Last updated on February 2018

Clinical and Immunological Efficiency of Bacterial Vaccines at Adult Patients With Bronchopulmonary Pathology


Brief description of study

Goal: to to examine the formation of postvaccination immunity and evaluate the therapeutic effect of bacterial vaccines in patients with inflammation diseases of bronchopulmonary system. Objectives of the study: assessment of microbiocenosis mucous membranes of the upper respiratory tract in patients with bronchopulmonary pathology before and after use of bacterial vaccines. Identification of mayor lymphocytes subpopulations, proinflammatory cytokines, inflammatory markers in patients in the dynamics of the vaccination process. Study the profile of humoral immune response in patients under different schemes of vaccination. Detection of levels of autoantibodies against tissue antigens in the sera of vaccinated patients with inflammatory diseases of the respiratory tract. Assessment of the clinic and functional status bronchopulmonary system in the immunized patients. Development of methodical recommendations / study guides for the improvement of therapy in patients with different inflammation diseases of the respiratory tract.

Detailed Study Description

Methods
  1. IgG-antibodies against S.pneumoniae - solid-phase ELISA.
  2. General levels of IgA, IgM, IgG, IgE in sera - radial immunodiffusion.
  3. Phagocytic activity (granulocytes, monocytes), nitroblue tetrazolium test; activated T-lymphocytes (CD3+CD69+); activated B-lymphocytes (CD3-CD69+); absolute content of leukocytes; absolute and relative content of lymphocytes, granulocytes, monocytes, T-lymphocytes (CD3+, CD4+, CD8+), B-lymphocytes (CD69+); natural killers (CD3-, CD16+, CD56+), activated T-cells (CD3+ HLA DR).
  4. Microbiological examination of sputum.
  5. Spirometry.
  6. Determining the clinical effectiveness of vaccination.
    • the number of exacerbations of chronic bronchopulmonary pathology for the year prior to vaccination and during the year after vaccination;
    • the number of courses of antibiotic therapy a year prior to vaccination and during the year after immunization;
    • the number of hospitalizations for acute exacerbations of chronic bronchopulmonary disease during the year prior to vaccination and during the year after immunization.
  7. Method of estimating quality of life associated with health in patients with chronic bronchopulmonary pathology.

For Arms 1-3. Screening: the collecting of complaints, anamnesis, physical examination, X-ray of chest,spirometry with bronchodilator, ORL examination, ACT-C, ACQ5, CAT, CCQ-tests, test the six-minute walk, clinical analysis of blood leukocyte count, allergiamelone (skin prick tests and/or determination of specific IgE), cytology tests of nasal secret.

Immunological examination (1, 2, 12, 60 days). CD45 PC7, CD3 FITC, CD16/32 PE NK, CD4 ECD, CD25 PE, CD19 PE, MHCII (I-A) PerCP, TLR2, TLR4, TLR7, TLR3, TLR9, IL1B, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-gamma, IFN-alpha.

(1, 13, 60, 180 days) - IgG and IgM levels against conditional pathogens by ELISA method.

1 day - definition of respiratory viruses by PCR in the oropharynx detachable, microbiological examination of sputum/throat of crops

Evaluation of the effectiveness of an investigational drug would be based on primary and secondary performance criteria. To assess the primary performance criteria will be analyzed the following indicators: improvement (recovery); lack of effect; relapse; it is impossible to estimate. Eradication, presumed eradication, persistence, the estimated persistence, recurrence, superinfection, colonization, eradication and reinfection, inconclusive results.

Continued registration of adverse events.

For Arms 4-6. Screening: the collecting of complaints, anamnesis, physical examination, X-ray of chest, clinical analysis of blood leukocyte count.

(1, 2, 13, 60 days). CD45 PC7, CD3 FITC, CD16/32 PE NK, CD4 ECD, CD25 PE, CD19 PE, MHCII (I-A) PRRS, TLR2, TLR4, TLR7, TLR3, TLR9, IL1B, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-gamma, TNF-alpha.

(1, 13, 60, 180 days) - IgG and IgM levels against conditional pathogens by ELISA method.

1 day - definition of respiratory viruses by PCR in the oropharynx detachable, microbiological examination of sputum/throat of crops; determination of S. pneumoniae in urine at admission.

Evaluation of the effectiveness of an investigational drug would be based on primary and secondary performance criteria. To assess the primary performance criteria will be analyzed the following indicators: improvement (recovery); lack of effect; relapse; it is impossible to estimate. Eradication, presumed eradication, persistence, the estimated persistence, recurrence, superinfection, colonization, eradication and reinfection, inconclusive results.

