Cohort Study Evaluating the Clinical Effectiveness, Safety and Immunogenicity to the Pandemic Influenza Vaccination
Cohort Study Evaluating the Clinical Effectiveness, Safety and Immunogenicity to the Pandemic Influenza Vaccination
Multicenter prospective cohort of approximately 1000 cystic fibrosis patients followed in the
 Ile de France during the 2009-2010 influenza season with the main objective to assess the
 effectiveness of antiviral vaccination (H1N1). All subjects will be included, without
 excluding factor. In particular populations at risk are additional infants 6 to 23 months,
 pregnant women and lung transplant will also be included. These people will be vaccinated
 with un-adjuvanted vaccine.

 If flu symptoms until the results of PCR to confirm or refute the diagnosis of influenza,
 oseltamivir is administered in accordance with official recommendations and based on the
 results of the pharmacokinetic study.
Main objective : To investigate the clinical efficacy of pandemic influenza vaccine (H1N1) v
 patients with cystic fibrosis (CF)

 Secondary objectives : Vaccine research

 -  Measure the adherence of this population to the pandemic influenza vaccination

 -  Measure the tolerance of the pandemic influenza vaccine (H1N1) v

 -  Study the immunogenicity vaccine against the H1N1 variant and factors associated with
 vaccine response

 Epidemiological and clinical study :

 -  Describe the incidence of asymptomatic forms of influenza A (H1N1) among unvaccinated
 and identify factors associated with the occurrence of these forms in patients with
 cystic fibrosis

 -  Describe the impact of influenza A (H1N1) in vaccinated and unvaccinated

 -  Characterizing the clinical expression of the influenza pandemic period in vaccinated
 and unvaccinated and identify factors associated with the occurrence of severe forms in
 patients with cystic fibrosis

 -  Characterize the serological response in patients who have a proven H1N1

 -  Characterize the impact of influenza A (H1N1) on the lung disease patients in the short
 and medium term

 Virological study :

 -  Description of the epidemiology of respiratory viruses and intracellular bacteria
 involved in influenza-like illness

 -  In-context of H1N1 infection:

 -  Study of co-infections by intracellular bacteria or viral

 -  Quantification of viral RNA in respiratory secretions

 -  Monitoring the kinetics of viral shedding and correlation of it to the severity of
 respiratory disease and immunological protection

 -  Sensitivity analysis of viral strains to antiviral drugs and search for potential
 selection of resistant strains in antiviral therapy

 Genomic study :

 Search for susceptibility genes increase the risk:

 -  A severe form

 -  A prolonged viral shedding (beyond day 10), including research polymorphism
 carboxylesterase 1

 -  A immunoprotection

 Methodology :

 Prospective, multicenter, nonrandomized. Multicenter prospective cohort of approximately 1000
 CF patients followed in the Ile de France during the 2009-2010 influenza season

 -  All patients with CF followed in Ile de France and the two transplant centers (IDF
 service of Thoracic Surgery at the European Hospital Georges Pompidou and Foch) will be
 included as much as possible, about 1000 patients (about 600 children).

 -  200 of them (100 children at least 6 months, 100 adults) participate in the study of
 immunogenicity after vaccination

 -  6 patients over 12 years will realize the pharmacokinetic study

 Product under consideration :

 Influenza vaccine (H1N1) v pandemic will be administered. It will mainly adjuvanted vaccine
 but also the un-adjuvanted vaccine in subjects at risk: infants 6 to 23 months, pregnant
 women, transplant.

 If flu symptoms until the results of PCR to confirm or refute the diagnosis of influenza,
 oseltamivir is administered in accordance with official recommendations and based on the
 results of the pharmacokinetic study.

 Criteria :

 Primary endpoint :vaccine efficacy

 To determine vaccine efficacy VE on susceptibility, the measure used is the complement to 1
 of the Hazard Ratio (HR hazard ratio) for the appearance of an influenza episode (Halloran,
 AJE, 1997). The existence of an effective vaccine will be tested by comparing HR 1. Using the
 HR measurement is preferred to that using the ratio of cumulative incidence rates among
 vaccinated than unvaccinated because of a change in the number of groups vaccinated /
 unvaccinated can occur over time.

 Indeed, the immunization schedule now includes two doses given at 3 weeks / 1 month apart,
 even if it appears that the antibody response can be achieved in the first half after the
 first dose. It is possible that some subjects may be infected before the first dose after the
 first but before the second, or after receiving the full presentation. On the other hand, the
 date of infection could be similar to that of vaccination, a time when efficiency is not
 optimal.

 In the primary analysis, individuals will be considered unvaccinated if they do not receive
 vaccination and during 15 days of initial vaccination. For the latter, a time-dependent
 variable representing the immunization status will take into account their relative
 contribution to periods vaccinated / unvaccinated. The analysis will be stratified by age
 groups corresponding to the quartiles of the population.

 In secondary analysis, the investigators vary the initial term conferring protection, the
 investigators also consider only those who received the full vaccination schedule, it will
 also determine the impact of using the cumulative incidence rate in the vaccinated population
 initially and ultimately vaccinated.

 Secondary endpoints:

 Membership in the vaccination will be measured as a proportion, together with a confidence
 interval 95%, as well as the incidence of clinical influenza in vaccinated and unvaccinated
 cohorts.

 The tolerance of pandemic influenza vaccine (H1N1) v will be evaluated by binomial confidence
 intervals. Individual factors leading to the decision of vaccination and immunization events
 will be determined by logistic regression.

 The clinical expression is described by the percentages of symptom onset. An analysis of the
 frequency of symptoms in groups of vaccination will be carried out. Factors related to the
 presence of symptoms will be sought using logistic regression. The percentage of serious
 forms will be measured. Vaccine efficacy against serious will be measured using techniques
 described by causal analysis Hudgens & Halloran.

 The longitudinal lung function of patients enrolled will be analyzed through the data
 provided in the patient tracking software in place in services. A mixed effects linear model
 will be used to analyze changes in respiratory function (including FEV) and test whether the
 infection is accompanied by a change in the current level of functioning or a change in the
 evolution Compared to the situation pre-infection.

 The pan-genomic analysis will evaluate SNPs (Single Nucleotide Polymorphisms) associated with
 the presence of (1) a prolonged infection, (2) of immunoprotection, (3) infection, (4) of a
 severe infection. Some patients, corresponding to extreme forms of the disease (severe and
 not severe) has been genotyped, and the whole cohort will be genotyped at term. Each patient
 has been genotyped about 300,000 SNPs. It is generally accepted that an association in this
 case is "genomically significant" when the significance level is smaller than 10-7. Actual
 calculations made in the project analysis of modifier genes Pr Clément, which resulted in the
 cohort, showed that in the comparison of two cohorts of 500 subjects, it was possible to
 obtain a significant result genomically a difference of about 20% between frequencies of
 genotypes for SNPs not rare (> 5%), with a risk factor (FDR) of approximately 10%. For the
 analysis of two groups of 150 subjects, under the same conditions, the FDR, however, was
 close to 1. The staff here will be compared between the two terminals, and often unbalanced.
 It is hoped to highlight the differences in genotype frequency, if any, of the order of 20%
 or more, in the case of a comparison involving the entire cohort, but the investigators will
 probably find that imbalances are larger (> 50%) in the analysis of smaller subgroups. In any
 case, it will be important to try and validate this information through independent study.
Inclusion Criteria:

 -  patients with cystic fibrosis