Tandem High-Dose Influenza Vaccine Offers Durable Seroprotection for Patients With Plasma Cell Dyscrasias

Tandem high-dose influenza vaccination may result in more durable serologic immunity in patients with plasma cell dyscrasias (PCDs), compared with standard vaccination, according to findings published in Blood Advances.

Patients with PCDs have innate and adaptive immunity alterations. The use of anti-myeloma therapy for hematologic disorders may lead to worsened immune deficiency, as well as reduced vaccine efficacy. In turn, patients with PCDs typically have an increased risk of influenza infections and may also have poor serologic response to flu vaccines.

Influenza infections are a significant cause of morbidity in patients with PCDs, the authors, led by Andrew Branagan, MD, PhD, of Massachusetts General Hospital, explained. The emergence of SARS-CoV-2 is an additional cause of concern for this patient population.

In this study, the researchers compared tandem high-dose and standard influenza vaccination in 122 patients with PCD who participated in the SHIVERING 2 (Study of High-Dose Influenza Vaccine Efficacy by Repeated Dosing in Gammopathy Patients: A 2 Arm Trial) during the 2015 to 2016 flu season. Seventy-five patients received the tandem vaccination, consisting of two doses administered 30 days apart, and 47 patients received standard vaccination.

In the standard of care vaccine group, patients over the age of 65 received a single standard dose; those who were under age 65 received a single high dose. These patients also received a second placebo vaccine dose consisting of saline.

The median baseline age of the overall cohort was 68 years. A total of 97 patients had either active multiple myeloma, Waldenström macroglobulinemia, or amyloid light-chain amyloidosis. Another 25 patients presented with asymptomatic monoclonal gammopathies.

Among patients who received tandem high-dose influenza vaccine, seroprotection rates were higher against all three of the predominant influenza vaccine strains (FluB, H1N1, and H3N2) following the second vaccine dose (86.3% vs. 63.9%; p=0.007). By the end of the flu season, the total seroprotection rates were also greater for the two-dose vaccine group relative to the single-dose arm (60.0% vs. 31.6%; p=0.04).

In addition, rates of seroconversion against the three dominant influenza strains were significantly higher among patients who received two high doses following the second dose (54.9% vs. 34.2%; p=0.04; see FIGURE).

Factors associated with higher odds of total seroprotection included female sex, receipt of active intravenous immunoglobulin (IVIG) treatment, and influenza infection in the prior flu season (p<0.05 for each). In contrast, advanced age, PCD that required therapy versus asymptomatic disease/monoclonal gammopathy of undetermined significance (MGUS), and active therapy with alkylating agent chemotherapy were associated with lower odds of total seroprotection (p<0.05 for each). Treatment with active IVIG therapy was associated with lower seroconversion against the three vaccine strains, according to logistic regression modeling (p<0.05).

Conversely, receipt of an active immunomodulatory drug was linked with a higher likelihood of seroprotection (p<0.05) and seroconversion (p<0.005) against H3N2.

According to the authors, these findings support the modification of current vaccination protocols for influenza in patients with PCD, suggesting these patients may require a two-dose influenza vaccination schedule during each flu season. The investigators noted that a similar vaccination approach may also be warranted against COVID-19 in these patients.

“At our hospital, we have made the decision to offer this strategy to all patients with PCDs including asymptomatic disease and MGUS based on these very encouraging results,” Dr. Branagan told ASH Clinical News. “We look forward to finding out to what extent clinically significant influenza infections and associated morbidity and mortality will be reduced as a result of this intervention.”

He added that while the authorized mRNA vaccines for COVID-19 already have a two-dose series, additional studies are required to determine the optimal timing of COVID-19 vaccinations for this patient population. “Patients with PCDs may require additional doses over healthy individuals, benefit from delayed booster does, and/or even may respond more robustly to certain types of COVID-19 vaccine,” he explained. Dr. Branagan noted that he and his research colleagues are actively investigating these questions in an ongoing COVID-19 vaccine study (NCT04830046).

The authors report no relevant conflicts of interest.


Branagan AR, Duffy E, Gan G, et al. Tandem high-dose influenza vaccination is associated with more durable serologic immunity in patients with plasma cell dyscrasias. Blood Adv. 2021;5:1535-1539.