Continued registration of adverse events.

For Arms 7-9. Screening: the collecting of complaints, anamnesis, physical examination, X-ray of chest,spirometry with bronchodilator, ORL examination, ACT-C, ACQ5, CAT, CCQ-tests, test the six-minute walk, clinical analysis of blood leukocyte count, allergiamelone (skin prick tests and/or determination of specific IgE), cytology tests of nasal secret.

Study of content of acute phase proteins - C-reactive protein, Alveolitis. Immunological examination (1, 2, 12, 60 days). CD45 PC7, CD3 FITC, CD16/32 PE NK, CD4 ECD, CD25 PE, CD19 PE, MHCII (I-A) PerCP, TLR2, TLR4, TLR7, TLR3, TLR9, IL1B, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-gamma, IFN-alpha.

(1, 13, 60, 180 days) - IgG and IgM levels against conditional pathogens by ELISA method.

1 day - definition of respiratory viruses by PCR in the oropharynx detachable, microbiological examination of sputum/throat of crops

Evaluation of the effectiveness of an investigational drug would be based on primary and secondary performance criteria. To assess the primary performance criteria will be analyzed the following indicators: improvement (recovery); lack of effect; relapse; it is impossible to estimate. Eradication, presumed eradication, persistence, the estimated persistence, recurrence, superinfection, colonization, eradication and reinfection, inconclusive results.

Continued registration of adverse events.

Characteristics of variables.

  1. The age of patients (years): mean (standard deviation) [min; median; max] for normally distributed variables; median [interquartile lat] - for variables with distribution different from normal.
  2. Gender: male/female.
  3. Index of pack-years.
  4. The severity of the disease. For COPD:
    • mild: FEV180% from proper values, the index tiffno of <0.7.
    • moderate: 50%FEV1<80% from proper values, the index tiffno of <0.7.
    • severe: 30%FEV1<50% from proper values, the index tiffno of <0.7.
    • very severe: FEV1<30% from the proper values, the index tiffno of <0.7.

For Asthma:

  • mild intermittent: symptoms less than 1 time a week exacerbations brief, night-time symptoms not more than 2 times a month FEV1 or PSV80% from proper values, a PSV or FEV1 variability<20%.
  • Easy for persisting symptoms more than 1 time per week, but less than 1 time per day; exacerbations may disturb activity and sleep, nocturnal symptoms more than 2 times a month FEV1 or PSV80% from proper values, the variability of PSV or FEV130%.
  • Asthma moderate daily symptoms, exacerbation may disturb activity and sleep, nocturnal symptoms more than 1 time a week, daily dose of inhaled 2-agonists short-acting FEV1 or PSV 60-80% from the proper values, a PSV or FEV1 variability>30%.
  • Asthma severe daily symptoms, frequent exacerbations, frequent nocturnal symptoms of ASTHMA, limited physical activity, FEV1 or PSV60% from the proper values, a PSV or FEV1 variability>30%.

The data source is the performance of spirometry.

