radiation power of (1450 ± 50) μW / cm ^{2 is used} .

The estimated amount of 1% TDTAB solution is added to the bottle with the diluted inactivated concentrate.

To obtain a purified concentrate of influenza virus antigens, the split virus concentrate is centrifuged at 16,000 rpm for 2 hours. Then, a tangential flow ultrafiltration is performed on a cassette with a membrane of 30,000 daltons until the detergent concentration in the filtrate decreases to 10 μg / ml .

The resulting concentrate of purified influenza antigens is considered as a monovaccine. Monovaccine is filtered through two series-connected filters with pore sizes of 0.45 and 0.22 μm.

A vaccine is prepared by mixing monovaccines of types A (H ₁ N ₁ ), A (H ₃ N ₂ ) and B through a filter filled with a 0.22 μm membrane. Then, the adjuvant copolymer of 2-methyl-5-vinylpyridine and N-vinylpyrrolidone in an antigen-carrier ratio of 1: 5 is added to the resulting semi-finished product. Filling the finished vaccine is carried out in syringes or ampoules.

Example 2

To obtain the influenza vaccine, influenza virus strains of type A (H ₅ N ₁ ), A (H ₃ N ₂ ) and B are used.

In a bottle with a diluted viral concentrate obtained as described in example 1, to inactivate the virus add formalin solution at the rate of 0.5% of its final concentration.

The purified vaccine is obtained by mixing monovaccines of types A (H ₅ N ₁ ), A (H ₃ N ₂ ) and B. At the final stage of vaccine production, the amount of adjuvant to be added to the tri-vaccine is determined by the carrier antigen ratio of 1:30.

Example 3. The study of the safety of the vaccine. The safety of the claimed vaccine was evaluated according to the results of abnormal toxicity and histopathology.

The study of abnormal toxicity was carried out with a single intraperitoneal administration to white mice weighing 10-12 g and subcutaneous administration to guinea pigs weighing 250-350 g

Animals were divided into groups. The first group of animals was administered a vaccination dose of the claimed vaccine containing an adjuvant of the copolymer of 2-methyl-5-vinylpyridine and N-vinylpyrrolidone - 250 μg (option No. 1), the second - a vaccination dose of the claimed vaccine with the adjuvant content - 500 μg (option No. 2), the third - a vaccination dose of the Grippol vaccine with the adjuvant content of polyoxidonium 500 μg per dose (option No. 3). The fourth group was control - animals were injected with saline.

As a result of the studies established the following.

All three vaccine variants are non-toxic; no negative effect of the drugs on the general condition, dynamics of body weight and behavioral reactions of animals was noted. No deviations from the normal state of the coat, changes in the physiology of the eyes, ears, teeth, urination and excrement were detected. In tests for accelerated aging in the claimed vaccine deviations of the qualitative characteristics from the original were not found.

For histological studies used samples of the liver, heart, spleen, lung, brain and small intestine. As a result of the studies, it was found that in laboratory animals immunized with the above vaccines, specific pathological changes were not found in the studied organs.

Example 4. The study of the immunogenic properties of the vaccine.

The immunogenic properties of vaccine preparations have been studied by evaluating antigenic activity and humoral immune response (immunogenicity).

When determining the antigenic activity of the above three vaccine variants, the formation of antibodies in animal blood serum was investigated. The experiments were carried out on white outbred mice weighing 10-12 g. After two intraperitoneal injections of the vaccine twice with an interval of 7 days, the sera of immunized mice were studied in the reaction of inhibition of hemagglutination (RTGA) with homologous antigens of the vaccine.

Indicators of antigenic activity of the claimed vaccine and prototype are shown in table 1.

A comparative assessment of the antigenic activity of the three vaccine variants revealed that the hemagglutinating titer of the compared drugs was at least 1:80 for each of the three strains of influenza A and B viruses included in it (according to the NTD no less than 1:40).

