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Гриппол® плюс — тривалентная вакцина для профилактики гриппа с доказанной эффективностью и безопасностью

GRIPPOL® PLUS — TRIVALENT INFLUENZA VACCINE WITH PROVEN EFFIСACY AND SAFETY

Grippol® Plus is a trivalent influenza adjuvanted vaccine that reduces antigen content: it contains 5 μg of each strain's virus antigens and the Polyoxidonium adjuvant. This allows the body's immune system to experience a smaller antigenic load, which causes fewer general or local reactions and complications after the vaccine is administered. Over more than 20 years of use, Grippol® Plus has proven its efficacy with maximum safety.

Influenza vaccination: the health of the vaccinated under the immune umbrella

The efficacy and safety of the Grippol® Plus vaccine is being investigated throughout the time of its application. For example, in 10 years (2009-2019) it was found that there were no cases of serious complications or pronounced post-vaccination reactions in children, adults, pregnant women or persons affected with chronic diseases (bronchial asthma, diabetes mellitus, etc.) after vaccination. The vaccine was well tolerated even by those at risk of developing adverse effects of the vaccination.

Clinical, epidemiological, and post-authorization studies of Grippol® plus in the Russian Federation and CIS countries with 8,739 children and 10,931 adults have shown that the vaccine is mildly reactogenic and meets all the criteria for efficacy of influenza vaccines. According to the requirements set out in the Guidelines for Harmonization of Requirements for Influenza Vaccines of the European Committee for Medicinal Products (CPMP/BWP/214/96) and EMA/CHMP/VWP/457259/2014, Grippol® Plus vaccine meets international requirements for influenza vaccines.

Immunogenicity of Grippol® Plus meets WHO requirements

Sulfur protection, %

Antibody titration fold increase

Seroconversion, %

Grippol^®provides effective protection to all three antigens of current influenza virus strains in 95-100% vaccinated
More than 70% of those vaccinated have a quadruple increase in antibody titration.
After vaccination, protective antibody titer increases 4 fold or more

A strong immune response is formed as early as 8-12 days after vaccination and lasts up to 12 months

Table 1. Clinical Trials of the Grippol® Plus vaccine.

