Measles, mumps and rubella (MMR) are 3 common childhood viral illnesses. They are highly infectious diseases, and their associated complications are responsible for a high level of morbidity and mortality throughout the world.1–3 A substantial decrease in the incidence of MMR has been reported in countries that routinely immunize against these diseases, including the United States.4–7 Although often regarded as a mild disease, varicella (chickenpox) caused by primary infection with varicella-zoster virus (VZV) can lead to serious complications such as secondary bacterial infection and pneumonia and may occasionally result in death.8 Despite evidence that national VZV immunization programs are associated with a large reduction in disease incidence and related health resource utilization,9–11 a relatively low level of immunization, particularly in healthy children, persists globally.
Trivalent MMR vaccine Priorix [GlaxoSmithKline (GSK) Biologicals, Rixensart, Belgium] and the monovalent VZV vaccine, Varilrix (GSK Biologicals), are licensed in many countries worldwide for use in early childhood, generally beginning at 9–12 months of age (depending on the country). The appeal of combining the benefits of MMR and VZV vaccines into a single injection, with a view to improving vaccination compliance due to increased convenience for both medical practitioners and parents, led GSK Biologicals to develop a combined tetravalent measles, mumps, rubella, VZV (MMRV) vaccine, Priorix-Tetra.12,13 Priorix-Tetra is currently licensed for use in Australia, Canada and many European countries but has not yet been tested in a US population. Furthermore, information regarding coadministration of Priorix-Tetra with hepatitis A vaccine (HAV)14 and 7-valent pneumococcal conjugate vaccine (PCV7)15 among children >12 months of age in the United States has not been available.
This study compared the immunogenicity and assessed the reactogenicity of Priorix-Tetra vaccine kept under 2 storage conditions [refrigerated at 4°C (GSK+4C) or frozen at −20°C (GSK-20C)] with Merck’s MMRV vaccine [ProQuad, Merck & Co, Inc. (Merck-20C), Whitehouse Station, NJ], when each was coadministered with HAV and PCV7. The 2 GSK MMRV formulations were evaluated to determine whether either or both could demonstrate noninferiority of immune response compared with ProQuad, which is freezer-stored.
MATERIALS AND METHODS
Subjects and Study Design
This phase 2, randomized, multicenter, observer-blind, parallel-group study was performed between November 2007 and March 2009 at 133 centers in the United States. The study was approved by the Institutional Review Boards and complied with Good Clinical Practice Guidelines and the Federal Code of Regulations. Written informed consent from a parent/guardian was obtained before enrollment.
Eligible healthy male or female subjects were 12–14 months old and had received 3 PCV7 doses within the first year of life. Key exclusion criteria included: known exposure to, previous vaccination against or history of MMR or varicella-zoster diseases; previous HAV; administration of immunoglobulins, blood products or chronic immunomodulators ≤ 6 months before study vaccination; administration of other vaccines (except influenza) ≤ 30 days before study vaccination until day 42; earlier (≤ 30 days) or planned use of investigational products during the study; serious chronic illness or major congenital defects; immunosuppressive/immunodeficient conditions; history of allergic disease or reactions likely to be exacerbated by any component of the vaccines used in the study; neurologic disorders or seizures (except uncomplicated febrile convulsions) and acute disease at enrollment.
Subjects were randomized 2:2:1 to receive 1dose of GSK+4C (Priorix-Tetra stored at 4°C), GSK-20C (Priorix-Tetra stored at −20°C) or Merck-20C (ProQuad) on day 0. All subjects concomitantly received a single dose of PCV7 (Prevnar; Wyeth)16 and HAV (Havrix; GSK Biologicals).17 The study consisted of 3 scheduled visits at day 0, day 42 and day 180, with blood samples collected on day 0 (preimmunization) and day 42 for antibody determination. GSK+4C, GSK-20C or Merck-20C were injected subcutaneously into the right upper arm. HAV and PCV7 were administered by intramuscular injection into the left and right thighs, respectively. A second HAV dose was administered into the left thigh at day 180.