The study of the stability of antigenic activity during storage of the claimed drug was carried out by the method of “accelerated aging”.

Samples of the claimed vaccines No. 1, 2 were laid for accelerated storage at a temperature of 37 ° C and 22 ° C. The results of the study of the stability of antigenic activity showed that the developed drug has high stability, while maintaining indicators that meet the requirements of regulatory documents.

Immunogenicity studies were carried out on ferrets weighing 1100-1500 g. Animals were divided into 4 groups, 10 ferrets in each group. The numbers of the groups correspond to the vaccine variants of Example 3, the fourth group was the control — 0.5 ml of physiological saline was injected into the animals.

The intensity of humoral immunity was assessed by determining the titer of antibodies to hemagglutinins of influenza viruses of type A and B. Blood serum of laboratory animals of groups No. 1-4 was obtained before immunization, on days 14 and 21 after immunization. The antibody titer was determined in rtga with chicken erythrocytes treated with RDE. The results of determining the titer of virus-specific antibodies in laboratory animals are presented in table.2.

The data presented in Table 2 indicate that intramuscular administration of one vaccination dose of the vaccine causes the formation of virus-specific immunity in each group of immunized animals. In this case, the vaccine, according to option No. 2, shows the maximum immunogenic response: the titer of virus-specific antibodies in rtga for influenza B virus was 14 days 1:10 and for 21 days 1:40, for influenza A virus (H ₃ N ₂ ) - on the 14th day 1:80 and on the 21st day 1: 640, and for the influenza A virus (H ₁ N ₁ ) - on the 14th day 1:40 and on the 21st day 1: 320.

Example 5. The safety and protective efficacy of the inventive vaccine in humans.

The effectiveness of the influenza virus vaccine is determined by the ability to induce immunity in the vaccinated organism and thereby prevent the incidence of influenza. The humoral immune response adequately reflects the protective effect of the influenza vaccine, since there is a correlation between the titer of specific antibodies to influenza hemagglutinins and the level of protection against influenza. When assessing the potential effectiveness of an influenza vaccine, a titer of specific antibodies to hemagglutinins of at least 1:40 is considered protective (21). The official requirements for the immunological effectiveness of influenza virus vaccines are based on this indicator (MU 3.3.2.1758-03 and CPEMP EMEA from 2001).

As part of a simple, blind, randomized, multicenter study, safety and immunogenic properties of the proposed influenza vaccine were evaluated. Seronegative volunteers selected during the screening were injected intramuscularly once into the upper third of the external surface of the shoulder (to the deltoid muscle) in a vaccination dose of 0.5 ml. The clinical study was carried out in two stages.

At the first stage of clinical trials, the tolerance, reactogenicity, and safety of the claimed vaccine were studied on a limited contingent of volunteers (90 volunteers) aged 18 to 60 years. Saline (placebo) was used as a control.

At the second stage, the tolerance, reactogenicity, safety and immunogenicity of the claimed vaccine were studied on an expanded contingent of volunteers (240 volunteers) aged 18-60 years in comparison with the commercial vaccine Grippol. The studied influenza vaccines (claimed and prototype) included the same strains of the influenza virus: A / California / 07/2009 A (H ₁ N ₁ ) v, A / Wisconsin / 15/2009 A (H ₃ N ₂ ) and B / Brisbane / 60/2008. These strains were recommended by WHO and the Commission on influenza vaccine and diagnostic strains (Decision No. 1 dated 02.25.2010) for the composition of influenza vaccines for the 2010-2011 season. The initial titer of specific antibodies to all three vaccine strains of influenza in all volunteers was not higher than 1:20, i.e. volunteers were seronegative. On the 21st day of vaccination, volunteers performed blood sampling to determine the titer of specific antibodies to influenza hemagglutinins.

