Fluzone® High-Dose Influenza Vaccine with a Booster Is Associated with Low Rates of Influenza Infection in Patients with Plasma Cell Disorders
Authors: Branagan Andrew R , Duffy Eamon , Boddupall Chandra Sekhar , Albrecht Randy A , Zhang Lin , Verma Rakesh , Cooper Dennis L , Seropian Stuart , Parker Terri L , Yao Xiaopan , Ferencz Thomas M , Dhodapkar Madhav V 
Published: October 2019

Abstract
Background:
Patients with plasma cell disorders (PCDs) are among the most susceptible to common infections including influenza and these infections are a major source of morbidity. Although seasonal influenza vaccination is routinely employed in patients with PCDs, the data about its efficacy are limited, as few studies have focused on this population. Based on historical data, PCD patients have a 10 fold increased risk of influenza and an expected yearly flu infection rate of at least 20%. The major surrogates for influenza vaccine response are hemaglutination antibody inhibition (HAI) titers; however rates of achieving protective HAI titers after standard influenza vaccination in PCD patients range from 5-19%. One approach to enhancing the efficacy of influenza vaccination is the use of standard dose boosters, and a recent study in multiple myeloma patients suggested improved seroprotection. Another approach may be increasing the amount of antigen in vaccines. Fluzone® high-dose vaccine was FDA approved in 2009 for adults aged 65 and older based on data regarding higher seroprotection rates but has not been studied specifically in PCD patients.
Methods:
In order to directly address the significant unmet need of improving vaccination strategies in patients with PCDs, we evaluated a novel vaccine strategy in patients with PCDs over the 2014-15 flu season that involved two doses of Fluzone® High-Dose influenza vaccination 30 days apart, regardless of age. Eligibility criteria allowed any patient with a PCD and no contraindication to trivalent inactivated influenza vaccine. The primary endpoint was laboratory confirmed flu infection rate. Patients were asked to report all flu-like illnesses for viral testing (PCR) and patients were asked about infectious symptoms at all study visits and at the end of the flu season in May 2015. A secondary endpoint is comparing rates of seroprotection with HAI titers and virus neutralization assays. Another secondary endpoint is to explore cell-mediated immunity through characterization of T cell subpopulations, cytokine profiles, and flu-specific T-cell responsiveness.
Results:
51 total PCD patients were enrolled (41 with disease requiring therapy and 10 with asymptomatic gammopathy) and all patients received two doses of Fluzone High-Dose vaccine. Median age was 75 years (range 36-90). This novel vaccination strategy was safely tolerated in all patients with no ≥ grade 2 adverse events attributed to vaccine. With close clinical follow-up, only 4% (2/51) of patients developed laboratory confirmed influenza. Preliminary data on a cohort of 30 multiple myeloma patients demonstrates that only 7% (2/30) had baseline protective HAI titers to all three seasonal influenza vaccine strains and after one Fluzone® High-Dose vaccine the seroprotection rate increased to 33% (10/30). Final seroprotection analysis and measurements of cell-mediated immunity are underway.
Conclusions:
This pilot study demonstrates that the two dose strategy of Fluzone® High-Dose influenza vaccine was safely tolerated in patients with PCD. The observed rate of seroprotective HAI after one dose of high dose vaccine was 33%, approximately double the historically observed rate of 5-19% after standard dose vaccine. The rate of seroconversion after the second dose is currently being analyzed and will be presented. Interestingly the rate of documented flu infections was only 4% compared to an expected 20% and may be due in part to the higher rate of seroconversion. These results suggest that this novel vaccination strategy is safe and may have a clinical benefit in improving HAI seroprotection and reducing documented flu infections in PCD patients. Given these encouraging clinical results, we are planning a randomized trial for the upcoming 2015-2016 influenza season comparing this novel vaccination strategy to standard of care vaccination in patients with plasma cell disorders.

Disclosures
Off Label Use: In order to directly address the significant unmet need of improving vaccination strategies in patients with plasma cell disorders, we present a pilot study which evaluated a novel vaccine strategy over the 2014-15 flu season. Fluzone® High-Dose influenza vaccine was administered in a booster strategy (two doses 30 days apart)..