Design, population, quantity	Parameters to evaluate	Results
Randomized double-blind Placebo Controlled in Healthy Volunteers aged 18-55¹, n=61	Safety Immunogenicity of vaccines containing 5 and 10 µg of haemagglutinin of each strain Groups: Grippol® Grippol Plus (5 µg per strain) Grippol plus (10 µg per strain)	Safety Mild normal overall vaccine reactions were reported in 6.9% of vaccinated persons (malaise, low grade fever). None of the vaccinated persons experienced severe general vaccine reactions or post-vaccination complications. Local reactions (soreness at the injection site for 30-60 minutes) were noted in 14.8% of vaccinated persons.
Randomized double-blind controlled study, Healthy volunteers aged 18-27, n=300	Proportion of individuals with a protective titer for A/H1 N1; A/H3 N2 and B strains: Grippol: 98%, 85%, 70%, respectively Grippol plus 5 µg: 95%, 84%, 76%, respectively Grippol plus 10 µg: 94%, 90%, 88% Percentage of persons with a 4-fold increase: Grippol: 97.5%, 78%, 63% Grippol plus 5 µg: 89.1%, 73.5%, 79.6% Grippol plus 10 µg: 95.5%, 88; 90.1% for the A/H1N1; A/H3N2 and B strains, respectively. Growth multiplicity Growth multiplicity A dose of 5 µg per strain is selected
Randomized double-blind controlled, comparative study in parallel groups². Children 3-17 years old N=153	Safety Immunogenicity 2 Groups: 1 - Grippol® plus 2 - Comparison vaccine	Safety: Common and Local Reaction Frequency — 5.6% No local reactions have been observed. Number of total reactions: headache -1, malaise — 2, abdominal pain — 1 Immunogenicity: Proportion of individuals with a 4-fold increase in A/H1N1; A/H3N2 and B titer strains: 96%, 87% and 100%, respectively, in baseline seronegative and 100%, 71.4% and 40%, respectively in baseline seropositive. Titers fold increase 19.9, 18.3, 6.0, respectively in seronegative baseline and 5.3, 6.5, 2.8 in seropositive baseline. Percentage of individuals with protective titer to the A/H1N1; A/H3N2 and B strains: to the A/H1N1; A/H3N2 and B strains:
Randomized double-blind controlled, comparative study in parallel groups³ Children 6 — 35 months, n=140	Comparison of safety and immunogenicity using two vaccination regimens: Group 1 - double dose 0.5 ml with 21-28 weeks interval Group 2 - double dose 0.25 ml with 21-28 weeks interval	Safety: None of the regimens affected clinical blood parameters Local reactions (pain, redness, swelling) after the first and second vaccination vary in the range: 3.1% – 7.4% General reactions (headache, malaise, poor appetite, sleep disturbance, sweating, runny nose, cough) range from 1.5% to 14.5%. They were all short-lived and did not require medicamental correction.
Open, prospective, case-control, randomized, blinded case-control study in the main group by endpoints Elderly citizens 60 + yrs. o.⁴, n=721	Safety Immunogenicity after 1 month and 6 months Preventive Efficacy	Safety: Local reactions (pain, redness, itching, induration at the injection site) were reported in 16.6% of those vaccinated. Were resolved without treatment within 3 days. Common reactions have been reported in 22% of those vaccinated. The most common are headache (14%-16%), joint pain (2.5%-3.4%), low grade fever (up to 37.5) - 2.5%. All reactions were short-lived and were resolved without treatment. Immunogenicity One month after vaccination: Percentage of individuals with protective titer: 67.4 % - 80.0% Percentage of persons with 4-fold increase: 39.0 % - 68.9% Antibody Titers fold increase: 2.6 (for influenza B) — 6.5 (for influenza A) 6 months after vaccination: Percentage of individuals with protective titer: 53.80% - 64.4% Percentage of persons with 4-fold increase: 21.7%- 55.1% Fold increase compared to baseline: 1.8 (for influenza B) -4.3 (for influenza A) Preventive Efficacy: A decrease in the morbidity of acute respiratory viral infections (ARVI) and the frequency of exacerbations of underlying chronic disease in the vaccinated group.
Randomized open controlled, blinded by endpoints in parallel groups⁵ Children 3-17 years old with allergic diseases, n=160: 106 with allergic diseases (food allergies, AD, grass pollen allergy), 54 - healthy babies	Safety Immunogenicity Vaccines: Grippol® plus Influvac	Safety Both vaccines have shown a favourable safety profile with respect to general and local reactions. No significant differences in safety and tolerability of the two vaccines have been found. Immunogenicity 1 month later, the fold increase in the A/H1N1, A/H3N2 and B strains were respectively: 2.1 to 4.7, 2.5 to 3.7 and 1.3 to 2.7 in children with allergies and 2.8 to 3.5, 1.8 to 2.1 and 1.4 to 1.6 in healthy children. The proportion with a 4-fold increase among those initially seronegative was 45.5%-52.9% in the Grippol® Plus group and 50.0%-63.6% in the Influvac group. The proportion of individuals with a protective titer was 69.2%-80.8% in the Grippol Plus group and 64.7%-94.1% in the Influvac group. No significant differences in vaccine immunogenicity were found

Design, population, quantity

Parameters to evaluate

Results

Randomized double-blind Placebo Controlled in Healthy Volunteers aged 18-55¹, n=61

Safety

Immunogenicity of vaccines containing 5 and 10 µg of haemagglutinin of each strain

Groups:

Grippol®

Grippol Plus (5 µg per strain)

Grippol plus (10 µg per strain)

Safety

Mild normal overall vaccine reactions were reported in 6.9% of vaccinated persons (malaise, low grade fever). None of the vaccinated persons experienced severe general vaccine reactions or post-vaccination complications. Local reactions (soreness at the injection site for 30-60 minutes) were noted in 14.8% of vaccinated persons.

Randomized double-blind controlled study, Healthy volunteers aged 18-27, n=300

Proportion of individuals with a protective titer for A/H1 N1; A/H3 N2 and B strains:

Grippol: 98%, 85%, 70%, respectively

Grippol plus 5 µg: 95%, 84%, 76%, respectively

Grippol plus 10 µg: 94%, 90%, 88%

Percentage of persons with a 4-fold increase:

Grippol: 97.5%, 78%, 63%

Grippol plus 5 µg:

89.1%, 73.5%, 79.6%

Grippol plus 10 µg: 95.5%, 88; 90.1% for the A/H1N1; A/H3N2 and B strains, respectively.

