Published online May 14, 2007
PEDIATRICS Vol. 119 No. 6 June 2007, pp. e1299-e1305 (doi:10.1542/peds.2006-2283)
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ARTICLE

Comparison of the Safety and Immunogenicity of a Refrigerator-Stable Versus a Frozen Formulation of ProQuad (Measles, Mumps, Rubella, and Varicella Virus Vaccine Live)

Henry H. Bernstein, DOa, Karen Eves, BSb, Kristy Campbell, MSb, Steven B. Black, MDc, Jerry D. Twiggs, MDd, Keith S. Reisinger, MDe, Ralph M. Conti, MDf, Carl-Erik Flodmark, MDg, Lars Rombo, MDh, Stephanie Klopfer, PhDb, Florian Schödel, MDb, Jonathan Hartzel, PhDb, Barbara J. Kuter, PhD, MPHb and the Refrigerator-Stable Formulation Study Group for ProQuad

a Dartmouth Medical School, Children's Hospital at Dartmouth, Lebanon, New Hampshire
b Merck Research Laboratories, West Point, Pennsylvania
c Kaiser Permanente Vaccine Study Center, Oakland, California
d Dixie Pediatrics, St George, Utah
e Primary Physicians Research, Pittsburgh, Pennsylvania
f Foothills Pediatrics, Henderson, Nevada
g Department of Pediatrics, University Hospital, Universitetssjukhuset MAS, Malmö, Sweden
h Department of Infectious Diseases, Malarsjukhuset, Eskiltuna, Sweden


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. A refrigerator-stable formulation of ProQuad has been developed to expand the utility of ProQuad to areas in which maintenance of a frozen cold chain (–15°C or colder) during storage and transport may not be feasible. The objective of this study was to demonstrate that the immunogenicity and safety profiles of a refrigerator-stable formulation of ProQuad are similar to the recently licensed 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 the refrigerator-stable formulation of ProQuad (N = 1006) or the frozen formulation of ProQuad (N = 513). Patients were followed for 42 days after vaccination for adverse experiences. Immunogenicity was evaluated 6 weeks after vaccination.

RESULTS. The refrigerator-stable formulation of ProQuad was generally well tolerated. The incidence of adverse experiences was similar between groups. No vaccine-related serious adverse experiences were reported. For both groups, the response rate was ≥97.7% for measles, mumps, and rubella, and the percentage of patients with a varicella zoster virus antibody titer of ≥5 U/mL glycoprotein antigen-based enzyme-linked immunosorbent assay after vaccination was ≥88.8%. The geometric mean titers for all antigens were numerically slightly higher in patients who received the refrigerator-stable formulation.

CONCLUSIONS. The refrigerator-stable formulation of ProQuad is generally well tolerated, highly immunogenic, and noninferior in terms of postvaccination antibody responses. This refrigerator-stable formulation may improve ease of vaccine administration, increase use of the vaccine throughout the world because of its improved storage conditions, and replace the frozen formulation of ProQuad or any dose of M-M-RII and Varivax in routine practice.

Key Words: measles • mumps • rubella • varicella • vaccine • ProQuad • Varivax • M-M-RII • immunization

Abbreviations: VRC—vaccination report card • VZV—varicella zoster virus • ELISA—enzyme-linked immunosorbent assay • gpELISA—glycoprotein antigen–based enzyme-linked immunosorbent assay • GMT—geometric mean titer • CI—confidence interval

In the United States and other countries, M-M-RII (Merck & Co, Inc, West Point, PA) has been highly effective in reducing the incidence of measles, mumps, and rubella.1–3 To date, vaccination rates against measles, mumps, and rubella have reached 93% in the United States and are generally high in most developed countries.1,4–6 Routine use of Varivax (Merck & Co, Inc) in the United States has resulted in a substantial reduction in the incidence of varicella.7,8 However, vaccination rates against varicella have reached only 87.5% in the United States despite Advisory Committee on Immunization Practices recommendations in 1996 for universal use in young children. Varivax is not currently recommended in most other countries.6

