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Analysis of safety data in children after receiving two doses of ProQuad® (MMRV)
Vaccine 32 (2014) 7154–7160
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Analysis of safety data in children after receiving two doses of ProQuad® (MMRV) Stephanie O. Klopfer a,∗ , Jon E. Stek a , Maria Petrecz a , Keith S. Reisinger b , Steven B. Black c , Michelle G. Goveia a , Ouzama Nicholson a,1 , Julie L. Gardner a , Anthony D. Grosso a , Michelle L. Brown a , Barbara J. Kuter a , Florian P. Schödel a,2 a
Merck & Co., Inc, Whitehouse Station, NJ, United States Primary Physicians Research, Pittsburgh, PA, United States c Cincinnati Children’s Hospital, Cincinnati, OH, United States b
a r t i c l e
i n f o
Article history: Received 10 October 2012 Received in revised form 25 August 2014 Accepted 28 August 2014 Available online 16 September 2014 Keywords: Safety MMRV ProQuad® Integrated analyses Tolerability NCT00975507 NCT00986232 NCT00109343 NCT00326183 NCT00312858
a b s t r a c t Background: In randomized clinical studies, over 11,800 children, 12 months to 6 years of age, were administered ProQuad® , a combination measles, mumps, rubella, and varicella vaccine (MMRV). This paper describes the safety following a 2-dose regimen of MMRV administered to children in the second year of life. Methods: Safety data from five clinical studies were combined for all children who were scheduled to receive two doses of MMRV ∼3–6 months apart. All vaccinated children were followed for safety following each dose of MMRV. Results: Of 3112 children who received a first dose of MMRV, 2780 (89.3%) received a second dose of MMRV. Overall, 70.5% and 57.7% of children reported ≥1 adverse experiences following first and second doses of MMRV, respectively. Injection-site redness was statistically significantly higher postdose 2 than postdose 1, while injection-site pain/tenderness was statistically significantly higher postdose 1 compared to postdose 2. Rashes were statistically significantly lower postdose 2 compared to postdose 1. Ten febrile seizures (8 postdose 1, 2 postdose 2) were reported following MMRV vaccination. The incidence of febrile seizures postdose 1 of MMRV was 0.26% (8/3019) compared to 0.07% (2/2695) postdose 2 of MMRV. Conclusions: Administration of two doses of MMRV has an acceptable safety profile in children 12 to 23 months of age. There is a small increase in the risk of febrile seizures following the first dose of MMRV as compared to the component vaccines, but the risk for any individual child is relatively low. © 2014 Elsevier Ltd. All rights reserved.
1. Introduction Widespread immunization against measles, mumps, rubella, and varicella has had a dramatic effect on the epidemiology of
Abbreviations: ACIP, Advisory Committee on Immunization Practices; AE, adverse experience; CI, confidence interval; HAV, hepatitis A vaccine; MMR, measles, mumps, rubella vaccine; MMRV, measles, mumps, rubella and varicella vaccine; PCV7, pneumococcal 7-valent conjugate vaccine; U.S., United States; VRC, vaccination report card. ∗ Corresponding author at: Merck & Co., Inc., PO Box 1000, Whitehouse Station, UG1CD-44 NJ, United States. Tel.: +1 267 305 7959. E-mail address: stephanie [email protected] (S.O. Klopfer). 1 ON was employed by Merck at the time of this research. She is now employed by GlaxoSmithKline. 2 FS was employed by Merck at the time of this research. He is now owner of Philimmune LLC. http://dx.doi.org/10.1016/j.vaccine.2014.08.067 0264-410X/© 2014 Elsevier Ltd. All rights reserved.
all four viruses in the United States (U.S.) and other parts of the world [1,2]. The U.S. Advisory Committee on Immunization Practices (ACIP) currently recommends the routine administration of measles, mumps, rubella, and varicella vaccines on or soon after the first birthday [3]. A second dose of a measles, mumps, rubella, and varicella containing vaccine is recommended at 4 to 6 years of age [4,5]. The combination vaccine, ProQuad® (MMRV; measles, mumps, rubella, and varicella virus vaccine live; Merck & Co., Inc., Whitehouse Station, NJ) [6], was developed to improve compliance with the recommended immunization schedule without increasing the number of injections, and may facilitate widespread uptake of the 2-dose varicella recommendation. Combination vaccines offer several advantages and are often preferred over monovalent vaccines or concomitant administration of vaccines at different injection sites on the same day [7–10]. Specifically, combination vaccines have the potential to increase coverage rates through the simultaneous administration
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Table 1 Listing of clinical studies. Study number
Clinical trials.gov identifier
Study title
1
NCT00975507
2
NCT00986232
3
NCT00109343
4 5
NCT00326183 NCT00312858
Safety, tolerability, and immunogenicity of ProQuad® and the concomitant administration of VARIVAX® and M-M-R® II in healthy children 12 to 23 months of age Dose selection study in healthy children 12 to 23 months of age comparing ProQuad® to M-M-R® II given concomitantly with process upgrade Varicella vaccine Safety, tolerability, and immunogenicity of ProQuad® given concomitantly with PREVNAR® in healthy children 12 to 15 months of age Safety and tolerability of VAQTA® and ProQuad® in healthy children 12 to 23 months of age Safety, tolerability, and immunogenicity of VAQTA® given concomitantly with ProQuad® and Prevnar® in healthy children 12 to 15 months of age
of multiple antigens during a single office visit [11,12]. In clinical studies, MMRV was shown to have generally comparable immunogenicity and safety to its component vaccines [13–18]. In the pre-licensure studies, the only systemic adverse experiences (AEs) that were reported significantly more frequently following vaccination with a first dose of MMRV as compared to component vaccines were fever and measles-like rash. Both usually occurred within 5 to 12 days following vaccination, were of short duration, and resolved with no long-term sequelae [19]. From 1997 to 2012, vaccine coverage for one or more doses of measles, mumps, and rubella (MMR) vaccine in the U.S. remained steady at 90% to 92% in children 19 to 35 months of age [20,21]. Over the same time period, varicella vaccine coverage for one or more doses of varicella vaccine among children of the same age group increased from 26% to 90% [20,22]. However, implementation of the second varicella vaccination in teens 13 to 17 years old still lags behind that of MMR vaccine (∼78% vs ∼92, respectively) [23]. In 2013, 2-dose varicella vaccine coverage rates varied considerably from state-to-state, ranging from 55 to 95% [23]. Much of this disparity may reflect failure to provide catch up doses to children who were previously recommended to receive only a single dose of a varicella-containing vaccine. As of early 2014, over 11 million doses of MMRV have been distributed. In randomized clinical studies, over 11,800 children, 12 months to 6 years of age, were administered MMRV. The purpose of this paper is to describe the safety following a 2-dose regimen of MMRV administered during five clinical studies to children in the second year of life.
with measles, mumps, rubella, or varicella vaccine alone or in any combination. Children were excluded if they: were receiving immunosuppressive therapy or had an immune deficiency; were allergic to any vaccine component; received an inactivated or conjugate vaccine within 14 days or a live vaccine within 30 days before enrollment (except for the protocol-specified concomitant vaccines given in studies 3, 4, and 5); received immunoglobulin within 5 months or any blood-derived product within 3 months of study entry, or planned to receive such products during the study follow-up period; had a history of seizure disorder; had a known or severe thrombocytopenia or a coagulation disorder; had a recent febrile illness; or had any condition that, in the opinion of the investigator, might have interfered with the study objectives. 2.2. Vaccine description MMRV is a sterile, lyophilized preparation of the components of M-M-R® II (measles, mumps, and rubella virus vaccine live, Merck & Co., Inc., Whitehouse Station, NJ) [26] and Varivax® [27]. The vaccine is comprised of the more attenuated vaccine strain of measles virus (derived from Enders’ attenuated Edmonston strain), the Jeryl-LynnTM (B level) strain of mumps virus, the Wistar RA 27/3 strain of live attenuated rubella virus, and the Oka/Merck strain of varicella-zoster virus. MMRV is administered subcutaneously in a single 0.5-mL dose. The vaccine used in these studies was stored frozen at −15 ◦ C (5 ◦ F) or colder. 2.3. Safety evaluation
2. Subjects and methods 2.1. Study subjects The present analysis was based on data from five multicenter clinical studies (Table 1) that evaluated a 2-dose regimen of MMRV in children 12 to 23 months of age. The studies were completed between 1998 and 2008. Studies 1 and 2 were conducted to evaluate the immunogenicity and safety of two doses of MMRV administered to children in the second year of life [17,18]. Studies 3, 4, and 5 were conducted to support the concomitant administration of MMRV with other pediatric vaccines, but also provided safety data on children who had received two doses of MMRV administered in the second year of life [[24,25], Merck & Co., Inc., unpublished data]. Four of the studies were randomized clinical studies, of which 2 were partially blinded (studies 1 and 2) and 2 were open-label (studies 3 & 5). Study 4 was open label, partially randomized, and did not include a control arm. The parents/guardians of all participating children were provided written informed consent before they were enrolled. Healthy children were eligible to participate if they had no clinical history of (including recent exposure to) measles, mumps, rubella, varicella, or herpes zoster; and no previous vaccination
All vaccinated children in studies 1 and 2 were followed for safety for 42 days following each dose of MMRV, while all recipients of MMRV in studies 3, 4, and 5 were followed for safety for 28 days post-vaccination. For the purpose of this pooled analysis, only 28 days of safety follow-up were included to be consistent and to allow for comparisons between all protocols. The data across all five protocols were combined in this summary. Although there were three different doses of MMRV administered in study 2 and the lots were generally comparable in terms of safety, only the middle and high doses met criteria for the minimum clinically acceptable varicella virus dose (≥3.97 log10 PFU) [18]. Therefore, in tables that summarize data across all studies, the low-dose group was not included. Serious AEs (SAEs) were followed for the duration of the study. Safety data were collected with a vaccination report card (VRC) that was completed by the child’s parent/legal guardian on a daily basis. Parents/caregivers were provided guidance on identifying solicited rashes/AEs, with all reported events reviewed by the study staff. Following the administration of MMRV, the VRC prompted for (1) AEs of injection-site pain/tenderness, redness, and swelling for 5 days after each vaccination; (2) vaccine-associated rashes (including measles-like, rubella-like, varicella/zoster-like, and injection-site rashes) for at least 28 days after each vaccination; (3) mumps-like symptoms for at least 28 days after each
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vaccination; and (4) daily temperatures for at least 28 days. Parents also recorded concomitant medications and vaccines and all local and systemic AEs. The investigator assessed each reported AE as to seriousness, action taken, and causal relationship to study vaccine.
