Measles antibody trough levels after treatment with immunoglobulin products and predicted levels assuming lower measles antibody specifications

Abstract

BACKGROUND Widespread vaccination against measles has resulted in decreasing measles antibody levels in human immune globulin (IG) products. As levels continue to decline, it needs to be determined whether the release specifications for measles antibody levels in IG products can be lowered and still provide protection against infection for patients who receive IG treatment for primary immunodeficiency disease. STUDY DESIGN AND METHODS Trough level measles neutralizing antibodies were measured in 10 pediatric patients with primary immunodeficiency disease (ages 2–16) treated with IG administered both by intravenous and subcutaneous infusion. The results were used to model worst‐case (lowest) serum measles antibody levels in two cases: 1) the current case with intravenous dosage at 300 mg/kg at a measles antibody level of 0.48× Center for Biologics Evaluation and Research Reference 176 and 2) a future case with intravenous dosage at 400 mg/kg and 0.30× Center for Biologics Evaluation and Research Reference 176. RESULTS Serum trough measles neutralizing antibody levels were an average of 11‐fold or greater above minimum protective levels for immunocompetent individuals of 0.12 IU/mL in both the intravenous and subcutaneous phases of the study. Modeling using both the current worst‐case dose and future case shows average levels for IG intravenous/subcutaneous infusion of 3.9/4.8‐ and 3.2/4.0‐fold above 0.12 IU/mL for the two cases, respectively. CONCLUSION Lowering the measles antibody level specification to 0.30× Center for Biologics Evaluation and Research Reference 176 in IG products will still provide trough serum antibody levels against measles infection of greater than 0.12 IU/mL when dosed at 400 mg/kg or higher.

Plasma Donors in the Southwestern United States Positively Contribute to the Diverse Therapeutic Antibody Profile of Immune Globulin Products

“…It supports the premise that regional differences in seroprevalence helps to maintain efficacious antibody levels in IG products. Despite the recent decline in anti-MeV titers observed for some products, current IG preparations and doses are still sufficient to provide protection against MeV infection for PIDD patients 24 .…”

Assuring immune globulin potency in a world of changing pathogen challenges

“…As predicted in 2007, measles titers have continued to decline, and a similar but not identical predicament must now be addressed . If the measles specification is lowered again, it is unlikely that all patients will maintain a trough level of 240 mIU/mL, based both on extrapolation from trough titer data, and on separate pharmacokinetic modeling assuming IG doses of 300 to 400 mg/kg . A range of possible solutions were discussed.…”

“…To avert IG shortages, manufacturers were allowed to lower the measles antibody specification from 0.6 to 0.48× Center for Biologics Evaluation and Research Standard Lot 176 in 2008. This was contingent on provision of trough measles antibody titer data from patients with PI, along with modeling, to show that if these patients received a lot at the lower specification, their trough serum measles antibody titer would be at least 240 mIU/mL . The serum level of 240 mIU/mL (double the protective level in immunocompetent individuals) was proposed by the FDA, as the level of protection for patients with PI is unknown and also may vary across different categories of these genetic immunodeficiencies.…”

“…This was contingent on provision of trough measles antibody titer data from patients with PI, along with modeling, to show that if these patients received a lot at the lower specification, their trough serum measles antibody titer would be at least 240 mIU/mL. [10][11][12] The serum level of 240 mIU/mL (double the protective level in immunocompetent individuals) was proposed by the FDA, as the level of protection for patients with PI is unknown and also may vary across different categories of these genetic immunodeficiencies. Individual patients with deficits in humoral and/or cellular immunity may need different levels of antibody for protection, and higher levels may be required for the latter category.…”

“…11 If the measles specification is lowered again, it is unlikely that all patients will maintain a trough level of 240 mIU/mL, based both on extrapolation from trough titer data, and on separate pharmacokinetic modeling assuming IG doses of 300 to 400 mg/kg. 11,12 A range of possible solutions were discussed. Reimmunization of plasma donors was shown not to provide strong or sustained increases in measles antibodies.…”