Treatment group was allocated by the investigator/designee using an Internet-based centralized randomization system. The randomization list was generated at GSK Biologicals using SAS software (SAS Institute Inc., Cary, NC). Vaccine recipients, parents/guardians and those evaluating study endpoints were blinded to study treatment. Vaccine preparation and administration were performed by authorized personnel who did not participate in the study clinical evaluation. Data were collected via electronic case report forms encoded using remote data entry.
At lot release, GSK+4C and GSK-20C (from the same vaccine lot but stored under different conditions) contained: 104.1 CCID50 (median cell culture infective dose) of Schwarz measles, 105.3 CCID50 of RIT4385 mumps, 104.0 CCID50 of RA27/3 rubella and 104.1 plaque-forming units (pfu) of Oka-RIT VZV virus strains. Merck-20C contained no less than 103.0 CCID50 of Edmonston-Enders measles, 104.3 CCID50 of Jeryl Lynn mumps, 103.0 CCID50 of RA27/3 rubella and 103.99 pfu of Oka/Merck VZV strains.
Serum antibody concentrations to measles, rubella, VZV and hepatitis A virus were determined by commercial immunoassay kits (Dade Behring Enzygnost, Marburg, Germany). Mumps antibody response was measured using a plaque reduction neutralization assay (GSK Biologicals).18,19 Antibodies to PCV7 pneumococcal serotypes were determined using an in-house enzyme-linked immunosorbent assay (GSK Biologicals).20 Antibody responses to HAV and PCV7 were determined in a subset of subjects enrolled up to July 4, 2008, whereas all subjects were evaluated for MMRV.
Assay seronegativity cut-off values for antibodies to MMRV vaccine components were measles, <150 mIU/mL; mumps, <24 ED50 (endpoint dilution 50%); rubella, <4 IU/mL; and VZV, <25 mIU/mL. Postvaccination seroresponses to vaccine components in baseline-seronegative subjects were measles ≥200 mIU/mL; mumps ≥51 ED50; rubella ≥10 IU/mL and VZV ≥75 mIU/mL. All assays were performed blinded at a central laboratory (GSK Biologicals).
Reactogenicity and Safety
Reactogenicity and safety were assessed at each visit by the investigators and via diary cards completed by the parents/guardians during days 0–42. Local symptoms (assessed at the MMRV vaccine injection site only) were monitored from days 0 to 3. Solicited general adverse events (fever, rash and parotid/salivary gland swelling), unsolicited adverse events or any event requiring medical advice were recorded from days 0 to 42. Symptoms were categorized according to intensity and relation to study vaccine. All solicited local symptoms were considered to be causally related to study vaccine. Rashes occurring postimmunization were examined by the investigator and classified as measles/rubella-like (macular or maculopapular), varicella-like (papulovesicular) or other (eg, heat or diaper rash); the investigator also determined whether the rash was localized to the administration site or other location or generalized. Serious adverse events were recorded from days 0 to180.
In total, 1600 evaluable subjects for the GSK+4C (n = 640), GSK-20C (n = 640) and Merck-20C (n = 320) groups were required to meet the primary objectives for immunogenicity with an overall power >85%. The primary immunogenicity analysis was performed on the according-to-protocol (ATP) cohort for immunogenicity, defined as subjects who received 1 dose of study vaccine via the correct administration route, who had pre- and postvaccination serology results available, who were seronegative for at least 1 MMRV antigen at baseline and who complied with the study protocol. Seroresponse rates were calculated and antibody concentrations/titers summarized by geometric mean concentrations/titers (GMC/GMT) with 95% confidence intervals (CIs).
The primary study objective was to demonstrate noninferiority of GSK+4C and/or GSK-20C when compared with Merck-20C with respect to seroresponse rates for antibodies to MMRV and GMCs for antibodies to VZV, hepatitis A virus and PCV7 pneumococcal serotypes at day 42 postvaccination. For seroresponse rates, noninferiority was met if the lower limit of the 2-sided 97.5% CI for the group difference in seroresponse rate [(GSK+4C or GSK-20C) minus Merck-20C] was ≥−5%, ≥−10%, ≥−5% and ≥−15% for antibodies to MMRV, respectively. For GMCs, noninferiority was met if the lower limit of the 2-sided 97.5% CI for the GMC ratio [(GSK+4C or GSK-20C) over Merck-20C] was ≥0.5. To quantify the risk of falsely concluding noninferiority, P values were determined using the 1-sided asymptotic standardized test for each primary objective null hypothesis and should be compared with 1.25%. Exploratory analyses included day 42 GMC/GMT ratios with 95% CIs for antibodies to MMR in baseline-seronegative subjects.