Randomized N=3125 13 randomized but not vaccinated with MMRV (do not appear in any other figure/table) Vaccinated Dose 1 n=3112 (99.6%) Reason discontinued n=332 (10.6%) Clinical AE = 9 Lost to follow-up = 131 Withdrew consent = 111 Protocol deviation = 18 Othera = 63
2.4. Statistical analyses Safety data were summarized for all children who received 1 or 2 doses of MMRV, without regard to concomitant vaccination. For all children for whom safety data were available either postdose 1 or postdose 2 of MMRV, the incidence rate, 2-sided 95% confidence interval (CI), and vaccine relationship are presented. In addition, data were summarized for those children who received both the first and second doses of MMRV and provided safety follow up data after both doses. These side-by-side comparisons of safety postdose 1 and postdose 2 of MMRV represent a matched analysis set, and allowed for a direct comparison of the safety profile of the first dose administered at ∼12 months of age versus the second dose administered 3 to 6 months later for the cohort of children who received both doses of the vaccine in the second year of life. The incidences of injection-site reactions (for 5 days following vaccination), vaccine-associated rashes and mumps-like symptoms, and elevated temperature (defined as a maximum temperature ≥102.2 ◦ F, oral equivalent) for 28 days following the administration of MMRV were statistically analyzed. For those children for whom safety data were available following both the first and second doses of MMRV, the proportions, risk differences, and 95% 2-sided CIs were provided using Tango’s method for correlated binomial proportions [28]. 3. Results 3.1. Subject accounting and demographics Across the five clinical studies, 3112 children received a first dose of MMRV and 2780 (89.3%) of these children received a second dose of MMRV approximately 3 to 6 months later. Overall, 2644 of
Vaccinated Dose 2 n=2780 (89.0%)
Reason discontinued n=136 (4.4%) Clinical AE = 0 Lost to follow-up = 92 Withdrew consent = 4 Protocol deviation = 31 Othera = 9
Completed Study Follow-Up n=2644 (84.6%)
a
Other includes, but is not limited to, incomplete safety follow-up, missed ≥1 blood draw, and moved N = number of children randomized in the age group n = number of children reaching each milestone AE = adverse experience Fig. 1. Subject accounting (across 5 studies, see below).
the 3112 (85.0%) children vaccinated with at least 1 dose of MMRV completed the respective studies. Fig. 1 presents an accounting of the number of children who were randomized to each protocol, who were vaccinated, and who completed or discontinued the study. The five studies were generally balanced with respect to gender and race. The median age by study ranged from 12 to 14 months for dose 1 and 15 to 20 months of age for dose 2 (Table 2).
Table 2 Subject demographics.
Gender (n, %) Male Female Age at study entry (months) Mean SD Median Range Age at receipt of dose 2 of ProQuad® (months) N Mean SD Median Range Race/ethnicity (n, %) African American Asian Caucasian Hispanic Other
Study 1 (N = 323)
Study 2 (N = 774)a
Study 3 (N = 1027)
Study 4 (N = 347)
Study 5 (N = 653)
Total (N = 3124)b
150 (46.4) 173 (53.6)
401 (51.8) 373 (48.2)
560 (54.5) 467 (45.5)
171 (49.3) 176 (50.7)
331 (50.7) 322 (49.3)
1613 (51.6) 1511 (48.4)
14.1 1.91 14 12 to 22
12.9 1.47 12 12 to 23
12.6 0.96 12 12 to 15
12.5 0.90 12 12 to 17
12.4 0.85 12 12 to 16
12.8 1.30 12 12 to 23
310 17.2 1.96 17 14 to 26
725 15.8 1.56 15 14 to 26
941 16.6 1.37 16 14 to 23
291 19.0 1.72 18 17 to 27
513 19.5 1.88 20 17 to 28
2780 17.2 2.14 17 14 to 28
41 (12.7) 30 (9.3) 211 (65.3) 30 (9.3) 11 (3.4)
119 (15.4) 30 (3.9) 518 (66.9) 66 (8.5) 41 (5.3)
155 (15.1) 31 (3.0) 670 (65.2) 103 (10.0) 68 (6.6)
10 (2.9) 6 (1.7) 164 (47.3) 148 (42.7) 19 (5.5)
141 (21.6) 7 (1.1) 394 (60.3) 62 (9.5) 49 (7.5)
466 (14.9) 104 (3.3) 1957 (62.6) 409 (13.1) 188 (6.0)
N = number vaccinated with the first dose of ProQuad® . n = number of children in each category. SD = standard deviation. Percentages are calculated based on the number of children vaccinated with the first dose of ProQuad® (N). a Demographic data of 1 randomized, but not vaccinated, child from Study 1 were not obtained. b 13 total children were randomized but not vaccinated with MMRV, but demographic data were obtained for 12 of those children.
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Table 3 Summary of vaccine-related injection-site adverse experiences (days 1 to 5) and rashes and mumps-like symptoms (days 1 to 28) after each dose of MMRV. Dose 1
2
n 3112 3019 All reported events
Redness (Erythema)a Swellinga Pain/tendernessa Measles-like rashb Rubella-like rashb Mumps-like symptomsb Varicella-like rashb Injection-site rashb Number of children Children with safety data
327 243 650 140 14 0 58 40 2780 2695 All reported events
Redness (Erythema)a Swellinga Pain/tendernessa Measles-like rashb Rubella-like rashb Mumps-like symptomsb Varicella-like rashb Injection-site rashb a b
% (95% CI)
Number of children Children with safety data
338 231 430 27 2 0 9 17
n
% (95% CI)
3112 3019 Vaccine-related events 10.8% (9.7, 12.0) 8.0% (7.1, 9.1) 21.5% (20.1, 23.0) 4.6% (3.9, 5.4) 0.5% (0.3, 0.8) 0.0% (0.0, 0.1) 1.9% (1.5, 2.5) 1.3% (0.9, 1.8)
12.5% (11.3, 13.9) 8.6% (7.5, 9.7) 16.0% (14.6, 17.4) 1.0% (0.7, 1.5) 0.1% (0.0, 0.3) 0.0% (0.0, 0.1) 0.3% (0.2, 0.6) 0.6% (0.4, 1.0)
10.7% (9.6, 11.9) 324 241 8.0% (7.0, 9.0) 647 21.4% (20.0, 22.9) 125 4.1% (3.5, 4.9) 11 0.4% (0.2, 0.7) 0 0.0% (0.0, 0.1) 51 1.7% (1.3, 2.2) 36 1.2% (0.8, 1.6) 2780 2695 Vaccine-related events 333 228 429 21 2 0 7 16
12.4% (11.1, 13.7) 8.5% (7.4, 9.6) 15.9% (14.6, 17.4) 0.8% (0.5, 1.2) 0.1% (0.0, 0.3) 0.0% (0.0, 0.1) 0.3% (0.1, 0.5) 0.6% (0.3, 1.0)
AEs of injection-site pain/tenderness, redness, and swelling assessed for 5 days after each vaccination. Vaccine-associated rashes and mumps-like symptoms assessed for 28 days after each vaccination.
