Lower Rates of Influenza Infection Following Two Dose Series of High Dose Vaccination in Plasma Cell Disorders: Results of a Randomized, Double-Blind, Placebo-Assisted Clinical Trial

Background:

Plasma cell disorders (PCDs) are commonly associated with immune paresis and these patients are susceptible to common infections, including influenza, which are a major source of morbidity. Although seasonal influenza vaccination is routinely employed in patients with PCDs, the data about its efficacy is limited. One approach to enhancing the efficacy of influenza vaccination is the use of standard dose boosters, and a prior study with multiple myeloma patients suggested modestly improved seroprotection. Another approach may be increasing the amount of antigen in vaccines. Combining the use of higher antigen dose and a booster strategy, we recently reported a pilot study utilizing a two dose series of high-dose influenza vaccine in patients with plasma cell disorders (Branagan, et al, ASH 2015). Specifically, protective hemagglutination antibody inhibition (HAI) titers rose to 49% after one high-dose influenza vaccine and up to 66% following the second dose. These results compared favorably to historical rates of seroprotection achieved in only 5-19% of PCD patients following standard influenza vaccination. Based on these encouraging results, we designed the present randomized study to further evaluate this novel influenza vaccination strategy in PCD patients.

Methods:

We conducted a double-blind, randomized clinical trial over the 2015-16 flu season, comparing two doses of Fluzone® High-Dose influenza vaccination (separated by 30 days) to the current standard of care influenza vaccination. Patients were allocated to the experimental arm in 2:1 ratio compared to standard of care arm. Standard of care influenza vaccination was considered single age-based vaccination (standard dose <65 years and high-dose ≥ 65 years) and patients in this arm received a saline placebo injection at 30 days to assist in blinding. Eligibility criteria allowed any patient with a plasma cell disorder 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 laboratory testing and patients were asked about infectious symptoms at all study visits and at the end of the flu season in May 2016. Secondary endpoints include HAI titer serologic response rates, clinical correlates of protection from influenza infection, and exploratory studies of cell-mediated immunity through characterization of T cell subpopulations, cytokine profiles, and flu-specific T-cell responsiveness.

Results:

122 total plasma cell disorder patients were enrolled (97 with disease requiring therapy and 25 with asymptomatic gammopathy). Forty-eight patients received a single standard of care influenza vaccination and 74 patients received two doses of Fluzone® High-Dose vaccine. Median age was 67 years (range 42-90). This two-dose vaccination strategy was safely tolerated in all patients with no ³grade 2 adverse events attributed to vaccine. With close clinical follow-up, only 4% of patients receiving two vaccine doses developed laboratory confirmed influenza versus 8.3% of those receiving single vaccine. When compared to the expected CDC influenza infection rate of 10-15%, one sample, two-tailed binomial testing revealed patients receiving two vaccines experienced a significantly lower rate of infection than the expected rate (p<0.05) whereas those receiving single vaccine showed no significant difference (p=0.38). Analysis of HAI titer results, clinical correlates of protection, and measurements of cell-mediated immunity are underway and will be updated for presentation at ASH 2016.

Conclusions:

This randomized study demonstrates that the two dose strategy of Fluzone® High-Dose influenza vaccine is safely tolerated in patients with plasma cell disorders and associated with significantly less than expected laboratory-confirmed influenza infections. The results suggest that this novel vaccination strategy may have a clinical benefit in reducing influenza infections in PCD patients and thus may have practice changing implications. Final analyses of serologic responses, clinical correlates of response, and cell-mediated immune correlates may provide valuable insights into in vivo "immune-competence" in PCD.