A Combination Measles, Mumps, Rubella, and Varicella Vaccine (ProQuad) Given to 4- to 6-Year-Old Healthy Children Vaccinated Previously With M-M-RII and Varivax
BACKGROUND. In the United States, children receive primary doses of M-M-RII (Merck & Co, Inc, West Point, PA) and Varivax (Merck & Co, Inc) beginning at 12 months, often at the same health care visit. Currently a second dose of M-M-RII is given to 4- to 6-year-old children, to increase vaccination rates and to reduce the number of individuals without detectable antibodies. A second dose of a varicella-containing vaccine may result in similar benefits.
OBJECTIVES. To demonstrate that ProQuad (measles, mumps, rubella, and varicella virus vaccine live; Merck & Co, Inc) may be given in place of a second dose of M-M-RII or second doses of M-M-RII and Varivax for 4- to 6-year-old children.
METHODS. Four- to 6-year-old children who had been immunized previously with M-M-RII and Varivax were assigned randomly to receive either ProQuad and placebo (N = 399), M-M-RII and placebo (N = 195), or M-M-RII and Varivax (N = 205) and were then monitored for safety and immunogenicity.
RESULTS. ProQuad was generally well tolerated. Similarity (noninferiority) was demonstrated in postvaccination antibody responses to measles, mumps, and rubella between recipients of ProQuad and all recipients of M-M-RII and in responses to varicella between recipients of ProQuad and recipients of Varivax. Postvaccination seropositivity rates for antibodies against all 4 viruses were nearly 100% in all 3 groups. Small fold increases were observed for measles, mumps, and rubella antibody titers. In contrast, substantial boosts in varicella antibody titers were observed among recipients of a second dose of varicella vaccine, administered as ProQuad or Varivax.
CONCLUSIONS. ProQuad may be used in place of a second dose of M-M-RII or second doses of M-M-RII and Varivax for 4- to 6-year-old children.
Measles, mumps, rubella, and varicella cause significant morbidity and death. Children in the United States are vaccinated routinely against measles, mumps, and rubella with M-M-RII (Merck & Co, Inc, West Point, PA) at 12 to 15 months of age, followed by a second dose at school entry (4–6 years of age).1 Routinely, the primary dose of Varivax (Oka/Merck) is administered concomitantly with M-M-RII at 12 to 15 months of age. Currently there is no recommendation for a second dose of varicella vaccine. The availability of an effective combined measles, mumps, rubella, and varicella vaccine (ProQuad; Oka/Merck), to be used in place of the routinely administered second dose of M-M-RII, could facilitate an increase in varicella vaccination rates and should result in seroconversion for all 4 viruses among children who did not exhibit seroconversion after the initial vaccination. ProQuad, when given at 12 to 15 months of age, would reduce the number of injections in this age group. Previous studies demonstrated that almost all initial varicella vaccine nonresponders exhibit seroconversion after a second dose of either ProQuad or Varivax.2,3 Furthermore, those studies showed that significant boosts in varicella antibody titers occur after a second dose is administered. Higher postvaccination antibody titers were correlated with a lower probability of development of breakthrough varicella disease, and a second dose of Varivax was shown to enhance the cumulative protective efficacy over 10 years (98%), compared with a single dose of Varivax (94%).3,4 The purpose of this study was to determine whether ProQuad could be administered instead of a second dose of M-M-RII or as a second dose of M-M-RII and Varivax for children 4 to 6 years of age.
This study was conducted at 17 centers in the United States, from August 2000 through April 2002. Each of the participating centers obtained institutional review board approval of the study before initiation. Written informed consent was obtained from the parent/legal guardian of each subject before enrollment. Healthy children 4 to 6 years of age were eligible if they had received primary doses of M-M-RII and Varivax, either concomitantly or nonconcomitantly, at ≥12 months of age and at least 1 month before study enrollment. Potential subjects were excluded if they had a clinical history of varicella, herpes zoster, measles, mumps, and/or rubella, had immune impairment, immunodeficiency, or neoplastic disease, or had a history of anaphylactoid reaction to neomycin, gelatin, or any other component of the vaccines, as stated in the package circulars for M-M-RII and Varivax. Individuals also were excluded if they had been exposed to measles, mumps, rubella, varicella, and/or herpes zoster in the 4 weeks before vaccination. Children who were vaccinated with inactivated nonstudy vaccines within 14 days or live nonstudy vaccines within 30 days before enrollment in the study, had plans to receive such vaccines within the 42 days after each scheduled vaccination, or had received immunoglobulin or blood products within 3 months before (or were scheduled to receive within 2 months after) each vaccination were not eligible for the study. Individuals with any contraindication to Varivax or M-M-RII, as stated in the package circulars, also were excluded.
