Date of Award
Medical Doctor (MD)
Background: Patients with plasma cell dyscrasias are at an increased risk for infections due to their dysfunctional immune system. Each year these vulnerable patients are advised to receive the flu shot, but this vaccine has been shown to induce a serologic response that is not sufficiently protective in these patients. More effective methods for vaccinating patients with plasma cell dyscrasias are necessary.
Methods: The Study of High-Dose Influenza Vaccine Efficacy by Repeated dosing IN Gammopathy patients (SHIVERING 1) Pilot Trial was implemented at the Yale Cancer Center during the 2014-2015 flu season. Patients with plasma cell dyscrasias (n=51) received the high-dose inactivated trivalent influenza vaccine followed by a booster dose of that same vaccine 30 days later. The SHIVERING 2 randomized, double-blind, placebo-controlled, interventional trial was implemented at the Yale Cancer Center during the 2015-2016 flu season. The experimental arm (n=81) received the two dose regimen and the control arm (n=41) received the standard of care. In both trials, patients were followed throughout the flu season for evidence of flu infections, and sera was collected for hemagglutinin titer analysis and correlation with clinical characteristics and patient demographics.
Results: SHIVERING 1 demonstrated that the double high-dose regimen was safe and resulted in significantly higher rates of seroprotection than have been previously reported. There were no grade 2 adverse events. The seroprotection rate increased from 4% at baseline, to 47% after the first vaccine, and to 65% after the second vaccine. SHIVERING 2 demonstrated significantly higher rates of seroprotection at day 60 and a lower rate of laboratory confirmed flu infections in the experimental arm versus the control arm. Analysis of the durability of serologic protection demonstrated a significant difference in HAI titer growth and direction between the two arms, with the standard of care arm experiencing a decline in HAI titer levels during the day 30 to day 60 interval following vaccine administration. Additionally, patients with early disease in the experimental arm were significantly more likely to remain seroprotected at study end than patients with advanced disease in the control arm. Finally, patients that are female and those that had undergone an autotransplant in the past were significantly more likely to remain seroprotected at study end.
Conclusion: These trials suggest that a boosted high-dose influenza vaccine regimen is safe and results in lower rates of infection and higher rates of seroprotection in patients with plasma cell disorders. Patients with early stage disease are able to mount a more durable serologic response than patients with advanced disease. Larger studies will be needed to confirm these preliminary findings.
Duffy, Eamon, "The S.h.i.v.e.r.i.n.g. Trials: A Novel Vaccine Strategy And Analysis Of Serologic Durability In Patients With Plasma Cell Dyscrasias" (2018). Yale Medicine Thesis Digital Library. 3391.