WO2012164928A1 - H5n1 influenza vaccine and kit for protection against infection - Google Patents

Abstract

Provided is an H5N1 influenza vaccine which can prevent the infection with an H5N1 influenza virus of a strain other than a strain to be vaccinated satisfactorily. The H5N1 influenza vaccine is used in such a manner that the initial vaccination comprising two times of administration is performed and the booster vaccination of a vaccine of the same strain as that of the initial vaccination is then performed at least one time after elapse of a predetermined time period for a human body. Both the H5N1 influenza vaccine for the initial vaccination and the H5N1 influenza vaccine for the booster vaccination are derived from the Qinghai strain. The above-mentioned predetermined time period after the initial vaccination is a time period ranging from 1 month to 3 years inclusive, specifically 6 months.

Description

H5N1 influenza vaccine and infection protection kit

The present invention relates to a specific usage of H5N1 influenza vaccine and an infection protection kit against H5N1 influenza virus.

Influenza is an acute infectious respiratory disease caused by an influenza virus that spreads through respiratory droplet infection. Influenza is one of the viral infectious diseases that may be prevalent on a global scale, and the establishment of an effective prevention method is desired.

Influenza viruses are classified into subtypes such as A Soviet type (H1N1) and A Hong Kong type (H3N2) depending on the type of hemagglutinin (HA) protein or neuraminidase (NA) protein, which is a major surface antigen present on the surface of virus particles. being classified.

It has also been known that influenza viruses hosted by other species of animals such as birds directly infect humans (Non-patent Document 1). Since May 1997, it has been confirmed in birds, but it was found in humans. A number of infected H5N1 influenza viruses were confirmed. In the future, there is no denying the possibility that this will be transformed into a virus that infects humans, resulting in a global pandemic.

It is reported that when humans are infected with this H5N1 influenza virus, it causes severe symptoms such as fever of 38 degrees or more, diarrhea, nosebleed, gingival bleeding, blood clot, dyspnea, etc. Has been.

Patent Document 1 describes a technique for immunizing against a pandemic influenza virus typified by H5N1 type, in which an immunogenic composition containing influenza virus is initially administered twice at intervals of less than 14 days. Has been.

Special table 2011-506290 gazette

K. Subbarao et al., Science 279: 393-396 (1998)

However, the above-mentioned method cannot sufficiently prevent infection of subtype H5N1 influenza other than the vaccinated strain, and a method capable of preventing many subtypes of H5N1 influenza infection with high probability is required.

The present invention has been made in view of such problems, and an object of the present invention is to provide an H5N1 influenza vaccine that can sufficiently prevent infection with H5N1 influenza viruses other than vaccinated strains.

In the H5N1 influenza vaccine according to the first aspect of the present invention, the H5N1 influenza vaccine is first inoculated to humans consisting of two doses, and after the passage of a predetermined period, It is characterized in that it is used such that the vaccine is boosted at least once.

It is preferable that the H5N1 influenza vaccine for the initial vaccination and the additional vaccination are both derived from the Aomi strain.

The predetermined period is preferably from January to 3 years.

The H5N1 influenza vaccine preferably has an adjuvant.

It is preferable that the H5N1 influenza vaccine of the first inoculation and the additional inoculation has an HA antigen amount of 1 μg to 200 μg per dose.

In the initial vaccination, it is preferable that the H5N1 influenza vaccine is administered twice at intervals of 2 weeks or more and 4 weeks or less.

The initial inoculation and the additional inoculation are preferably intramuscular inoculation or subcutaneous inoculation.

An infection protection kit against H5N1 influenza virus according to the second aspect of the present invention is the H5N1 influenza vaccine according to any one of claims 1 to 7 and the H5N1 influenza vaccine for humans. And a device for administration.

The H5N1 influenza vaccine according to the present invention does not cause an adverse event more than necessary, and can significantly increase cross immunity. In addition, the vaccine strain used in the booster vaccination is the same as the vaccine strain used in the initial vaccination, and it is not necessary to prepare a different vaccine strain, so that cross immunity can be increased at a low cost. A pandemic vaccine can only be manufactured after a pandemic has actually occurred and the pathogenic virus has been identified, and its production requires at least 6 months. The pre-pandemic vaccine used for can be made into a pandemic vaccine. Thus, the benefits obtained by the present invention are immeasurable.