5. Indicators of immune status

  • IgG antibodies to S. pneumoniae
  • IgA, g/l [0,4-3,5]
  • IgM, g/l [0,7-2,8]
  • IgG, g/l [8-18]
  • IgE, IU/ml [< 100]
  • Phagocytic index (granulocyte), % [82-90]
  • Phagocytic index (monocytes), % [75-85]
  • The participation rate of spontaneous NBT-test (neutrophils), % with intensity of 0.2.e. [7-14]
  • The index of activity induced NBT-test (neutrophils), % if intensity >of 0.36.e. [>28]
  • The percentage of NBT-positive cells in spontaneous test, % [2-19]
  • Activated T-lymphocytes CD3+CD69+, % [50-69]
  • Activated B-lymphocytes + EKK CD3-CD69+, % [15-34]
  • CEC cond. units [0,055-0,11]
  • White blood cells, 106/l [4000-9000]
  • Lymphocytes, 106/l [1200-3000]
  • Lymphocytes, % [19-37]
  • Granulocyte, 106/l [1800-7700]
  • Granulocytes, % [40-60]
  • Monocytes, 106/l [0-800]
  • Monocytes, % [1-6]
  • CD3+, 106/l [800-2200]
  • CD3+, % [55-80]
  • CD3+CD4+, 106/l [600-1600]
  • CD3+CD4+, % [31-49]
  • CD3+CD8+, 106/l [190-650]
  • CD3+CD8+, % [12-30]
  • CD19+, 106/l [100-500]
  • CD19+, % [5-19]
  • CD3-CD16+CD56+, 106/l [150-600]
  • CD3-CD16+CD56+, % [6-20]
  • CD3+CD16+CD56+, % [<10]
  • CD3-HLA DR+, 106/l [60-600]
  • CD3-HLA DR+, % [5-20]
  • CD3+HLA DR+, % [<12]
  • CD45RO. The reference value of the coefficient of sensitization = 0,2. 6. Microbiological examination of sputum: frequency of selection of certain microorganisms are presented as absolute number of cases and % in the respective groups. 7. Evaluation of early post-vaccination period
  • The General condition (satisfactory/unsatisfactory in the opinion of the test)
  • Local reactions: pain (n/%), redness (n/%, cm), consolidation (n/%, cm)
  • General reactions:
    • Temperature 37,0-37,5 (n/%)
    • Temperature of 37.6-38,5 (n/%)
    • A temperature of 38.6 and > (n/%)
    • Headache (n/%)
    • Malaise, fatigue (n/%)
    • Joint pain (n/%)
    • Muscle pain (n/%) All adverse events were coded using the latest version of international vocabulary of standard medical terminology (MedDRA) preferred terms and lower level terms. 8. Indices of spirometry:
  • FVC [80% from proper values]
  • FEV1 [80% from proper values]
  • FEV1/FVC index tiffno [0,7]
  • MMEF25 [80% from proper values]
  • 50 [80% from proper values]
  • 75 [80% from proper values] 9. Clinical efficacy of vaccination:
  • the number of acute exacerbations of chronic bronchopulmonary pathology for the year prior to vaccination and during the year after vaccination
  • the number of courses of antibiotic therapy a year prior to vaccination and during the year after immunization
  • the number of hospitalizations for acute exacerbations of chronic bronchopulmonary disease during the year prior to vaccination and during the year after immunization.
     Under chronic bronchopulmonary pathology were understood to be two types of diseases:
     COPD and bronchial asthma.

     Under the exacerbation of chronic bronchopulmonary pathology refers to the increased
     symptoms of dyspnea, cough, sputum, emergence or strengthening of wheezing and whistling
     in the chest, feeling of compression in the chest, requiring treatment and modification
     of therapy, and are confirming information in the initial documentation of patients.

     Under the number of courses of antibacterial drugs refers to the number of courses of
     antibiotics during the year prior to vaccination and during the year after vaccination
     due to exacerbation of chronic bronchopulmonary diseases, and also for any other reasons
     not associated with chronic bronchopulmonary pathology. This information also was
     confirmed by the presence of primary records in documentation of patients.

     Under hospitalization refers to the admission of the subject for treatment in a hospital
     for chronic bronchopulmonary disease, both in routine and emergency indications.
     Confirmation of hospitalization served as the medical history of the disease, or the
     entry in the medical card of the examinee. In the course of the work gathered
     information about all the hospitalizations the year before and the year after
     vaccination.

10. Method of estimating quality of life associated with health For the measurement of

     indicators of quality of life associated with health in COPD patients prior to
     vaccination and during the year after vaccination was used a sociological research
     method with the use of the SAT test (COPD Assessment Test). The value of the test from 0
     to 10 points indicates no significant influence of COPD on the patient's life, from 11
     to 20 points - a moderate impact of COPD on the patient's life, from 21 to 30 points -
     the strong effect of COPD on the patient's life, with the result of 31 points and above
     COPD exerts an extremely strong influence on the life of the patient.

Assessment of the quality of life of patients with bronchial asthma was carried out in dynamics with the use of the questionnaire ACQ-5 (Asthma Control Questionnaire). Total score ACQ-5 is calculated as the arithmetic mean of 5 responses: <0,5-0,75 - good control of asthma, 0,75-1,5 - partial control of asthma, >1.5 to uncontrolled asthma.

PRIMARY SOURCE VERIFICATION ACT

Protasov Andrey Dmitrievich, M.D., assistant professor of the Department of General and Clinical Microbiology, Immunology and Allergology of the State-Funded Educational Institution of Higher Professional Education "Samara State Medical University" (SFEI HPE "SSMU"), an applicant seeking the Doctor of Medical Sciences degree based on the thesis entitled "Systemic approach to vaccine prophylaxis and vaccine therapy of pneumococcal infection in patients with chronic bronchopulmonary pathology" (14.03.09 - "clinical immunology and allergology"; 14.01.25 - "pulmonology").