The primary safety analysis was performed on the total vaccinated cohort (TVC), defined as all subjects who received 1 dose of study vaccine. Safety data were analyzed using descriptive statistics. Symptom incidence was calculated with exact 95% CIs for each group. Exploratory analyses were performed using the standardized asymptotic 2-sided 95% CIs and corresponding 2-sided P values. A P value of <0.05 indicated a potential safety signal; however, because P values were not adjusted for multiplicity of endpoints and do not necessarily denote a clinically relevant difference, statistically significant findings should be interpreted with caution. A permutation test, quantifying the risk of erroneously finding at least 1 event according to different P value thresholds, revealed that an event detected using a P value <5% (P < 0.05) had >60% chance of being erroneously identified for the GSK+4C versus Merck-20C comparison and 40% for GSK-20C versus Merck-20C. Data were analyzed with SAS software version 9.1 (SAS Institute Inc., Cary, NC) and Proc StatXact 7.0 (Cytel Software Corporation, Cambridge, MA).
Subject Disposition and Baseline Demographics
A total of 1850 subjects were enrolled and 1783 subjects were vaccinated (TVC): 705 received GSK+4C, 689 received GSK-20C and 389 received Merck-20C (Fig. 1). Of these, 1646 subjects completed visit 3 (day 180) and 137 were withdrawn. The ATP cohort for immunogenicity comprised 1621 subjects in total: GSK+4C (n = 632), GSK-20C (n = 636) and Merck-20C (353); reasons for exclusion (n = 162) are shown in Figure 1.
Demographic characteristics of the 3 treatment arms were comparable in both the TVC and the ATP cohort for immunogenicity with respect to age and gender. The mean (standard deviation) age at enrollment for the TVC was 12.3 (0.59) months (range: 12–15 months) and 50.2% were male; mean age in the ATP-immunogenicity cohort was 12.3 (0.58) months (range: 12–14 months) and 50.7% were male. Both analysis cohorts were predominantly of Caucasian/European heritage (TVC: 69.8%, ATP-immunogenicity: 69.5%). With respect to prevaccination status, 100%, 88.2%, 99.9% and 98.9% of subjects in the ATP cohort for immunogenicity were seronegative for antibodies to measles, mumps, rubella and VZV, respectively.
In the ATP cohort, seroresponse rates to vaccine components at day 42 were ≥97.7% across all 3 treatment arms for measles and rubella viruses and ≥92.3% across all arms for mumps virus (Table 1). Noninferiority of GSK+4C and GSK-20C compared with Merck-20C was demonstrated for seroresponse rates for measles, MMR viruses according to their respective clinical margins (Table 1). However, for VZV, seroresponse rates were lower in the GSK MMRV groups (GSK+4C: 57.1%; GSK-20C: 69.8%) than in the Merck-20C group (86.7%). Seroresponse rates for VZV did not meet criteria for noninferiority versus Merck-20C for either GSK MMRV vaccine, as the lower limit of the 97.5% CI for the group difference was below the −15% clinical margin in both cases (Table 1).
GMC/GMTs for Antibodies
GMCs for antibodies to VZV were lower for the GSK MMRV groups (GSK+4C: 83.8 mIU/mL; GSK-20C: 110.1 mIU/mL) compared with the Merck-20C group (163.9 mIU/mL). Calculated anti-VZV GMC ratios for GSK+4C/Merck-20C and GSK-20C/Merck-20C were 0.512 (97.5% CI: 0.444, 0.589) and 0.672 (97.5% CI: 0.584, 0.774), respectively (Table 2). Therefore, noninferiority was demonstrated for the GSK-20C versus Merck-20C comparison (lower 97.5% CI limit was ≥0.5; P < 0.001), but not for GSK+4C versus Merck-20C (lower 97.5% CI was <0.5; P = 0.360). GMC ratios for antibodies to the coadministered vaccines HAV and PCV7 demonstrated noninferiority for both GSK MMRV groups compared with Merck-20C (Table 2). GMC/T ratios of antibodies to MMR for GSK vaccines versus Merck-20C are presented in Table 2 (although these were not associated with a prespecified noninferiority hypothesis).