3.2. Safety Safety follow-up was obtained for 97.0% (3019/3112) of children vaccinated with the first dose of MMRV (with or without other vaccines), and 96.9% (2695/2780) of children vaccinated with a second dose of MMRV (with or without other vaccines). The number and percentage of children with clinical AEs reported within 28 days postvaccination was analyzed, by dose, for children vaccinated with MMRV across the 5 protocols. Overall, one or more clinical AEs was reported by 70.5% of children following the first dose of MMRV and 57.7% of children following the second dose of MMRV. A vaccinerelated systemic AE was reported by 31.7% of children following dose 1 and 14.6% of children following dose 2. The majority of the AEs were considered by the investigator to be mild or moderate in intensity. Twenty-two (22) subjects reported a SAE after dose 1. Nine (9) of these subjects received MMRV alone and 13 received MMRV with other vaccines. Of the 9 SAEs reported after MMRV alone, only one was considered vaccine related. This child was reported to have a fever and a febrile seizure 7 days after vaccination. Three (3) of the 13 subjects who received MMRV with other vaccine reported a vaccine-related SAE. One child developed cellulitis 18 days after receipt of MMRV + hepatitis A vaccine, another child had a febrile convulsion 9 days after MMRV + PCV7 (pneumococcal 7-valent conjugate vaccine, Wyeth Pharmaceuticals, Philadelphia, PA), and a third child who received MMRV + PCV7 followed 6 weeks later by hepatitis A vaccine developed dehydration and gastroenteritis 13 days after the hepatitis A vaccine. A SAE was reported by six subjects after the second dose of MMRV, three of whom received MMRV alone and three of whom received MMRV with other vaccines. None of these six SAEs was considered vaccine related. One child died on Day 218 as a result of Stage IV neuroblastoma (diagnosis made Day 8) after having received a single dose of MMRV (Day 1); this was considered to be definitely not related to study vaccine by the investigator. As shown in Table 3, pain/tenderness was the most commonly reported VRC-prompted injection-site AE across the combined studies, regardless of dose. The incidence of pain/tenderness at the injection-site was lower postdose 2 (15.9%) than that observed postdose 1 (21.4%). There was a numerically higher incidence of
redness (erythema) at the injection-site postdose 2 (12.4%) than postdose 1 (10.7%). Almost all injection-site AEs prompted for on the VRC were considered vaccine related by the investigator. rashes (measles-like, rubella-like, Vaccine-associated varicella/zoster-like, injection-site) and mumps-like symptoms were solicited systemic AEs and were prompted-for on the VRC of all 5 studies. Measles-like rash was the most commonly reported vaccine-related-rash. The incidence of measles-like, rubella-like, varicella-like and injection-site rashes were lower postdose 2 than postdose 1 (Table 3). Mumps-like symptoms and zoster-like rash were not reported in any of the five studies. The incidence rates, 95% CI, and risk differences for VRCprompted events were compared for the cohort of children who received both doses of MMRV and had safety follow up after each dose (Table 4). Injection-site redness was statistically significantly higher following dose 2 compared to dose 1 (12.6% vs. 10.8%, respectively), while injection-site pain/tenderness was statistically significantly higher following dose 1 compared to dose 2 (21.9% vs 16.1%, respectively). The reporting of measles-, rubella-, and varicella-like rashes, and injection-site rashes were all statistically significantly lower postdose 2 as compared to postdose 1, confirming the observations made on the complete (un-matched) data set. The reporting rate of elevated temperature (≥102.2 ◦ F oral equivalent) was statistically significantly lower postdose 2 as compared to postdose 1 of MMRV. This was true for the entire 28-day safety follow-up period (postdose 2: 10.8%; postdose 1: 19.1%), as well as during the first 6 to 13 days postvaccination (postdose 2: 3.9%; postdose 1: 13.6%), the period associated with the highest rate of fever in the pre-licensure clinical studies. A total of 10 febrile seizures were reported following the receipt of MMRV (with or without other vaccines) in all five protocols (Table 5). Eight (8) of the 10 febrile seizures occurred postdose 1 of vaccine(s). Three (3) of the seizures were reported by the investigator as possibly related to vaccination and 7 were reported as probably or definitely not related to vaccination. The 8 febrile seizures following the first dose of MMRV occurred between 8 and 29 days (mean 13 days) postvaccination; the 2 febrile seizures following the second dose of MMRV occurred on days 13 and 25. Seven (7) of the 10 febrile seizures reported had one or more concurrent conditions and 5 of the children received pneumococcal conjugate
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Table 4 Number (%) of children with vaccine report card-prompted adverse experiences for the cohort with safety data after both doses of MMRVa Dose 1 n
%
Children with safety data 2679 Injection-site AEs (Days 1 to 5 after each dose) Redness (Erythema) 289 Swelling 213 Pain/tenderness 586 Rashes and mumps-like symptoms (days 1 to 28 after each dose) 133 Measles-like rash Rubella-like rash 13 Mumps-like symptoms 0 Varicella-like rash 52 Injection-site rash 35 Elevated temperature (maximum reported temperature ≥ 102.2 ◦ F) Days 1 to 28 after each dose (n = 2408) 461 Days 1 to 5 after each dose (n = 2404) 62 Days 6 to 13 after each dose (n = 2405) 327 Days 14 to 28 after each dose (n = 2404) 133 a b
Dose 2 n
Risk difference (dose 1 and dose 2) (95% CI)
%
2679 10.8 8.0 21.9
338 231 430
12.6 8.6 16.1
5.0 0.5 0.0 1.9 1.3
27 2 0 9 17
1.0 0.1 0.0 0.3 0.6
19.1 2.6 13.6 5.5
261 60 94 144
10.8 2.5 3.9 6.0
−1.8 (−3.3,−0.3)b −0.7 (−2.0,0.6) 5.8 (4.1,7.6)b 4.0 (3.1,4.9)b 0.4 (0.1,0.8)b N/A 1.6 (1.1,2.2)b 0.7 (0.2,1.2)b 8.3 (6.4,10.3)b 0.1 (−0.8,1.0) 9.7 (8.1,11.3)b −0.5 (−1.7,0.8)
Only subjects with safety data after both doses of vaccine are included in this analysis. Statistically significant.
and/or hepatitis A vaccines concomitantly (details in Table 5). All of the febrile seizures reported resolved without any sequelae. The incidence rate of febrile seizures was 0.26% (8/3019) postdose 1 of MMRV and 0.07% (2/2695) postdose 2 of MMRV.
4. Discussion A 2-dose regimen for measles, mumps, rubella, and varicella vaccination has been widely adopted in the U.S. [3]. Widespread use of a 2-dose schedule of MMR vaccine [29,30] has been responsible for a ≥99% reduction in the incidence and associated complications of measles, mumps, and rubella in the U.S. and other countries [1,2,31,32]. However, most non-U.S. countries have only recently licensed varicella vaccine for routine use in children
[33]. Reaching the high coverage rates necessary to achieve the full benefits of varicella vaccination would be facilitated by the existing infrastructure for MMR 2-dose vaccination [2]. Therefore, the introduction of a quadrivalent MMRV vaccine could help increase 2-dose varicella coverage. Because of the increase in the frequency of fever following the administration of the first dose of MMR compared with the concomitant administration of component vaccines, the incidence of febrile seizures was of interest [34]. It is known that fever can precipitate febrile seizures in the susceptible child between the ages of 6 months and 5 years [35]. It has been estimated that 2% to 4% of all children in this age group will experience at least one febrile seizure [35], most commonly in the 12- to 23-month age range. Risk factors for a first febrile seizure include very high fever, family history of febrile seizures, a neonatal hospital stay of ≥28 days duration,
Table 5 Febrile Seizures reported after MMRV (with or without concomitant receipt of other vaccines). Dose of MMRV
Study Age (months)
Vaccine(s) received
Day of Onset Postdose
Maximum temperature Severityc (◦ F) (method)
Other concurrent conditions
Vaccine relatedd
Outcome
1
1
13
MMRV
9
103.0 (Rectal)
Severe
Possibly
Recovered
2 2 3
12 12 12
MMRV MMRV MMRV PCV7
8 8 10
102.8 (Rectal) 105.5 (Axillary) 102.9 (Axillary) 104.4 (Rectal)
Moderate Severe Severe
Probably not Possibly Definitely not related
Recovered Recovered Recovered
3
12
MMRV
29
Severe
12
22
Severe
5
14
Severe
None
5b
12
9
105.2 (Rectal)
Severe
Viral illness
Possibly related Recovered
5
18
HAV MMRV PCV7 MMRV HAV MMRV PCV7 MMRV HAV MMRV
Probably not related Probably not related Probably not related
Recovered
4
103.6 (Method not specified) 102.3 (Axillary) 104.9 (Rectal) 101.1 (Axillary) 103.4 (Rectal)
Diarrhea, otitis media, injection-site rash Cough None Fussiness; Pneumonia; upper respiratory infection Upper respiratory infection Otitis media
25
103 (Axillary) 104 (Rectal) 105.2 (Rectal)
Moderate
None
Moderate
Viral febrile illness
Probably not related Probably not related
2
5
b
20
9
13
Recovered Recovered
Recovered Recovered
PCV7 = Pneumococcal conjugate vaccine. HAV = Hepatitis A vaccine. a One child (Study 3) experienced a complex febrile seizure. b One child (Study 5) experienced 2 febrile seizures (Day 9 after Dose 1, Day 13 after Dose 2). c Severity was assessed by the clinical investigator using the following definitions: mild-awareness of symptom, but easily tolerated; moderate–definitely acting like something is wrong; severe–extremely distressed or unable to do usual activities. d Vaccine relationship was determined by the clinical investigator.
