The overall objective is to establish an influenza Controlled Human Infection Model (CHIM) in Canada that can be used to assess the safety and efficacy of candidate vaccines, biologics, and therapeutics targeting influenza viruses.

Inclusion Criteria:

1. Written informed consent obtained from the participant.

2. 18-45 years of age.

3. Good general health status, as determined by history and physical examination conducted no longer than 30 days prior to the challenge date.

4. HAI antibody titer ≤1:40 against influenza A/Texas/71/2017 (H3N2).

5. Eligibility laboratory values* (complete blood cell count with differential (CBC-D), biochemistry (creatinine (Cr), total bilirubin, blood urea nitrogen (BUN), aspartame aminotransferase (AST), alanine transaminase (ALT), and c-reactive protein (CRP))*Labs within normal range or grade 1 abnormalities deemed not clinically significant by a study investigator are considered acceptable.

6. Vital signs** as follows:

   1. Pulse is 47 to 99 beats per minute
   2. Systolic blood pressure is 85 to 139 mmHg
   3. Diastolic blood pressure is 55 to 89 mmHg
   4. SpO2 ≥ 95%; RR ≤ 18
   5. Oral temperature is less than 38.1°C **Clinical judgement when characterizing vital signs will be used in the context of certain populations according to the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (e.g. conditioned athletes, white coat hypertension etc.)

7. If a person is at risk of becoming pregnant, has practiced adequate contraception for 28 days prior to challenge, and has a negative pregnancy test on the screening day and the day before influenza A/H3N2 challenge (Check-in Day) and has agreed to continue adequate contraception until 60 days after challenge.

   Risk of pregnancy is defined as any individual assigned female at birth or with reproductive capacity who is sexually active with individuals with sperm-producing capabilities. Individuals who have received the following are considered to not have reproductive capacity:

   • Documented hysterectomy
   • Documented bilateral salpingectomy
   • Documented bilateral oophorectomy
   • Documented and current bilateral tubal ligation or occlusion
   • Credible self-reported history of diagnosed infertility
   • Hormone therapy (e.g. testosterone), provided it is administered consistently and medically assessed as sufficient to reduce pregnancy such that ovulation has ceased
   • Any other condition, as determined by the Principal Investigator/study physician, that would render an individual incapable of becoming pregnant

   Adequate contraception is defined as a contraceptive method with a failure rate of <1% per year when used consistently and correctly and, when applicable, in accordance with the product label. Examples include the following:

   • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal
   • Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable CI2403.03November2025_V3.0 52
   • Intra-uterine device (IUD) with or without hormonal release
   • Vasectomized partner, if this is the participant's sole partner and the partner has received a medical assessment of the surgical success
   • Credible (as deemed by the Investigator/study physician) self-reported history of abstinence for at least 28 days prior to challenge

8. Participants who, in the opinion of the Investigator/study physician, can and will comply with the requirements of the protocol (e.g., inpatient stay, complete eDiary Cards, return for follow-up visits).

Exclusion Criteria:

1. Underlying chronic medical condition requiring ongoing follow-up and monitoring by a physician (e.g., diabetes, seizure disorder).

2. Underlying renal disease or disorders requiring ongoing follow-up and monitoring by a physician. In the event a participant has a minimally elevated BUN and/or Cr at screening, the participant will either be excluded or an eCRF or creatinine clearance may be conducted to determine eligibility.

3. Underlying coagulation disorder history. In the event a participant reports a personal history of undiagnosed prolonged bleeding and/or recurrent nosebleeds or a personal or family history of coagulation disorders, a bleeding panel (PTT, INR, fibrinogen) will be used to rule out coagulopathy.

4. Underlying cardiac conditions including:

   1. Hypertension, angina, or prior myocardial infarction
   2. Structural or functional cardiac disease (e.g., dilated cardiomyopathy, congestive heart failure)
   3. With a history of arrhythmias/dysrhythmias (e.g., torsades de pointes, atrial fibrillation)
   4. Cardiac conduction abnormalities (e.g., congenital or acquired heart block)
   5. Uncorrected or ongoing serum electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia)

5. Underlying pulmonary disease including asthma, emphysema, chronic bronchitis, pulmonary tuberculosis or any other structural or functional pulmonary condition (e.g., history of severe airway hyper-responsiveness).

6. FEV1/FEV6 < 0.73 as an indication of potential airflow limitation.

7. Known allergy to excipients in the challenge virus inoculum and placebo. The excipient (diluent and placebo) is SPG: sucrose, KH2PO4, K2HPO4, L-glutamic acid.

8. Moderate or severe symptoms of health anxiety, anxiety, and mood symptoms. Self-reported current diagnosis of a major psychiatric illness, including, but not limited to, a schizophrenia spectrum disorder, bipolar disorder, posttraumatic stress disorder, obsessive compulsive disorder, substance use disorder, or eating disorder, based on standardized mental health screening tools.

