High vs. Standard Dose Influenza Vaccine in Lung Allograft Recipients

Study Design: The proposed study is a phase II, multi-center, double-blind, randomized controlled immunogenicity and safety trial comparing two doses of HD-QIV to two doses of SD-QIV in lung allograft recipients.

1. Hypothesis 1: We hypothesize that lung allograft recipients 1-35 months post-transplant who receive two doses of HD-QIV will develop higher HAI GMTs to influenza antigens compared to lung allograft recipients receiving two doses of SD-QIV.

Specific Aim 1: To compare the HAI GMTs to influenza antigens in lung allograft recipients after receiving either two doses of HD-QIV or two doses of SD-QIV.

2. Hypothesis 2: We hypothesize that administration of two doses of HD-QIV in lung transplant recipients will be well tolerated and the safety profile will be similar to two doses of SD-QIV with regard to solicited local and systemic side effects.

Specific Aim 2: To compare the frequency and severity of solicited local and systemic adverse events in lung allograft recipients after receiving either two doses of HD-QIV or two doses of SD-QIV.

3. Hypothesis 3: We hypothesize that baseline immunophenotypic markers of exhaustion, immune senescence, and immune activation at the pre-vaccine timepoint will correlate with post-vaccine HAI titers.

Specific Aim 3: To define the relationship between baseline phenotypes of T- and B-cell subsets, T-cell activation and post-vaccination HAI titers among lung allograft recipients receiving either two doses of HD-QIV or two doses of SD-QIV.

Study Population: The study will enroll a total of approximately 270 subjects ≥16 years who have undergone lung transplantation within 1-35 months.

Study Enrollment: The enrollment period will be over a three-years. Subjects will be randomized into one of two groups. Group 1 will receive two doses of HD-QIV (0.7 mL; 60μg of each influenza antigen), whereas Group 2 will receive two doses of SD-QIV (0.5 mL; 15μg of each influenza antigen).

Influenza Surveillance: Active surveillance for influenza-like symptoms will begin when influenza season starts in each site's community, defined in previous trials as identification of at least two positive respiratory tests for influenza, with at least 10% of diagnostic tests positive during two consecutive weeks in the local clinical or research laboratory.41,42 Enrollment will continue during influenza season with nasal swabs obtained at all main visits to document the occurrence of influenza virus both prior to and after vaccination. During the influenza season, the study staff will attempt to do a weekly telephone and/or electronic communication with the participants to detect and document any influenza-like illness (ILI) and any specific COVID-19 like symptoms.

If subjects meet ILI criteria and/or any specific COVID-19 like symptoms (see below), an additional nasal swab will be collected\*.

ILI criteria are met by occurrence of one of the conditions below:

* Fever: ≥38°C (100.4°F)

* Two or more of any of the following: respiratory symptoms (rhinorrhea, sinus congestion, post-nasal drip, shortness of breath, cough, wheezing, sputum production, sore throat, sneezing, watery eyes, ear pain, hoarseness); or systemic symptoms (myalgias, chills, chest pain, or headache); or new loss of taste or new loss of smell; or gastrointestinal symptoms (diarrhea or vomiting).

* Per investigators' discretion at each individual site, a swab is not needed if there is a known non-respiratory cause of symptoms.

Primary Outcome Measures

1. Geometric Mean Titers of influenza vaccine antibodies.
   Antibody titers will be measured by hemagglutination inhibition assay.
2. The number of participants reporting solicited injection site reactions and systemic reactions.
   Post-vaccination local adverse events (pain, tenderness, swelling/induration, erythema/redness, swelling/induration size, and erythema/redness size) and systemic adverse events (Fatigue/malaise, headache, nausea, body ache/myalgia (not at the injection site), general activity level, vomiting, and fever).

Secondary Outcome Measures

1. Geometric Mean Titers Ratio of influenza vaccine antibodies (post-/pre-vaccination).
   Antibody titers will be measured by hemagglutination inhibition assay.
2. The number of participants achieving seroprotection and seroconversion for influenza virus.
   Antibody titers will be measured by hemagglutination inhibition assay. Seroconversion is defined as ≥ 4-fold rise in hemagglutination inhibition assay titers. Seroprotection is defined as ≥1:40 hemagglutination inhibition assay titer.