ProQuad is a combined measles, mumps, rubella, and varicella virus vaccine developed by Merck & Co, Inc. Concerns regarding an already complex vaccination schedule and additional costs to both parents and health care providers are notable obstacles surrounding vaccine administration.9 As a combination vaccine, ProQuad is expected to decrease the number of injections that are given to children and ultimately improve compliance and immunizations rates for the 4 diseases worldwide.9 The frozen formulation of ProQuad, licensed in the United States and Europe, has been shown to be as immunogenic and generally well tolerated as its component vaccines, M-M-RII and Varivax, and is starting to be widely used in the United States.10,11 However, its utility is limited to geographic areas where a frozen cold chain (–15°C or colder) during transport and storage in clinics, pharmacies, and physicians' offices can be maintained. Maintaining a refrigerated cold chain (2–8°C), as is done with most other vaccines, would be feasible in a much larger part of the world. Because of this, Merck & Co, Inc, has developed a refrigerator-stable formulation of ProQuad, incorporating ≤2.5 mg of a urea-based stabilizer in each dose. The effect of this stabilizer on immunogenicity and safety profiles was previously evaluated in a clinical study of Varivax (varicella virus vaccine live [Oka/Merck]). Both Varivax formulations, with and without the stabilizer, were generally well tolerated, were comparable with respect to the occurrence of injection-site and systemic adverse experiences, and were highly immunogenic.12

The purpose of this study was to demonstrate that the immunogenicity and the safety of a refrigerator-stable formulation of ProQuad are similar to the recently licensed frozen formulation. This study removes 1 barrier to effective vaccine delivery by lessening the burden for health care professionals of the storage and handling of frozen vaccines.13


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Patients
This study was approved by the institutional review board/independent ethics committee of each of the 32 participating sites. The study sites consisted of academic institutions, regional and pediatric medical centers, managed care organizations, and private physician offices, with 30 sites in the United States and 2 sites in Sweden. The study was conducted from September 2002 through June 2003. Written informed consent was obtained from the parent/legal guardian of each patient before enrollment.

Healthy 12- to 23-month-old children with negative vaccination and clinical histories for measles, mumps, rubella, varicella, and zoster were eligible to participate. Patients were excluded for any of the following reasons: previously received measles, mumps, rubella, and/or varicella vaccine either alone or in combination; immunodeficient or receiving immunosuppressive therapy; history of a seizure disorder; known allergy to any vaccine component; recent exposure to measles, mumps, rubella, varicella, and/or zoster; receipt of any inactivated nonstudy vaccines within 14 days or live nonstudy vaccines within 30 days before enrollment; receipt of immune globulin or blood products within the 5 months before enrollment or had scheduled to receive such products within 42 days after vaccination; or, in the opinion of the investigator, had any condition that would have interfered with study objectives.

Vaccine/Randomization
Patients were randomly assigned at a 2:1 ratio to receive either the refrigerator-stable or the frozen formulation of ProQuad on day 1. All clinical materials were manufactured by Merck & Co, Inc. ProQuad is a sterile, lyophilized quadrivalent vaccine that after reconstitution is administered as a 0.5-mL subcutaneous injection. This study was double blind with regard to treatment group. The parent/legal guardian of the patient, the study personnel who administered the vaccine and handled all safety and serologic follow-up, and sponsor personnel were blinded to which vaccine formulation each patient received. Because of obvious differences in vaccine storage conditions and slight differences in appearance, the vaccines that were used in this study were prepared and accounted for by an unblinded third party who was otherwise not involved in the conduct of the study.

Safety Surveillance
Parents/legal guardians were asked to record on a vaccination report card (VRC) their child's daily temperature (axillary), all local and systemic adverse experiences, and any other vaccines or medications administered both on the day of vaccination and for 41 additional days after vaccination. Parents/legal guardians were asked to notify study personnel immediately if their child experienced measles, a measles-like rash, rubella, a rubella-like rash, varicella, a varicella-like rash, zoster, a zoster-like rash, mumps, or mumps-like symptoms or if any serious adverse experience occurred. Serious and vaccine-related adverse experiences were followed to resolution. Parents/legal guardians were instructed to measure the patient's rectal temperature if the patient's axillary temperature was ≥98.6°F (≥37.0°C). When a patient's temperature was ≥102°F (≥38.9°C) oral or equivalent (≥101°F [≥38.3°C] axillary or ≥103°F [≥39.4°C] rectal), study personnel recorded the fever as an adverse experience. The parent/legal guardian was responsible for evaluating the maximum intensity of each adverse experience. Local adverse experiences of swelling and redness were evaluated by maximum size. The investigator assessed each reported adverse experience as to seriousness, action taken, and causal relationship to study vaccine.