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parental report of slow development, attendance at daycare, and a low serum sodium level [36]. There is no evidence suggesting that the occurrence of febrile seizures increases the risk of death, brain damage, injury, or learning disorders [33–40]. In two large post-licensure safety studies, among children 12 to 23 months of age who had neither been vaccinated against measles, mumps, rubella, or varicella nor had a history of wild-type infection, the rate of febrile seizures was examined [41,42]. In the first study conducted at Southern California Kaiser, during the 30 days postdose 1, no increased risk in febrile seizures between MMRV and component vaccines (relative risk = 1.10; 95% CI: 0.72, 1.69) was found. However, when the 5 to 12 day period postdose 1 was examined, MMRV recipients had approximately a 2-fold higher increased risk of febrile seizure as compared to recipients of the component vaccines (relative risk = 2.20; 95% CI: 1.04, 4.65) [41]. No febrile seizures were observed during the 5 to 12 day period postdose 2 among 26,455 children who received a second dose of MMRV or the first dose of MMRV following primary vaccination with component vaccines [41]. The second study was conducted through the Vaccine Safety Datalink (VSD), a collaboration between the Centers for Disease Control and Prevention and 8 managed care organizations [42]. The VSD study concluded that following administration of a first dose of any measles-containing vaccine to children 12 to 23 months of age, occurrence of fever and seizure were elevated for 7 to 10 days postvaccination [42]. Similar to the Southern Kaiser study, MMRV increased the risk of febrile seizures ∼2-fold between days 7 and 10 postdose 1 compared to MMR plus varicella vaccination (relative risk = 2.04; 95% CI: 1.44, 2.90) [42]. Another study conducted using VSD data showed that MMRV and MMR and varicella vaccines were not associated with an increased risk of febrile seizures among 4-to 6-year olds, the age at which both a second dose of MMR and varicella containing vaccines are recommended in the US [29,30,44]. Based on the results of these studies, the first dose of MMRV was associated with an attributable risk of approximately one extra febrile seizure for every 2300 to 2600 doses administered compared to MMR plus varicella vaccines [43]. Similar results of an increase in febrile seizures after the first dose have been found with another MMRV vaccine used in Canada where the attributable risk was approximately one extra febrile seizure for every 2841 vaccine recipients [45]. The five studies reported here did not allow the calculation of an attributable risk since only two of the studies included recipients of MMR plus varicella vaccine and the sample size was limited. However, similar to the two postlicensure studies, the rate of febrile seizures in these five studies was considerably lower after the second dose of MMRV as compared to the first dose. Based on the data from the postlicensure safety studies, the ACIP recommended MMR plus varicella vaccines for the first dose of a measles, mumps, rubella, and varicella-containing vaccine for children <4 years of age [43]. However, MMRV may be used for the first dose according to parental/guardian preference, once the benefits and risks of both options have been fully discussed. For the second dose and for children ≥4 years of age receiving a first dose, the ACIP deferred to the combination vaccine recommendations which state that combination vaccines are generally preferred over components [43]. For any dose, children with a known personal or family history of febrile seizures or epilepsy are at increased risk for febrile seizures, and thus should receive the MMR plus varicella component vaccines. One of the strengths of the data presented here is that all the safety data were collected using a similar VRC at multiple sites across the five randomized clinical studies. In addition, use of a matched set analysis among a large cohort of 2-dose recipients allowed for direct comparison of dose 1 and dose 2 safety data. However, despite representing a matched set, the postdose 1 and postdose 2 comparison groups differed in age and previous exposure to each of the antigens in the vaccine which could introduce
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some bias in the comparisons. Another limitation of the data presented here is that the sample size was not large enough to detect any difference in the rate of febrile seizures in recipients of MMRV versus the component vaccines, but the rate of febrile seizures was low. 5. Conclusions In summary, administration of 2 doses of MMRV is generally well tolerated in children 12 to 23 months of age. In general, the rate of systemic and injection-site AEs, rashes, and elevated temperatures was lower after dose 2 compared to dose 1. There is a small increase in the risk of febrile seizures following the first dose of MMRV as compared to the component vaccines, but this risk for any individual child is relatively low. Financial disclosures Funding for this research was provided by Merck & Co., Inc. Current and past employees of the sponsor (indicated on the title page) may own stock or stock options in the company. KR and SB have served as paid investigators for the sponsor. Disclosure This study was funded by Merck & Co., Inc. (sponsor). In conjunction with the external investigators, this study was designed, executed, and analyzed by the sponsor. The sponsor formally reviewed and provided comments on a penultimate draft of this manuscript. All co-authors approved the final version of the manuscript. Employees of the sponsor (indicated on the title page) may own stock or stock options in the company. KR and SB have served as paid investigators and consultants for Merck. Author contributions All Authors: analysis and interpretation of data, and preparation of manuscript. KR and SB: enrollment of children and data collection. BK, SK, and FS: study concept and design. Acknowledgements The authors would like to thank all the children and study staff who participated in the five clinical studies. We also acknowledge Frans Helmond for his careful review of the manuscript. References [1] Atkinson W, Wolfe C, Hamborsky J, McIntyre L, editors. Epidemiology and prevention of vaccine-preventable diseases. 11th ed. Washington, DC: Public Health Foundation; 2009. [2] Vesikari T, Sadzot-Delvaux C, Rentier B, Gershon A. Increasing coverage and efficiency of measles, mumps, and rubella vaccine and introducing universal varicella vaccination in Europe: a role for the combined vaccine. Pediatr Infect Dis J 2007;26:632–8. [3] Centers for Disease Control and Prevention. Recommended immunization schedules for persons aged 0–18 years: United States, 2008. MMWR 2008;57:Q1–4. [4] Watson JC, Hadler SC, Dykewicz CA, Reef S, Phillips L. 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;47:1–57. [5] Marin M, Guris D, Chaves SS, Schmid S, Seward JF. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007;56:1–40.
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[6] ProQuad®. ProQuad® [package insert]. Whitehouse Station, NJ: Merck; 2014. Available at: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/Approved Products/ucm188806.htm. Accessed: August 25, 2014. [7] Decker MD. Principles of pediatric combination vaccines and practical issues related to use in clinical practice. Pediatr Infect Dis J 2001;20:S10–8. [8] MMWR. Combination vaccines for childhood immunization. MMWR Recomm Rep 1999;48:1–14. [9] Meyerhoff AS, Weniger BG, Jacobs RJ. Economic value to parents of reducing the pain and emotional distress of childhood vaccine injections. Pediatr Infect Dis J 2001;20:S57–62. [10] Pellissier JM, Coplan PM, Jackson LA, May JE. The effect of additional shots on the vaccine administration process: results of a time-motion study in 2 settings. Am J Manage Care 2000;6:1038–44. [11] Davis RL, Coplan P, Mell L, Black S, Shinefield H, Lewis E. Impact of the introduction of a combined Haemophilus B conjugate vaccine and hepatitis B recombinant vaccine on vaccine coverage rates in a large West Coast health maintenance organization. Pediatr Infect Dis J 2003;22:657–8. [12] Dietz VJ, Stevenson J, Zell ER, Cochi S, Hadler S, Eddins D. Potential impact on vaccination coverage levels by administering vaccines simultaneously and reducing dropout rates. Arch Pediatr Adolesc Med 1994;148: 943–9. [13] Bernstein HH, Eves K, Campbell K, Black SB, Twiggs JD, Reisinger KS, et al. Comparison of the safety and immunogenicity of a refrigerator-stable versus a frozen formulation of ProQuad (measles, mumps, rubella, and varicella virus vaccine live). Pediatrics 2007;119:e1299–305. [14] Kuter BJ, Brown ML, Hartzel J, Williams WR, Eves KA, Black S, et al. Safety and immunogenicity of a combination measles, mumps, rubella and varicella vaccine (ProQuad). Hum Vaccin 2006;2:205–14. [15] Lieberman JM, Williams WR, Miller JM, Black S, Shinefield H, Henderson F, et al. The safety and immunogenicity of a quadrivalent measles, mumps, rubella and varicella vaccine in healthy children: a study of manufacturing consistency and persistence of antibody. Pediatr Infect Dis J 2006;25:615–22. [16] Reisinger KS, Brown ML, Xu J, Sullivan BJ, Marshall GS, Nauert B, et al. 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. Pediatrics 2006;117:265–72. Erratum in: Pediatrics. 2006;117: 2338. [17] Shinefield H, Black S, Digilio L, Reisinger K, Blatter M, Gress JO, et al. Evaluation of a quadrivalent measles, mumps, rubella and varicella vaccine in healthy children. Pediatr Infect Dis J 2005;24:665–9. [18] Shinefield H, Black S, Williams WR, Marchant C, Reisinger K, Stewart T, et al. Dose-response study of a quadrivalent measles, mumps, rubella and varicella vaccine in healthy children. Pediatr Infect Dis J 2005;24:670–5. Erratum in: Pediatr Infect Dis J. 2005;24:983. [19] FDA Center for Biologics Evaluation and Research. Clinical review of studies submitted in support of licensure of ProQuadTM . FDA Center for Biologics Evaluation and Research; 2005. Available at: http://www.fda.gov/downloads/ BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM123800.pdf Accessed: December 18, 2009. [20] Centers for Disease Control and Prevention. National, state, and local area vaccination coverage among children aged 19–35 months—United States, 2008. MMWR 2009;58:921–6. [21] Centers for Disease Control and Prevention. National, state, and local area vaccination coverage among children aged 19–35 months—United States, 2012. MMWR 2013;62:733–40. [22] Luman ET, Ching PL, Jumaan AO, Seward JF. Uptake of varicella vaccination among young children in the United States: a success story in eliminating racial and ethnic disparities. Pediatrics 2006;117:999–1008. [23] Centers for Disease Control and Prevention. National, regional, state, and selected local area vaccination coverage among adolescents aged 13–17 years—United States, 2013. MMWR 2014;63:625–33.