Vaccine and Randomization
This was a double-blind (study personnel, subjects, and study sponsor were blinded) multicenter study. Subjects were assigned randomly to 1 of 3 treatment groups, on a 2:1:1 basis. Subjects in group 1 received ProQuad and placebo concomitantly, at separate injection sites. Subjects in group 2 were given M-M-RII and placebo concomitantly, at separate injection sites; this regimen was used to represent the standard of care at the time of the study. Subjects in group 3 were given M-M-RII and Varivax concomitantly, at separate injection sites. This third treatment group represented the potential standard of care if a second-dose recommendation for varicella vaccine is made. All clinical materials (ProQuad, Varivax, M-M-RII, and placebo) were manufactured by Merck & Co, Inc (West Point, PA), and each vaccine was administered as a 0.5-mL subcutaneous injection. ProQuad is a frozen, sterile, quadrivalent vaccine combining the components of M-M-RII and Varivax. The measles, mumps, and rubella components in ProQuad are the same as those in M-M-RII; ProQuad contains a higher concentration of varicella vaccine virus than does Varivax.
All subjects who received study vaccine were evaluated for safety. Parents/legal guardians of subjects were asked to record on a vaccination report card (VRC) their child's daily temperature and all local and systemic complaints, as well as any other vaccines or medications given on the day of vaccination and for 42 days after the vaccination visit. Serious and vaccine-related adverse experiences were monitored to resolution. Data on certain commonly reported, injection-site, adverse experiences (ie, pain, redness, and swelling) were solicited specifically on the VRC. Daily temperatures also were recorded on the VRC. In the absence of a measured temperature, the parent/legal guardian was requested to indicate whether the subject felt warm to touch; reports of a child feeling warm were entered into the database as “abnormal.” If a temperature was ≥102°F (≥38.9°C) measured orally or the equivalent (rectal: 103°F or 39.4°C; axillary: 101°F or 38.3°C), or “abnormal,” then the study personnel were instructed to report the elevated temperature as an adverse experience of fever. For each adverse experience reported, the investigator was requested to assess the seriousness, actions taken, and relationship to test vaccine. The parent/legal guardian was responsible for evaluating the maximal intensity of all adverse experiences. Local reactions of swelling and redness were evaluated according to size. In addition, parents/legal guardians were instructed to contact study personnel immediately if their child experienced mumps-like symptoms or a measles-like, rubella-like, and/or varicella-like rash or if any serious or unexpected adverse experience occurred.
Blood samples were collected immediately before vaccination and ∼42 days after vaccination. To determine antibody levels for each viral component, serum samples were tested at Merck Research Laboratories (West Point, PA), with appropriately sensitive, enzyme-linked immunosorbent assay (ELISA) methods for measles, mumps, and rubella antibodies and a glycoprotein antigen-based ELISA (gpELISA) for varicella antibodies.5–7 The geometric mean titer (GMT) for each virus 6 weeks after vaccination was the primary end point used to demonstrate similar antibody responses among treatment groups.
All analyses were performed with SAS statistical software (version 8.2; SAS Institute, Cary, NC). To establish the similarity (noninferiority) of group 1 (ProQuad plus placebo), compared with both group 2 (M-M-RII plus placebo) and group 3 (M-M-RII and Varivax), 2 hypothesis tests were performed. The first primary hypothesis regarding similarity (noninferiority) of the measles, mumps, and rubella GMTs 42 days after vaccination between group 1 and group 2 was based on 3 one-sided equivalence tests, 1 for each virus. For each GMT comparison, an analysis of variance model was implemented with the natural logarithm of the postvaccination titer as the response and study center, treatment group, vaccination history status, and natural logarithm of the prevaccination titer as fixed effects, with the assumption of normality of the transformed titers. Least-square means from this analysis of variance model were used as estimates of GMTs on a natural logarithm scale, and a 2-sided 90% confidence interval (CI) for the difference in GMTs on the natural logarithm scale was constructed on the basis of the t distribution and mean squared error from the analysis of variance model as an estimate of variance. The GMTs and CI were then exponentiated. This CI being entirely above 0.5 was taken as the basis of rejecting the null hypotheses (H0: GMTA/GMTB ≤ 0.5, where A and B represent subjects in groups 1 and 2, respectively) at the 1-sided .05 level, thus establishing noninferiority of group 1, compared with group 2. The same method was used to test the second primary hypothesis of similarity (noninferiority) of group 1, compared with group 3, regarding GMTs of antibodies to measles, mumps, rubella, and varicella 42 days after vaccination. No multiplicity adjustment was made because the success of this study required that similarity (noninferiority) be established for group 1 in comparison with group 2 regarding GMTs of antibodies to measles, mumps, and rubella (3 hypothesis tests) and in comparison with group 3 regarding GMTs of antibodies to measles, mumps, rubella, and varicella (4 hypothesis tests). Each of these 7 hypothesis tests was conducted at the 1-sided .05 level; this controlled the overall type I error rate at the 1-sided .05 level. Secondarily, the analysis of variance model approach also was used to test the secondary hypothesis regarding similarity (noninferiority) of group 3, compared with group 2, regarding GMTs of antibodies to measles, mumps, and rubella 42 days after vaccination.