In the TVC, the observed proportions of subjects who reported at least 1 symptom during days 0–42 were 74.8%, 74.9% and 74.6% in the GSK+4C, GSK-20C and Merck-20C groups, respectively. During the 3-day postvaccination period, pain at the MMRV injection site was the most frequently reported solicited local symptom, although grade 3 pain (cries when limb is moved/spontaneously painful) was reported in ≤ 0.6% of subjects across all groups. Grade 3 swelling or redness (>20.0 mm diameter) were both reported in ≤ 1.1% of subjects in each group.
Fever peaked 7–10 days after vaccination in each group (Fig. 2). Incidence of grade 3 fever (>39.5°C) in the GSK+4C, GSK-20C and Merck-20C groups, respectively, was 4.9%, 7.2% and 3.7% from days 0 to 14 and 7.7%, 10.6% and 6.3% from days 0 to 42 (Table 3). Incidence of localized measles/rubella-like rash from days 0 to 42 in the GSK+4C, GSK-20C and Merck-20C groups was 2.1%, 1.3% and 0.5%, respectively, whereas the incidence of generalized measles/rubella-like rash during the same interval was 3.6%, 2.7% and 3.4% (Table 3).
Exploratory analyses revealed differences in localized measles/rubella-like rash for GSK+4C compared with Merck-20C (P = 0.0491) and grade 3 fever for GSK-20C compared with Merck-20C (P = 0.0214). Exploratory analysis of the percentages of subjects with solicited local symptoms, solicited general symptoms or unsolicited symptoms did not identify any additional potential safety signals.
Other Adverse Events
A total of 41 subjects experienced at least 1 serious adverse event during days 0–180. The incidence of serious adverse events among the 3 groups was 2.0%, 2.9% and 1.8% for GSK+4C, GSK-20C and Merck-20C, respectively. Febrile seizures occurring from days 0 to 42 were reported in 0.3% of subjects in each treatment group: 2 subjects in the GSK+4C group (days 16 and 24), 2 in the GSK-20C group (days 24 and 42) and 1 in the Merck-20C group (day 6). No fatal events were reported.
Use of Concomitant Medication
From days 0 to 42, the proportion of subjects using concomitant medication in the GSK+4C, GSK-20C and Merck-20C treatment arms was, respectively, 54.0%, 52.1% and 55.9% for antipyretics and 68.8%, 69.4%, and 70.7% for “any medication.”
This phase 2 study compared the immunogenicity and assessed the safety of a first dose of GSK MMRV vaccine [Priorix-Tetra stored in a refrigerator (GSK+4C) or stored frozen (GSK-20C)] to that of Merck-20C (ProQuad), when coadministered with HAV and PCV7 to 12- to 14-month-old US children. The results demonstrated the noninferiority of both GSK+4C and GSK-20C compared with Merck-20C for seroresponse rates to MMR viruses at 42 days postvaccination. Immunogenicity results for the MMR components were observed similar to those previously reported for GSK MMRV vaccine in other study populations.12,21,22 Analysis of baseline-adjusted GMC ratios for antibodies to PCV7 pneumococcal serotypes and anti-HAV antibodies also demonstrated noninferiority for the GSK MMRV groups versus Merck-20C, suggesting that the use of either GSK vaccine does not affect the immune response to these concomitantly administered vaccines when compared with Merck-20C.