[24] Leonardi M, Bromberg K, Baxter R, Gardner JL, Klopfer S, Nicholson O, et al. Immunogenicity and safety of MMRV and PCV-7 administered concomitantly in healthy children. Pediatrics 2011;128:e1387–94. [25] Yetman RJ, Shepard JS, Duke A, Stek JE, Petrecz M, Klopfer SO, et al. Concomitant administration of hepatitis a vaccine with measles/mumps/rubella/varicella and pneumococcal vaccines in healthy 12 to 23 month-old children. Hum Vaccines 2013;9(8):1691–7. [26] M-M-R® II. M-M-R® II [package insert]. Whitehouse Station, NJ: Merck; 2014. Available at: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ ApprovedProducts/ucm094050.htm Accessed at: August 25, 2014. [27] VARIVAX®. VARIVAX® [package insert]. Whitehouse Station, NJ: Merck; 2013. Available at: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ ApprovedProducts/ucm094073.htm Accessed: August, 25, 2014. [28] Tango T. Equivalence test and confidence interval for the difference in proportions for the paired-sample design. Stat Med 1998;17:891–908. [29] Kroger AT, Atkinson WL, Marcuse EK, Pickering LK. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006;55:1–48. Erratum in: MMWR. 2006;55:1303. Pediatrics. 2007;119:1008. MMWR. 2007;56:256. [30] American Academy of Pediatrics. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, editors. Red book: 2009 report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009. [31] Böttiger M, Christenson B, Romanus V, Taranger J, Strandell A. Swedish experience of two dose vaccination programme aiming at eliminating measles, mumps, and rubella. Br Med J 1987;295:1264–7. [32] McNabb SJ, Jajosky RA, Hall-Baker PA, Adams DA, Sharp P, Worshams C, et al. Summary of notifiable diseases—United States, 2006. MMWR 2008;55:1–92 (Erratum in: MMWR. 2008;57:466). [33] EUVAC.NET. A surveillance network for vaccine-preventable diseases. Available at: http://www.euvac.net/graphics/euvac/vaccination/vaccination.html Accessed: December 18, 2009. [34] Barlow WE, Davis RL, Glasser JW, Rhodes PH, Thompson RS, Mullooly JP, et al. The risk of seizures after receipt of whole-cell pertussis or measles, mumps, and rubella vaccine. N Engl J Med 2001;345:656–61. [35] Lorin MI. Fever: pathogenesis and treatment. In: Feigin RD, Cherry JD, editors. Textbook of pediatric infectious diseases, vol. 1, 4 ed. Philadelphia, PA: W.B. Saunders Company; 1998. p. 89–95. [36] Hirtz DG. Febrile seizures. Pediatr Rev 1997;18:5–8. [37] Freeman JM, Vining EPG. Decision making and the child with febrile seizures. Pediatr Rev 1992;13(8):298–304. [38] Verity CM, Golding J. Risk of epilepsy after febrile convulsions: a national cohort study. Br Med J 1991;303:1373–6. [39] Berg AT, Shinnar S, Hauser WA, Alemany M, Shapiro ED, Salomon ME, et al. A prospective study of recurrent febrile seizures. N Engl J Med 1992;327:1122–7. [40] Bergman DA, Baltz RD, Cooley JR, Hickson GB, Miles PV, Shook JE, et al. Practice parameter: long–term treatment of the child with simple febrile seizures. Pediatrics 1999;103:13079. [41] Jacobsen SJ, Ackerson BK, Sy LS, Tran TN, Jones TL, Yao JF, et al. Observational safety study of febrile convulsion following first dose MMRV vaccination in a managed care setting. Vaccine 2009;27:4656–61. [42] Klein NP, Fireman B, Yih WK, Lewis E, Kulldorff M, Ray P, et al. Measles–mumps–rubella–varicella combination vaccine and the risk of febrile seizures. Pediatrics 2010;126:e1–8. [43] Marin M, Broder KR, Temte JL, Snider DE, Seward JF. Use of combination measles, mumps, rubella, and varicella vaccine. MMWR 2010;58:1–12. [44] Klein NP, Lewis E, Baxter R, Weintraub E, Glanz J, Naleway A, et al. Measlescontaining vaccines and febrile seizures in children age 4 to 6 years. Pediatrics 2012;129:809–14. [45] MacDonald SE, Dover DC, Simmonds KA, Svenson LW. Risk of febrile seizures after first dose of measles-mumps-rubella-varicella vaccine: a populationbased cohort study. Can Med Assoc J 2014;186:824–9.
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Analysis of safety data in children after receiving two doses of ProQuad® (MMRV) Stephanie O. Klopfer a,∗ , Jon E. Stek a , Maria Petrecz a , Keith S. Reisinger b , Steven B. Black c , Michelle G. Goveia a , Ouzama Nicholson a,1 , Julie L. Gardner a , Anthony D. Grosso a , Michelle L. Brown a , Barbara J. Kuter a , Florian P. Schödel a,2 a
Merck & Co., Inc, Whitehouse Station, NJ, United States Primary Physicians Research, Pittsburgh, PA, United States c Cincinnati Children’s Hospital, Cincinnati, OH, United States b
a r t i c l e
i n f o
Article history: Received 10 October 2012 Received in revised form 25 August 2014 Accepted 28 August 2014 Available online 16 September 2014 Keywords: Safety MMRV ProQuad® Integrated analyses Tolerability NCT00975507 NCT00986232 NCT00109343 NCT00326183 NCT00312858
a b s t r a c t Background: In randomized clinical studies, over 11,800 children, 12 months to 6 years of age, were administered ProQuad® , a combination measles, mumps, rubella, and varicella vaccine (MMRV). This paper describes the safety following a 2-dose regimen of MMRV administered to children in the second year of life. Methods: Safety data from five clinical studies were combined for all children who were scheduled to receive two doses of MMRV ∼3–6 months apart. All vaccinated children were followed for safety following each dose of MMRV. Results: Of 3112 children who received a first dose of MMRV, 2780 (89.3%) received a second dose of MMRV. Overall, 70.5% and 57.7% of children reported ≥1 adverse experiences following first and second doses of MMRV, respectively. Injection-site redness was statistically significantly higher postdose 2 than postdose 1, while injection-site pain/tenderness was statistically significantly higher postdose 1 compared to postdose 2. Rashes were statistically significantly lower postdose 2 compared to postdose 1. Ten febrile seizures (8 postdose 1, 2 postdose 2) were reported following MMRV vaccination. The incidence of febrile seizures postdose 1 of MMRV was 0.26% (8/3019) compared to 0.07% (2/2695) postdose 2 of MMRV. Conclusions: Administration of two doses of MMRV has an acceptable safety profile in children 12 to 23 months of age. There is a small increase in the risk of febrile seizures following the first dose of MMRV as compared to the component vaccines, but the risk for any individual child is relatively low. © 2014 Elsevier Ltd. All rights reserved.
1. Introduction Widespread immunization against measles, mumps, rubella, and varicella has had a dramatic effect on the epidemiology of
Abbreviations: ACIP, Advisory Committee on Immunization Practices; AE, adverse experience; CI, confidence interval; HAV, hepatitis A vaccine; MMR, measles, mumps, rubella vaccine; MMRV, measles, mumps, rubella and varicella vaccine; PCV7, pneumococcal 7-valent conjugate vaccine; U.S., United States; VRC, vaccination report card. ∗ Corresponding author at: Merck & Co., Inc., PO Box 1000, Whitehouse Station, UG1CD-44 NJ, United States. Tel.: +1 267 305 7959. E-mail address: stephanie [email protected] (S.O. Klopfer). 1 ON was employed by Merck at the time of this research. She is now employed by GlaxoSmithKline. 2 FS was employed by Merck at the time of this research. He is now owner of Philimmune LLC. http://dx.doi.org/10.1016/j.vaccine.2014.08.067 0264-410X/© 2014 Elsevier Ltd. All rights reserved.