It is a figure which shows the neutralizing antibody titer with respect to a Vietnamese strain. It is a figure which shows the neutralizing antibody titer with respect to an Aomi sea strain. It is a figure which shows the neutralizing antibody titer with respect to an Indonesian strain. It is a figure which shows the neutralizing antibody titer with respect to an Anne strain.

Hereinafter, embodiments of the present invention will be specifically described with reference to the accompanying drawings. However, the embodiments are for facilitating understanding of the principle of the present invention, and the scope of the present invention is as follows. The present invention is not limited to the embodiments, and other embodiments in which those skilled in the art appropriately replace the configurations of the following embodiments are also included in the scope of the present invention.

The pre-pandemic vaccine is a whole-particle vaccine obtained by inactivating and purifying all particles of influenza virus, and the vaccine of a given strain has been administered twice, and an increase in neutralizing antibody titer has been recognized by the inoculator. Even after vaccination of the same strain after the administration, it was thought that cross immunity could not be obtained, but the present inventors have found that a new cross immunity was obtained as a result of the experiment. The present invention was completed based on the above.

The H5N1 influenza vaccine of this embodiment is first inoculated to humans. The first inoculation is given twice. Next, after the first inoculation, the vaccine of the same strain as that of the initial inoculation is used at least once after a predetermined period.

The influenza vaccine is a multivalent vaccine mainly composed of an infection-protecting antigenic substance produced by culturing influenza virus in growing chicken eggs and decomposing and purifying virus particles collected from the chorioallantoic fluid. During the purification process, all microorganisms are inactivated with formalin. The influenza vaccine may be a live vaccine containing live attenuated microorganisms or a component vaccine detoxified so as not to impair the immunogenicity of the toxin.

Both the initial and booster H5N1 influenza vaccines are from the same strain. For example, Indonesian strain (clade2.1), Anhui strain (clade2.3), or Vietnam strain (clade1), preferably Qinghai strain (clade2.2).

The predetermined period from the first inoculation to the additional inoculation is not particularly limited, but is, for example, 1 to 3 years, preferably 3 to 2 years, more preferably 6 to 1 years. Is the year.

Additional booster is given at least once. When multiple boosters are given, the interval between the nth booster and the (n + 1) th booster (n is a natural number of 1 or more) is the same as the interval between the first booster and the first booster For example, it is January to 3 years, preferably 3 to 2 years, and more preferably 6 to 1 year. For example, when the additional inoculation is performed three times, the first inoculation consisting of two administrations is performed, the first additional inoculation is performed after a predetermined period, and the second additional inoculation is performed after the predetermined period has elapsed. After a predetermined period of time, a third booster inoculation is performed. If the booster is given multiple times, cross immunity can be further increased.

The initial and booster H5N1 influenza vaccines can contain an adjuvant. The adjuvant is not particularly limited, and for example, aluminum salts such as aluminum hydroxide and aluminum phosphate, chitosan, oligodeoxynucleotide, oil-in-water emulsion and the like can be used. Aluminum hydroxide is preferable, and immunogenicity can be enhanced by using aluminum hydroxide as an adjuvant.

Hemagglutinin (HA) is the primary immunogen in inactivated influenza vaccines, and vaccine doses typically refer to HA levels as measured by a single radial immunodiffusion (SRID) assay. To be standardized. The amount of HA antigen in the H5N1 influenza vaccine of the first and booster inoculations is not particularly limited, but is 1 μg to 200 μg, preferably 10 μg to 30 μg, more preferably 15 μg per dose. is there. One dose is, for example, 0.5 mL.

In the initial vaccination, the H5N1 influenza vaccine is administered twice, for example, at intervals of 2 to 4 weeks, and preferably administered twice at intervals of 3 weeks.