Both GSK MMRV vaccines elicited a lower anti-VZV antibody response than the licensed comparator, and seroresponse rates did not meet criteria for noninferiority compared with Merck-20C. For GMC ratios, while noninferiority was demonstrated for GSK-20C versus Merck-20C, noninferiority was not shown for GSK+4C. This study used a commercial enzyme-linked immunosorbent assay to determine the anti-VZV seroresponse. Earlier studies evaluating the VZV component of GSK MMRV vaccine with this assay used a seroresponse threshold of 50 mIU/mL, whereas the current study utilized a more stringent threshold of 75 mIU/mL. Nevertheless, observed anti-VZV seroresponse rates and GMCs after a single dose of GSK+4C were lower than expected compared with previous studies using the enzyme-linked immunosorbent assay.23 One possible reason for this observation may be related to interaction of multivalent vaccine components, potentially leading to interference with or potentiation of the immune response to other vaccine components.12,24 Alternatively, there may be an inherent difference in immunogenicity between the varicella strain Oka-RIT (used in Priorix-Tetra) and Oka/Merck (ProQuad). In a study comparing the immunogenicity of Merck’s monovalent VZV vaccine (Varivax) to the GSK VZV vaccine (Varilrix),25 seroresponses appeared lower for the GSK vaccine at 6 weeks postvaccination (although observed differences were less than those seen in the current study). The authors attributed this effect to possible differences in the vaccine manufacturing process, namely a higher degree of attenuation of the Oka-RIT VZV strain compared with Oka/Merck. In another study investigating brand-specific varicella vaccine effectiveness during outbreaks in day care centers in Germany,26 estimated vaccine effectiveness (VE) for 1dose of Varilrix [VE = 56% (95% CI: 29, 72)] or Priorix-Tetra (VE = 55% (95% CI: 8, 78)] was <1 dose of Varivax [VE = 86% (95% CI: 56, 96)] or 2 doses of Priorix-Tetra [VE = 91% (95% CI: 65, 98)]. A reduced antibody response to a first VZV vaccine dose implies a potentially increased risk of breakthrough varicella disease upon exposure to VZV in the interval before a second dose of vaccine is administered. While the magnitude of the increased risk cannot be reliably estimated, the majority of breakthrough disease cases would be expected to be mild and less contagious compared with wild-type disease in unvaccinated individuals, particularly for breakthrough cases with <50 lesions.27
A limitation of the current study is that immune responses to a 2-dose schedule of each of the MMRV vaccines were not tested. The US Center for Disease Control Advisory Committee on Immunization Practices recommends that all healthy children should receive their first dose of VZV-containing vaccine routinely at age 12–15 months and a second dose at age 4–6 years (ie, before entering prekindergarten, kindergarten or first grade), although the second dose may be administered at an earlier age provided that the interval between the first and second dose is at least 3 months.28 Consistent with Advisory Committee on Immunization Practices guidelines, GSK also recommends the use of a 2-dose vaccination schedule for VZV-containing vaccines to achieve optimal protection from varicella. This recommendation is based on a clinical trial in which the GMT for antibodies to VZV increased approximately 20-fold after a second GSK MMRV dose relative to the first dose administered 6 weeks earlier to children in the second year of life.29 It is not known if the differences in varicella response between the 3 treatment arms observed in the current study after a single MMRV administration would also be apparent after a second dose.
The GSK MMRV vaccines were taken from a single lot, but their storage temperatures differed on release (4°C or −20°C). While not a prespecified endpoint in the current study, for which the type I error was controlled, anti-VZV antibody responses to GSK+4C and GSK-20C varied in an exploratory analysis. Vaccine potency, tested over the 9-month study enrollment period, showed a difference of no more than 0.1 log10 pfu in varicella potencies between the refrigerator- and freezer-stored vaccines. Considering the similarity in varicella potency between the 2GSK vaccines >9 months, it is not apparent that storage conditions affected anti-VZV immune response in this study. Neither freezer-stored GSK monovalent VZV vaccine nor GSK MMRV has previously been evaluated in clinical trials. Although both GSK MMRV vaccines showed similar seroresponse rates (and noninferiority versus Merck-20C) for the other vaccine components, it is not clear from this study why, despite no obvious differences in potency over time, the GSK vaccines stored at 4°C and −20°C appeared to differ in anti-VZV antibody response.
