Randomized Controlled Trial of LAIV vs TIV Vaccines in Schools
Randomized Controlled Trial of LAIV vs TIV Vaccines in Schools
Overall, this study will determine (1) the effect of vaccine type (FluMist vs. TIV) on
 immunization rates, (2) assess the feasibility of school immunization clinics, and (3) inform
 a larger study to understand the effects of these two vaccines on reducing influenza.
Our study partnership (Public Health Agency of Canada [PHAC] / Canadian Institutes of Health
 Research [CIHR] Influenza Research Network [PCIRN], Public Health Ontario [PHO], and PCCHU),
 with the support of Ontario's Ministry of Health and Long-Term Care [MOHLTC], will conduct an
 open-label randomized trial in elementary schools within the geographic boundaries of PCCHU
 during the 2013-14 influenza vaccination campaign.

 In order to address the four study objectives in our comparison of LAIV vs. TIV via SBII, we
 will use multiple methodologies: questionnaires, interviews, and household surveillance.

 Overall study design PCCHU implemented SBII in elementary schools from 2000 to 2010, and we
 have approval from the Kawartha Pine Ridge District School Board (KPRDSB) to renew this
 program for the upcoming influenza season (2013-14). Ten schools (each school having an
 average of 300 students) will be recruited to participate in this study. The schools will be
 randomized on a 1:1 basis (i.e., five schools in each arm) to having its students offered (at
 no cost) 0.2 mL of LAIV or 0.5 mL of TIV at SBII clinics organized by PCCHU.

 Intervention (LAIV): Healthy children and adolescents between Junior Kindergarten (JK) and
 Grade 8 in the intervention schools will be immunized with LAIV (FluMist influenza vaccine)
 recommended for the 2013-14 the influenza season. A 0.2 ml dose of the vaccine will be
 administered intranasally. TIV will also be available for children whose parents decline LAIV
 but would still like their child immunized against influenza, and for children who, according
 to 2012-13 NACI recommendations, have contraindications for LAIV: severe asthma (defined as
 currently on oral or high-dose inhaled glucocorticosteroids or active wheezing) or medically
 attended wheezing in the 7 days prior to vaccination; receiving aspirin or aspirin-containing
 therapy because of the association of Reye's syndrome with aspirin and wild-type influenza
 infection; and immune-compromising conditions due to underlying disease and/or therapy, as
 the vaccine contains live attenuated virus.

 Control (TIV): Healthy children and adolescents between JK and Grade 8 in schools assigned to
 TIV will be immunized with inactivated influenza vaccine (Vaxigrip vaccine) recommended for
 the 2013-14 influenza season. A 0.5 ml dose of the vaccine will be administered
 intramuscularly. Children with one or more of the following contraindications, according to
 NACI recommendations, will not be eligible for vaccination with TIV: an anaphylactic reaction
 to a previous dose; an anaphylactic reaction to any of the vaccine components, with the
 exception of egg; or Guillain-Barré Syndrome (GBS) within six weeks of a previous influenza
 vaccination.

 Children in either arm of the study who are younger than 9 years of age and have not
 previously received influenza vaccines require two doses; following the dose administered at
 school, they will be given a reminder letter to inform their parent/guardian that a second
 dose can be received at healthcare settings including their family physician's office or a
 community-based public health clinic, four weeks after the first dose as per influenza
 immunization recommendations.

 For the purpose of this study, the vaccines will only be offered to children enrolled at
 participating schools; other groups such as school staff, and students' parents and siblings
 may obtain TIV at no cost at the settings listed above or LAIV from a physician or pharmacy
 (paid for privately).

 Objective 1: To determine whether offering LAIV vs. TIV via SBII leads to higher vaccine
 coverage

 Study design: A web-based questionnaire will be sent to all parents/guardians of students in
 participating schools for whom we have contact information, to ask, among other questions,
 about vaccination status of their child, and if the child was vaccinated, where this
 occurred.

 Study procedures: All parents/guardians who provided an email address will be contacted in
 January 2014 via email with an invitation to complete an online (or paper-based, if
 preferable) Parents' Vaccination Questionnaire on behalf of their child. Prior to beginning
 the questionnaire, the parent/guardian will access a screen which describes the purpose of
 the questionnaire, which data are being collected, and why. They will also be informed that
 all questions (except for whether or not their child was vaccinated, and with which influenza
 vaccine) are optional, and that completion of the questionnaire implies consent. The
 questionnaire will include questions about student demographics, presence of chronic
 conditions and other important risk factors for influenza, receipt of influenza vaccines
 during previous influenza seasons, and receipt of influenza vaccines outside of the school
 setting (e.g., doctor's office, pharmacy, PCCHU community-based clinic) during the current
 influenza season. We will also request health card numbers and permission for future linkage
 to provincial health administrative data sets housed at the Institute for Clinical Evaluative
 Sciences (ICES) to assess healthcare utilization, in order to determine which of TIV and LAIV
 is associated with fewer physician and emergency room visits. In cases where the health card
 number is not provided or is incorrect, the first and last name, sex, and birthdate of the
 student will be used for linkage. In April 2014, the questionnaire will be sent out again to
 parents/guardians of children who, based on the questionnaire sent in January, had not
 received influenza vaccine, to capture anyone whose vaccination status changed between
 January and April, and to also provide another opportunity for parents who did not yet
 complete the questionnaire. After the email with the questionnaire web link is sent out in
 both January and April 2014, two email reminders will be sent over the next three weeks. For
 parents/guardians who provide their phone number to the study team, an RA will also remind
 them by telephone to complete the questionnaire.

