RU2736788C1 - Strain a/chiken/kostroma/3175/17 h5n2 of avian influenza virus subtype h5n2 infuenza a virus of genus alphainfluenzavirus to control antigenic and immunogenic activity of avian influenza vaccines and for making antigen-containing diagnosticums - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: invention relates to the field of biotechnology. Disclosed is a strain of avian influenza virus A/chicken/Kostroma/3175/17 H5N2 subtype H5N2 Influenza A virus, genus Alphainfluenzavirus, family Orthomyxoviridae, obtained during sequential passaging in 10-day SPF-embryos of chickens and deposited in a collection of strains of microorganisms FGBU "VNIIZZH" under the name "A/chicken/Kostroma/3175/17 H5N2 (diagnostic - D) avian influenza virus strain". Avian influenza virus strain has high biological activity in native form and preserves antigenic and hemagglutinating activity after inactivation.

EFFECT: strain A/chicken/Kostroma/3175/17 H5N2 strain can be used for control of antigenic and immunogenic activity of avian influenza vaccines, as well as for production of antigen-containing diagnostics used in virological, molecular-genetic and serological studies.

1 cl, 1 dwg, 5 tbl, 7 ex

Description

The invention relates to the field of veterinary virology and biotechnology, in particular to a new strain of Influenza A virus and can be used to control the antigenic and immunogenic activity of vaccines against influenza A subtype H5, as well as for the manufacture of antigen-containing diagnostics used in virological, molecular genetic and serological research.

Avian influenza is a viral disease that affects various bird species. The severity of the disease varies from asymptomatic to acute generalized infection with high mortality in poultry [7, 8].

The avian influenza virus (VIV) (Influenza A virus) belongs to the Orthomyxoviridae family, the Alphainfluenzavirus genus [9].

Virions of VGP traditionally have a rounded shape from spherical to pleomorphic, with a diameter of 80-120 nm. Viral particles contain: RNA - 1%, proteins - 70%, fats - 20% and carbohydrates - up to 8%.

The genome of the virus is formed by a single-stranded negative polarity (-) RNA, which consists of 8 segments and encodes 11 proteins of the virus: the internal protein nucleoprotein (NP); proteins of the polymerase complex (PB1, PB2 and PA); matrix proteins (M1 and M2); non-structural proteins (NS1 and NS); surface glycoproteins (hemagglutinin (HA) and neuraminidase (NA)). The total genome size is about 13600 nucleotides [7, 8, 15].

Surface glycoproteins HA and NA carry the main invasive functions of the virus: the attachment and penetration of genetic material into the cell. According to their structure, the influenza A virus is classified into subtypes: at the moment, there are 18 known subtypes for HA and 11 for NA. It is against these proteins that antiviral immunity is formed.

The pathogenicity of the virus is determined by the rate of death of chickens during intravenous infection (IVPI test) and by the amino acid composition of the hemagglutinin cutting site, as a result of which the AIV isolates can be divided into low pathogenic and highly pathogenic, the latter include only the H5 and H7 subtypes [12].

Currently, the epizootic situation in the world for highly pathogenic influenza remains tense. According to the World Organization for Animal Health 2017-2019 cases of the disease caused by influenza A / H5 and A / H7 viruses were registered among domestic and wild birds in 65 countries of the world, during this time more than 300 outbreaks were recorded and 10 subtypes of the virus were identified: H5N1, H5N2, H5N3, H5N5, H5N6, H5N8 , H5N9, H7N1, H7N3, H7N9 [11].

This global spread of the virus is believed to be caused by wild migratory waterfowl, many of which are not susceptible to highly pathogenic forms of avian influenza, but are carriers of the disease. Therefore, the introduction of the virus into unadapted populations of agricultural birds leads to severe epizootics with colossal economic damage [7, 8, 15].

Outbreaks of the highly pathogenic form of AIV A / H5N2 have been reported worldwide since 2011 in South Africa. From 2012 to the present, this pathogen has been endemic for the territories of the PRC. [eleven].

At the end of 2014, highly pathogenic influenza A / H5N2 spread to North America (USA and Canada). The isolates isolated during outbreaks were a reassortant variant of AIV that appeared as a result of the exchange of segments between highly pathogenic (presumably H5N8) and low pathogenic virus subtypes [10]. In 2015-2017. In Europe, poultry farms in France have also reported cases of the disease caused by AIV A / H5N2. In 2019, it became known again about the appearance of this pathogen among poultry in South Africa (Egypt) [11].

This problem became apparent for the first time in Russia in 2017: isolate A / H5N2, was detected during an outbreak of acute infection in a large poultry complex (about 500 thousand heads) in the Kostroma region.