GSK+4C and GSK-20C safety profiles appeared similar to that of Merck-20C and overall, were consistent with previously reported data for a first-dose GSK MMRV in other subject populations.21,22,30 Exploratory analyses revealed 2 adverse events requiring further investigation: localized measles/rubella-like rash (GSK+4C) and grade 3 fever (GSK-20C). Although there appeared to be a small increase in fever 7–10 days after vaccination for GSK MMRV when compared with the licensed vaccine, there were no differences in the proportions of subjects taking antipyretics or seeking medical advice.
Merck MMRV vaccine has been associated with an increase in febrile seizures in 12–23 month olds compared with MMR and varicella vaccines administered separately at the same visit.31,32 Consequently, the current Advisory Committee on Immunization Practices recommendation28 is that for the first dose of MMRV vaccines at age 12–47 months, either MMR vaccine and VZV vaccine or MMRV may be used; however, families without a strong preference for MMRV should receive MMR and VZV vaccine separately. Similarly, the American Academy of Pediatrics33 also recommends the use of either MMR and VZV vaccines separately or MMRV for the first dose at 12–47 months. They state that the benefits and risks of both options should be discussed with parents/caregivers and that separate MMR and VZV injections should be given in cases where the risk-benefit can not be clearly communicated.
The recognized period of increased risk for febrile seizure after a first dose of MMRV is either 5–12 days32 or 7–10 days31 after vaccination, although 4 of the 5 cases of febrile seizure in the current study occurred outside of the 5–12 day window. The risk of febrile seizure after administration of GSK MMRV vaccine relative to separate coadministration of MMR and monovalent VZV vaccine has not been investigated in a clinical trial of adequate power but, based on the reported fever profiles of the GSK and Merck vaccines,31 would be expected to be similar.
In conclusion, this study provides evidence that GSK+4C and GSK-20C vaccines are comparable with Merck-20C in terms of immunogenicity, for 3 of the 4 vaccine components, and have a clinically acceptable reactogenicity/safety profile when given concomitantly with HAV and PVC7. The clinical significance of the differences in anti-VZV seroresponse after a first dose of GSK MMRV requires further investigation.
The authors would like to thank the parents, children and investigators who participated in this clinical trial. They also gratefully acknowledge the work of the nurses and other staff members involved. Ms. Victoria Pearson and Dr. Helen Baldwin (Scinopsis) provided medical writing services and Mrs. Véronique Duquenne and Dr. Luise Kalbe (GSK Biologicals) provided editorial assistance.
1. World Health Organization.. Rubella vaccinesWHO position paper. Wkly Epidemiol Rec. 2000;75:161–172
2. World Health Organization.. Mumps virus vaccines. Wkly Epidemiol Rec. 2001;76:346–355
3. World Health Organization. . Measles vaccines. Wkly Epidemiol Rec.. 2004;79:130–142
4. Zhou F, Reef S, Massoudi M, et al. An economic analysis of the current universal 2-dose measles-mumps-rubella vaccination program in the United States. J Infect Dis. 2004;189(suppl 1):S131–S145
5. Watson JC, Hadler SC, Dykewicz CA, et al. Measles, mumps, and rubella–vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1998;47(RR-8):1–57
6. Peltola H, Heinonen OP, Valle M, et al. The elimination of indigenous measles, mumps, and rubella from Finland by a 12-year, two-dose vaccination program. N Engl J Med. 1994;331:1397–1402
7. Orenstein WA, Papania MJ, Wharton ME. Measles elimination in the United States. J Infect Dis. 2004;189(suppl 1):S1–S3
8. World Health Organization. . Varicella vaccines. WHO position paper. Wkly Epidemiol Rec. 1998;73:241–248
9. Galil K, Lee B, Strine T, et al. Outbreak of varicella at a day-care center despite vaccination. N Engl J Med. 2002;347:1909–1915
10. Guris D, Jumaan AO, Mascola L, et al. Changing varicella epidemiology in active surveillance sites--United States, 1995–2005. J Infect Dis. 2008;19:S71–S75
