RU2082433C1 - Method of influenza vaccine prophylaxis - Google Patents

Abstract

FIELD: medicine, medicinal virology. SUBSTANCE: immunization is carried out with vaccine containing at least two strains of influenza virus type B and/or each of influenza virus subtype A. Vaccine concentration is at the range from 2.7-4.2 mcg/0.5 ml to 2.7-4.2 ng/0.5 ml hemagglutinin for inactivated vaccine and from 3 x 4.5 lg ID₅₀/0.2 ml - 3 x 6.5 lg ID₅₀/0.2 ml to 3 x 3.5 lg ID₅₀/0.2 ml - 3 x 5.5 lg ID₅₀/0.2 ml for live antiinfluenza vaccine. Immunization requires the corresponding vaccine involving polyvalent preparation with that strain composition. EFFECT: enhanced effectiveness and safety of vaccine prophylaxis. 2 cl, 9 tbl

Description

 The invention relates to medicine, namely to medical virology and can be used in the prevention of infectious diseases.

 A method of influenza vaccination is known, based on the parenteral administration of an inactivated vaccine / cm. e.g. Smorodintsev A.A. Influenza and its prevention. Medicine, L, 1984, p. 233-255 /.

 The disadvantages of these methods is a certain damaging effect associated with the introduction of a foreign protein.

 The closest to the claimed method of influenza vaccination is the method of intranasal administration of an inactivated or live influenza vaccine, which consists in the fact that 0.25 ml of a standard preparation is introduced into each nasal passage. e.g. Kostyuchek N.V. Erofeeva M.K. Maksakova V.L. et al. "The results of testing the intranasal use of inactivated influenza vaccines" // Prevention of influenza and other acute respiratory infections in adults and children. Collection of scientific. Proceedings of the All-Russian Research Institute of Influenza of the Ministry of Health of the USSR, 1987, p. 29-33, as well as Orlov V.A. Malikova E.V. Yudova O.E. et al. "Results of the study of the compatibility of live influenza vaccines of subtypes A / H1 N1 / and A / H3 N2 /" // Problems of the design of influenza vaccines. Collection of scientific. Proceedings of the All-Russian Research Institute of Influenza of the Ministry of Health of the USSR, 1988, p. 69-74 /.

 The disadvantage of this method is the relatively low efficiency of influenza vaccination and low safety due to the introduction of foreign protein into the body in relatively high concentrations.

 The aim of the invention is to increase the efficiency and safety of vaccination.

 To obtain both inactivated and live vaccines, at least two strains are used, for example, representatives of different circulation periods of each subtype of influenza A virus: A / H1N1 / and A / H3N2 / and / or two different strains of type B influenza virus. Thus , the vaccine should contain at least 6 strains, two from each antigenic component.

The goals in relation to the method of influenza vaccination are achieved in that a vaccine containing at least two strains of each subtype of influenza A virus and / or two strains of influenza B virus is diluted to 4.2 μg of 2.7 ng of hemagglutinin per dose for inactivated and up to 3 • 5.5 lg ID _{50 / 0.2} ml 3 • 3.5 lg ID _{50 / 0.2} ml for live influenza vaccine and administered once or several times.

 The claimed sign of vaccine polyvalency within the subtype is new, because never before in order to save production have the strain composition of vaccines been complicated in practice and immunization with several strains within the subtypes of virus A or type B.

The claimed combination of features according to the method of influenza vaccination is new and gives completely new properties to the method, since it was never previously known that such a multivalent vaccine can be administered in such a diluted form. All known methods of vaccine prevention were aimed at the introduction of drugs above a certain threshold concentration. The receipt of influenza vaccines has also always been aimed at achieving higher concentrations, which are determined by all the requirements in our country for inactivated vaccines of 9-11 μg / 0.5 ml for each subtype of influenza A virus, 12-14 μg / 0.5 ml for viruses type B. And for drugs of foreign manufacture up to 12-15 μg / 0.5 ml and even up to 15-20 μg / 0.5 ml for military influenza vaccines in the USA. For live vaccines, the standard concentration is 5.5 lg ID _{50 / 0.2;} 7.5 lg ID _{50 / 0.2} ml, depending on the type of influenza virus in the preparation. Therefore, the claimed combination of features according to the method of preventing influenza is unexpected, confirming the materiality of the inventive step of this decision. It is also obvious the impossibility of implementing the method of prevention without specially obtained, multivalent within the subtypes A and type B vaccines.