To address the primary hypothesis regarding safety, the safety profile for group 1 was compared with the safety profiles for groups 2 and 3 separately. Data on selected adverse experiences of special interest, including elevated temperature (≥102°F or ≥38.9°C measured orally or equivalent or abnormal), injection-site erythema, injection-site pain, injection-site swelling, injection-site rash, varicella-like rash, measles-like rash, rubella-like rash, and mumps-like symptoms, were solicited on the VRC. For these adverse experiences of special interest, the treatment difference in the proportions of subjects with the adverse event, the associated 2-sided 95% CI, and the P value were provided. For the adverse experiences that were not solicited on the VRC but occurred with an incidence rate of ≥1%, the treatment difference and the associated 2-sided 95% CI were provided but the P value was not.
A total of 799 healthy children, ie, 399 in group 1 (ProQuad plus placebo), 205 in group 2 (M-M-RII plus placebo), and 195 in group 3 (M-M-RII plus Varivax), were enrolled in the study. Overall, 53.3% of subjects were male, 78.6% were white, and 11.6% were black. The mean age was 4.3 years. The 3 treatment groups seemed comparable with respect to subject characteristics such as age, race, and gender (Table 1).
No vaccine-related serious adverse experiences were reported. Table 2 presents a summary of overall clinical and specific systemic adverse experiences after vaccination. Overall, the proportions of subjects with ≥1 adverse event were comparable between group 1 (ProQuad plus placebo) and group 2 (M-M-RII plus placebo) and between group 1 and group 3 (M-M-RII and Varivax). The proportions of subjects with overall systemic adverse experiences were also comparable between group 1 and group 2 and between group 1 and group 3. The most commonly reported specific systemic adverse experiences (incidence of ≥10% in any treatment group) for all 3 treatment groups were fever, nasopharyngitis, and cough; the proportions of subjects with these specific systemic adverse experiences were comparable between group 1 and group 2 and between group 1 and group 3. The proportions of subjects with solicited adverse experiences such as vaccine-specific rashes (range: 0.0–0.8%) were comparable among all 3 treatment groups.
The proportions of subjects with overall injection-site adverse experiences were comparable between group 1 and group 2 and between group 1 and group 3 (Table 2). The proportions of subjects with specific injection-site adverse experiences are presented in Table 3. Pain/tenderness/soreness, erythema, and swelling at the injection site were solicited on the VRC during days 1 to 5 after vaccination and were the most commonly reported injection-site adverse experiences (incidence of ≥5% in any treatment group) in all 3 treatment groups. When comparisons were made for specific types of injection-site adverse experiences (eg, redness or swelling) at each individual injection site, the data showed some small differences in the proportions of subjects with these events. Group 1 had a statistically significantly greater proportion of subjects with erythema at the injection site for ProQuad than either group 2 (P = .012) at the injection site for M-M-RII or group 3 at the injection site for M-M-RII (P = .006) and the injection site for Varivax (P = .014) for days 1 to 5 after vaccination. In addition, group 1 had a greater proportion of subjects with swelling, compared with the proportion of subjects in group 3 with swelling at the injection site for M-M-RII (P = .008) for days 1 to 5 after vaccination. However, as seen in Table 3, most of the specific injection-site adverse experiences were rated as mild by the parent/legal guardian or were of the smallest size category (≤1 inch).
