Two Dose Series of High-Dose Influenza Vaccine Is Associated with Longer Duration of Serologic Immunity in Patients with Plasma Cell Disorders

Background:

Patients with plasma cell disorders (PCDs) are highly susceptible to infections, including influenza, which are a major source of morbidity. Seasonal influenza vaccination is routinely administered to patients with PCDs, yet influenza infections remain common. Combining the use of higher antigen dose and a booster strategy, we recently reported a randomized study of a two dose series of high-dose influenza vaccine, which was associated with fewer influenza infections than standard influenza vaccination in patients with PCDs (Branagan, et al, ASH 2016). However, the immunologic effects following this vaccination strategy remains unknown. Few studies have focused on serologic responses to influenza vaccination in PCD patients and there are none to the authors' knowledge which have measured longitudinal serologic responses over a single flu season.

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 standard of care influenza vaccination. Patients were allocated to the experimental arm in 2:1 ratio. 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. HAI titers were analyzed by standardized procedure at four time points, baseline, 30 days following the initial vaccine, 30 days following the second vaccine, and at the end of the flu season (April 30).

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). Following the second vaccine / placebo, rates of total seroprotection (against all 3 influenza vaccine strains) were 86.3% for patients who received two high dose vaccines and 63.9% for standard vaccination patients. At the end of the flu season, rates of total seroprotection were 58.5% for patients who received two high dose vaccines and 33.3% for standard vaccination patients. Chi-square testing revealed that patients receiving the two dose vaccine strategy experienced significantly higher rates of total seroprotection following second vaccine (p<0.05). At the end of the flu season rates of seroprotection trended toward significance at the end of the flu season against all 3 vaccine strains (p=0.07), against the H3N2 strain (p=0.05) and were significantly higher against the H1N1 strain (p<0.05).

Conclusions:

We previously reported that a two dose strategy of Fluzone® High-Dose influenza vaccine is safely tolerated in patients with plasma cell disorders and associated with fewer laboratory-confirmed influenza infections. Unexpectedly, the current analysis revealed that protective HAI antibody titers rapidly fall in PCD patients. Typically, HAI titers slowly decrease following a peak protective response, but do not drop below protective levels until after 6 months. However, PCD patients in this study began to lose HAI seroprotection within 4 months and even as little as 30 days. Interestingly, patients who received the two dose series of high-dose influenza vaccine maintained higher rates of seroprotection at the end of the influenza season compared to those who received standard vaccination. The maintenance of seroprotection was greatest against the seasonal H1N1 strain (which was the predominate circulating strain during that particular 2015-2016 flu season). Importantly, these results suggest that a two dose series of high-dose vaccine provides may mitigate loss of vaccine-induced HAI titers and allow more durable serologic protection throughout the flu season. Studies are ongoing to further explore immune function following influenza vaccination, including cell-mediated responses. More studies are warranted to help determine the optimal dose and timing of influenza vaccination in PCD patients. Understanding the unique kinetics of serologic responses in PCD patients may have practice changing implications for other vaccines and therapies in this population.