Fluarix inactivated split virus influenza vaccine

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You will be subject to the destination website's privacy policy when you follow the link. CDC is not responsible for Section compliance accessibility on other federal or private website. Cancel Continue. The types of unsolicited AEs reported most frequently in this study were illnesses or symptoms common to the age groups studied.

The same electronic dataset was analyzed for the number of subjects with Grade 3 unsolicited events. In the month age group, Grade 3 AEs were reported in 27 subjects in the Fluarix arm and in 34 subjects in the Fluzone arm. Grade 3 AEs reported in more than two subjects in the Fluarix arm were fever 7 subjects , diarrhea 5 , vomiting 4 and URI 3.

Grade 3 AEs reported in more than two subjects in the Fluzone arm were fever 6 , gastroenteritis 4 , conjunctivitis 3 , and otitis media 3. Grade 3 AEs reported in more than two subjects in this age group were fever 4 , vomiting 3 , and gastroenteritis 3 in the Fluarix arm and fever 6 in the Fluzone arm.

In the year age group, there were 68 subjects in the Fluarix arm and 22 in the Fluzone arm with Grade 3 unsolicited AEs; this is consistent with the randomization in this age group. Grade 3 AEs reported in this age group for Fluarix recipients were vomiting 18 ; fever 15 ; headache; streptococcal pharyngitis and throat pain 7 subjects each ; abdominal pain and gastroenteritis 6 subjects each ; cough, nausea, and URI 4 subjects each ; and diarrhea 3.

In the Fluzone arm, vomiting was reported in 4 subjects, fever in 3, and pain in 3. The number of subjects in the two treatment arms with Grade 3 unsolicited AEs was similar between the two arms. Cases of influenza-like illness or influenza were not followed by either active or passive surveillance. Influenza was reported as an AE preferred term of influenza in 16 subjects: nine 0.

Reviewer comment: On examination of the unsolicited AE dataset, there were an additional seven cases of influenza-like illness in the Fluarix arm and two in the Fluzone arm. New onset chronic diseases were reported in 11 subjects 0. The only new onset chronic disease reported in more than one study subject was asthma, which was reported in three subjects in the Fluarix arm and one in the Fluzone arm.

Other new onset chronic diseases reported in Fluarix recipients were autoimmune thyroiditis, increased cholesterol, increased triglycerides, cardiac murmur cough, allergic rhinitis, alopecia areata, psoriasis, and eczema. The other new onset chronic diseases reported in the Fluzone arm were food allergy and atopic dermatitis. A total of 28 serious adverse events were reported in 22 study subjects 11 in each vaccine arm. SAEs were reported for six subjects in the time period from the first vaccination until 21 days after the second vaccination and in 16 subjects during the time from 21 days after the second vaccination until the end of the follow-up period.

The percentage of subjects with SAEs by treatment arm and age subgroup is shown in the table below. The only SAEs reported in more than a single subject in either vaccine arm were pneumonia 3 Fluarix subjects and 2 Fluzone subjects , lymphadenitis 2 Fluarix subjects and none in Fluzone arm , and febrile seizures 1 in Fluarix subject and 2 in Fluzone subject.

The SAEs of pneumonia in the Fluarix arm were termed pneumonia, viral pneumonia, and lobar pneumonia. The SAEs of lympadenitis were reported 84 days after the second vaccination in a subject with cellulitis and days after vaccination in a subject with mononucleosis. One SAE was judged as vaccine related. This was a febrile seizure reported four days after the second vaccination in a 13 month old Fluarix recipient; the subject also had a viral upper respiratory infection. The seizure lasted approximately two minutes and the subject was taken to the emergency room afterwards; no electroencephalogram or laboratory studies were done, and the only medication used was ibuprofen.

There were no sequelae. The SAEs observed in this study were consistent with the ages studied: 8 of the 11 subjects with SAEs in the 6 to 35 month old cohort had infections as did four of the subjects in the 36 to 59 month cohort. The SAEs in the 5 to 17 year old cohort were from various causes including suicide attempt, appendicitis, head injury, and spontaneous abortion.

Prophylactic antipyretics were administered to 3. Reviewer comment: On analysis of the electronic dataset, antiyr, the percentage of subjects who received concomitant medications during the seven days post-vaccination was similar between the two treatment arms.

Concomitant medication usage was lower in the older age groups during the week after vaccination. In the 3 to 5 year age group, The most common type of medication received in all age groups was antipyretics. The primary objective of this study was to demonstrate the non-inferiority of Fluarix to Fluzone in children from 6 months to 59 months of age.