ProQuad is administered in 1 injection instead of 2 injections. Therefore, the proportion of subjects with specific injection-site adverse experiences at both injection sites combined (M-M-RII and Varivax) in group 3 was compared with the value for the single injection site for ProQuad in group 1 (Table 3). When the data for recipients of M-M-RII and Varivax were combined, an injection-site adverse experience was counted only once, regardless of whether it was reported after 1 or both vaccines. The results of this analysis are provided in Table 3. The comparison showed no substantial difference in specific adverse experiences at the injection site for ProQuad, compared with the combined rates for the injection sites for M-M-RII and Varivax.
Table 4 presents the comparison of GMTs for antibodies to all 4 viruses for each treatment group. Because the lower bounds of the 90% CIs of the treatment differences for all 4 of these viruses excluded ≤0.5, the postvaccination GMTs of groups 1 and 3 for antibodies to measles, mumps, rubella, and varicella were similar (noninferior). The postvaccination GMTs of groups 1 and 2 for antibodies to measles, mumps, and rubella were similar (noninferior), as were the GMTs of antibodies to the same viruses for groups 3 and 2. In each case, the difference was statistically less than twofold.
Some differences not exceeding a twofold difference were noted. The GMTs of antibodies to mumps among recipients of ProQuad (group 1) were statistically lower than those among recipients of M-M-RII in groups 2 and 3, the GMTs of antibodies to rubella among recipients of ProQuad (group 1) were higher than those among recipients of M-M-RII in groups 2 and 3, and the GMTs of antibodies to varicella were higher among recipients of ProQuad (group 1) than among recipients of M-M-RII and Varivax (group 3).
Seropositivity rates for recipients of ProQuad (group 1) at the prevaccination and postvaccination time points are shown in Table 4. All subjects exhibited seropositivity to measles, mumps, and rubella 6 weeks after vaccination, with a few exceptions; 1 subject who received M-M-RII plus Varivax exhibited seronegativity to measles, 2 subjects who received ProQuad plus placebo exhibited seronegativity to mumps, and 1 subject who received M-M-RII plus Varivax exhibited seronegativity to rubella. The proportions of subjects with varicella antibody titers of ≥5 gpELISA U/mL increased from 88.0% to 98.9% for subjects who received ProQuad plus placebo and from 88.9% to 99.4% for subjects who received M-M-RII plus Varivax. Subjects who received M-M-RII plus placebo did not receive Varivax in this study; therefore, no data are provided for this group.
Although significant increases in postvaccination antibody titers were not expected because subjects had received M-M-RII and Varivax previously, geometric mean fold increases in titers from before vaccination to after vaccination were summarized for this study. Geometric mean fold increases in GMTs of antibodies to measles, mumps, and rubella ranged from 1.21 to 3.00 after vaccination with ProQuad and from 1.28 to 3.69 after vaccination with M-M-RII. A more significant increase in postvaccination GMTs was observed for antibodies to varicella; the geometric mean fold increase in varicella GMTs was 12.43 for recipients of ProQuad and 8.50 for subjects who received M-M-RII and Varivax.
This investigation examined a potential future role of ProQuad in immunizing children 4 to 6 years of age against 4 diseases, ie, measles, mumps, rubella, and varicella. The tolerability profile of ProQuad was quite comparable to that observed with M-M-RII and Varivax. In addition, the immunogenicity data demonstrated clearly that ProQuad could be used in place of a second dose of M-M-RII, whether or not it was administered with Varivax. Postvaccination seropositivity to measles, mumps, and rubella approximated 100% for all subjects. ProQuad induced a robust antibody response to varicella, comparable to that observed with Varivax administered concomitantly with M-M-RII. Although the acquisition of any detectable antibodies to varicella (seroconversion) after vaccination has been demonstrated to provide protection against disease, rates of breakthrough disease have been shown to be significantly lower among children with titers of antibodies to varicella of ≥5 gpELISA U/mL.4,8 The immune response to varicella in this study was evaluated on the basis of antibody titers of ≥5 gpELISA U/mL. The proportion of subjects with prevaccination varicella antibody titers of ≥5 gpELISA U/mL in this study was 88.0%, and values increased to >98% both among subjects given ProQuad (group 1) and among those given M-M-RII and Varivax (group 3). The lower GMTs of antibodies to mumps among recipients of ProQuad, relative to recipients of M-M-RII, is of no clinical relevance with titers well above (∼20 times) the assay cutoff for detection of antibodies in this study. Efficacy studies have established that any detectable antibody to mumps is a strong correlate of protection against mumps.9