all four viruses in the United States (U.S.) and other parts of the world [1,2]. The U.S. Advisory Committee on Immunization Practices (ACIP) currently recommends the routine administration of measles, mumps, rubella, and varicella vaccines on or soon after the first birthday [3]. A second dose of a measles, mumps, rubella, and varicella containing vaccine is recommended at 4 to 6 years of age [4,5]. The combination vaccine, ProQuad® (MMRV; measles, mumps, rubella, and varicella virus vaccine live; Merck & Co., Inc., Whitehouse Station, NJ) [6], was developed to improve compliance with the recommended immunization schedule without increasing the number of injections, and may facilitate widespread uptake of the 2-dose varicella recommendation. Combination vaccines offer several advantages and are often preferred over monovalent vaccines or concomitant administration of vaccines at different injection sites on the same day [7–10]. Specifically, combination vaccines have the potential to increase coverage rates through the simultaneous administration
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Table 1 Listing of clinical studies. Study number
Clinical trials.gov identifier
Study title
1
NCT00975507
2
NCT00986232
3
NCT00109343
4 5
NCT00326183 NCT00312858
Safety, tolerability, and immunogenicity of ProQuad® and the concomitant administration of VARIVAX® and M-M-R® II in healthy children 12 to 23 months of age Dose selection study in healthy children 12 to 23 months of age comparing ProQuad® to M-M-R® II given concomitantly with process upgrade Varicella vaccine Safety, tolerability, and immunogenicity of ProQuad® given concomitantly with PREVNAR® in healthy children 12 to 15 months of age Safety and tolerability of VAQTA® and ProQuad® in healthy children 12 to 23 months of age Safety, tolerability, and immunogenicity of VAQTA® given concomitantly with ProQuad® and Prevnar® in healthy children 12 to 15 months of age
of multiple antigens during a single office visit [11,12]. In clinical studies, MMRV was shown to have generally comparable immunogenicity and safety to its component vaccines [13–18]. In the pre-licensure studies, the only systemic adverse experiences (AEs) that were reported significantly more frequently following vaccination with a first dose of MMRV as compared to component vaccines were fever and measles-like rash. Both usually occurred within 5 to 12 days following vaccination, were of short duration, and resolved with no long-term sequelae [19]. From 1997 to 2012, vaccine coverage for one or more doses of measles, mumps, and rubella (MMR) vaccine in the U.S. remained steady at 90% to 92% in children 19 to 35 months of age [20,21]. Over the same time period, varicella vaccine coverage for one or more doses of varicella vaccine among children of the same age group increased from 26% to 90% [20,22]. However, implementation of the second varicella vaccination in teens 13 to 17 years old still lags behind that of MMR vaccine (∼78% vs ∼92, respectively) [23]. In 2013, 2-dose varicella vaccine coverage rates varied considerably from state-to-state, ranging from 55 to 95% [23]. Much of this disparity may reflect failure to provide catch up doses to children who were previously recommended to receive only a single dose of a varicella-containing vaccine. As of early 2014, over 11 million doses of MMRV have been distributed. In randomized clinical studies, over 11,800 children, 12 months to 6 years of age, were administered MMRV. The purpose of this paper is to describe the safety following a 2-dose regimen of MMRV administered during five clinical studies to children in the second year of life.
with measles, mumps, rubella, or varicella vaccine alone or in any combination. Children were excluded if they: were receiving immunosuppressive therapy or had an immune deficiency; were allergic to any vaccine component; received an inactivated or conjugate vaccine within 14 days or a live vaccine within 30 days before enrollment (except for the protocol-specified concomitant vaccines given in studies 3, 4, and 5); received immunoglobulin within 5 months or any blood-derived product within 3 months of study entry, or planned to receive such products during the study follow-up period; had a history of seizure disorder; had a known or severe thrombocytopenia or a coagulation disorder; had a recent febrile illness; or had any condition that, in the opinion of the investigator, might have interfered with the study objectives. 2.2. Vaccine description MMRV is a sterile, lyophilized preparation of the components of M-M-R® II (measles, mumps, and rubella virus vaccine live, Merck & Co., Inc., Whitehouse Station, NJ) [26] and Varivax® [27]. The vaccine is comprised of the more attenuated vaccine strain of measles virus (derived from Enders’ attenuated Edmonston strain), the Jeryl-LynnTM (B level) strain of mumps virus, the Wistar RA 27/3 strain of live attenuated rubella virus, and the Oka/Merck strain of varicella-zoster virus. MMRV is administered subcutaneously in a single 0.5-mL dose. The vaccine used in these studies was stored frozen at −15 ◦ C (5 ◦ F) or colder. 2.3. Safety evaluation
2. Subjects and methods 2.1. Study subjects The present analysis was based on data from five multicenter clinical studies (Table 1) that evaluated a 2-dose regimen of MMRV in children 12 to 23 months of age. The studies were completed between 1998 and 2008. Studies 1 and 2 were conducted to evaluate the immunogenicity and safety of two doses of MMRV administered to children in the second year of life [17,18]. Studies 3, 4, and 5 were conducted to support the concomitant administration of MMRV with other pediatric vaccines, but also provided safety data on children who had received two doses of MMRV administered in the second year of life [[24,25], Merck & Co., Inc., unpublished data]. Four of the studies were randomized clinical studies, of which 2 were partially blinded (studies 1 and 2) and 2 were open-label (studies 3 & 5). Study 4 was open label, partially randomized, and did not include a control arm. The parents/guardians of all participating children were provided written informed consent before they were enrolled. Healthy children were eligible to participate if they had no clinical history of (including recent exposure to) measles, mumps, rubella, varicella, or herpes zoster; and no previous vaccination
All vaccinated children in studies 1 and 2 were followed for safety for 42 days following each dose of MMRV, while all recipients of MMRV in studies 3, 4, and 5 were followed for safety for 28 days post-vaccination. For the purpose of this pooled analysis, only 28 days of safety follow-up were included to be consistent and to allow for comparisons between all protocols. The data across all five protocols were combined in this summary. Although there were three different doses of MMRV administered in study 2 and the lots were generally comparable in terms of safety, only the middle and high doses met criteria for the minimum clinically acceptable varicella virus dose (≥3.97 log10 PFU) [18]. Therefore, in tables that summarize data across all studies, the low-dose group was not included. Serious AEs (SAEs) were followed for the duration of the study. Safety data were collected with a vaccination report card (VRC) that was completed by the child’s parent/legal guardian on a daily basis. Parents/caregivers were provided guidance on identifying solicited rashes/AEs, with all reported events reviewed by the study staff. Following the administration of MMRV, the VRC prompted for (1) AEs of injection-site pain/tenderness, redness, and swelling for 5 days after each vaccination; (2) vaccine-associated rashes (including measles-like, rubella-like, varicella/zoster-like, and injection-site rashes) for at least 28 days after each vaccination; (3) mumps-like symptoms for at least 28 days after each
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vaccination; and (4) daily temperatures for at least 28 days. Parents also recorded concomitant medications and vaccines and all local and systemic AEs. The investigator assessed each reported AE as to seriousness, action taken, and causal relationship to study vaccine.
Randomized N=3125 13 randomized but not vaccinated with MMRV (do not appear in any other figure/table) Vaccinated Dose 1 n=3112 (99.6%) Reason discontinued n=332 (10.6%) Clinical AE = 9 Lost to follow-up = 131 Withdrew consent = 111 Protocol deviation = 18 Othera = 63
2.4. Statistical analyses Safety data were summarized for all children who received 1 or 2 doses of MMRV, without regard to concomitant vaccination. For all children for whom safety data were available either postdose 1 or postdose 2 of MMRV, the incidence rate, 2-sided 95% confidence interval (CI), and vaccine relationship are presented. In addition, data were summarized for those children who received both the first and second doses of MMRV and provided safety follow up data after both doses. These side-by-side comparisons of safety postdose 1 and postdose 2 of MMRV represent a matched analysis set, and allowed for a direct comparison of the safety profile of the first dose administered at ∼12 months of age versus the second dose administered 3 to 6 months later for the cohort of children who received both doses of the vaccine in the second year of life. The incidences of injection-site reactions (for 5 days following vaccination), vaccine-associated rashes and mumps-like symptoms, and elevated temperature (defined as a maximum temperature ≥102.2 ◦ F, oral equivalent) for 28 days following the administration of MMRV were statistically analyzed. For those children for whom safety data were available following both the first and second doses of MMRV, the proportions, risk differences, and 95% 2-sided CIs were provided using Tango’s method for correlated binomial proportions [28]. 3. Results 3.1. Subject accounting and demographics Across the five clinical studies, 3112 children received a first dose of MMRV and 2780 (89.3%) of these children received a second dose of MMRV approximately 3 to 6 months later. Overall, 2644 of
Vaccinated Dose 2 n=2780 (89.0%)
Reason discontinued n=136 (4.4%) Clinical AE = 0 Lost to follow-up = 92 Withdrew consent = 4 Protocol deviation = 31 Othera = 9
Completed Study Follow-Up n=2644 (84.6%)
a
Other includes, but is not limited to, incomplete safety follow-up, missed ≥1 blood draw, and moved N = number of children randomized in the age group n = number of children reaching each milestone AE = adverse experience Fig. 1. Subject accounting (across 5 studies, see below).
the 3112 (85.0%) children vaccinated with at least 1 dose of MMRV completed the respective studies. Fig. 1 presents an accounting of the number of children who were randomized to each protocol, who were vaccinated, and who completed or discontinued the study. The five studies were generally balanced with respect to gender and race. The median age by study ranged from 12 to 14 months for dose 1 and 15 to 20 months of age for dose 2 (Table 2).
Table 2 Subject demographics.
Gender (n, %) Male Female Age at study entry (months) Mean SD Median Range Age at receipt of dose 2 of ProQuad® (months) N Mean SD Median Range Race/ethnicity (n, %) African American Asian Caucasian Hispanic Other
Study 1 (N = 323)
Study 2 (N = 774)a
Study 3 (N = 1027)
Study 4 (N = 347)
Study 5 (N = 653)
Total (N = 3124)b
150 (46.4) 173 (53.6)
401 (51.8) 373 (48.2)
560 (54.5) 467 (45.5)
171 (49.3) 176 (50.7)
331 (50.7) 322 (49.3)
1613 (51.6) 1511 (48.4)
14.1 1.91 14 12 to 22
12.9 1.47 12 12 to 23
12.6 0.96 12 12 to 15
12.5 0.90 12 12 to 17
12.4 0.85 12 12 to 16
12.8 1.30 12 12 to 23
310 17.2 1.96 17 14 to 26
725 15.8 1.56 15 14 to 26
941 16.6 1.37 16 14 to 23
291 19.0 1.72 18 17 to 27
513 19.5 1.88 20 17 to 28
2780 17.2 2.14 17 14 to 28
41 (12.7) 30 (9.3) 211 (65.3) 30 (9.3) 11 (3.4)
119 (15.4) 30 (3.9) 518 (66.9) 66 (8.5) 41 (5.3)
155 (15.1) 31 (3.0) 670 (65.2) 103 (10.0) 68 (6.6)
10 (2.9) 6 (1.7) 164 (47.3) 148 (42.7) 19 (5.5)
141 (21.6) 7 (1.1) 394 (60.3) 62 (9.5) 49 (7.5)
466 (14.9) 104 (3.3) 1957 (62.6) 409 (13.1) 188 (6.0)
N = number vaccinated with the first dose of ProQuad® . n = number of children in each category. SD = standard deviation. Percentages are calculated based on the number of children vaccinated with the first dose of ProQuad® (N). a Demographic data of 1 randomized, but not vaccinated, child from Study 1 were not obtained. b 13 total children were randomized but not vaccinated with MMRV, but demographic data were obtained for 12 of those children.