A number of foreign A / H5N2 AIV strains are known, isolated in North America in the 80-90s. of the last century, used for the manufacture of diagnostic and vaccine preparations:

- A / Chicken / Mexico / 232/94 / CPA;

- A / chicken / Queretaro / 14588-19 / 95;

- A / chicken / Mexico / 31381-7 / 94;

- A / turkey / Minnesota / 10734-5 / 95;

- A / chicken / Puebla / 28159-474 / 95;

- A / chicken / Chiapas / 28159-488 / 95;

- A / turkey / Minnesota / 3689-1551 / 81 [13,14,16].

Known strain A / mallard duck / Pennsylvania / 10218/84 H5N2, used in studies to study the virus crossing the interspecies barrier from birds to mammals by conducting a series of passages of the original virus through the lungs of white mice. The invention received a patent (the right holder of the Russian Federation) "Strain of the influenza virus A / H5N2 / TKB No. 2340 birds for modeling influenza infection" [1].

All of the above strains are low pathogenic and were isolated more than 25 years ago in territories geographically remote from Russia, therefore, they are not relevant for our country at present.

A number of domestic strains of the highly pathogenic avian influenza virus A / H5 are known:

- strain No. 125-DEP H5N1 "Novosibirsk", used to control the immunogenic and antigenic activity of vaccines and the manufacture of biological products for the diagnosis and specific prevention of avian influenza [3];

- strain A / duck / Novosibirsk / 56/05 H5N1, used to simulate viral infection in scientific experiments when studying the effectiveness of antiviral drugs on cell cultures [2];

- strain A / Goose / Krasnoozerskoye / 627/05 H5N1, used to study the biology of the influenza virus, as well as the effectiveness of therapeutic and prophylactic drugs against influenza [4];

- strain A / common gull / Chany / 2006 H5N1, used for the preparation of antigen-containing diagnostic or vaccine preparation [5];

- strain A / goose / Kalmykia / 813/16 H5N8, used to control the antigenic and immunogenic activity of vaccines against avian influenza and for the manufacture of biological products for the diagnosis and specific prevention of avian influenza type A, subtype H5 [6].

The disadvantage of previously presented inventions on strains of avian influenza A / H5 virus is that at present these pathogens do not fully cover the biological diversity of influenza virus isolates identified in Russia, which is extremely important for improving methods of diagnosis and prevention of avian influenza in the country. ...

The technical problem to be solved by the present invention is to expand the arsenal of modern strains of the influenza A / H5 virus, which have high infectious and antigenic activity, which is necessary for testing the protective properties of vaccines against circulating strains, as well as for the manufacture of biological products that improve the quality of diagnostic methods. highly pathogenic avian influenza.

This problem was solved by obtaining a newly isolated strain of the avian influenza A / chicken / Kostroma / 3175/17 H5N2 virus in Russia, which has unique genetic characteristics and is used to control the immunogenic activity of vaccines and to manufacture antigen-containing biological products for the diagnosis of influenza A / H5N2.

The viral isolate, which served as a source for obtaining a strain of the avian influenza A / chicken / Kostroma / 3175/17 H5N2 virus was isolated from pathological material from a chicken, which was received by the FGBI "ARRIAH" on 12/18/17 from ZAO "Poultry farm Kostroma", Kostroma region, Kostroma area.

The strain is able to multiply in 10-day-old SPF-chicken embryos (SPF-CE) without preliminary adaptation and cause the death of embryos within 24-48 hours of incubation. The viral preparation of the strain A / chicken / Kostroma / 3175/17 H5N2 of the avian influenza virus in the form of an extraembryonic suspension was obtained after two passages in SPF-EC.

It has been experimentally proven that the strain has optimal biotechnological properties (high antigenic and infectious activity; stable growth rates after 4 consecutive passages in SPF-CE) and has unique genetic characteristics, which suggests its use for the production of diagnostic antigens and sera, for testing the immunogenicity of vaccines, and to study the biodiversity of the influenza virus.

Strain A / chicken / Kostroma / 3175/17 H5N2 of avian influenza virus, deposited on March 30, 2018 in the Collection of strains of microorganisms of the Federal Center for Animal Health Protection under the registration name A / chicken / Kostroma / 3175/17 H5N2 ( diagnostic - D) ".

The essence of the invention is illustrated in a graphical representation. A dendrogram is presented that reflects the phylogenetic relationships of the A / chicken / Kostroma / 3175/17 H5N2 strain with epizootic and vaccine strains (the dendrogram is based on a comparison of the complete nucleotide sequences of the H5 hemagglutinin gene region 848-1105 bp).