In the United States, primary doses of M-M-RII and Varivax are administered beginning at 12 months of age, often at the same health care visit. Currently a second dose of M-M-RII is given to 4- to 6-year-old children, to increase vaccination rates and to reduce the number of individuals with no detectable antibodies after primary vaccination. The measles, mumps, and rubella vaccination program has reduced the occurrence of all 3 diseases since licensure of the combination vaccine (1971). The current varicella vaccination program in the United States relies on the administration of 1 dose of Varivax to children 12 months through 12 years of age, preferably administered at 12 to 18 months of age. The primary goal of varicella vaccination is to reduce the number of severe cases of varicella disease, which represent the primary cause of varicella-associated hospitalizations and deaths (prevaccine-era hospitalizations: ∼11000 per year; deaths: ∼145 per year).10,11 Only 8 varicella-related deaths were reported in the United States during 2003 and the first half of 2004.12 The incidence of hospitalizations attributable to varicella in the 3 active surveillance areas in the United States between 1999 and 2000 declined 50% to 80%, compared with the incidence reported in 1995 through 1998.13,14 In addition, a recent study showed that the incidence of varicella-related deaths in the United States decreased by 66% in 1999 through 2001, compared with the incidence reported in the prevaccination years of 1990 through 1994.11 Furthermore, recent data from the Centers for Disease Control and Prevention indicated that the incidence of varicella at 2 Varicella Active Surveillance Project sites decreased by ∼85% in 1995 through 2003.12 Other postlicensure studies documented that 1 dose of Varivax was ≥95% effective in preventing severe disease and 79% to 85% effective in preventing all disease.15–17
No vaccine results in development of antibody titers among 100% of its recipients after primary vaccination. After primary vaccination with Varivax, a certain proportion of the population fails to develop titers of antibodies to varicella at all and, among responders, a certain proportion fails to achieve titers of antibodies to varicella of ≥5 gpELISA U/mL (the level correlated with strong long-term protection against breakthrough disease).18 In addition, vaccination programs fail to reach all individuals eligible for vaccination. In 2003, the national coverage rate for varicella vaccine for 19- to 35-month-old children in the United States was ∼85%.19 Although a 1-dose recommendation has been highly effective, if coverage rates are insufficient, then there is the theoretical possibility of creating a small population of susceptible adults who are at risk for more-severe disease than are children if exposed to varicella. Previous studies with Varivax suggested that use of a second dose of varicella vaccine would produce seroconversion for nearly all of those who failed to develop antibodies after a single dose.20,21 In the study reported here, 11% to 12% of 4- to 6-year-old children who had received a primary dose of Varivax 3 to 5 years before study entry did not have varicella antibody titers of ≥5 gpELISA U/mL at study entry. After receipt of a second dose of varicella vaccine (given as ProQuad or Varivax), the number of children with antibody titers below this threshold dropped to ∼1%. In addition, after receipt of the second dose of varicella vaccine (in the form of ProQuad or Varivax), subjects had varicella antibody titers to in the range of 200 to 300 gpELISA U/mL. The data from this study therefore suggest that a 2-dose regimen of varicella vaccine would increase the percentage of children with varicella antibody titers above the threshold of 5 gpELISA U/mL and would increase antibody titers among individuals who responded after primary vaccination. It is also likely, on the basis of previous experience with implementation of a 2-dose regimen of M-M-RII, that use of a 2-dose regimen of varicella vaccine would increase vaccination rates among individuals who missed being vaccinated.
A large majority of physicians use guidance from the Advisory Committee on Immunization Practices to administer the first dose of Varivax when infants are 12 to 18 months of age. A significant majority of physicians link the administration of Varivax to the concomitant administration of M-M-RII. Since 1989, when a second dose of M-M-RII was recommended, commonly it has been given at school entry, when children are 4 to 6 years of age; however, according to the recommended childhood and adolescence immunization schedule, M-M-RII can be administered as soon as 4 weeks after the first dose.1 Acceptable immunogenicity data were obtained when a second dose of varicella vaccine in the form of ProQuad was given to children as young as 15 months of age.2,22 Although the data from this study support the use of ProQuad at 4 to 6 years of age, a second dose of varicella vaccine could be administered even earlier, because varicella breakthrough disease, which was described previously for children as young as 2 years of age, can be contagious.3,23 In a 10-year study, breakthrough disease was reduced from an average annual incidence of 0.8% for 1-dose recipients to 0.2% for those given 2 doses of varicella vaccine (estimated efficacy against varicella disease was 94% for 1 dose and 98% for 2 doses).3
The Advisory Committee on Immunization Practices and the American Academy of Pediatrics have recommended repeatedly that pharmaceutical companies develop combination vaccines that prevent disease safely and effectively, to reduce the number of injections that children receive.24 Use of ProQuad will help accomplish this goal.