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Table 3 Summary of vaccine-related injection-site adverse experiences (days 1 to 5) and rashes and mumps-like symptoms (days 1 to 28) after each dose of MMRV. Dose 1
2
n 3112 3019 All reported events
Redness (Erythema)a Swellinga Pain/tendernessa Measles-like rashb Rubella-like rashb Mumps-like symptomsb Varicella-like rashb Injection-site rashb Number of children Children with safety data
327 243 650 140 14 0 58 40 2780 2695 All reported events
Redness (Erythema)a Swellinga Pain/tendernessa Measles-like rashb Rubella-like rashb Mumps-like symptomsb Varicella-like rashb Injection-site rashb a b
% (95% CI)
Number of children Children with safety data
338 231 430 27 2 0 9 17
n
% (95% CI)
3112 3019 Vaccine-related events 10.8% (9.7, 12.0) 8.0% (7.1, 9.1) 21.5% (20.1, 23.0) 4.6% (3.9, 5.4) 0.5% (0.3, 0.8) 0.0% (0.0, 0.1) 1.9% (1.5, 2.5) 1.3% (0.9, 1.8)
12.5% (11.3, 13.9) 8.6% (7.5, 9.7) 16.0% (14.6, 17.4) 1.0% (0.7, 1.5) 0.1% (0.0, 0.3) 0.0% (0.0, 0.1) 0.3% (0.2, 0.6) 0.6% (0.4, 1.0)
10.7% (9.6, 11.9) 324 241 8.0% (7.0, 9.0) 647 21.4% (20.0, 22.9) 125 4.1% (3.5, 4.9) 11 0.4% (0.2, 0.7) 0 0.0% (0.0, 0.1) 51 1.7% (1.3, 2.2) 36 1.2% (0.8, 1.6) 2780 2695 Vaccine-related events 333 228 429 21 2 0 7 16
12.4% (11.1, 13.7) 8.5% (7.4, 9.6) 15.9% (14.6, 17.4) 0.8% (0.5, 1.2) 0.1% (0.0, 0.3) 0.0% (0.0, 0.1) 0.3% (0.1, 0.5) 0.6% (0.3, 1.0)
AEs of injection-site pain/tenderness, redness, and swelling assessed for 5 days after each vaccination. Vaccine-associated rashes and mumps-like symptoms assessed for 28 days after each vaccination.
3.2. Safety Safety follow-up was obtained for 97.0% (3019/3112) of children vaccinated with the first dose of MMRV (with or without other vaccines), and 96.9% (2695/2780) of children vaccinated with a second dose of MMRV (with or without other vaccines). The number and percentage of children with clinical AEs reported within 28 days postvaccination was analyzed, by dose, for children vaccinated with MMRV across the 5 protocols. Overall, one or more clinical AEs was reported by 70.5% of children following the first dose of MMRV and 57.7% of children following the second dose of MMRV. A vaccinerelated systemic AE was reported by 31.7% of children following dose 1 and 14.6% of children following dose 2. The majority of the AEs were considered by the investigator to be mild or moderate in intensity. Twenty-two (22) subjects reported a SAE after dose 1. Nine (9) of these subjects received MMRV alone and 13 received MMRV with other vaccines. Of the 9 SAEs reported after MMRV alone, only one was considered vaccine related. This child was reported to have a fever and a febrile seizure 7 days after vaccination. Three (3) of the 13 subjects who received MMRV with other vaccine reported a vaccine-related SAE. One child developed cellulitis 18 days after receipt of MMRV + hepatitis A vaccine, another child had a febrile convulsion 9 days after MMRV + PCV7 (pneumococcal 7-valent conjugate vaccine, Wyeth Pharmaceuticals, Philadelphia, PA), and a third child who received MMRV + PCV7 followed 6 weeks later by hepatitis A vaccine developed dehydration and gastroenteritis 13 days after the hepatitis A vaccine. A SAE was reported by six subjects after the second dose of MMRV, three of whom received MMRV alone and three of whom received MMRV with other vaccines. None of these six SAEs was considered vaccine related. One child died on Day 218 as a result of Stage IV neuroblastoma (diagnosis made Day 8) after having received a single dose of MMRV (Day 1); this was considered to be definitely not related to study vaccine by the investigator. As shown in Table 3, pain/tenderness was the most commonly reported VRC-prompted injection-site AE across the combined studies, regardless of dose. The incidence of pain/tenderness at the injection-site was lower postdose 2 (15.9%) than that observed postdose 1 (21.4%). There was a numerically higher incidence of
redness (erythema) at the injection-site postdose 2 (12.4%) than postdose 1 (10.7%). Almost all injection-site AEs prompted for on the VRC were considered vaccine related by the investigator. rashes (measles-like, rubella-like, Vaccine-associated varicella/zoster-like, injection-site) and mumps-like symptoms were solicited systemic AEs and were prompted-for on the VRC of all 5 studies. Measles-like rash was the most commonly reported vaccine-related-rash. The incidence of measles-like, rubella-like, varicella-like and injection-site rashes were lower postdose 2 than postdose 1 (Table 3). Mumps-like symptoms and zoster-like rash were not reported in any of the five studies. The incidence rates, 95% CI, and risk differences for VRCprompted events were compared for the cohort of children who received both doses of MMRV and had safety follow up after each dose (Table 4). Injection-site redness was statistically significantly higher following dose 2 compared to dose 1 (12.6% vs. 10.8%, respectively), while injection-site pain/tenderness was statistically significantly higher following dose 1 compared to dose 2 (21.9% vs 16.1%, respectively). The reporting of measles-, rubella-, and varicella-like rashes, and injection-site rashes were all statistically significantly lower postdose 2 as compared to postdose 1, confirming the observations made on the complete (un-matched) data set. The reporting rate of elevated temperature (≥102.2 ◦ F oral equivalent) was statistically significantly lower postdose 2 as compared to postdose 1 of MMRV. This was true for the entire 28-day safety follow-up period (postdose 2: 10.8%; postdose 1: 19.1%), as well as during the first 6 to 13 days postvaccination (postdose 2: 3.9%; postdose 1: 13.6%), the period associated with the highest rate of fever in the pre-licensure clinical studies. A total of 10 febrile seizures were reported following the receipt of MMRV (with or without other vaccines) in all five protocols (Table 5). Eight (8) of the 10 febrile seizures occurred postdose 1 of vaccine(s). Three (3) of the seizures were reported by the investigator as possibly related to vaccination and 7 were reported as probably or definitely not related to vaccination. The 8 febrile seizures following the first dose of MMRV occurred between 8 and 29 days (mean 13 days) postvaccination; the 2 febrile seizures following the second dose of MMRV occurred on days 13 and 25. Seven (7) of the 10 febrile seizures reported had one or more concurrent conditions and 5 of the children received pneumococcal conjugate
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Table 4 Number (%) of children with vaccine report card-prompted adverse experiences for the cohort with safety data after both doses of MMRVa Dose 1 n
%
Children with safety data 2679 Injection-site AEs (Days 1 to 5 after each dose) Redness (Erythema) 289 Swelling 213 Pain/tenderness 586 Rashes and mumps-like symptoms (days 1 to 28 after each dose) 133 Measles-like rash Rubella-like rash 13 Mumps-like symptoms 0 Varicella-like rash 52 Injection-site rash 35 Elevated temperature (maximum reported temperature ≥ 102.2 ◦ F) Days 1 to 28 after each dose (n = 2408) 461 Days 1 to 5 after each dose (n = 2404) 62 Days 6 to 13 after each dose (n = 2405) 327 Days 14 to 28 after each dose (n = 2404) 133 a b
Dose 2 n
Risk difference (dose 1 and dose 2) (95% CI)
%
2679 10.8 8.0 21.9
338 231 430
12.6 8.6 16.1
5.0 0.5 0.0 1.9 1.3
27 2 0 9 17
1.0 0.1 0.0 0.3 0.6
19.1 2.6 13.6 5.5
261 60 94 144
10.8 2.5 3.9 6.0
−1.8 (−3.3,−0.3)b −0.7 (−2.0,0.6) 5.8 (4.1,7.6)b 4.0 (3.1,4.9)b 0.4 (0.1,0.8)b N/A 1.6 (1.1,2.2)b 0.7 (0.2,1.2)b 8.3 (6.4,10.3)b 0.1 (−0.8,1.0) 9.7 (8.1,11.3)b −0.5 (−1.7,0.8)
Only subjects with safety data after both doses of vaccine are included in this analysis. Statistically significant.
and/or hepatitis A vaccines concomitantly (details in Table 5). All of the febrile seizures reported resolved without any sequelae. The incidence rate of febrile seizures was 0.26% (8/3019) postdose 1 of MMRV and 0.07% (2/2695) postdose 2 of MMRV.