11. Marin M, Meissner HC, Seward JF. Varicella prevention in the United States: a review of successes and challenges. Pediatrics. 2008;122:e744–e751
12. Czajka H, Schuster V, Zepp F, et al. A combined measles, mumps, rubella and varicella vaccine (Priorix-Tetra): immunogenicity and safety profile. Vaccine. 2009;27:6504–6511
13. Dietz VJ, Stevenson J, Zell ER, et al. Potential impact on vaccination coverage levels by administering vaccines simultaneously and reducing dropout rates. Arch Pediatr Adolesc Med. 1994;148:943–949
14. Fiore AE, Wasley A, Bell BP. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-7):1–23
15. American Academy of Pediatrics Committee on Infectious Diseases.. Policy statement: recommendations for the prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine (Prevnar), pneumococcal polysaccharide vaccine and antibiotic prophylaxis. Pediatrics. 2000;106:362–366
18. Dodet M, Dessy F, Parent I, et al. Use of a neutralization assay as an alternative for assessing mumps immunization status. Program and Abstracts of the 24th Annual Meeting of the European Society for Pediatric Infectious Diseases. May 3–5, 2006
19. Sato H, Albrecht P, Hicks JT, et al. Sensitive neutralization test for virus antibody. 1. Mumps antibody. Arch Virol. 1978;58:301–311
20. Poolman JT, Frasch CE, Käyhty H, et al. Evaluation of pneumococcal polysaccharide immunoassays using a 22F adsorption step with serum samples from infants vaccinated with conjugate vaccines. Clin Vaccine Immunol. 2010;17:134–142
21. Goh P, Lim FS, Han HH, et al. Safety and immunogenicity of early vaccination with two doses of tetravalent measles-mumps-rubella-varicella (MMRV) vaccine in healthy children from 9 months of age. Infection. 2007;35:326–333
22. Zepp F, Behre U, Kindler K, et al. Immunogenicity and safety of a tetravalent measles-mumps-rubella-varicella vaccine co-administered with a booster dose of a combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-Haemophilus influenzae type b conjugate vaccine in healthy children aged 12-23 months. Eur J Pediatr. 2007;166:857–864
23. Vinals C, Gaulis S, Coche T. Using in silico transcriptomics to search for tumor-associated antigens for immunotherapy. Vaccine. 2001;19:2607–2614
24. Kuter BJ, Brown ML, Hartzel J, et al.Study Group for ProQuad. Safety and immunogenicity of a combination measles, mumps, rubella and varicella vaccine (ProQuad). Hum Vaccin. 2006;2:205–214
25. Lau YL, Vessey SJ, Chan IS, et al. A comparison of safety, tolerability and immunogenicity of Oka/Merck varicella vaccine and VARILRIX in healthy children. Vaccine. 2002;20:2942–2949
26. Spackova M, Wiese-Posselt M, Dehnert M, et al. Comparative varicella vaccine effectiveness during outbreaks in day-care centres. Vaccine. 2010;28:686–691
27. Seward JF, Zhang JX, Maupin TJ, et al. Contagiousness of varicella in vaccinated cases: a household contact study. JAMA. 2004;292:704–708
28. Marin M, Broder KR, Temte JL, et al.Centers for Disease Control and Prevention (CDC). Use of combination measles, mumps, rubella, and varicella vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010;59(RR-3):1–12
29. Schuster V, Otto W, Maurer L, et al. Immunogenicity and safety assessments after one and two doses of a refrigerator-stable tetravalent measles-mumps-rubella-varicella vaccine in healthy children during the second year of life. Pediatr Infect Dis J. 2008;27:724–730
30. Knuf M, Habermehl P, Zepp F, et al. Immunogenicity and safety of two doses of tetravalent measles-mumps-rubella-varicella vaccine in healthy children. Pediatr Infect Dis J. 2006;25:12–18
31. Klein NP, Fireman B, Yih WK, et al. Measles-mumps-rubella-varicella combination vaccine and the risk of febrile seizures. Pediatrics. 2010;126:e1–e8
32. Jacobsen SJ, Ackerson BK, Sy LS, et al. Observational safety study of febrile convulsion following first dose MMRV vaccination in a managed care setting. Vaccine. 2009;27:4656–4661
33. American Academy of Pediatrics Committee on Infectious Diseases.. Prevention of varicella: update of recommendations for use of quadrivalent and monovalent varicella vaccines in children. Pediatrics. 2011;128:630–632.
Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
measles; mumps; rubella; varicella