A double-blind, randomized, controlled, multi-center safety and immunogenicity study of a refrigerator-stable formulation of VARIVAX®

Abstract

Objective

VARIVAX® (varicella virus vaccine, live Oka/Merck, Merck & Co., Inc., Kenilworth, NJ, USA) was originally licensed as a frozen formulation. A refrigerator-stable formulation of VARIVAX was subsequently developed to allow for increased availability of the product around the world. The objective of this study (V210-051) was to demonstrate that the safety, tolerability and immunogenicity profile of the refrigerator-stable formulation of VARIVAX was similar to the frozen formulation.

Methods

In this double-blind, randomized, multicenter study, healthy 12- to 23-month-old children with negative vaccination and clinical histories for measles, mumps, rubella, varicella, and zoster were vaccinated with either a refrigerator-stable formulation of VARIVAX (at two dosage levels; 8000 PFU [N = 320] or 25,000 PFU [N = 315]) or the frozen formulation of VARIVAX (10,000 PFU, N = 323) given concomitantly with M-M-RII® (measles, mumps, and rubella virus vaccine live, Merck & Co., Inc., Kenilworth, NJ, USA). Children were followed for 42 days after vaccination for adverse experiences. Immunogenicity was evaluated 6 weeks after vaccination.

Results

The refrigerator-stable formulation of VARIVAX was generally well tolerated. The incidence of adverse experiences was similar between all three groups. No vaccine-related serious adverse experiences were reported with any of the vaccine formulations. The immune response (percentage of subjects with varicella antibody titers ≥5 gpELISA units) for both refrigerator-stable formulations of VARIVAX at 6 weeks postvaccination was similar to that of the frozen formulation. Administration of either refrigerator-stable formulation of VARIVAX with M-M-RII yielded seroconversion rates and GMTs for measles, mumps and rubella that were comparable to those achieved after administration of the frozen formulation of VARIVAX with M-M-RII.

Conclusion

The safety, tolerability, and immunogenicity profile of the refrigerator-stable varicella vaccine was similar to that of the frozen formulation.

Introduction

Two important elements in the development and implementation of any vaccine are the temperature sensitivity of the pathogen of interest and the available cold chain where the vaccine will be used. Varicella zoster virus (VZV) is a cell associated virus that is heat labile [1]. The first varicella vaccine developed in the United States, VARIVAX was developed as a formulation that required storage at −20 °C or colder. This limited its ability to be used in parts of the world where the cold chain for vaccine storage consists only of refrigeration at 2 °C to 8 °C.

In 1998, several improvements were made to the originally licensed manufacturing process for varicella vaccine. These changes, known collectively as Process Upgrade, were designed to improve the yield of Oka/Merck VZV from MRC-5 cells in order to supply a higher potency vaccine for future refrigerator-stable formulations of varicella vaccine and for a quadrivalent measles, mumps, rubella, and varicella vaccine which includes a higher dose of varicella virus. Vaccine manufactured by the Process Upgrade is referred to as 1998 Production Lots Process Upgrade Varicella Vaccine (PUVV).

In previous clinical trials, over 1870 healthy, varicella history-negative children 12 months to 12 years of age received a single immunization with PUVV at doses ranging from 1450 to 78,000 plaque-forming units (PFU)/0.5-mL dose; at least 700 of these children received PUVV at doses ≥50,000 PFU [2]. The varicella antibody response to PUVV was similar to that induced by vaccine manufactured using earlier processes, both in terms of the immune response (percentage of subjects with a 6-week postvaccination varicella antibody titer ≥5 glycoprotein enzyme-linked immunosorbent assay [gpELISA] units) and the geometric mean titer (GMT) [2]. No PUVV-related serious adverse experiences were reported in these studies [2]. The rates of systemic adverse experiences, non-injection-site varicella-like rashes, and elevated temperatures (≥102°F [38.9 °C] oral equivalent or abnormal) were similar across the dose range of PUVV that was tested, and was consistent with rates reported in previous studies with vaccine manufactured by earlier processes. Only the rate of local injection-site reactions appeared to show a dose-related increase, although more than 90% of reactions were rated as mild by the parent/guardian [2]. PUVV was licensed as a frozen formulation in the United States in March 2000.

The manufacture of a refrigerator-stable varicella vaccine required two additional changes. The varicella potency release range was increased and the stabilizer containing phosphate, gelatin, and sucrose was supplemented with urea to help stabilize the vaccine virus at temperatures between 2 °C and 8 °C. These adjustments to the vaccine formulation maintained the minimum claimed potency of 1350 PFU/0.5-mL dose after 24 months of storage at 2 °C to 8 °C. This formulation is henceforth referred to as the refrigerator-stable formulation of varicella vaccine.

The purpose of this study (V210-051) was to compare the safety, tolerability, and immunogenicity of the refrigerator-stable formulation to the frozen formulation of varicella vaccine when each was administered concomitantly with M-M-RII (henceforth referred to as MMR) to healthy, varicella-history negative children 12 to 23 months of age. Two dose levels of the refrigerator-stable formulation (8000 PFU/dose [3.9 log₁₀] and 25,000 PFU/dose [4.4 log₁₀]) were compared with one dose level of the frozen formulation (10,000 PFU/dose [4.0 log₁₀]). The doses for the refrigerator-stable formulation of varicella vaccine were selected as representative of the average release-dose range for this formulation. A lot of the frozen formulation of varicella vaccine that contained a similar PFU/dose as the lower dose of the refrigerator formulation of varicella vaccine was selected as a comparator.