Laboratory Methods
A 5- to 10-mL blood sample was collected immediately before and ~6 weeks after vaccination. To determine measles, mumps, rubella, and varicella zoster virus (VZV) antibody levels, serum samples were tested by Merck Research Laboratories (West Point, PA) using appropriately sensitive enzyme-linked immunosorbent assay (ELISA) methods for measles, mumps, and rubella and a glycoprotein antigen–based enzyme-linked immunosorbent assay (gpELISA) for VZV.14–16 Serum samples with antibody levels <255 mIU/mL for measles, <10 antibody U for mumps, <10 IU/mL for rubella, and <1.25 gpELISA U/mL for VZV were considered to be seronegative. For measles, mumps, and rubella, the antibody response rates were defined as the proportion of patients who were seronegative before vaccination and became seropositive after vaccination. The antibody response rate for VZV was defined as the proportion of patients who were seronegative at baseline and whose postvaccination titer was ≥5 gpELISA U/mL. A VZV postvaccination titer ≥5 gpELISA U/mL has been previously shown to be highly correlated with long-term protection.17,18

Statistical Methods
The primary immunogenicity analysis was performed on a per-protocol basis. The analysis of antibody response rates to each vaccine antigen was based on the noninferiority test developed by Miettinen and Nurminen19 with study center stratification. Noninferiority of geometric mean titers (GMTs) was based on an analysis of variance model of log-adjusted titers for each antigen with study center stratification. To conclude noninferiority of the refrigerator-stable formulation of ProQuad (using a 1-sided .025 significance level), the response rates could be no more than 5 percentage points lower for measles, mumps, and rubella and no more than 10 percentage points lower for VZV. The GMTs could be no more than 1.5-fold lower for all antigens. In addition, it could be concluded that the refrigerator-stable formulation of ProQuad induced acceptable antibody response rates when the lower bound of the 95% confidence interval (CI) for each antigen was entirely above the prespecified criteria (90% for measles, mumps, and rubella and 76% for varicella). Success of the trial required satisfaction of all 3 immunogenicity hypotheses.

To address the primary hypothesis regarding safety, we compared the safety profiles of the refrigerator-stable and frozen formulations of ProQuad. For injection-site adverse experiences that occurred on days 1 to 5 after vaccination and for specific systemic clinical adverse experiences that occurred on days 1 to 42 after vaccination, risk differences were estimated, and the 95% 2-sided CI was provided. For adverse experiences that specifically were prompted for on the VRC, including injection-site redness, injection-site swelling, injection-site pain/tenderness, measles-like rashes, rubella-like rashes, varicella-like rashes, zoster-like rashes, and mumps-like symptoms, as well as the incidence of elevated temperature (defined as ≥102°F [≥38.9°C] oral equivalent), the corresponding P values were provided.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Population
A total of 1519 healthy children, 12 to 23 months of age, were vaccinated with either the refrigerator-stable formulation (N = 1006) or the frozen formulation (N = 513) of ProQuad. At vaccination, both groups were comparable with respect to gender, age, and race; ~50% of patients were female, and 73% were white. The mean age was 13.3 months at study entry.

Safety
No vaccine-related serious adverse experiences were reported within the follow-up period. The overall rate of serious adverse experiences between recipients of the refrigerated and frozen formulations of ProQuad was not statistically significant (0.7% and 0.4%, respectively). All serious adverse experiences were medical conditions that are generally expected of a pediatric population. The serious adverse experiences that were reported by the 7 patients who received the refrigerator-stable formulation were respiratory syncytial virus infection, pneumonia, dehydration, pharyngitis, gastroenteritis, and accidental exposure. The serious adverse experiences that were reported by the 2 patients who received the frozen formulation were gastroenteritis, pneumonia aspiration, and neuroblastoma. The patient with neuroblastoma did not receive the diagnosis until 5 days after vaccination and continued in the study with no additional adverse experiences reported.

Table 1 summarizes the specific injection-site adverse experiences that were reported days 1 to 5 after vaccination. Overall, the proportion of patients who reported injection-site adverse experiences was comparable between the treatment groups. Injection-site adverse experiences that were specifically prompted for on the VRC were erythema, pain, and swelling and were the most commonly reported specific injection-site reactions (≥10%) in either treatment group.