Reactogenicity and safety of influenza vaccines were assessed by vital signs (blood pressure, heart rate, body temperature), neurological examination, laboratory tests (OAM, AOK, blood chemistry, IgE) and adverse events (local and systemic reactions). Evaluation of local and systemic reactions was carried out according to MU 3.3.2.1758-03 "Methods for determining the quality indicators of immunobiological preparations for the prevention and diagnosis of influenza."

The vast majority of volunteers immunized with the claimed vaccine and the Grippol vaccine (91.8% and 92.4%, respectively) had no adverse reactions. A statistically significant difference between the incidence of post-vaccination reactions in the groups vaccinated with the compared drugs was not detected (p> 0.05).

In the course of the clinical study, local and systemic reactions of a strong degree of severity were not identified. All reactions, both local and systemic, did not require treatment and were of a short-term nature.

The average blood count and biochemical analysis in all groups of volunteers during dynamic observation remained within normal values. General urine analysis showed no pathological changes.

The data of a neurological examination in dynamics did not reveal any deviations from normal values.

Analysis of the level of total IgE in serum did not reveal significant changes in the dynamics in all groups and did not reveal significant differences between the groups (t≤2).

As a result of the studies revealed that the claimed vaccine is areactogenic, has good tolerance and a high safety profile. The data obtained indicate her lack of allergenic properties.

Immunogenic activity of the vaccines was evaluated in the hemagglutination inhibition test (RTHA), examining the paired blood serum of volunteers taken at the screening stage (before vaccination) and on the 21st day after vaccination. Assessment of immunogenicity was carried out in accordance with the immunogenicity criteria of CPMP EMEA (2001) and MU 3.3.2.1758-03. According to the normative and technical documentation, antibody titers of at least 1:40 are considered protective.

The results of a study of the immunogenicity of vaccines are presented in table 3.

The data obtained indicate that the inventive vaccine against influenza virus causes the formation of a protective antibody titer in people: the seroconversion level of the inventive vaccine for the three strains of influenza virus varied between 74.7-82.3% (according to the requirements of CPEMP EMEA should be more than 40%), the seroconversion factor is 6.7-9.9 (more than 2.5 according to the requirements of CPEMP EMEA) and the level of seroprotection is 70.9-77.2% (more than 70% according to the requirements of EMEP EMP; according to the requirements of MU 3.3.2.1758- 03 - for influenza virus type A - more than 70%, type B - 60%). Thus, the claimed vaccine in its qualitative characteristics (criteria of immunogenicity) meets the requirements of regulatory and technical documentation. The proposed vaccine provides high levels of seroconversion and seroprotection for all three strains of the influenza virus and slightly exceeds the corresponding values of the prototype. The inventive vaccine meets all the criteria of immunogenicity MU 3.3.2.1758-03 and CPMP EMEA.

Thus, as a result of the studies, it was found that the qualitative characteristics of the developed drug - safety, antigenic activity and immunogenicity satisfy the requirements of regulatory and technical documentation for influenza vaccines. The claimed vaccine is safe for people, has good protective efficacy and stability during storage.

The presence in the preparation of a polymer carrier immunostimulant provides greater stability of antigens and an increase in the immunogenicity of the vaccine while reducing the vaccination dose of antigens. The proposed method for obtaining a vaccine against influenza virus allows to obtain a drug with high antigenic (immunogenic) activity, safe for use.

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Claims (2)

1. A vaccine against influenza virus, comprising combining purified antigens of influenza viruses with a polymer carrier, which is a copolymer of 2-methyl-5-vinylpyridine and N-vinylpyrrolidone in a ratio of 1: 5-30. 2. The method of obtaining a vaccine against influenza virus according to claim 1, comprising cultivating strains of the influenza virus in chicken embryos, obtaining a purified viral concentrate, inactivating, cleaving the viral concentrate, followed by obtaining purified influenza antigens and combining them with a polymer carrier, which is a copolymer 2 -methyl-5-vinylpyridine and N-vinylpyrrolidone in a ratio of 1: 5-30.