p < 0.05 vs. baseline values in Group II (Student's test).-

& p ˂ 0.05; &&& p < 0.001—differences between Groups I and II (Student's test).-

**Table 6.** Dynamics of 6MWT in COPD patients from Groups I and II over 12 months.-

Detailed characteristics of spirometry data in COPD patients from Groups III and IV are presented in **Table 7**.-


Data are presented as means (standard deviation).-

& p < 0.05—differences between Groups III and IV at 12 months (Student's test).-

**Table 7.** Spirometry values in COPD patients vaccinated against influenza (Group III) and in unvaccinated control- patients (Group IV).-

The analysis of the 6-minute walk test results showed a trend to distance increase by 13 m- (+3.7%) 1 year after mono-vaccination (p > 0.05, Student's test).-

Thus, the study demonstrated statistically significantincrease in FEV1 [57.4% (2.0%)] at- 12 months after complex vaccination when compared to unvaccinated COPD patients [50.4%- (2.8%)]. This FEV1 increase was 3.5%, that is, not statistically significantvs. baseline value,- although the positive trend was observed.-

The group of mono-vaccination against influenza also demonstrated the positive trend of FEV1- increase, but the increase was only 2.11%, which is less than 3.5% in the group of complex- vaccination.-

In the group of complex vaccination, patients demonstrated significantlyimproved 6MWT- results at 12 months vs. baseline distance. In Group I, the increase was 7.4% (+34 m), that is,- statistically significant-(p < 0.05). In patients vaccinated against influenza,-6MWT increase- approached trend levels of significance.-

## **3.3. Immunological effect of vaccination in patients with COPD-**

Previously, we have reported the dynamics of specificantibodies against influenzavirus in- COPD patients after complex vaccination against S. pneumoniae, H. influenzaetype b, and- influenza [11].-

Combined vaccination against pneumococcal, H. influenzaetype b and influenzais accompanied by production of antibodies to these infections, which persist during 1 year (observation- period), regardless of disease severity. In patients with stage 4 COPD, the level of antibodies- to influenzavirus (strains A/H1N1, A/H3N2 and B) in post-vaccination period was lower than- in patients with stages 1, 2, and 3. Probably, these patients should be vaccinated against- influenzatwice. Despite the fact that patients with COPD had lower levels of post-vaccination- antibodies than control, they demonstrated apparent clinical effectthroughout 12 months,- which was recorded as reduction of both exacerbation number and the need in antibacterial- medications. Combined vaccination against bacterial and viral infections contributes to the- achievement of antibody levels leading to the development of significantclinical effectin- patients with COPD.-

**Table 8**demonstrates lists immunogenicity parameter of the new immunoadjuvant vaccine- against influenza after mono vaccination of COPD patients.-

 No statistically significantdifferencesin immunogenicity were found between COPD patients- and healthy participants vaccinated only against influenza,the latter, however, demonstrated- a trend toward higher immune response to vaccination.-

In the comparative analysis of COPD patients, in whom antibodies to all three influenza virus- strains were detected at arbitrarily protective titres (≥1:40) at 6 months after vaccination, and- patients, in whom, despite vaccination, antibody titres were <1:40, COPD patients at risk of- low response to vaccination were identified.-These patients had a long history of COPD with- frequent respiratory infections and COPD exacerbations requiring hospitalization and- systemic glucocorticosteroids or antibiotic chemotherapy.-


**Table 8.** Immunogenicity parameters of the new immunoadjuvant vaccine against influenza after mono-vaccination of- COPD patients (n = 15).-

## **4. Conclusions-**

During post-vaccination period, treating physicians and patients as well focus their attention- on the main disease course. The clinical course of the disease may be characterized by number- of COPD exacerbations and the need for antibiotic chemotherapy. Both complex vaccination- against S. pneumoniae, H. influenzaetype b, and influenzaand mono-vaccination with a new- immunoadjuvant influenzavaccine led to statistically significantreduction in the number of- COPD exacerbations and of antibiotic chemotherapy courses.-