Growth multiplicity

A dose of 5 µg per strain is selected

Randomized double-blind controlled, comparative study in parallel groups².

Children 3-17 years old

N=153

Safety

Immunogenicity

2 Groups:

1 - Grippol® plus

2 - Comparison vaccine

Safety:

Common and Local Reaction Frequency — 5.6%

No local reactions have been observed.

Number of total reactions: headache -1, malaise — 2, abdominal pain — 1

Immunogenicity:

Proportion of individuals with a 4-fold increase in A/H1N1; A/H3N2 and B titer strains:

96%, 87% and 100%, respectively, in baseline seronegative and

100%, 71.4% and 40%, respectively in baseline seropositive.

Titers fold increase

19.9, 18.3, 6.0, respectively in seronegative baseline and 5.3, 6.5, 2.8 in seropositive baseline.

Percentage of individuals with protective titer

to the A/H1N1; A/H3N2 and B strains:

Randomized double-blind controlled, comparative study in parallel groups³

Children 6 — 35 months, n=140

Comparison of safety and immunogenicity using two vaccination regimens:

Group 1 - double dose 0.5 ml with 21-28 weeks interval

Group 2 - double dose 0.25 ml with 21-28 weeks interval

Safety:

None of the regimens affected clinical blood parameters

Local reactions (pain, redness, swelling) after the first and second vaccination vary in the range: 3.1% – 7.4%

General reactions (headache, malaise, poor appetite, sleep disturbance, sweating, runny nose, cough) range from 1.5% to 14.5%. They were all short-lived and did not require medicamental correction.

Open, prospective, case-control, randomized, blinded case-control study in the main group by endpoints

Elderly citizens 60 + yrs. o.⁴,

n=721

Safety

Immunogenicity after 1 month and 6 months

Preventive Efficacy

Safety:

Local reactions (pain, redness, itching, induration at the injection site) were reported in 16.6% of those vaccinated. Were resolved without treatment within 3 days.

Common reactions have been reported in 22% of those vaccinated. The most common are headache (14%-16%), joint pain (2.5%-3.4%), low grade fever (up to 37.5) - 2.5%. All reactions were short-lived and were resolved without treatment.

Immunogenicity

One month after vaccination:

Percentage of individuals with protective titer: 67.4 % - 80.0%

Percentage of persons with 4-fold increase: 39.0 % - 68.9%

Antibody Titers fold increase: 2.6 (for influenza B) — 6.5 (for influenza A)

6 months after vaccination:

Percentage of individuals with protective titer: 53.80% - 64.4%

Percentage of persons with 4-fold increase: 21.7%- 55.1%

Fold increase compared to baseline: 1.8 (for influenza B) -4.3 (for influenza A)

Preventive Efficacy:

A decrease in the morbidity of acute respiratory viral infections (ARVI) and the frequency of exacerbations of underlying chronic disease in the vaccinated group.

Randomized open controlled, blinded by endpoints in parallel groups⁵

Children 3-17 years old with allergic diseases, n=160:

106 with allergic diseases (food allergies, AD, grass pollen allergy),

54 - healthy babies

Safety

Immunogenicity

Vaccines:

Grippol® plus

Influvac

Safety

Both vaccines have shown a favourable safety profile with respect to general and local reactions. No significant differences in safety and tolerability of the two vaccines have been found.

Immunogenicity

1 month later, the fold increase in the A/H1N1, A/H3N2 and B strains were respectively:

2.1 to 4.7, 2.5 to 3.7 and 1.3 to 2.7 in children with allergies and 2.8 to 3.5, 1.8 to 2.1 and 1.4 to 1.6 in healthy children.

The proportion with a 4-fold increase among those initially seronegative was 45.5%-52.9% in the Grippol® Plus group and 50.0%-63.6% in the Influvac group.

The proportion of individuals with a protective titer was 69.2%-80.8% in the Grippol Plus group and 64.7%-94.1% in the Influvac group.