 The choice of the optimal mode of the vaccination method is confirmed by the following data. As can be seen from the table. 1, the introduction of two strains of influenza A seropodotype A / H3N2 / into the drug led to a significant decrease in the death of mice when infected with influenza A / Aichi virus / 68 seropodotype A / H3N2 /.

 A much more convincing effect of vaccination according to the proposed method was achieved on large groups of vaccinated volunteers. As a result, performance indices according to the most stringent criterion of incidence in the experimental groups that received multivalent vaccines according to the claimed method, with a high reliability, were 1.6-2.9 times higher than the corresponding indices in the control groups / cm. tab. 2 3 /. Moreover, the protective effect was observed both with inactivated and live influenza vaccines and was determined only by the number of strains of this subtype / virus type /, i.e. multivalency of the drug.

The effect of dilution of a standard inactivated influenza vaccine with an initial concentration of hemagglutipin of 9-14 μg / 0.5 ml per component and dilution of a standard live influenza vaccine with an initial concentration of 6.5 lg ID _{50 / 0.2} ml of subtype A / H3N2 / virus on the effectiveness of protection are presented in table. 4 and 5. As you can see, the dilution of the inactivated vaccine from 4.2 μg / 0.5 ml to 2.7 ng / 0.5 ml of the total hemagglutinin content did not reduce its effectiveness in relation to the incidence of influenza and acute respiratory infections during the epidemic. Whereas, with a decrease in hemagglutinin content ranging from 0.27 0.42 ng / 0.5 ml, a significant decrease in efficiency occurred, and at a concentration of 27-42 ng / 0.5 ml, there was no effectiveness. Dilution of live influenza monovaccine from viruses of subtype A / H3N2 / from 5.5 lg to 4.5 lg ID _{50 / 0.2} ml also did not reduce its effectiveness in relation to the incidence of influenza during the epidemic, which follows from the data of serological correction of diagnoses in patients persons.

 Thus, the claimed method includes two essential features - polyvalency of the strain composition of the drugs and the possibility of their dilution. The optimal dilution of the vaccine used to implement the method depends on the initial indicators of biological activity. As follows from the data in Table 6, the most pronounced effect was achieved under epidemiological observation when, when diluting the initial 4-valent preparation containing two strains of influenza viruses A / H1N1 / and A / H3N2 /, 1000 times, i.e. to 27-42 ng / 0.5 ml of the total hemagglutinin content, the efficacy index increased to 0.2 compared with 1.4 for the group vaccinated with the whole standard vaccine.

 Preservation of effectiveness when using the standard inactivated influenza vaccine in various concentrations, according to the serological correction of the diagnoses, was observed regardless of the route of administration / cm. tab. 7 /.

 Improving the safety of the proposed method of influenza vaccination is confirmed by the results summarized in table. 8 and 9.

 Monitoring of vaccinated standard influenza vaccines for 6 months revealed a significant increase in somatic morbidity due to immunization / table. 8/. Dynamic monitoring of vaccinated against influenza revealed during the epidemic a significant increase in the incidence of non-influenza respiratory viral infections / table. nine/. As you can see, the claimed method did not cause such significant immunological changes in the body of the vaccinated and did not lead to the growth of other respiratory diseases among vaccinated using minimal concentrations of the drug. A direct clear relationship was found between the damaging effect of the drug and its concentration.

 The effectiveness of the claimed invention is illustrated by the following examples.

 Example 1

On November 23, 1990, 270 volunteers were inoculated with the commercial inactivated influenza vaccine of series 141 intravasally once in a 0.25 ml dose in each nasal passage using an RJ-M4 liquid nebulizer. The vaccine contained 10 μg / 0.5 ml of the influenza virus hemagglutinin A / Taiwan / 1/86 / H1N1 / and A / USSR / 2/85 / H3N2 / and 13 μg / 0.5 ml of the influenza B virus hemagglutinin / Kharkov / 249 / 88. Another 120 people were vaccinated with the same drug at a 1:10 dilution, i.e. at a concentration of 1 μg / 0.5 ml for type B virus. The control group receiving placebo included 180 people. The incidence of influenza and other acute respiratory diseases in these groups was respectively equal to 31.9% / IE efficiency index 1.4 /, 25.8% / IE 1.7 / and 45.0%
Thus, the dilution of a standard vaccine not only did not reduce, but also led to some increase in the effectiveness of immunization.

