Evaluation of a Recombinant Quadrivalent Influenza Vaccine Versus a Marketed Quadrivalent Inactivated Influenza Vaccine in Children 3 to 17.
Evaluation of a Recombinant Quadrivalent Influenza Vaccine Versus a Marketed Quadrivalent Inactivated Influenza Vaccine in Children 3 to 17.
Multicentric study, Phase III; this study is a randomized, participant- and observer-blind,
 parallel group evaluation to evaluate the immunogenicity, relative efficacy, safety and
 reactogenicity of a recombinant quadrivalent hemagglutinin influenza vaccine versus an
 inactivated quadrivalent influenza vaccine in pediatric subjects and adolescents of 3-17
 years of age. Investigational vaccine is indicated for active immunization against influenza
 A and B for strains contained in the vaccine marketed in the United States for persons 18
 years of age or older.
Abbreviated title Evaluation of immunogenicity, relative efficacy, safety and reactogenicity
 of Flublok Quadrivalent® in healthy children and adolescents aged 3 to17 years.

 Sponsor Product Identifiers Flublok® Quadrivalent of Laboratories Liomont, S.A. de C.V.

 Flublok Quadrivalent consists of 180 μg total recombinant hemagglutinins Study Phase Phase 3
 Study National multicentric Participating sites: Mexico: At least 10 research sites
 distributed in different states.

 Clinical indication Vaccine indicated for active immunization against influenza A and B for
 strains contained in the vaccine; authorized in the United States for persons 18 years of age
 or older.

 It will be evaluated in a population aged 3 to 17 years. Treatment Groups Flublok®
 Quadrivalent (research product) Fluzone® Quadrivalent (active comparator) Number of
 participants in the study 1,556 Estimated study duration: 25 months Duration of participation
 6 months Randomization ratio 1:1 Study visits Visit 1: It corresponds to the screening visit,
 baseline blood sampling and administration of the study vaccine that can be performed on Day
 0.

 Visit 1A and 2: Remote contacts on day 2 and 7 post-vaccination. Visit 3: i. Follow up and
 blood sampling (for the 1-dose group); ii. Visit 3A, follow-up and application of the second
 dose of the vaccine (for the corresponding group); iii. Visit 3B, follow-up and blood
 sampling for the 2-dose group. The visits occur on Day 28.

 Months 3, 4, 5: Remote Contacts for safety tracking Visit 4: Remote contact for study closure
 and safety tracking at Month 6. Statistical analysis plan • Primary efficacy analysis:
 Proportion of subjects in each age category and vaccine group who seroconvert, with
 seroconversion being defined as (a) a >4-fold rise in HAI antibody titer in those subjects
 seropositive (titer >10) at baseline or (b) achievement of an HAI titer of >40 in those
 seronegative at baseline. Seroconversion will be evaluated against each of the 4 vaccine
 antigens, on Study Day 28 (or Day 56 for 2-dose subjects), by category A and B separated

 • Geometric Mean Titer (GMT) of HAI antibody against each vaccine antigen in each age
 category and vaccine group 28 days after immunization (Day 56 for 2-dose subjects) by
 category A and B separated Secondary efficacy analysis. Efficacy analysis and analysis of
 safety results associated to reactogenicity and other adverse events.

 Final contribution of the study results The direct benefit for subjects, individually, is
 expected to be seasonal influenza protection with the expected degree of protection,
 specially among recipients of the IIV4 control vaccine, which is also approved for use in the
 age groups of the study population, evaluating in detail the comparative response of the
 research product.

 The results of the study are intended to evaluate the immunogenicity, efficacy and safety of
 Flublok Quadrivalent in this population age and in this way, support the use of Flublok
 Quadrivalent for children and adolescents 3-17 years of age.

 If the results are favorable and if the hypothesis is fulfilled, the extension of the
 indication to the evaluated age segment may result in greater protection of the child
 population so as, not to be unprotected by the limited resources in health, the shortage of
 vaccines in certain regions, and to improve the supply and accessibility of the population in
 general for influenza prevention.