No significant differences in vaccine immunogenicity were found

A number of post-authorization studies have also been performed since the vaccine was registered and placed on the market. All studies can be divided into 4 groups:

1) cohort epidemiological studies (evaluation of preventive effectiveness of vaccination as measures for immunization of organized teams);

2) evaluation of safety, prophylactic and clinical efficacy and in different populations at risk of influenza (pregnant women, patients with various chronic diseases, the elderly);

3) comparative studies of safety and/or immunogenicity of the Grippol® plus vaccine with other influenza vaccines; assessment of vaccine safety in combined use with other vaccines;

4) evaluation of the impact of the vaccine on humoral and cellular immunity.

TABLE 2. RESULTS OF EPIDEMIOLOGICAL POST-AUTHORIZATION COHORT STUDIES OF GRIPPOL® PLUS VACCINE

Season, city	Contingent, number of participants	Influenza incidence per 1,000 with serological confirmation		Total ARVI morbidity per 1,000 throughout season		Other Outcomes
Season, city	Contingent, number of participants	Vaccinated	Not vaccinated	Vaccinated	Not vaccinated	Other Outcomes
2008-2009 Saint-Petersburg, Russia⁶	Schoolchildren 7-17 years, n=2768 (5 schools)	69,2	172,1	214,8	301,4	1. The vaccine efficacy, calculated using serological confirmation of influenza diagnosis, with an average vaccination coverage of 36.1% of the study population has amounted to 59.8% 2. No severe general or local reactions or complications have been registered in any vaccinated persons 3. Vaccination with Grippol® Plus helped to reduce the number of complications among those who fell ill: the unvaccinated group contracted 2.5 times as many acute respiratory infections as the vaccinated group
2008-2009 Podolsk, Russia⁷	Schoolchildren 7-15 years, n=3203 (9 schools)	75	16	399,3	546,8	1. The efficacy of the vaccine, calculated on the basis of serological confirmation of influenza diagnosis, was 78.7% [72.4% — 90.9%]. 2. Schools with vaccination coverage of ≥ 60% of students had a 40% lower overall morbidity of ARVI (cases per 1,000) than schools with vaccination coverage of about 60% 3. Schools with ≥ 60% coverage had 3.4 times fewer RRI children than schools with a low “immune layer” (3.1% and 10.6% of children, respectively, p < 0.01)
Vitebsk, Grodno, Minsk, Republic of Belarus⁸	Schoolchildren 6-17 years, n=5391 (6 schools)	39	113	240	557	4. Vaccine efficacy for influenza was 66.2% 5. Vaccinated children have a significantly lower number of recurrences and complications (maxillary sinusitis, bronchitis, pneumonia) compared to unvaccinated children.
Vitebsk, Grodno, Minsk, Republic of Belarus⁸	Adults 18 and older, n=6917 (3 enterprises)	15	31	97	187	6. Vaccine efficacy for influenza in adults was 50.3% 7. With an overall low morbidity rate in all 3 cities, the risk of disease (RD) of vaccinated persons was significantly lower (p < 0.05) than that of unvaccinated persons: RD [95% CI]: Grodno: 0.63 [0.53 — 0.75]; Vitebsk: 0.26 [0.15 — 0.43]; Minsk: 0,72*0,60^0,86

More than 10 post-authorization studies conducted between 2009 and 2019 have evaluated the safety, immunogenicity, prophylactic and clinical efficacy of Grippol® Plus vaccine in different risk groups, such as

pregnants^{9, 10, 11} and newborns from vaccinated pregnants^{12, 13};
elderly people aged 60 + with circulatory disease^{14, 15};
children and adults with bronchial asthma and other chronic obstructive respiratory diseases^{16, 17, 18};
children with diabetes mellitus¹⁹.

All listed populations are at risk of influenza and are subject to vaccination under the Russian National Immunization Program. Experience and evaluation of the safety and preventive efficacy of the vaccine are therefore of particular relevance to these populations.

In patients with chronic diseases (COPD, circulatory diseases) vaccinated against influenza, there has been noted a decrease in ARVI morbidity and a decrease in the number of episodes of exacerbated main chronic disease compared to those unvaccinated throughout the epidemic season. In assessing the immunological efficacy of the vaccine in adult patients with chronic obstructive pulmonary disease, the seroconversion rate at 6 months was 44%-75% in initially seronegative patients and 25%-50% in initially seropositive patients; the geometric mean antibody titer (GMA) at 6 months after vaccination was 70-135, remaining above protective levels by one year after vaccination (55-211)¹⁷.