Thesis advisory panel that included:

Chairman of the panel: professor of the Department of Intermediate Level Therapy, Doctor of Medical Sciences, professor V.V. Simerzin;

Members of the panel:

  • Head of the Department of Family Medicine of the Advanced Training Institute, Doctor of Medical Sciences, associate professor V.I. Kupaev;
  • Associate professor of the Department of Propedeutic Therapy A.V. Germanov, M.D.;
  • Professor of the Department of General and Clinical Pathology, anatomical pathology and pathological physiology, Doctor of Medical Sciences, professor M.I. Panina,

Reviewed the following dissertation materials:

  1. Extracts from medical histories (outpatient cards) - 219.
  2. Data of patient clinical examination (protocols of patient questioning and examination, clinical diagnoses, questionnaire results).
  3. Data of patient laboratory investigations, spirometry results, sputum culture (copies).
  4. Signed patient's informed consent forms authorizing health care intervention.
  5. Copies of research papers - 37.
  6. Materials of statistical analysis of study results in electronic form.

The author has carried out a pilot, prospective, non-randomized, one-center, non-placebo-controlled study that enrolled a total of 219 patients with chronic bronchopulmonary pathology who have been followed up for 4 years. The study was conducted at a specialist consulting and diagnostic clinical center of the State-Funded Educational Institution of Higher Professional Education "Samara State Medical University" of the Ministry of Healthcare of Russia in collaboration with the Federal State-Funded Research Institute "Moscow Scientific Research Institute of Vaccines and Sera named after I.I. Mechnikov".

The investigations were those commonly used in clinical trials and included physical examination, laboratory, immunological and microbiological investigations, assessment of functional tests and health-related quality of life parameters in dynamics including a short-term (one-year) and long-term (four-year) follow-up in adult patients with chronic bronchopulmonary pathology (e.g., chronic obstructive pulmonary disease, bronchial asthma) against the backdrop of using different pneumococcal vaccination regimens.

Statistical analysis was carried out using the StatPlus 2009 Professional 5.8.4 applied software package and appropriate statistical methods. Study results presented in the dissertation fully match the data in primary medical records and comply with the international system of units (SI). The correctness of all parameters are confirmed by corresponding entries in the primary documents.

The author was personally involved in all steps of this study and analysis of results. The statistical significance and authenticity of primary source materials raises no doubt. The results of statistical analysis fully agree with the data presented in tables illustrating the dissertation.

All results presented in the dissertation and abstract have been published in scientific papers and meeting abstracts. The author was personally involved in studying clinical, microbiological and immunological effects of vaccination against pneumococcal infection in patients with chronic bronchopulmonary pathology and the effect of different vaccination regimens on the dynamics of functional test parameters and the short- and long-term quality of life outcomes. He also developed a scientifically sound regimen for using the pneumococcal vaccines in patients with chronic bronchopulmonary pathology. The presence of a complete set of primary documents and sufficient statistical analysis of study results allows us to conclude that the data obtained are correct and conclusions and recommendations justified.

No violations of requirements of the Higher Attestation Commission (HAC) of the Ministry of Education and Science of Russia applicable to primary documents have been found.

The thesis advisory panel came to the conclusion that the completeness and quality of submitted materials is in conformance with the topic and content of the dissertation by A.D. Protasov "Systemic approach to vaccine prophylaxis and vaccine therapy of pneumococcal infection in patients with chronic bronchopulmonary pathology" (14.03.09 - "clinical immunology and allergology"; 14.01.25 - "pulmonology").

The panel chairman:

Professor of the Department of Intermediate Level Therapy of the "SFEI HPE "SSMU", Doctor of Medical Sciences, professor V.V. Simerzin

The panel members:

Head of the Department of Family Medicine of the Advanced Training Institute of the "SFEI HPE "SSMU", Doctor of Medical Sciences, associate professor V.I. Kupaev

Professor of the Department of General and Clinical Pathology, anatomical pathology and pathological physiology of the "SFEI HPE "SSMU", Doctor of Medical Sciences, professor M.I. Panina

Associate professor of the Department of Propedeutic Therapy of the "SFEI HPE "SSMU" A.V. Germanov, M.D.

Clinical Study Identifier: NCT02787863

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Elena S Korovkina, Ph.D.

Institute of Sera and Vaccines RAS
Moscow, Russian Federation
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Recruitment Status: Open


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