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%.

Eligibility Criteria:
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.