Grippol® plus immunogenicity evaluation in pregnant women immunized in the 2nd and 3rd trimesters has shown that one month after vaccination the seroconversion rate ranged from 65.2% to 74.1%; seroprotection rates ranged from 77% to 91.3% one month after vaccination and from 62% to 81.5% 3 months after vaccination¹¹.

The immunological efficacy of the Grippol® plus vaccine in patients of 60 years old and over with circulatory system diseases (CSD) has been manifested in seroconversion rate in the range 49.5%-68.5%, an increase rate of 2.8-5.7, and a seroprotection rate of 83.7%-84.8%¹⁴.

No studies of the Grippol Plus vaccine among at-risk groups have reported serious post-vaccination events, unexpected reactions or complications resulting from the vaccination. All researchers note the good tolerability of the vaccine and the lack of negative effects on the general condition of those vaccinated, and on the course of the underlying disease.

The studies dedicated to comparative assessment of the safety, immunogenicity and clinical efficacy of Grippol® plus vaccine with other vaccines, and the safety and efficacy of combined administration included healthy adults, highly allergic children, persons affected by diabetics mellitus and various pathologies^{20,
21, 22, 23, 24, 25, 26}.

A comparative assessment of immunogenicity and safety with Vaxigrip and Influvac vaccines has shown that Grippol® Plus has comparable immunogenicity and tolerability, and a more favourable local reaction profile. When administered in combination with other vaccines, Grippol® Plus induces an effective immune response and does not negatively affect the development of a specific response to other vaccines²⁷.

TABLE 3. COMPARING THE EFFICACY OF GRIPPOL PLUS, INFLUVAC AND VAXIGRIP VACCINES ON the 28 th DAY AFTER VACCINATION.

Vaccine immunogenicity parameter	CPMP Requirement ^*	Test results
Vaccine immunogenicity parameter	CPMP Requirement ^*	Grippol plus	Influvac	Vaxigrip
A/H1N1 strain
Seroconversion factor	More than 2,5	7,20	7,57	8,06
Seroconversion level	More than 40%	93,2%	94,6%	94,4%
Seroprotection level	More than 70%	95,0%	95,0%	96,0%
A/H3N2 strain
Seroconversion factor	More than 2,5	3,78	4,59	4,32
Seroconversion level	More than 40%	67,4%	77,8%	92,5%
Seroprotection level	More than 70%	90,9%	90,0%	96,0%
Strain B
Seroconversion factor	More than 2,5	2,70	2,50	3,27
Seroconversion level	More than 40%	71,4%	90,0%	93,8
Seroprotection level	More than 70%	99,0%	100,0%	100,0%
* - For each strain, at least one indicator must meet the indicated requirements.

A special feature of influenza vaccination is that it is the only vaccination that takes place every year. For influenza vaccines containing adjuvant, the issue of immunological safety and realizing mechanisms of action is an important factor. For the Grippol® plus vaccine, studies have been conducted to assess the effects on cellular immunity. A comparative assessment of the effect of different types of influenza vaccines (subunit, split vaccine, adjuvanted subunit vaccine) on the subpopulation composition of human lymphocytes under in vitro conditions showed that Grippol Plus vaccine had a highly pronounced effect on effectors of cellular and humoral immune response. Thus, the number of NK cells and NKT cells in the culture under the influence of the Grippol plus vaccine increased in comparison with the control group 3.3 and 2.1 fold, respectively, under the influence of the Influvac vaccine the increase was 2.8 and 2 fold, while under the influence of the Vaxigrip vaccine the increase was 3 and 2.26 fold. Grippol plus and Influvac caused a reliable and comparable increase in the number of B-lymphocytes, 1.5 and 2.5 fold, respectively²⁸.

Thus, a fairly extensive evidence base has been accumulated, allowing to say that the Grippol® plus adjuvanted vaccine with reduced antigens content was a safe and effective medicinal product and, with mass use, had good preventive efficacy.

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