The essence of the invention is illustrated by the following sequence lists:

SEQ ID NO: 1 is the nucleotide sequence of a fragment of the hemagglutinin gene (258 bp) of the A / chicken / Kostroma / 3175/17 H5N2 strain.

SEQ ID NO: 2 is the amino acid sequence of the hemagglutinin fragment (aa 86) of the A / chicken / Kostroma / 3175/17 H5N2 strain.

The A / chicken / Kostroma / 3175/17 H5N2 avian influenza virus strain is characterized by the following features and properties.

Morphological characteristics

The A / chicken / Kostroma / 3175/17 H5N2 AIV strain belongs to the Orthomyxoviridae family, the Alphainfluenzavirus genus, the Influenza A virus species and has morphological features characteristic of the influenza A influenza virus.

Influenza virus virions are enveloped, pleomorphic. The diameter of the spherical particles is about 100 nm; filamentary particles about 17 nm in diameter, 250 nm long or more. On the surface of the virion there are spike-like projections (up to 14 nm) formed by HA homotrimers. In type A viruses, NA molecules are located between the HA clusters.

The lipid membrane surrounds loop-shaped filaments of nucleocapsids with eight fragments of the viral genome, each of which is represented by a linear single-stranded antisense RNA.

The total genome length is about 13,600 nucleotides (nt). The largest fragment (No. 1) contains about 2350 IO; No. 2 - slightly less than 2350 Acting; No. 3, as a rule, - 2250 AU; No. 4 - 1780 acting; No. 5 - 1575 acting; No. 6 - 1420 Acting; No. 7 - 1050 Acting; No. 8 - 900 n.a.

At both ends of each genomic RNA strand there are repeated segments, and the repeats of the 5'-terminal region (in influenza A viruses they look like 5'-AGUAGAAACAAGG) are complementary to inverted repeats located at the 3'-end. In addition, the 3'-terminal regions of some fragments of the genome contain conservative segments typical of viral strains infecting subjects of a certain biological species [9].

Antigenic properties

The antigenic variability of the virus is based on the identification of two major surface proteins, HA and NA.

The A / chicken / Kostroma / 3175/17 H5N2 AIV strain has an antigenic formula H5N2. The H5N2 subtype was identified by PCR, nucleotide sequencing, RTGA (hemagglutination inhibition reaction) and PTHA (neuraminidase activity inhibition reaction) [12].

The virus is stably neutralized by a homologous antiserum. The hemagglutinating activity of the strain is 1:32 and is suppressed by a specific serum to AIV A / H5N1 (IZSVe, Italy).

The neuraminidase activity of the strain is suppressed by a specific serum to AIV A / H6N2 (IZSVe, Italy).

Geno- and chemotaxonomic characteristics

VGP strain A / chicken / Kostroma / 3175/17 H5N2 is an RNA-containing virus with a molecular weight of 250 × 10 ⁶ D.

The genome of the influenza virus is represented by single-stranded RNA of negative polarity in the form of 8 strands (segments) in a complex with the nucleoprotein (NP) protein.

Influenza virus virions have an outer lipoprotein membrane, often spherical in shape. The diameter of the spherical shapes is about 100 nm. Viral particles contain RNA - 1%, proteins - 70%, fats - 20%, carbohydrates - up to 8%.

Resistance to external factors

The A / chicken / Kostroma / 3175/17 H5N2 strain of VGP is sensitive to detergents, formaldehyde, beta-propiolactone, aziridine derivatives, and is rapidly inactivated upon heating (56 ° C), ultraviolet irradiation and at pH below 5.0.

After freeze-drying, the strain does not lose antigenic and infectious activity, and has stable growth rates after 3 consecutive passages in SPF-EC.

Additional signs and properties

Pathogenicity - pronounced for birds: the structure of the HA cleavage site contains basic amino acids and has the REKRRKR (Arg Glu Lys Arg Arg Lys Arg) structure, which is characteristic of highly pathogenic forms of influenza.

Virulence - high: Chick Intravenous Infection Index (IVPI) is 3 [12].

Contagiousness - contagious. Non-immune chickens become infected when they are kept together with infected ones.

Free from contamination by bacteria, mycoplasmas and foreign viruses.

The essence of the invention is illustrated by examples of its use, which do not limit the scope of the invention.

