Abstract
ABSTRACT Measles (Me) and rubella (Ru) viral diseases are targeted for elimination by ensuring a high level of vaccination coverage worldwide. Less costly, more convenient MeRu vaccine delivery systems should improve global vaccine coverage, especially in low – and middle – income countries (LMICs). In this work, we examine formulating a live, attenuated Me and Ru combination viral vaccine with Nanopatch™, a solid polymer micro-projection array for intradermal delivery. First, high throughput, qPCR-based viral infectivity and genome assays were established to enable formulation development to stabilize Me and Ru in a scaled-down, custom-built evaporative drying system to mimic the Nanopatch™ vaccine coating process. Second, excipient screening and optimization studies identified virus stabilizers for use during the drying process and upon storage in the dried state. Finally, a series of real-time and accelerated stability studies identified eight candidate formulations that met a target thermal stability criterion for live vaccines (<1 log10 loss after 1 week storage at 37°C). Compared to −80°C control samples, the top candidate formulations resulted in minimal viral infectivity titer losses after storage at 2–8°C for 6 months (i.e., <0.1 log10 for Me, and ~0.4 log10 for Ru). After storage at 25°C over 6 months, ~0.3–0.5 and ~1.0–1.4 log10 titer losses were observed for Me and Ru, respectively, enabling the rank-ordering of the stability of candidate formulations. These results are discussed in the context of future formulation challenges for developing microneedle-based dosage forms containing stabilized live, attenuated viral vaccines for use in LMICs.
Highlights
Measles (Me) and rubella (Ru) are enveloped, single-stranded viruses with negative and positive polarity, respectively.[1,2] Me virus infection is highly contagious and can lead to lifethreatening complications
The throughput of the infectivity RT-qPCR assay was doubled by demonstrating similar results in a duplex vs. simplex assay format allowing for measuring viral titers of Me and Ru simul taneously in one assay
To confirm Me and Ru stability results from the RT-qPCR assay correlated with the standard QC assay for MeRu in vitro potency (CCID50 assay), both Me and Ru were combined in a phosphate buffer, air-dried onto discs, and stored at 37°C for up to 10 days
Summary
Measles (Me) and rubella (Ru) are enveloped, single-stranded viruses with negative and positive polarity, respectively.[1,2] Me virus infection is highly contagious and can lead to lifethreatening complications. Me and Ru containing vaccines are currently in widespread use, either individually, in combination as a divalent vaccine, or as com ponents of a trivalent formulation (with a live, attenuated mumps vaccine, M-M-R®II and PRIORIX®) as well as a quadrivalent formulation (with live, attenuated mumps and varicella vaccine, ProQuad®).[5] Together, Me and Ru con taining vaccines have greatly reduced the infection incidence, for example, the M-M-R®II vaccine is >90% efficacious for each of the three targeted diseases with a 2-dose vaccination regime.[3,4,5,6] Global measles vaccinations between 2000 and 2015 have been estimated to have led to the prevention of >20 million deaths worldwide.[5]
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