 Our study had some limitations, that is, its pilot character, absence of randomization and- blinding, and small sample size. As follows from the study results, complex vaccination of- COPD patients against bacterial and viral respiratory infections have more expressed- beneficialeffectson their functional status when compared to mono-vaccination against- influenza.-Further well-designed multicenter clinical studies devoid of these limitations are- needed to refinethe hypothesis. Nevertheless, based on the obtained results, widespread- implementation of mono-vaccination against influenza with a new immunoadjuvant influenza- vaccine, as well as complex vaccination against bacterial respiratory infections and influenza- can be recommended for COPD patients, as vaccination is beneficialfor their functional status,- that is, improves FEV1 and 6-minute walk test results.-

Mono-vaccination of COPD patients using immunoadjuvant vaccines of a new class as well as- combined vaccination against S. pneumoniae, H. influenzae, and influenza is associated with- protective antibody titres. In our study, we evaluated immunogenicity of the new influenza- immunoadjuvant vaccine administered as mono-vaccine to COPD patients in accordance with- CPMP requirements. Immune response to vaccine strains of influenzavirus was more intense- and durable in initially seropositive patients compared to seronegative.-

Combined vaccination against pneumococcal, H. influenzaetype b and influenzais accompanied by production of antibodies to these infections. In patients with stage 4, COPD the level- of antibodies to influenzavirus (strains A/H1N1, A/H3N2 and B) in post-vaccination period- was lower than in patients with stages 1, 2, and 3. Probably, these patients should be vaccinated- against influenzatwice. Combined vaccination against bacterial and viral infections contributes to the achievement of antibody levels leading to the development of significantclinical- effect in patients with COPD.-

 Influenzaprophylaxis in COPD patients implies annual influenzavaccination of all individuals having no contraindications regardless of the disease severity. Influenzavaccine prophylaxis must be included into patient's care plan and into the list of recommendations given by- a pulmonologist at an outpatient visit or at discharge from hospital. If possible, simultaneous- vaccination against S. pneumoniae, H. influenzaetype b, and influenzais recommended as- early as possible before the season of respiratory infections starts. Combined vaccination- against respiratory infections has more significanteffectson clinical characteristics and- functional status of COPD patients and promotes production of specificantibodies not only- against vaccine strains of influenzavirus but also against S. pneumoniae and H. influenzae- antigens contained in the corresponding vaccines.-

## **Author details-**

Andrey Dmitrievich Protasov1,2\*, Mikhail Petrovich Kostinov1,2,- Alexander Victorovich Zhestkov1,2, Mikhail L'vovich Shteiner1,2,- Svetlana Vyacheslavovna Kazharova1,2, Yuriy Vladimirovich Tezikov1,2 and- Igor Stanislavovich Lipatov1,2-

 \*Addressallcorrespondenceto:crosss82@mail.ru-

 1-Samara-State-Medical-University,-Samara,-Russian-Federation-

2 Mechnikov Research Institute of Vaccines and Sera, Moscow, Russian Federation-

#### **References-**


## *Edited by Manal Mohammad Baddour*

Te World Health Organization (WHO) estimates that 3–5 million cases of severe infuenza worldwide will result in 250,000–500,000 deaths annually. Collectively, data are shared via the WHO's Global Infuenza Surveillance and Response System (GISRS), which includes 143 institutions in 113 WHO member states, to help alert the emergence of antigenic variants or the beginning of a pandemic. In April 2009, the Centers for Disease Control and Prevention (CDC) cited the frst incidence of human-to-human transmission of pandemic H1N1, also referred to as swine infuenza A, which was antigenically distinct from other circulating human H1N1. As the frst infuenza pandemic of the twenty-frst century, pandemic H1N1 was not included in the annual trivalent vaccine regimen, leaving a large majority of the population unprotected from the newly emerging pathogen.

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