Example 1. Determination of the subtype antigenic characteristics of the strain was performed in RTGA with reference sera against AIV subtypes H1-H16 for hemagglutinin and in PTHA with reference sera against AIV subtypes N1-N9 for neuraminidase. Samples of the viral suspension were preliminarily studied in the hemagglutination reaction (HA) to determine the hemagglutinating activity of the virus. The activity of the A / chicken / Kostroma / 3175/17 H5N2 VGP strain in the RHA was 1:32. Normal chicken serum (IZSVe, Italy) was used as a negative control.

In RTGA, the hemagglutinating activity of the test sample was suppressed by a specific serum to AIV A / H5N1 (IZSVe, Italy). The serum titer was 1: 128 (7 log ₂ ). In PTHA, the neuraminidase activity of the test sample was inhibited by a specific serum to AIV A / H6N2 (IZSVe, Italy). The results are shown in Tables 1 and 2.

According to the studies, the A / chicken / Kostroma / 3175/17 H5N2 AIV strain was assigned to the avian influenza virus of the H5N2 subtype.

Example 2

To identify the AIV genome, total RNA was isolated from tissue samples of birds and extraembryonic fluid of infected chicken embryos, which was used for polymerase chain reaction (PCR) and reverse transcription polymerase chain reaction (RT-PCR) reactions. Primary indication of the M gene was performed using primers AIVM49F and AIVM941R.

PCR and RT-PCR methods were used to confirm the absence in the suspension of the extraembryonic fluid of the strain of contamination with the genomes of Newcastle disease viruses, infectious bronchitis of chickens, infectious bursal disease, egg production syndrome, infectious laryngotracheitis of birds, avian reovirus, as well as mycoplasmas of synovia and gallisepticum.

As a result of the tests, it was proved that the A / chicken / Kostroma / 3175/17 H5N2 strain of AIV is not contaminated with foreign viruses and mycoplasmas and contains only the genome of the influenza A subtype H5 virus.

Example 3

The studies were based on the determination of the primary structure of the HA gene fragment of the test sample of the A / chicken / Kostroma / 3175/17 H5N2 strain with subsequent analysis of the phylogenetic relationship with other AIV strains and isolates of the H5N2 subtype.

After amplification of the DNA obtained using the above primers, as a result of sequencing, the nucleotide (258 nt) and amino acid (86 aa) sequences of the HA gene fragment of the A / chicken / Kostroma / 3175/17 H5N2 strain were determined.

The HA cleavage site of the A / chicken / Kostroma / 3175/17 H5N2 strain of HA contained basic amino acids and had the REKRRKR structure characteristic of highly virulent forms of the virus.

When conducting a comparative analysis of the nucleotide sequence, it was found that the isolate under study belongs to the Asian genetic line of the highly pathogenic avian influenza virus (line A / Goose / Guangdong / 96, clade 2.3.4.4).

Phylogenetic analysis showed (Fig. 1) that according to the HA gene fragment for the A / chicken / Kostroma / 3175/17 H5N2 strain, the most closely related are those isolated in a number of subjects of the Russian Federation, Egypt, South Korea, Belgium and the Czech Republic in 2016-2017 ... avian influenza virus A / H5N8, as well as viruses of the H5N2, H5N6 and H5N8 subtypes isolated in the territory of South-East Asia in 2012-2014. (98-99.5% similarity).

Thus, based on molecular biological and phylogenetic studies, it was established that the A / chicken / Kostroma / 3175/17 H5N2 avian influenza virus strain is potentially highly pathogenic for birds and belongs to clade 2.3.4.4. Asian genetic line (A / Goose / Guangdong / 96).

Example 4

To assess the virulence of the A / chicken / Kostroma / 3175/17 H5N2 strain of the avian influenza virus, we used the method for determining the pathogenicity index for intravenous infection of 6-week-old chickens (IVPI) recommended by the World Organization for Animal Health [12]. A viral suspension of the VGP strain A / chicken / Kostroma / 3175/17 H5N2 at a dilution of 1:10 in sterile saline was injected intravenously to ten 6-week-old chickens at a dose of 0.1 cm ³ . The birds were monitored daily for 10 days and the clinical condition of each bird was taken into account using the coefficient: 0 - the bird is clinically healthy; 1 - sick (some signs of the disease are noted, such as depression, refusal of food and water, cyanosis of the skin or its derivatives, disorders of the respiratory or digestive tract, nervous phenomena); 2 - seriously ill (several clear clinical signs of infection are observed simultaneously); 3 - the bird died. The pathogenicity index was calculated by the formula:

where B _i is the number of patients per day

TB _i - the number of seriously ill patients per day g;

P _i - the number of deaths per day i;

N is the total number of birds in the experiment.

