Development of a New Lyophilized Live-Attenuated Measles–Rubella (MR) Vaccine Formulation Designed for Lower-Cost Production in Africa

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Abstract
Background/Objectives: This work describes the development of a new, lyophilized, live-attenuated measles–rubella (MR) vaccine formulation designed for lower-cost production in Africa. The formulation consists of a stabilizer solution (containing only non-animal-derived excipients) and high-titer MR viral bulks (produced in MRC-5 cells by a modernized process) prepared at a ratio of 95% and 5% (v/v), respectively. Methods: Both lab-scale and pilot-scale freeze-drying cycles were developed, a high-throughput RT-qPCR-based viral infectivity assay was implemented, and effective excipient screening conditions to identify stabilizing additives for MR viruses were employed. Based on the down-selected hits, candidate lyophilized MR formulations were designed, prepared, and evaluated by comparative storage stability assessments. Results: First, protein-based bulking agents (used in many commercial lyophilized MR-containing vaccines) were avoided in favor of sucrose/mannitol mixtures. Second, ~50 excipients were screened, and two additional key stabilizing components were identified (both previously reported to stabilize MR viruses): sodium phosphate buffer and urea. Next, stability assessments were performed on different variations of a candidate lyophilized MR formulation to elucidate the inter-relationships between sucrose–mannitol ratios, cake integrity, and MR virus stability. An optimized MR vaccine formulation composition (post-reconstitution) of 5% (w/v) mannitol, 5% (w/v) sucrose, 50 mM urea, 25 mM sodium phosphate buffer (pH 6.5), and 5% (v/v) viral bulks was established. When this formulation was lyophilized at lab-scale in a single-dose format, both MR viruses displayed promising stability profiles during storage under real-time and accelerated conditions. A five-dose format was then evaluated in a pilot-scale freeze-dryer by using a 2X formulation filled into larger vials, lyophilized, and then reconstituted to 1X concentration. Conclusions: Results demonstrated the feasibility of a new, lower-cost, lyophilized, multidose MR formulation for potential use with a live-attenuated MR vaccine candidate targeted for local production in Africa.
Funding Information
  • Bill and Melinda Gates Foundation (INV-038051)

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