9. Habitual*** smoker of tobacco, e-cigarettes or marijuana. ***Habitual smokers are those who smoke more than four cigarettes, other tobacco products, e-cigarettes (to include vaping and Juuling products) or marijuana in a week and cannot agree to abstain from smoking cigarettes, other tobacco products, e-cigarettes and/or marijuana products during participation in the study.

10. Any current daily use of illicit drugs whereby the individual and/or study staff assess that the individual cannot abstain from during the isolation period.

11. Any current daily alcohol consumption whereby the individual and/or study staff assess that the individual cannot abstain during the isolation period.

12. History of allergic rhinitis and/or any condition that causes similar symptoms, including chronic cough.

13. Pregnant (known before or established at the time of screening using a urine pregnancy test) or breastfeeding.

14. Immunocompromised (with HIV/AIDS or receiving immunosuppressive therapy involving steroids) or any medical condition or medication that leads to a compromised immune system.

15. Screening blood work positive for HBV, HCV, or HIV.

16. Influenza virus detected in NPS sample prior to challenge using RT-qPCR and/or culture isolation, or detection of other respiratory infection.

17. Received influenza vaccination within the last 4 months prior to screening based on history described by participant or planned receipt up to Study Day 57.

18. Living with, working with, or in close contact with children less than 6 months of age, or a household member(s) highly recommended to receive an annual influenza vaccination by NACI**** and that have not been immunized with influenza vaccine within the last year or immunized less than 3 weeks prior to challenge.

    ****Individuals that are highly recommended by NACI to receive an influenza vaccine and potentially at risk include the following (52): (52):

    1. All children 6-59 months of age
    2. Adults and children with the following chronic health conditions:

    i. Cardiac or pulmonary disorders (including bronchopulmonary dysplasia, cystic fibrosis and asthma) ii. Diabetes mellitus and other metabolic diseases iii. Cancer, immune compromising conditions (due to underlying disease, therapy, or both, such as solid organ transplant or hematopoietic stem cell transplant recipients) iv. Renal disease v. Anemia or hemoglobinopathy vi. Neurologic or neurodevelopmental conditions (includes neuromuscular, neurovascular, neurodegenerative, neurodevelopmental conditions and seizure disorders [and, for children, includes febrile seizures and isolated developmental delay], but excludes migraines and psychiatric conditions without neurological conditions) vii. Morbid obesity (defined as Body Mass Index (BMI) ≥ 40 kg/m2) viii. Children six months to 18 years of age undergoing treatment for long periods with acetylsalicylic acid, because of the potential increase of Reye syndrome associated with influenza c. All individuals who are pregnant d. All individuals of any age who are residents of nursing homes and other chronic care facilities e. Adults 65 years of age and older f. Indigenous Peoples

19. Any contraindication to receiving oseltamivir or zanamivir including known history of negative/anaphylactic reactions. Inability to take capsules containing gelatin or sorbitol (oseltamivir) or lactose-intolerant (zanamivir)

20. Recent (within the 6 months before Screening Day) nasal or sinus surgery or diagnosis with nasal polyps.

21. Recent use (4 weeks of Screening Day) of intranasal steroids, antihistamines, or any substance (including legally prohibited or prescription drug) that is administered nasally.

22. Receipt of any investigational drug or vaccine within 6 months prior to challenge. An investigational drug or vaccine is one that is still being tested in clinical trials that has not yet been authorized for use in Canada for administration by public programs.

23. Receipt of any authorized vaccines within 2 weeks prior to being challenged.

24. Previous moderate or severe laboratory-confirmed SARS-CoV-2/COVID-19, influenza infection, or any other respiratory virus infection (e.g., RSV) that required hospitalization.

25. Head trauma (e.g., fracture of the cribriform plate) within 1 year of screening.

26. Symptoms indicative of acute respiratory illness (such as fever, cough, difficulty breathing) identified during the physical examination done on Study Day -1 (check-in) or Day 1 before a participant is challenged. In the event a participant reports changes to their medical history since screening up until check-in, a history-directed respiratory panel will be administered and any positive respiratory virus including SARS-COV-2 will be exclusionary

27. History of Bell's Palsy, Guillain-Barre, and/or facial paralysis.

28. Receipt of facial cosmetic filler, or any facial neuromodulator, in the past 3 months.

29. Self-reported sleep apnea that requires a continuous positive airway pressure (cPap) machine

30. Receipt of blood or blood products during the six months prior to the planned date of challenge.

31. Plans to donate blood anytime throughout the study.

32. Any other finding that the Investigator/study physician considers will make the participant unsuitable for the study or unable to comply with the study requirements.