After 1 day of the experiment, all infected birds died, which made it possible to draw a conclusion about the acute course of the disease. The results of observations of the clinical state of birds and the value of the pathogenicity index are presented in Table 3. The A / chicken / Kostroma / 3175/17 H5N2 strain of AIV had a maximum pathogenicity index of 3.0, therefore the studied virus was identified as highly virulent (pathogenicity index 1.2 and more) [12].

Example 5

The infectious activity of the A / chicken / Kostroma / 3175/17 H5N2 AIV strain was determined by titration in SPF-EC. A series of 10-fold serial dilutions (from 10 ^-1 to 10 ^-10 ) were prepared. Each dilution of the virus was inoculated into the allantoic cavity with four 9-11-day SPF-CE in a volume of 0.2 cm ³ . Four embryos of the control group were injected with PBS in the same way in a volume of 0.2 cm ³ . The specificity of death was confirmed in the RHA by examining the extra-emryonic fluid from each infected embryo. The titer of the virus in the deposited sample was determined by the Kerber method and expressed in units of EID ₅₀ / cm ³ (table 4).

Thus, the infectious activity of the VGP strain A / chicken / Kostroma / 3175/17 H5N2 with 2-fold titration in SPF-CE was 8.38 ± 0.12 lg EID ₅₀ / cm ³ .

Example 6

The stability of the A / chicken / Kostroma / 3175/17 H5N2 AIV strain was determined by the reproduction of a lyophilized and recovered virus during two consecutive passages in 9-11-day SPF-CE, determining the infectious activity of each passage of the virus in 2-fold replication in the same biosystem ... The methodology is described in detail in example 5. The titer of the virus was calculated by the method of Kerber (table 5).

Based on the data obtained, it was established that the indicator of the infectious activity of the A / chicken / Kostroma / 3175/17 H5N2 AIV strain after lyophilization for two consecutive passages in 9-11-day SPF-EC did not decrease less than 8.25 lg EID ₅₀ / cm ³ , which confirms its stability during reproduction in the specified biosystem.

Example 7

Obtaining an angens-containing preparation for diagnostic purposes. The viral suspension of the A / chicken / Kostroma / 3175/17 H5N2 strain was inactivated with beta-propiolactone (BPL) at a final concentration of 0.05%. To inactivate the virus, a 10% LTP working solution prepared in sterile demineralized water was used. The LTP working solution was prepared immediately before inactivation and introduced into a vessel with a virus-containing liquid. Each vessel with the resulting mixture, after gentle stirring (without the formation of foam), was incubated on a shaker at a temperature of (37 ± 2) ° C for 1 h. Then, the suspension was left overnight in a refrigerator at (4 ± 2) ° C. After that, a sample of raw materials in a volume of 2 cm ^{3 was} taken from the vessel to determine the completeness of the virus inactivation, and the viral material was stored at a temperature of (4 ± 2) ° C until the end of the control.

The completeness of inactivation was assessed by carrying out two consecutive passages in the SPF-CE. When testing the extraembryonic fluid in the RHA, the absence of hemagglutinating activity was observed.

Then, the quality of the obtained inactivated drug was assessed in RGA, RTGA, RTNA and RT-PCR. It was found that the hemagglutinating activity of the A / chicken / Kostroma / 3175/17 H5N2 VGP strain did not change and amounted to 32 HAU. With the help of RTGA and RTNA, the antigenic formula of the studied inactivated preparation of the H5N2 VGP strain was determined. The RT-PCR reaction confirmed the presence of the A / H5 AIV genome in the sample. All the tests carried out allowed us to conclude that the A / chicken / Kostroma / 3175/17 H5N2 strain of AIV is completely inactivated by LTP at a final concentration of 0.05%, while it does not lose its antigenic and hemagglutinating activity, therefore it is suitable for the manufacture of antigen-containing diagnostic preparations.

Sources of information taken into account in the preparation of the description of the invention to the application for the grant of a patent of the Russian Federation for the invention "Strain A / chicken / Kostroma / 3175/17 H5N2 of avian influenza virus of subtype H5N2 Influenza A virus, genus Alphainfluenzavirus for control of antigenic and immunogenic activity of vaccines against influenza birds and for the manufacture of antigen-containing diagnostics ”.

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Claims (1)

VGP strain A / chicken / Kostroma / 3175/17 H5N2 of the family Orthomyxoviridae, genus Alphainfluenzavirus of the species Influenza A virus subtype H5N2, deposited in the Collection of strains of microorganisms of the Federal Center for Animal Health under registration number: "Strain Kostroma / chicken / 3175/17 H5N2 (diagnostic - D) "for monitoring the antigenic and immunogenic activity of vaccines against avian influenza and for the manufacture of antigen-containing diagnostic kits.

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