 Example 2

 In the same period, 120 volunteers received an inactivated influenza vaccine of series 141 at a dilution of 1: 10,000 containing 1 ng / 0.5 ml of hemagglutinin A virus / Taiwan / 1/86 / H1N1 /, 1 ng / 0.5 ml hemagglutinin influenza virus A / USSR / 3/85 / H3N2 / and 1.3 ng / 0.5 ml of virus B / Kharkov / 249/88. A control group of 180 people received a placebo. The incidence of influenza and other acute respiratory infections during the epidemic in the experimental group was 23.7% and was significantly 1.9 times lower than in the control (45.0%).

 Thus, the dilution of a standard vaccine preparation even 10,000 times not only did not reduce, but also led to some increase in the effectiveness of immunization.

 Example 3

 In the autumn period of 1990, 120 volunteers received, intravasally, as described in Example 1, a mixture of three inactivated influenza vaccines prepared from 8 components based on the A / Taiwan / 1/86 / H1N1 / + N 1B - 16 / H1N1 / + A viruses / Kiev / 59/79 / H1N1 /, A / USSR / 2/85 / H3N2 / + A / Mississippi / 1/85 / H3N2 / + A / Leningrad / 385/80 / H3N2 / and B / Kharkov / 249/88 + B / Leningrad / 179/86 with a total hemagglutinin content of each of the two seroptypes of influenza A virus of 10 μg / 0.5 ml and type B viruses of 13 μg / 0.5 ml. A similar group of 270 people received the same method of inactivated conventional commercial vaccine, including viruses A / Taiwan / 1/86 / H1N1 / + A / USSR / 2/85 / H3N2 / + B / Kharkov / 249/88 in the same standard concentration . The incidence of influenza and acute respiratory infections during an outbreak in these groups was 21.6% and 31.9%, respectively, and the performance indices were 2.1 and 1.4, respectively, i.e. there was a significant increase in efficiency when using a multivalent drug. In both vaccinated groups, significant differences were established compared with the control.

 Example 4

36 people in September 1987 were vaccinated with an intravasally live influenza vaccine of the composition A / Philippines / 82 / 17F / H3B2 / in a standard concentration of 6.5 lg ID _{50 / 0.2} ml. At the same time, 0.25 ml of the drug was injected into each nasal passage with a RJ-M4 nebulizer. Another group of individuals with a total number of 42 people introduced the same drug at a 1:10 dilution. Serological registration of the incidence of influenza subtype A / H3N2 / during the epidemic showed that the effectiveness of a commercial drug in a standard concentration and its 10-fold dilution are almost equally effective. The incidence in vaccinated groups was respectively 13.2% and 14.3% versus 42.9% in the control group, which consisted of 80 people. The incidence of influenza in vaccinated groups was significantly, respectively, 3.3 and 3.0 times lower than in the control group.

 Example 5

In the same season (see example 4), 30 volunteers were intranasally inoculated with live influenza monovirus A / Philippines / 82 / 17F / H3N2 / at a concentration of 4.5 log ID _{50 / 0.2} ml. When taking into account the incidence during the epidemic after serological correction, the flu was detected in 13.8% of volunteers and was significantly 3.1 times less likely than in the control group of 80 volunteers who received a placebo. Thus, the dilution of a live vaccine not only 10, but also 100 times in comparison with the standard concentration, did not reduce its effectiveness.

 Example 6

In September 1987, 154 volunteers were vaccinated (see Example 4) with a live influenza vaccine of the composition A / Philippines / 82 / 17F / H3N2 / + A / Bangkok / _1/79 / H3N2 / in a standard concentration of 6.5 lg ID _{50/0 , 2} ml total for two strains of the virus subtype A / H3N2 /. Another group of 150 people in the same way received a live influenza monovaccine composition A / Philippines / 82 / 17F / H3N2 / in the same standard concentration of 6.5 lg ID _{50 / 0.2} ml. The incidence during the flu epidemic was respectively 12.5% and 20.4%. In the control group of 189 volunteers, 20.0% fell ill
Thus, an increase in the number of strains in the preparation led to a significant decrease in the incidence rate by 1.6 times, while the monovalent standard preparation was ineffective.