 Outcome: The number of students at each school for whom the Parents' Vaccination
 Questionnaire is completed will serve as the denominator for the vaccine coverage
 measurement, and the number of students who receive LAIV or TIV and have the questionnaire
 completed by their parent/guardian will serve as the numerator. Separate estimates of vaccine
 coverage will be calculated for healthy children and those with chronic conditions that place
 them at elevated risk of serious influenza infection. As a secondary measure of immunization
 rates, we will use vaccination data obtained by PCCHU at the beginning of January 2014, of
 the number of doses (by vaccine type) given during the school-based clinics (numerator). We
 will ask each principal for the number of students at their school as of November 1, 2013, to
 use as the denominator.

 Sample size: To calculate the sample size required to detect a 10% increase in coverage with
 LAIV compared to TIV (i.e., primary outcome), we used the sample size calculation for two
 proportions based on 80% power and an alpha level of 0.05 (two-sided). The unit of
 randomization will be the school level while the unit of analysis will be the individual
 students in the schools. To account for the clustering effect of schools, we inflated the
 sample size by 20% (i.e., variance inflation factor), resulting in a sample size of 451
 students/group. We anticipate that we should have an adequate sample size since we only need
 a response rate of 30% (902/3000), and we hope that with the incentives that we will have a
 response rate of over 70%.

 Data analysis: Bivariate analysis of statistical significance of continuous variables will be
 performed using two-tailed Student's t-tests. Proportions will be compared using Chi-Square
 tests or Fisher's exact tests. We will identify predictors of the outcome (vaccinated or not)
 using stepwise regression methods. To account for the clustering effect in schools, we will
 use generalized estimating equations or mixed models to determine statistical significance of
 continuous or dichotomous variables adjusted for covariates and interaction terms. The
 exposure of interest will be the vaccine type (LAIV or TIV). The null hypothesis will be
 rejected fixing the probability of type I error at 0.05 and a type II error at 0.20.
 Two-tailed probability distributions will be used for all statistical analyses unless
 specified. Variables will be excluded from the model if they lead to complete separation of
 data, have >10% missing values, exhibit collinearity, or have no observations in one group.
 We will also examine the residuals to identify if model assumptions are invalid or are
 affected by influential observations. We will use STATA version 10.0 (2007, StataCorp, LP,
 College Station, TX) to analyze the data.

 Objective 2: To assess the acceptance of administering LAIV vs. TIV via SBII based on school
 administrator, public health, and parent/guardian perceptions

 Study design: In order to assess perceptions of the LAIV and TIV SBII programs, we will
 interview school management staff, and public health managers, and administer questionnaires
 to parents/guardians of students in the participating schools.

 Inclusion/exclusion criteria: Interviewees must be members of the management staff
 (principal, vice principal) of the participating schools, or PCCHU manager or immunization
 nurse, and have been involved in some aspect of the coordination of the SBII clinic. The
 Parents' Vaccination Questionnaire will be used to gauge parental perceptions of the
 different vaccine types, and will be administered to all parents/guardians for whom we have
 contact information, regardless of whether or not their child was vaccinated.

 Study procedures:

 -  Interviews with school management staff immediately following the SBII clinic days to
 understand their experiences with coordinating the program, any facilitators/barriers to
 its continued existence, and also experiences/interactions with parents regarding this
 program. The Information Letter and preliminary interview guide are outlined in
 Appendices H and I. These interviews will take place over the telephone in November or
 December, 2013.

 -  Interviews with public health immunization staff (manager(s) and nurses) to gauge
 perceptions of the program, and of administration of LAIV vs. TIV, based on logistical
 factors including time to coordinate the program, communication with parents, and staff
 time. These interviews are scheduled to take place in November or December, 2013;
 however, if the public health staff are unavailable at this time due to conducting
 vaccination clinics, we will conduct these telephone interviews in January 2014 instead.

 -  Questions related to parent/guardian experiences with SBII clinics, as well as their
 perceptions of LAIV vs. TIV, specifically regarding safety, effectiveness, and
 acceptability (invasiveness, concerns about administration, adverse events, etc.), will
 be included in the Parents' Vaccination Questionnaire.