Non-inferiority of Fluarix to Fluzone, a licensed vaccine in this age group in the U. Of the three endpoints for which non-inferiority was not demonstrated, the non-inferiority margin was only narrowly missed. Therefore, the results were very close to satisfying the non-inferiority criteria, and any differences are unlikely to be of clinical significance.

Furthermore, the evaluation of immunogenicity of the subgroup of study subjects from 36 to 59 months of age is valid, because study subjects were stratified by age and evaluation of immunogenicity by age was a secondary endpoint. Therefore, in the opinion of this reviewer, the results of Study Fluarix-US support the effectiveness of Fluarix in children from 36 months to 59 months of age.

Local solicited adverse reactions were reported commonly in study subjects with pain reported in at least one-third of all subjects in each age subgroup. However, Grade 3 local adverse reactions were uncommon.

Solicited general adverse reactions were reported more frequently in the youngest age subgroup. Grade 3 general solicited events were also reported uncommonly. The unsolicited adverse events and serious adverse events reported in this study reflected common illnesses in the age groups studied, and no safety signal was observed by this reviewer.

At the time of that the study was conducted, the thimerosal-reduced formulation of Fluarix was the formulation licensed for use in the U.

However, the currently licensed formulation of Fluarix is thimerosal free. Study subjects were stratified by age months and months and randomized in a ratio into one of the two vaccine groups. The study was designed to enroll with subjects in each age group. All subjects received two doses of study vaccine on Day 0 and Day Subjects were monitored for 30 minutes immediately following vaccination.

Pain was graded as Grade 1 minor reaction to touch , Grade 2 cries or protests on touch , and Grade 3 cries when arm is moved or spontaneously moves arm.

The temperature in degrees Celsius was recorded; the temperature was to be measured rectally in children 6 to 35 months of age and axillary in children 36 to 71 months of age. Temperature measured rectally was Grade 1 if Axillary temperatures were Grade 1 if Other systemic adverse events were assessed as Grade 1 easily tolerated with no effect on normal activity , Grade 2 interferes with normal activity , and Grade 3 prevents normal activity.

All solicited adverse events were considered related to study vaccination. Study subjects were excluded if they had previously received a vaccine for influenza prevention. Subjects were excluded or vaccine administration was delayed for acute disease at the time of enrollment or of vaccination. Acute disease was defined as the presence of a moderate or severe illness with or without fever. Vaccines could be administered to children with a minor illness such as diarrhea, mild upper respiratory infection with or without low-grade febrile illness, e.

Subjects did not receive the second vaccine if they had an allergic reaction after the first vaccination that might have been caused by any ingredient of the vaccine or an anaphylactic reaction after the first study vaccine.

The study vaccines were supplied in ready-to-use syringes containing a single 0. Thimerosal-reduced Fluarix contained 0. The primary endpoint was the description of post-vaccination geometric mean titers GMTs of serum hemagglutination-inhibiting antibodies HAI for each vaccine strain on Day Blood draws for antibody determination were obtained on Day 0, Day 49, Month 4, and Month 7.

The primary endpoint was the description of antibody response post-vaccination by geometric mean titers GMTs of HI antibodies for each vaccine strain on Day The GMT of HI antibodies at Day 0 and post-vaccination was calculated by taking the anti-log of the mean of the log titer transformations titers below the cut-off will be given the arbitrary value of half the cut off for calculation purpose. The antibody response would also be used to calculate the following:.

The sample size was based on the requirements for annual licensing in Europe in adults, which stipulates a minimum of 50 subjects per age group. The Total vaccinated cohort included all subjects with data available for the analysis in question. The analysis of safety was based primarily on the total vaccinated cohort. The analysis of immunogenicity was based primarily on the ATP cohort.

The definition of the ATP cohort was revised post-hoc to allow for wider windows for each study visit. According to the sponsor, use of the time windows pre-defined in the study protocol would have severely limited the number of evaluable subjects.

The pre-defined windows and revised windows are shown below. The first subject was enrolled in the study on October 8, and the last study visit for the last subject was August 27, The study was conducted at 12 centers in Germany.

A total of subjects were enrolled in the study: were included in the ATP safety cohort, in the ATP immunogenicity cohort, and in the strict ATP immunogenicity cohort.

The disposition of subjects is shown in the table below. Reviewer comment: As a result of the small number of subjects in the strict ATP immunogenicity cohort, it is difficult to reach any conclusions about vaccine immunogenicity from this study.

Ninety-three percent of all subjects were White. The primary cohort for analysis of immunogenicity was the ATP cohort. In the 6 to 35 month age groups, the proportion of subjects who were seropositive e. Reviewer comment: Antibody response, as measured by detectable serum HI antibody, was observed to all three influenza antigens in both the thimerosal-free and Fluarix thimerosal-reduced arms.