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  		TABLE 1 Injection-Site Adverse Experiences 1 to 5 Days After Administration of ProQuad

 
Table 2 summarizes the overall clinical and most frequent (≥5%) specific systemic adverse experiences by treatment group after vaccination. The proportion of patients who reported at least 1 systemic adverse experience was comparable between the treatment groups. The most frequently reported specific systemic adverse experiences (≥10% in either treatment group) were elevated temperature (≥102°F [≥38.9°C], oral equivalent), upper respiratory tract infection, nasopharyngitis, otitis media/ear infection, and diarrhea. The 2 treatment groups were comparable with respect to the incidence rates of specific systemic adverse experiences except for 3 adverse experiences. Insomnia and dermatitis were reported in a greater number of patients who received the refrigerator-stable formulation (1.1% and 1.3%, respectively) as compared with the patients who received the frozen formulation (0% and 0.2%, respectively). Fewer patients who received the refrigerator-stable formulation (0.3%) experienced viral upper respiratory tract infection as compared with patients who received the frozen formulation (1.2%). The observed proportions of all patients who reported these adverse experiences were all ≤1.3%, seemed to be of little clinical relevance, and in view of the high number of comparisons made for safety end points, could be attributable to chance alone. When the rates of vaccine-related systemic adverse experiences were compared, there were no significant differences between treatment groups.


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  		TABLE 2 Systemic Adverse Experiences (≥5% in Either Treatment Group) 1 to 42 Days After Administration of ProQuad

 
The proportion of patients with elevated temperatures (≥102°F [≥38.9°C], oral equivalent) was comparable between treatment groups. More than 45% of fevers were reported during days 6 to 13 after vaccination. The majority of the fever episodes were classified as either mild or moderate and were of short duration.

The proportions of patients with a VRC-prompted rash (measles-like, rubella-like, and varicella-like) were comparable in both treatment groups, with no statistically significant differences observed. Mumps-like symptoms were also prompted for on the VRC, although none were reported. For both treatment groups, the percentage of patients who reported a measles-like, rubella-like, and varicella-like rash was ≤6.4%, ≤1.2%, and ≤3.0%, respectively.

Immunogenicity
Response rates and GMTs 6 weeks after vaccination for measles, mumps, rubella, and varicella are shown in Table 3. For both the refrigerator-stable and frozen formulations of ProQuad, the response rates for measles, mumps, and rubella were ≥97.7% and the percentage of patients who had a baseline VZV antibody titer <1.25 gpELISA U/mL and achieved a postvaccination VZV antibody titer ≥5 gpELISA U/mL was ≥88.8%. Because the lower bound of the 95% CI on the difference in response rates between treatment groups was ≤5 percentage points for measles, mumps, and rubella and ≤10 percentage points for VZV, the response rates to each vaccine antigen in patients who received the refrigerator-stable formulation of ProQuad were considered similar to the frozen formulation. The proportion of patients who had a baseline VZV titer <1.25 gpELISA U/mL and achieved a postvaccination VZV titer ≥1.25 gpELISA U/mL was 98.9% for those who received the refrigerator-stable formulation of ProQuad and 97.9% for those who received the frozen formulation of ProQuad (data not shown). The response rates that were induced by the refrigerator-stable formulation of ProQuad were found to be acceptable because the lower bound of the 95% CIs was >90% for measles, mumps, and rubella, and the percentage of patients with a postvaccination VZV titer ≥5 gpELISA U/mL was >76%.


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  		TABLE 3 Measles, Mumps, Rubella, and VZV Response Rates and GMTs 6 Weeks After Vaccination

 
Postvaccination GMTs were numerically slightly higher in patients who received the refrigerator-stable formulation of ProQuad; however, the difference was statistically <1.5-fold between the formulations for each vaccine antigen. Because the difference in GMTs was <1.5-fold, the refrigerator-stable formulation of ProQuad was considered similar to the frozen formulation. Success of the trial required that the statistical analysis show that the refrigerator-stable formulation induced both response rates and GMTs that were noninferior and that the response rates were entirely above the prespecified criteria (90% for measles, mumps, and rubella and 76% [≥5 gpELISA U/mL] for varicella).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
The refrigerator-stable formulation of ProQuad was highly immunogenic in 12- to 23-month-old children and was generally well tolerated. No vaccine-related serious adverse experiences were reported, and there were no clinically significant differences in injection-site and systemic adverse experiences between the 2 formulations. These results were generally comparable to those reported in earlier trials with the frozen formulation,10,11 except for the rates of elevated temperature (≥102°F [≥38.9°C], oral equivalent), which were lower in this study. The lower rates were most likely attributed to a change in data collection methods in this study, including confirmation of elevated axillary temperatures by the rectal method and exclusion of qualitative reports of "warm to touch" as temperatures ≥102°F (≥38.9°C).