4. Discussion A 2-dose regimen for measles, mumps, rubella, and varicella vaccination has been widely adopted in the U.S. [3]. Widespread use of a 2-dose schedule of MMR vaccine [29,30] has been responsible for a ≥99% reduction in the incidence and associated complications of measles, mumps, and rubella in the U.S. and other countries [1,2,31,32]. However, most non-U.S. countries have only recently licensed varicella vaccine for routine use in children
[33]. Reaching the high coverage rates necessary to achieve the full benefits of varicella vaccination would be facilitated by the existing infrastructure for MMR 2-dose vaccination [2]. Therefore, the introduction of a quadrivalent MMRV vaccine could help increase 2-dose varicella coverage. Because of the increase in the frequency of fever following the administration of the first dose of MMR compared with the concomitant administration of component vaccines, the incidence of febrile seizures was of interest [34]. It is known that fever can precipitate febrile seizures in the susceptible child between the ages of 6 months and 5 years [35]. It has been estimated that 2% to 4% of all children in this age group will experience at least one febrile seizure [35], most commonly in the 12- to 23-month age range. Risk factors for a first febrile seizure include very high fever, family history of febrile seizures, a neonatal hospital stay of ≥28 days duration,
Table 5 Febrile Seizures reported after MMRV (with or without concomitant receipt of other vaccines). Dose of MMRV
Study Age (months)
Vaccine(s) received
Day of Onset Postdose
Maximum temperature Severityc (◦ F) (method)
Other concurrent conditions
Vaccine relatedd
Outcome
1
1
13
MMRV
9
103.0 (Rectal)
Severe
Possibly
Recovered
2 2 3
12 12 12
MMRV MMRV MMRV PCV7
8 8 10
102.8 (Rectal) 105.5 (Axillary) 102.9 (Axillary) 104.4 (Rectal)
Moderate Severe Severe
Probably not Possibly Definitely not related
Recovered Recovered Recovered
3
12
MMRV
29
Severe
12
22
Severe
5
14
Severe
None
5b
12
9
105.2 (Rectal)
Severe
Viral illness
Possibly related Recovered
5
18
HAV MMRV PCV7 MMRV HAV MMRV PCV7 MMRV HAV MMRV
Probably not related Probably not related Probably not related
Recovered
4
103.6 (Method not specified) 102.3 (Axillary) 104.9 (Rectal) 101.1 (Axillary) 103.4 (Rectal)
Diarrhea, otitis media, injection-site rash Cough None Fussiness; Pneumonia; upper respiratory infection Upper respiratory infection Otitis media
25
103 (Axillary) 104 (Rectal) 105.2 (Rectal)
Moderate
None
Moderate
Viral febrile illness
Probably not related Probably not related
2
5
b
20
9
13
Recovered Recovered
Recovered Recovered
PCV7 = Pneumococcal conjugate vaccine. HAV = Hepatitis A vaccine. a One child (Study 3) experienced a complex febrile seizure. b One child (Study 5) experienced 2 febrile seizures (Day 9 after Dose 1, Day 13 after Dose 2). c Severity was assessed by the clinical investigator using the following definitions: mild-awareness of symptom, but easily tolerated; moderate–definitely acting like something is wrong; severe–extremely distressed or unable to do usual activities. d Vaccine relationship was determined by the clinical investigator.
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parental report of slow development, attendance at daycare, and a low serum sodium level [36]. There is no evidence suggesting that the occurrence of febrile seizures increases the risk of death, brain damage, injury, or learning disorders [33–40]. In two large post-licensure safety studies, among children 12 to 23 months of age who had neither been vaccinated against measles, mumps, rubella, or varicella nor had a history of wild-type infection, the rate of febrile seizures was examined [41,42]. In the first study conducted at Southern California Kaiser, during the 30 days postdose 1, no increased risk in febrile seizures between MMRV and component vaccines (relative risk = 1.10; 95% CI: 0.72, 1.69) was found. However, when the 5 to 12 day period postdose 1 was examined, MMRV recipients had approximately a 2-fold higher increased risk of febrile seizure as compared to recipients of the component vaccines (relative risk = 2.20; 95% CI: 1.04, 4.65) [41]. No febrile seizures were observed during the 5 to 12 day period postdose 2 among 26,455 children who received a second dose of MMRV or the first dose of MMRV following primary vaccination with component vaccines [41]. The second study was conducted through the Vaccine Safety Datalink (VSD), a collaboration between the Centers for Disease Control and Prevention and 8 managed care organizations [42]. The VSD study concluded that following administration of a first dose of any measles-containing vaccine to children 12 to 23 months of age, occurrence of fever and seizure were elevated for 7 to 10 days postvaccination [42]. Similar to the Southern Kaiser study, MMRV increased the risk of febrile seizures ∼2-fold between days 7 and 10 postdose 1 compared to MMR plus varicella vaccination (relative risk = 2.04; 95% CI: 1.44, 2.90) [42]. Another study conducted using VSD data showed that MMRV and MMR and varicella vaccines were not associated with an increased risk of febrile seizures among 4-to 6-year olds, the age at which both a second dose of MMR and varicella containing vaccines are recommended in the US [29,30,44]. Based on the results of these studies, the first dose of MMRV was associated with an attributable risk of approximately one extra febrile seizure for every 2300 to 2600 doses administered compared to MMR plus varicella vaccines [43]. Similar results of an increase in febrile seizures after the first dose have been found with another MMRV vaccine used in Canada where the attributable risk was approximately one extra febrile seizure for every 2841 vaccine recipients [45]. The five studies reported here did not allow the calculation of an attributable risk since only two of the studies included recipients of MMR plus varicella vaccine and the sample size was limited. However, similar to the two postlicensure studies, the rate of febrile seizures in these five studies was considerably lower after the second dose of MMRV as compared to the first dose. Based on the data from the postlicensure safety studies, the ACIP recommended MMR plus varicella vaccines for the first dose of a measles, mumps, rubella, and varicella-containing vaccine for children <4 years of age [43]. However, MMRV may be used for the first dose according to parental/guardian preference, once the benefits and risks of both options have been fully discussed. For the second dose and for children ≥4 years of age receiving a first dose, the ACIP deferred to the combination vaccine recommendations which state that combination vaccines are generally preferred over components [43]. For any dose, children with a known personal or family history of febrile seizures or epilepsy are at increased risk for febrile seizures, and thus should receive the MMR plus varicella component vaccines. One of the strengths of the data presented here is that all the safety data were collected using a similar VRC at multiple sites across the five randomized clinical studies. In addition, use of a matched set analysis among a large cohort of 2-dose recipients allowed for direct comparison of dose 1 and dose 2 safety data. However, despite representing a matched set, the postdose 1 and postdose 2 comparison groups differed in age and previous exposure to each of the antigens in the vaccine which could introduce
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some bias in the comparisons. Another limitation of the data presented here is that the sample size was not large enough to detect any difference in the rate of febrile seizures in recipients of MMRV versus the component vaccines, but the rate of febrile seizures was low. 5. Conclusions In summary, administration of 2 doses of MMRV is generally well tolerated in children 12 to 23 months of age. In general, the rate of systemic and injection-site AEs, rashes, and elevated temperatures was lower after dose 2 compared to dose 1. There is a small increase in the risk of febrile seizures following the first dose of MMRV as compared to the component vaccines, but this risk for any individual child is relatively low. Financial disclosures Funding for this research was provided by Merck & Co., Inc. Current and past employees of the sponsor (indicated on the title page) may own stock or stock options in the company. KR and SB have served as paid investigators for the sponsor. Disclosure This study was funded by Merck & Co., Inc. (sponsor). In conjunction with the external investigators, this study was designed, executed, and analyzed by the sponsor. The sponsor formally reviewed and provided comments on a penultimate draft of this manuscript. All co-authors approved the final version of the manuscript. Employees of the sponsor (indicated on the title page) may own stock or stock options in the company. KR and SB have served as paid investigators and consultants for Merck. Author contributions All Authors: analysis and interpretation of data, and preparation of manuscript. KR and SB: enrollment of children and data collection. BK, SK, and FS: study concept and design. Acknowledgements The authors would like to thank all the children and study staff who participated in the five clinical studies. We also acknowledge Frans Helmond for his careful review of the manuscript. References [1] Atkinson W, Wolfe C, Hamborsky J, McIntyre L, editors. Epidemiology and prevention of vaccine-preventable diseases. 11th ed. Washington, DC: Public Health Foundation; 2009. [2] Vesikari T, Sadzot-Delvaux C, Rentier B, Gershon A. Increasing coverage and efficiency of measles, mumps, and rubella vaccine and introducing universal varicella vaccination in Europe: a role for the combined vaccine. Pediatr Infect Dis J 2007;26:632–8. [3] Centers for Disease Control and Prevention. Recommended immunization schedules for persons aged 0–18 years: United States, 2008. MMWR 2008;57:Q1–4. [4] Watson JC, Hadler SC, Dykewicz CA, Reef S, Phillips L. 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;47:1–57. [5] Marin M, Guris D, Chaves SS, Schmid S, Seward JF. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007;56:1–40.
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