However, this endpoint is not commonly used by CBER to determine vaccine immunogenicity, and the clinical significance of this finding is not clear. The percentage of subjects with post-vaccination HI titers of or greater and the seroconversion rate are shown in the table below.

In spite of this, the CBER criteria were met for four of the six endpoints in both age groups for subjects who received the thimerosal-free vaccine, which is the currently marketed formulation of Fluarix in the United States. The seroprotection power was similar in all age groups, to all strains, and for both vaccines with one exception; the seroprotection power was statistically significantly higher to the H3N2 strain in subjects months of age who received the thimerosal-reduced formulation.

According to the CHMP criteria for subjects 18 to 60 years of age, influenza vaccines should induce a seroconversion factor greater than 2. This was achieved in both age groups, for both vaccines, and for all three strains. In the month age group, The percentage of subjects with local solicited events after either the first or second vaccination is shown in the following table.

In subjects months of age, a greater percentage reported local solicited events in the thimerosal-free arm than in the Fluarix arm. This was not observed in the month age group. Redness was also observed more frequently in older subjects receiving Fluarix compared to those receiving the thimerosal-free vaccine; however, swelling was more common in recipients of the thimerosal-free vaccine.

Reviewer comment: In the younger age group, there were fewer local solicited adverse reactions after vaccination with the thimerosal-reduced vaccine compared to vaccination with the thimerosal-free vaccine. In the older age group, the reverse was observed. Therefore, it is impossible to reach any conclusions about the effect of a reduced amount of thimerosal on local solicited adverse reactions. The percentage of subjects with systemic solicited events after either the first or second dose of study vaccine is shown in the table below.

Overall, systemic solicited AEs were reported more frequently in the younger age group than in the older age group. Overall, systemic solicited symptoms were observed more commonly in thimerosal-free vaccine recipients than in Fluarix recipients. The only exception was the increased rate of drowsiness in the older age group receiving Fluarix. Grade 3 systemic solicited events were uncommon. Grade 3 fever was observed in three recipients of the thimerosal-free vaccine and in four recipients of Fluarix.

The only other Grade 3 systemic solicited events were one event of drowsiness and one of loss of appetite; both reported in the Fluarix arm. Reviewer comment: In general, the percentage of subjects with individual systemic solicited adverse events was higher in the month age group. There was no correlation between the frequency of solicited general adverse reactions and thimerosal content of the vaccine.

Unsolicited AEs were reported slightly more often in children months of age 50 subjects compared to those months of age The organ system most commonly involved was the respiratory tract, which, as the sponsor notes, is not surprisingly given that the study was conducted during fall and winter. The majority of respiratory AEs was infectious and included bronchitis, ear infection, and rhinitis.

There were two Grade 3 unsolicited AEs in the Fluarix group fever and gastroenteritis ; neither was judged to be vaccine-related. There were no Grade 3 unsolicited AEs in the thimerosal-free vaccine group.

Reviewer comment: The unsolicited adverse events reported in Study FLU were consistent with common childhood illnesses observed in winter and fall. There were three serious AEs: brain trauma, gastroenteritis, and constipation. None were considered to be vaccine related. Study FLU was a randomized, Phase III study comparing thimerosal-free Fluarix, which is the currently licensed formulation with the previously licensed, thimerosal-reduced formulation of Fluarix in children from 6 months of age to 71 months of age.

The study was small and lacked the statistical power to identify the more immunogenic of the two vaccines or to determine the immunogenicity of the study vaccines using CBER accelerated approval criteria. There were trends for higher antibody titers post-vaccination in the thimerosal-free arm compared to the thimerosal-reduced vaccine arm.

The CBER criteria were met for all three strains and for both study vaccines in children 36 to 71 months of age. In annual European registration trials, Fluarix has consistently exceeded the immunogenicity criteria set by the EU Committee for Medicinal Products for Human Use for adults and the elderly. Fluarix demonstrated immunogenicity in small, open-label studies in at-risk subjects.

In addition, Fluarix vaccination of pregnant women demonstrated efficacy in reducing the rate of laboratory-confirmed influenza in the infants and reducing febrile respiratory illnesses in the mothers and their new-born infants in a randomized trial. Multiple registration trials in all age groups in Europe have demonstrated that the vaccine was safe and well tolerated and of immunogenicity standards that met the requirements of the European Committee for Medicinal Products for Human Use.

There are no published clinical trials evaluating the effectiveness or efficacy of Fluarix against influenza and its complications.