Among children 4 to 6 years of age who received primary vaccination against measles, mumps, rubella, and varicella previously, ProQuad may be administered in place of a second dose of M-M-RII or as a second dose of both M-M-RII and Varivax. ProQuad has a tolerability profile comparable to those of M-M-RII and Varivax. A second dose of varicella-containing vaccine resulted in a robust boosting of varicella antibody titers and in an increase in the number of subjects with postvaccination varicella antibody titers of ≥5 gpELISA U/mL to >98%.
Use of ProQuad will allow for simultaneous vaccination against measles, mumps, rubella, and varicella in 1 rather than 2 separate injections. This should help to improve varicella immunization rates significantly.
This study was funded by a grant from Merck & Co, Inc.
Members of the Protocol 014 Study Group for ProQuad include the following: Mark M. Blatter, MD; Stephen R. Barone, MD; Ralph Conti, MD; David P. Greenberg, MD; Frederick W. Henderson, MD; Louise K. Iwaishi, MD; Colin Marchant, MD; Gary S. Marshall, MD; David O. Matson, MD, PhD; Philip D. Milnes, MD; Beth Nauert, MD; Bernard Pollara, MD; Keith S. Reisinger, MD, MPH; Edward Rothstein, MD; Shelly D. Senders, MD; Lawrence Sher, MD; Peter E. Silas, MD; Bradley J. Sullivan, MD.
We acknowledge the participants and their families for their assistance in this research project.
- Accepted April 13, 2005.
- Address correspondence to Keith S. Reisinger, MD, MPH, Primary Physicians Research, 1580 McLaughlin Run Rd, Pittsburgh, PA 15241. E-mail:
Financial Disclosure: Drs Reisinger, Marshall, and Matson are speakers for Merck and receive research funding from Merck. Drs Sullivan, Nauert, and Silas and the Protocol 014 Study Group for ProQuad participated in this research study, which was sponsored by Merck.
- ↵Centers for Disease Control and Prevention. Recommended childhood and adolescent immunization schedule: United States, July–December 2004. MMWR Morb Mortal Wkly Rep.2004;53(16) :Q1– Q3
- ↵Shinefield H, Black S, Eves K, et al. Tolerability and immunogenicity of one and two dose regimen of ProQuad in healthy children. Presented at the 41st annual meeting of the Infectious Disease Society of America; October 9–12,2003; San Diego, CA
- ↵Maupin T, Civen R, Jumaan A, et al. Varicella outbreaks in an active surveillance site: Antelope Valley, CA, 1995–2003. Presented at the 38th Annual National Immunization Conference; May 11–14,2004; Nashville, TN
- ↵Galil K, Fair E, Mountcastle N, Britz P, Seward J. Younger age at vaccination may increase risk of varicella vaccine failure. J Infect Dis.2002;186 :102– 105
- ↵Merck & Co, Inc. USA package circular: Varivax (varicella virus [Oka/Merck & Co, Inc] vaccine live). West Point, PA: Merck & Co, Inc;2003
- ↵Watson B, Rothstein E, Bernstein H, et al. Safety and cellular and humoral immune responses of a booster dose of varicella vaccine 6 years after primary immunization. J Infect Dis.1995;172 :217– 219
- ↵Shinefield H, Black S, Marchant C, et al. A dose selection study in healthy children comparing measles, mumps, rubella, and varicella (ProQuad) vaccine to M-M-RII given concomitantly with process upgrade varicella vaccine (PUVV) in separate injections. Presented at the 20th Annual Meeting of the European Society for Paediatric Infectious Diseases; May 29–31,2002; Vilnius, Lithuania
- ↵Tugwell BD, Lee LE, Gillette H, et al. Chickenpox outbreak in a highly vaccinated school population. Pediatrics.2004;113 :455– 459
- ↵Centers for Disease Control and Prevention. Combination vaccines for childhood immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP). MMWR Recomm Rep.1999;48(RR-5) :1– 15
- Copyright © 2006 by the American Academy of Pediatrics