 Outcome: The outcome of this study component is stakeholder (school staff, public health, and
 parents) perceptions of the LAIV and TIV SBII programs, specific to coordination,
 facilitators/barriers, and overall experiences.

 Sample size: We anticipate that we will interview approximately one principal or
 vice-principal from each of the 10 schools, as well as five PCCHU managers or staff members.
 However, the number of interviews conducted with each of these stakeholder groups will
 ultimately be based on the number of individuals who were involved in planning of the SBII
 clinics; therefore, fewer or more interviews may be conducted, as appropriate. The Parents'
 Vaccination Questionnaire will be used to gauge parental perceptions of the different vaccine
 types, and will be administered to all parents/guardians for whom we have contact
 information.

 Data analysis: The interviews will be imported into qualitative analysis software (N-Vivo
 Version 10.0) to aid in data organization, review, coding, and analysis, and to facilitate an
 exploration of themes that emerge from the data. Themes will be analyzed by type of vaccine
 given, and other factors including the school's population size. At least two team members
 will read each transcript once to get an overall sense of the data, and then again to
 identify major topics or issues in the data. Consensus decision-making will be used when
 needed to arrive at mutually agreed-upon coding.

 We will use the two-proportion z-test to compare the proportion of parents/guardians with
 children in the LAIV group and those with children in the TIV group, based on perceptions of
 vaccine safety and effectiveness, and overall preference for vaccine type. We will also
 assess these outcomes for parents/guardians who did not vaccinate their children this season.
 To account for multiple comparisons, we will adjust the p values using Benjamini-Hochberg's
 method for controlling false discovery rates (FDR), which controls for the number of
 comparisons falsely declared significant.

 Objective 3: To compare the costs associated with delivering LAIV vs. TIV via SBII

 Study design: To obtain costing data associated with coordination of the LAIV and TIV SBII
 programs, principals at participating schools and immunization program managers at PCCHU will
 be interviewed.

 Inclusion/exclusion criteria: We will use the same criteria, as for Objective 2, since the
 cost data will be obtained during interviews.

 Study process: During the interviews with school board and school management staff, and
 public health managers, we will ask about the costs associated with administering LAIV and
 TIV, including but not limited to training costs, equipment costs, and staff resource use
 (nursing time for coordinating the campaign, communication with parents/guardians, delivery
 of vaccine and post-vaccination monitoring, as well as data entry clerk time, where
 appropriate).

 Outcome: The outcome of this component of the study is the costs that PCCHU, participating
 schools, and the MOHLTC incurred in order to deliver LAIV and TIV through SBII programs.

 Sample size: We anticipate that we will interview approximately one principal or
 vice-principal from each of the 10 schools, as well as the immunization program manager at
 PCCHU. However, we may need to conduct additional or fewer interviews, depending on how many
 individuals are able to provide us with costing data.

 Objective 4: To inform a future RCT to evaluate the direct and indirect benefits (protection
 against influenza) of LAIV vs. TIV via SBII

 Study design: From each of the 10 study schools, 25 vaccinated students and their households
 will participate in the Household Surveillance Study, involving surveillance for
 laboratory-confirmed influenza during the 2013-2014 influenza season, to assess the effect of
 LAIV and TIV on influenza incidence. The purpose of this component is to generate parameter
 estimates (e.g., incidence of laboratory-confirmed influenza, intraclass correlations) to
 inform a future RCT.

 Inclusion/exclusion criteria: Households will be eligible for the Household Surveillance
 Study if: i) they include a child who was vaccinated against influenza at one of the 10
 school-based clinics; and (ii) all household members consent/assent to participating.
 However, as stated above, we will only maintain inclusion criterion (ii) if feasible.
 Additionally, the students selected from each school must have received the vaccine to which
 their school was assigned (e.g., a student at an LAIV-assigned school must have received
 LAIV).

 Study procedures: Once consent/assent has been obtained for the household, the HRA will also
 collect and record baseline data from each household member, including demographics, risk
 factor status, and current influenza vaccination status. We are collecting this information
 to be able to describe the baseline characteristics of our population, as is reported on a
 standard basis in scientific publications. In addition, we will need to control for
 demographic and risk factor variables when we are analyzing trends in the data, to better
 compare the effects of each type of vaccine. Each individual will be asked the baseline
 questions in turn, and in private, to help encourage honesty. Each household will be provided
 with either paper or electronic diaries for recording daily symptoms as well as a digital
 thermometer (which they will be taught to use). They will also be supplied with Copan flocked
 nasal swabs, and will be taught by the HRA how to self-swab nasally. Participating households
 will be asked to:

 i. Complete the daily diary to record whether any household member has cold, influenza, or
 acute respiratory illness symptoms, illness history (e.g., hospitalizations related to lower
 respiratory tract infections and pneumonia, physician visits for respiratory illness),
 medical history (e.g., medication use), and missed days of school or work due to acute
 respiratory infection. The diary will be available in both paper and electronic form.

 ii. Have any household member exhibiting any one of the three symptoms for influenza (cough,
 sore throat, fever) or at least two other related symptoms perform an intranasal self-swab as
 soon as symptoms appear (within 48 hours), and call a Research Assistant (RA).