In the initial vaccination and booster vaccination, the administration method is not particularly limited, and for example, nasal, subcutaneous, intradermal, transdermal, intraocular, mucosal, or oral administration, preferably intramuscular administration. is there.

Moreover, the infection protection kit against the H5N1 influenza virus according to the present embodiment has the above-mentioned H5N1 influenza vaccine and a device for administering the H5N1 influenza vaccine to humans. The device for administering the vaccine to the human patient is not particularly limited, and examples thereof include a syringe, an inhaler, a nebulizer, and a pipette.

The infection protection kit can also contain pharmaceutically acceptable excipients that help administer the H5N1 influenza vaccine. Excipients include, for example, saline, glycerol, dextrose, lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, phosphoric acid and sodium sulfate And calcium salt, gelatin, acacia gum, sodium alginate, polyvinyl alcohol, polyvinylpyrrolidone and the like.

The present invention relates to a composition that enhances immunogenicity against an H5N1 influenza vaccine in a human patient, the vaccine comprising an antigen against H5N1 influenza is first inoculated to a human patient, and consists of a predetermined period of time. After the elapse of time, a composition of the same strain as that of the initial vaccination can be administered to the human patient to give a booster dose at least once.

Influenza virus Qinghai strain was grown in hen eggs along with gentamicin sulfate, minocycline hydrochloride, fosfomycin sodium, dibekacin sulfate and prednisolone, and the resulting virus was collected, purified by filtration and inactivated with formalin In order to enhance the originality, the vaccine was produced by making it adsorbed on aluminum hydroxide gel and making it insoluble.

For the unvaccinated persons targeting H5N1 type, the Qinghai strain was first inoculated twice at three-week intervals, and additional inoculation was performed once six months after the first inoculation. The HA content of influenza virus was 30 μg / ml. In the first inoculation, 0.5 mL was injected twice intramuscularly at intervals of 3 weeks. Before first vaccination, 2 weeks after vaccination (after 2 vaccinations), before additional vaccination (before 3rd vaccination), 1 week after additional vaccination (1 week after 3rd vaccination), 3 weeks after vaccination (3rd vaccination) Three weeks later), blood was collected a total of 5 times, and cross immunity and immunity persistence against 4 strains of H5N1 influenza virus were examined. In addition, we collected data on local and systemic responses and examined safety.

The subjects were 79 females (65.8%) (average age 36.2 years) and 41 males (34.2%) (average age 39.0 years). Among women, 24 were under 29, 25 were in their 30s, 23 were in their 40s, 6 were in their 50s, and 1 was over 60. Among men, there were 8 people under the age of 29, 16 people in their 30s, 10 people in their 40s, 6 people in their 50s, and 1 person over 60s.

The results are shown in FIGS. 1 to 4 and Tables 1 to 4. FIG. 1 shows neutralizing antibody titers against Vietnamese strains. FIG. 2 shows the neutralizing antibody titer against Aomi strain. FIG. 3 shows neutralizing antibody titers against Indonesian strains. FIG. 4 shows neutralizing antibody titers against Anhui strains.

Table 1 is a table showing the effects (geometric mean antibody titer increase rate, PC analysis) of initial vaccination and additional vaccination (3 times vaccination) of Qinghai strain-derived influenza vaccine, and shows the magnification against Vietnamese strains. Table 2 is a table showing the effects (geometric mean antibody titer increase rate, PC analysis) of the initial inoculation and additional inoculation (three times inoculation) of the Aomi strain-derived influenza vaccine, and shows the magnification with respect to the Aomi strain. Table 3 is a table showing the effects (geometric mean antibody titer increase rate, PC analysis) of initial vaccination and booster vaccination (3 times vaccination) of influenza vaccine derived from Qinghai strain, and shows the magnification against Indonesian strains. Table 4 is a table showing the effects (geometric mean antibody titer multiplication factor, PC analysis) of the initial inoculation and additional inoculation (three times inoculation) of the Aomi strain-derived influenza vaccine, and shows the magnification against the Anhui strain. The brackets are 95% confidence intervals.