One limitation of this study was that the number of patients was not adequate to detect rare adverse experiences that occurred at a rate of 1 per 10000 or less. Such rare adverse experiences may be studied best in routine postlicensure surveillance. Long-term, postlicensure, passive surveillance already provides extensive safety experience for the components of ProQuad (M-M-RII and Varivax).

In recent years, the recommended immunization schedule for children in the United States has become increasingly complex, with children receiving 20 or more injections in their first 18 months of life. The use of combination vaccines, such as ProQuad, is an effective way to overcome health care provider and parental concerns with multiple injections. In addition, combination vaccines may improve the timely administration of vaccines, increase vaccination coverage rates, reduce costs, and allow for the addition of new vaccines into the routine immunization schedule.9,20

Frozen vaccines add complexity to storage and handling in various settings. ProQuad is currently available only as a frozen formulation, and the need to store it in the freezer limits its utility outside the United States.21

World Health Organization guidelines for countries that are considering the implementation of a new vaccine that is intended for large-scale public health use mandate that the ability to overcome technical limitations such as vaccine storage temperature and physical storage capacity be considered.20,22 For many developing and remote areas of the world, successful implementation of a vaccine necessitates use of a product that does not require frozen storage.23,24 Accordingly, vaccines, with the exception of oral polio vaccine, that are supplied as part of the World Health Organization–sponsored Expanded Program on Immunization are recommended to be thermostable at refrigerated temperatures through the cold chain, originating with the manufacturer and ending with either regional/district vaccine stores or local health/daily use centers.25,26 Availability of the refrigerator-stable formulation of ProQuad, especially where the vaccine distribution infrastructure is not sufficient to manage frozen vaccine storage and handling, will further aid the reduction of measles, mumps, and rubella diseases and significantly decrease the incidence of varicella disease in countries other than the United States by facilitating the ease of routine immunization against varicella.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Adopting this refrigerator-stable formulation of ProQuad will lessen the burden of distribution and storage on pediatric practices, increase the ease of vaccine administration, and allow additional global expansion of current recommendations throughout the world. This combination vaccine with its improved storage conditions may also replace any separate dose of M-M-RII and Varivax for immunization against measles, mumps, rubella, and varicella. The refrigerator-stable formulation of ProQuad would be expected to sustain already high global vaccination rates against measles, mumps, and rubella and increase vaccination rates against varicella.


   ACKNOWLEDGMENTS
 
Members of the Refrigerator-Stable Formulation Study Group for ProQuad include Wilson P. Andrews, MD, Jerry C. Bernstein, MD, Joseph Bertino, PharmD, Steven B. Black, MD, Stanley L. Block, MD, Louis Brine, MD, Kevin Browngoehl, MD, Ralph M. Conti, MD, Matthew Cox, MD, Robert Dracker, MD, Carl-Erik Flodmark, MD, Michael Gerber, MD, Gregory C. Gray, MD, J. Randy Hedgepeth, MD, Harry Keyserling, MD, Paul Lei, MD, Michael Levin, MD, Carl Lindgren, MD, Stephen Luber, MD, Edgardo Malacaman, MD, Colin Marchant, MD, Michelle Ogle, MD, Keith S. Reisinger, MD, Lars Rombo, MD, Shelly D. Senders, MD, Julie Shepard, MD, Douglas Short, MD, Malcolm Sperling, MD, Robert Stacks, MD, James Troutman, MD, and Jerry D. Twiggs, MD.

We acknowledge the housestaff, faculty, nurses, and administrative staff at each participating institution for participation and support of this study. The editorial assistance and meticulous attention to detail of Alyssa Scott is appreciated. We thank the children and their families for participation in this research project.


   FOOTNOTES
 
Accepted Nov 21, 2006.

Address correspondence to Henry H. Bernstein, DO, General Academic Pediatrics, Dartmouth Hitchcock Medical Center, 1 Medical Center Dr, Lebanon, NH 03756. E-mail: henry.bernstein{at}hitchcock.org

Financial Disclosure: Drs Bernstein, Black, Conti, Twiggs, Flodmark, and Rombo and the Refrigerator-Stable Formulation Study Group for ProQuad participated in this research study, which was sponsored by Merck & Co, Inc. Drs Reisinger and Keyserling also participated in this research study and are speakers for Merck & Co, Inc.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics



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