 The hypothesis underlying the study design and sample size estimated for the trial population
 from 3 to 17 years of age is based on the immunogenicity of Flublok Tetravalent, considering
 that the haemagglutination inhibition (HAI) seroconversion titers and the geometric mean of
 post-vaccination titers for the four hemagglutinin antigens in the vaccines after completion
 of vaccination with Flublok Quadrivalent are not inferior to those titers observed in those
 vaccinated with IIV4.

 Statistical considerations. sample size is 330 subjects in each age cohort for each treatment
 group, reaching a power of 80% to detect a marginal difference of non-inferiority for the
 seroconversion rate between the groups of -0.1000. The seroconversion rate of the control
 group is 0.7000. The Flublok Quadrivalent seroconversion rate is assumed to be 0.6000 under
 the null hypothesis of inferiority. The power was estimated for the case that the relative
 seroconversion rate of Flublok Quadrivalent is 0.7000. The statistical test use is a one
 tailed Z test (unpooled). The significance level for the test was established in 0.0250.

 A total of 1,556 subjects (330 complete cases per treatment group in subjects from 3 to 17
 years of age) will be enrolled, considering possible losses up to a maximum of 15%.
Inclusion Criteria:

 -  Male or female age 3 to 17 years.

 -  History of two previous influenza immunizations at any time, or influenza infection
 during the previous year.

 -  Female subjects of child-bearing potential (as defined by the onset of menses) must
 agree to prevent pregnancy and usage of an effective contraception, or having
 practiced sexual abstinence for at least 28 day prior to the first study vaccine
 administration. Female subjects of child-bearing potential must be tested for
 pregnancy within 24 hours prior to vaccine administration.

 -  In good general health, healthy or medically stable, as determined by the medical
 history, physical examination and the Investigator's judgment.

 -  Parent(s) or legal representative of each potential subject must comprehend the study
 requirements, sign the informed consent before any procedure, and agree to comply with
 planned study procedures and visits. Provide written consent prior to enrollment and
 initiation of any study procedure.

 -  Pediatric consent will be attained as per the Research Ethics Committee's
 determination when subject is aged 8 or older.

 Exclusion Criteria:

 -  Known allergy to eggs (anaphylaxis, angioedema, respiratory distress), severe allergy
 (e.g. anaphylaxis) to other components of the vaccine or contraindications to receive
 the comparator IIV4.

 -  Use of systemic steroids at doses of 2mg/kg/day for more than 10 days of prednisone or
 its equivalent.

 (The use of nasal or topical steroids will be allowed).

 -  Active neoplastic disease or a history of any malignancy.

 -  History of receiving the influenza vaccine within the previous 6 months.

 -  Plan to receive another influenza vaccine, during the study term.

 -  History of receiving immunoglobulin or another blood product within the 3 months prior
 to enrollment in this study.

 -  Acute or chronic medical condition that, in the opinion of the Investigator, would
 render immunization unsafe or would interfere with the evaluation of efficacy or the
 immune response to the vaccine.

 -  An acute illness, including a body temperature greater than 37.7°C, within 3 days
 prior to immunization.

 -  Receive an experimental vaccine or medication within 1 month prior to enrollment in
 this study, or the expectation to receive an experimental vaccine, medication, or
 blood product during the study period.

 -  Developmental delay, neurologic disorder, or seizure disorder requiring ongoing
 medical assistance (note: history of febrile seizure is not considered an exclusion
 criterion).

 -  History of Guillain-Barré syndrome within 6 weeks after the application a previous
 influenza vaccine.

 -  Concurrent participation in another clinical trial (active or follow-up phase).

 -  Any other condition or situation that would, in the opinion of the investigator, place
 them at an unacceptable risk of injury or render the subject unable to meet the
 requirements of the protocol.