Subjects with a neutralizing antibody titer of 40 times or more against Qinghai strain were 58% after 3 weeks inoculation against 0% before inoculation, geometric mean antibody titer multiplication factor 6.8 times (95% confidence interval 5.8-8. 1) and it was confirmed that the two inoculations of Aomi strain are immunogenic.

The geometric mean antibody titer increase ratio comparing neutralizing antibody titer 3 weeks after the 2nd inoculation with Qinghai strain and before the first inoculation is 2.0 times for Vietnam strain, 1.7 times for Indonesia strain, and Anhui strain On the other hand, it was 1.4 times, and did not reach 2.5 times or more, which was recognized as sufficient immunogenicity.

Half a year after the second inoculation, the neutralizing antibody titer against the Aomi strain decreased (the proportion of subjects with a neutralizing antibody titer of 40 times or more was 58% after the second inoculation, compared with 19% half a year later).

However, at 3 weeks after the third inoculation, the ratio of the neutralizing antibody titer of 40 times or more was 69%, and the geometric mean antibody titer increase ratio before the inoculation was 9.1 times, which was higher than after the second inoculation.

When a third person (six months later) influenza vaccine derived from the Qinghai strain was inoculated to a person who received two Qinghai strain-derived influenza vaccines, the booster effect on the Qinghai strain was not high, but as shown in FIG. 1, FIG. 3 and FIG. Cross immunity has appeared. As is clear from FIG. 3 and FIG. 4, cross immunity particularly against Indonesian strains and Anhui strains appeared strongly.

Next, the results regarding safety are shown in Tables 5 to 7 below. Table 5 summarizes adverse events, Table 6 is systemic adverse events, and Table 7 is local response adverse events. Each numerical value indicates the number of people, and the parentheses indicate the ratio.

Among other adverse events, only one case of angioedema (the first) was included in the adverse reaction report. Only one case of breast cancer was detected after the first vaccination was a serious adverse event (hospitalization).

Angioedema was a 34-year-old female, and edema with itching appeared around both eyelids and around the mouth 2 days after the first vaccination. The patient recovered spontaneously the next day, but relapsed 4 days after vaccination. The next day, she visited the hospital and was diagnosed with angioedema and started taking Allegra. The symptoms were alleviated by internal use, and recovered 6 days after vaccination. A serious adverse event was a breast cancer in a 39-year-old woman who had been lumped into the breast about 3 months before the first vaccination and was diagnosed with mastitis. However, since the lump tended to increase thereafter, a retest was conducted 8 days after the first vaccination, and breast cancer was diagnosed. After 25 days, he was hospitalized and discharged. These adverse event cases are not causally related to the vaccination of the present invention. Based on the above, it is considered that there are no particular safety concerns.

Can be used in the field of influenza vaccine production and development.

Claims (8)

The H5N1 influenza vaccine is used for the first vaccination consisting of two doses to humans, and after the passage of a predetermined period, the vaccine of the same strain as that of the first vaccination is used at least once. H5N1 influenza vaccine characterized. The H5N1 influenza vaccine according to claim 1, wherein the H5N1 influenza vaccine of the first inoculation and the additional inoculation are both derived from the Qinghai strain. The H5N1 influenza vaccine according to claim 1 or 2, wherein the predetermined period is from 1 month to 3 years. The H5N1 influenza vaccine according to any one of claims 1 to 3, wherein the H5N1 influenza vaccine has an adjuvant. The H5N1 influenza vaccine according to any one of claims 1 to 4, wherein the H5N1 influenza vaccine of the first inoculation and the additional inoculation has an HA antigen amount of 1 µg to 200 µg per dose. . The H5N1 influenza vaccine according to any one of claims 1 to 5, wherein the H5N1 influenza vaccine is administered twice at intervals of 2 weeks or more and 4 weeks or less in the initial inoculation. The H5N1 influenza vaccine according to any one of claims 1 to 6, wherein the initial inoculation and the additional inoculation are intramuscular inoculation or subcutaneous inoculation. The H5N1 influenza vaccine according to any one of claims 1 to 7,
A kit for administering the H5N1 influenza vaccine to a human, an infection protection kit against the H5N1 influenza virus.

Images