High vs. Standard Dose Influenza Vaccine in Adult SOT Recipients

Study Design. The proposed study is a multi-center, phase II, randomized, controlled, immunogenicity and safety trial comparing two doses of the trivalent HD-IIV vs. two doses of the quadrivalent SD-IIV vs. one dose of HD-IIV followed by one dose of placebo in adult SOT recipients (kidney, heart, and liver)

Primary and Secondary Objectives

I. Primary:

Immunogenicity Objective To compare the hemagglutination inhibition (HAI) geometric mean titers (GMT) to influenza A antigens in adult SOT recipients after receiving either one dose of high dose quadrivalent influenza vaccine (HD-QIV), two doses of standard dose (SD)-QIV, or two doses of HD-QIV over one influenza season.

Safety Objectives

• To compare the frequency and severity of local solicited adverse events in adult SOT recipients after receiving either one dose of HD-QIV, two doses of SD-QIV, or two doses of HD-QIV over one influenza season.
• To compare the frequency and severity of systemic solicited adverse events in adult SOT recipients after receiving either one dose of HD-QIV, two doses of SD-QIV, or two doses of HD-QIV over one influenza season.

II. Secondary:

Immunogenicity Objectives

• To compare the GMT to influenza B antigens in adult SOT recipients after receiving either one dose of HD-QIV, two doses of SD-QIV, or two doses of HD-QIV over one influenza season.
• To compare the frequency of seroconversion (achieving a ≥4-fold rise in HAI titer) or seroprotection (presence of ≥1:40 HAI titer) in adult SOT recipients after receiving either one dose of HD-QIV, two doses of SD-QIV, or two doses of HD-QIV over one influenza season.

Study Population. A target of a minimum of 396 (132 subjects per year) adult subjects≥18 years, who received kidney, heart, or liver SOT), and are 1-11 months post-transplant will be enrolled over a three-years period. Approximately 99 subjects per site (33 subjects per year) will be enrolled from the following four clinical sites: Vanderbilt University Medical Center, Northwestern University Feinberg School of Medicine, University of Washington Medical Center, and University Hospital, University of Alabama at Birmingham.

Study Procedures. Consented and eligible subjects will be randomized in a 1:1:1 fashion to one of three groups to receive either two doses of 0.5 mL HD-IIV (60µg of each influenza antigen), two doses of SD-IIV (15µg of each influenza antigen), or one dose of HD-IIV (60µg of each influenza antigen) followed by one dose of placebo (normal saline).

HAI and microneutralization (MN) titers to influenza virus specific vaccine antigens, phenotypic B and T cell responses, B and T cell specific influenza responses, and complete blood count with differential and platelets (CBC d/p) will be measured prior to the first and second vaccine dose, 28-42 days after the second vaccine dose, and approximately 6 months after second vaccine. Quantitative CD4+/CD8+/CD19+ levels, and quantitative serum IgG and IgM concentrations will only be measured prior to the first vaccine. Approximately 30-50 mLs of blood will be collected at each visit. Nasal swabs will be collected at each visit. Subjects will record solicited events for 7 days after each vaccination (Day 0-7). On days 1-3 and 8-10, telephone and/or electronic communication will be made to assess for solicited AEs following each vaccination. Nasal swabs will also be collected at each study visit, regardless of symptoms.

Influenza Surveillance. Active surveillance for influenza-like symptoms will begin when influenza season starts in each site's community. Influenza season in the specific community is defined -as in previous trials- by 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.

Enrollment will continue during influenza season with nasal swabs obtained during study visits -regardless of influenza-like symptoms- and from symptomatic subjects to document the detection 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).

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

ILI criteria: One of the following criteria met:

• Fever: ≥38°C (100.4°F); or
• 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, or 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

Inclusion criteria

• Adult SOT recipients who have undergone kidney, heart, and/or liver transplantation I. Multiple organ recipients are permitted (i.e. any combination of organs including kidney, heart and/or liver).

II. Subjects undergoing re-transplantation are permitted

• Age ≥18 years at vaccination
• ≥1 month and <12 months post-SOT
• Anticipated to be available for duration of study
• Can be reached by telephone, email, or text message

Exclusion criteria

• History of severe hypersensitivity to previous influenza vaccination or anaphylaxis to eggs/egg protein
• History of Guillain-Barre syndrome
• History of known active infection with HIV
• History of known severe latex hypersensitivity
• History of receiving the current season's influenza vaccine post-transplant prior to enrollment in the study
• Pregnant female
• Proven influenza disease after September 1st and before first study vaccine (patient can still receive the second influenza vaccination despite proven influenza disease once enrolled)
• History of lung or intestine transplant
• CMVIG/IVIG/SCIG receipt in the 28 days prior to or planned administration within 84-126 days of the calendar date of first vaccination
• Subjects must have a platelet count of <20,000 to receive the immunizations