This randomized phase II studies the side effects of high-dose trivalent influenza vaccine or standard-dose quadrivalent inactivated influenza and how well they work in treating adult patients undergoing stem cell transplant. Season influenza can cause more severe infections in patients who have had a stem cell transplant since their immune system doesn't work as well. Influenza vaccine may provide better protection against flu in adults.

PRIMARY OBJECTIVES:

I. To determine whether high dose (HD)-trivalent influenza vaccine (TIV) compared with standard dose (SD)-quadrivalent inactivated influenza vaccine (QIV) will increase the probability of achieving a >= 4-fold rise in hemagglutination inhibition assay (HAI) titer, >= 1:40 HAI titer, or a higher geometric mean titer (GMT) titer to influenza A antigens in adult hematopoietic cell transplantation (HSCT) recipients.

SECONDARY OBJECTIVES:

I. To determine whether HD-TIV compared with SD-QIV will increase the probability of achieving a >= 4-fold rise in HAI titers, >= 1:40 HAI titer, or higher GMT titers to influenza B antigens in adult HSCT recipients.

II. To determine the frequency and severity of solicited local injection site adverse events (e.g. pain/tenderness, redness, and swelling at injection site) with HD-TIV compared to SD-QIV in adult HSCT recipients.

III. To determine the frequency and severity of solicited systemic adverse events (e.g. fevers, headache, fatigue/malaise, nausea, body ache/myalgia, general activity level, and vomiting) with HD-TIV compared to SD-QIV in adult HSCT recipients.

IV. To define the relationship between HAI titers, in vivo T and B cell phenotype, and in vitro influenza-specific T and B cell response in adult HSCT recipients receiving either HD-TIV or SD-QIV.

V. To correlate HAI responses to microneutralization responses. VI. To compare the persistent HAI and microneutralization assay (MN) titers for all four antigen seven months after the last vaccine dose to assess for persistence of antibody titers.

VII. To compare influenza detection by polymerase chain reaction (PCR) during influenza season in adult HSCT recipients receiving either HD-TIV or standard dose QIV.

OUTLINE: Patients are randomized into 1 of 2 groups.

GROUP I: Patients receive HD-TIV intramuscularly once at baseline and once between 28-42 days.

GROUP II: Patients receive SD-QIV intramuscularly once at baseline and once between 28-42 days.

After completion of study treatment, patients are contacted at 1-3 and 8-10 days after each vaccination visit.

Inclusion criteria

1. Allogeneic HSCT recipients who are 3-23 months post-transplant;
2. ≥ 18 years of age;
3. Available for duration of study;
4. Patients with stable GVHD for at least 4 weeks will be eligible (stable is defined as no major change in systemic immunosuppressive therapy for worsening GVHD; adjustment of actual dose to obtain a stable target level is acceptable).
5. Can be reached by telephone and/or electronic communication
6. Subjects must have a platelet count of ≥30,000 to receive the immunizations. Patients requiring platelet transfusions are eligible to enroll and must have a platelet count ≥30,000 within 72 hours prior to their immunization, or platelet count ≥75,000 without transfusion documented within 30 days for subjects <12 months post- transplant and within 90 days for subjects 12-23 months post-transplant.

Exclusion criteria

1. History of hypersensitivity to previous influenza vaccination or severe hypersensitivity to eggs/egg protein;
2. History of Guillain-Barre syndrome;
3. Evidence of hematologic malignancy or disease relapse post-transplant (stable mixed chimerism is permitted);
4. History of receiving current seasonal influenza vaccine post-transplant;
5. Pregnant female;
6. History of proven influenza disease after September 1, 2018 prior to enrollment;
7. Non-allogeneic (e.g. autologous) or syngeneic hematopoietic SCT recipients;
8. History of known active infection with HIV
9. History of cirrhosis
10. History of known latex hypersensitivity;
11. Subjects who have received stem cell boost or delayed donor lymphocyte infusion within 90 days of enrollment, including day of enrollment
12. Receipt of. IVIG/SCIG <28 days prior to vaccination

Criteria for temporarily delaying vaccine administration: The following conditions are temporary or self-limiting, and a subject may be included in the study once the condition has resolved, provided that the subject is otherwise eligible:

1. Fever ≥100.4ºF/38.0ºC (oral measurement), or an acute illness within 48 hours of enrollment
2. Receipt of any live vaccines within four weeks or any inactivated vaccines within two weeks prior to potential study vaccination.

Note: if patients were eligible for vaccine 1, they will be eligible to receive vaccine 2 regardless of any changes on their GVHD status, unless it is deemed not medically safe to receive influenza vaccine.

For subjects who were enrolled and vaccinated in 2017-18, and 2018-19, the goal is to enroll these same subjects who participated the previous influenza season year and then administer the same vaccination as the previous year. These subjects are referred to as repeaters. For example, subjects enrolled in 2017-18 year were eligible to enroll again in 2018-19 as repeaters. For subjects enrolled in 2018-19 year and received at least one vaccine, will be eligible to be enrolled as repeaters for 2019-2020 season.