 Data collection for the Household Surveillance study will begin when the weekly percentage of
 tests positive for influenza from the Peterborough area (tested via PHO) exceeds 5%, while
 the end date will be when the weekly percentage of tests positive for influenza from the
 Peterborough area falls below 5%, indicating the end of the 2013-14 influenza season. Once
 the study begins, an RA will contact each household to let them know to start recording their
 data daily in the symptom diaries. For households who opt for paper diaries, the RA will
 provide them with paper copies of the symptom diary to complete on a daily basis. The RA will
 contact each of these households twice weekly by telephone to obtain the data for each
 household member, and will record this directly into FluidSurveys. Weekly emailed reminders
 will also be sent to these participating households. Those households who opt for electronic
 diaries will receive a daily link to the patient diary in FluidSurveys. This email will be
 sent to the main contact of each household, who will fill out the form for each household
 member. The SRC will monitor diary entries, and if no entries are submitted for a household
 for three consecutive days, an RA will call that household to remind them to complete the
 diary. If any individual is experiencing at least two cold or influenza symptoms or any one
 of the three specific symptoms for influenza [cough, sore throat, fever]), the SRC will let
 the RA know to contact the individual to: i) remind them to self-swab; and ii) arrange a
 household visit to take a nasal swab of that individual within 48 hours of the symptom onset
 (as reported by the individual). Thus there should be two swabs per episode. A repeat swab
 will be collected 7 days after the collection of the initial swab (indicating a new episode)
 if the individual has at least one additional symptom, as well as the initial 2 symptoms; or
 if the individual has at least two new symptoms (different from the initial two symptoms and
 the first two have resolved).

 The RAs will collect all nasal swabs during household visits, and transport them to the
 regional laboratory in Peterborough, where they will be stored in a freezer until transported
 to the central laboratory in Toronto where testing will take place.

 At the end of the study, the RA will request that the parent/guardian for each participating
 household complete the Parents' Vaccination Questionnaire for their child, if they have not
 yet done so.

 Sample size: The Household Surveillance study will include 25 vaccinated students and their
 households, from each of the 10 participating schools. The students must have been vaccinated
 during the SBII clinic at their school.

 Laboratory testing: The specimens will be tested by means of a reverse-transcriptase
 polymerase chain reaction (RT-PCR) assay to detect the presence of influenza A or B virus. We
 will estimate primary and secondary attack rates, based on the proportion of household
 contacts in whom influenza developed (as determined by RT-PCR assay), as well as rates of
 acute respiratory illness.

 PHO has a regional laboratory in Peterborough so all the specimens will be dropped off there
 and sent along with the routine clinical specimens to the central laboratory in Toronto for
 PCR testing. We will test the specimens in batches since real-time results are not required
 for the purposes of this study. We will culture the specimens that test positive for
 influenza on PCR and explore strain identification by the National Microbiological Laboratory
 at a future date.

 Data analysis: To calculate influenza incidence among household members, we will count only
 the first infection by a specific influenza type/subtype (i.e., A/H3N2, A/H1N1, B) as the
 numerator (age-specific), while the denominator is age-specific uninfected person-days. If a
 participant is swabbed more than once within 14 days, and if the same virus is detected on
 more than one occasion in this time frame, only the first episode detected will be used in
 the analysis. This will be calculated for both influenza and non-influenza viruses. We will
 calculate incidence using events per 1000 person-days and estimate differences in rates
 assuming a Poisson distribution.
Children in schools randomized to LAIV cannot receive this vaccine if they have any of the
 following contraindications: severe asthma (defined as currently on oral or high-dose
 inhaled glucocorticosteriods or active wheezing) or medically attended wheezing in the 7
 days prior to vaccination; receiving aspirin or aspirin-containing therapy because of the
 association of Reye's syndrome with aspirin and wild-type influenza infection; or
 immune-compromising conditions due to underlying disease and/or therapy, as the vaccine
 contains live attenuated virus. These children will receive TIV instead, unless they have a
 contraindication to receiving TIV. Children in schools assigned to TIV cannot receive this
 vaccine if they have any of the following contraindications: an anaphylactic reaction to a
 previous dose; an anaphylactic reaction to any of the vaccine components, with the
 exception of egg; or Guillain-Barré Syndrome (GBS) within six weeks of a previous influenza
 vaccination.