 Technical and economic efficiency of the invention.

The claimed method of vaccine prevention significantly and reliably 1.6 to 2.9 times increases the effectiveness of protection. With economic losses from one case of influenza or ARI equal to 128 rubles / cm. Ivannikov Yu.G. Ismagulov A.T. Epidemiology of influenza. Kazakhstan. Alma-Ata 1983 p. 76-77 /, and taking into account the inflation rate of 1280 rubles, and the epidemic incidence rate, for example, equal to 14.5% (see Table 2), economic losses when converted to 1000 people will be respectively equal (prices of 1992):
unvaccinated persons 146 cases zab. x 1280 rub. 185.600 p.

 in prototype protected 133 cases zab. x 1280 rub. 170.240 p.

 in protected by the claimed method 52 cases zab. x 1280 rub. 66.560 RUB

Thus, the savings from reducing the incidence of influenza and acute respiratory infections are:
when using the prototype method:
185.600 170.240 15.360 rubles.

when using the claimed method:
185.600 66.560 119.040 rub.

 It should be noted that the maximum reduction in the epidemic incidence recorded by us by the claimed method was 6.7 times / P≅0.05 / in the absence of the effect of the prototype method. In addition, the claimed method due to antigenic enrichment of the drug, when compared with the prototype method, provides high reliability protection with high variability of the epidemic variants of the influenza virus.

 The vaccine consumption during the event according to the claimed method is reduced by at least 10 times, due to the dilution of the standard drug. The cost of 1000 doses of inactivated influenza vaccine is 21.100 rubles. Thus, the savings in reducing the concentration of the drug spent per 1000 vaccinees are: 21.100 /21.100:10/18.990 rubles. The cost of 1000 doses of live influenza vaccine is 4,500 rubles. Therefore, the savings with a decrease in the concentration of the drug by only 10 times will be: 4.500 /4.500:10/4050 rubles.

An increase in the incidence of other nosological forms / somatic morbidity of an inflammatory nature, non-influenza acute respiratory infections / after vaccination has not yet been taken into account. Meanwhile, the administration of inactivated and live influenza vaccines is accompanied by an increase in non-influenza respiratory morbidity by 2.4–2.6 times, respectively, and somatic morbidity by 1.3 and 1.4 times (see Tables 8 and 9). A decrease in the concentration of inactivated and live influenza vaccines by only 10 times is accompanied by a less damaging effect: non-influenza respiratory morbidity increases by 1.6 and 1.7 times when compared with control groups of unvaccinated individuals. The economic effect of reducing the respiratory incidence of non-influenza origin in this case, when calculated per 1000 people (table. 9):
for inactivated vaccine / 83-57 / case. diseases: x 1280 rub. 33.280 rub.

for live influenza vaccine:
/ 92-60 / cases of disease x 1,280 rubles. 40.960 RUB

 Given the massive nature of the flu, the need to protect tens of millions of people, the economic calculations presented do not seem exaggerated.

Finally, the possibility of using low concentrations of viral antigens for vaccination opens up the possibility of using tissue influenza vaccines, the production of which has not yet been economically justified. The claimed method, in addition to medicine, can be used in veterinary medicine. The transition to the use of tissue vaccines, in turn, will lead to the replacement of food raw materials
chicken embryos, still widely used in the production of influenza vaccines. The economic feasibility of this can be assessed only approximately so far, but it will also provide a significant economic and social effect.

Claims (2)

 1. The method of influenza vaccination by introducing an inactivated multivalent influenza vaccine, characterized in that the vaccination is carried out parenterally or intranasally with at least two strains of influenza virus type B and / or each influenza A subtype in a total dose for each subtype / type from 2.7 to 4 , 2 μg to 2.7 4.2 ng of hemaglutinin in a volume of 0.5 ml with appropriate dilution with an isotonic sodium chloride solution. 2. The method vaccinal influenza by administering a multivalent live influenza vaccine, characterized in that the immunization is carried out by at least two strains of influenza virus and / or each subtype of influenza A in a total dose of 4,5 6,5 lq ID _{5 0/0, l} to _{2 m} 3,5 5,5 lq ID _{5 0/0, l m 2} in a volume of 0.5 mL with appropriate dilution with isotonic sodium chloride solution.

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