Statement on Measles-Mumps-Rubella-Varicella Vaccine

†Members: Dr. J. Langley (Chair), Dr. B. Warshawsky (Vice-Chairperson), Dr. S. Ismail (Executive Secretary), Dr. N. Crowcroft, Ms. A. Hanrahan, Dr. B. Henry, Dr. D. Kumar, Dr. S. McNeil, Dr. C. Quach-Thanh, Dr. B. Seifert, Dr. D. Skowronski, Dr. C. Cooper.

Liaison Representatives: Dr. B. Bell (Center for Disease Control and Prevention), Ms. K. Pielak (Canadian Nursing Coalition for Immunization), Dr. S. Rechner (College of Family Physicians of Canada), Dr. M. Salvadori (Canadian Pediatric Society), Dr. S. Pelletier (Community Hospital Infection Control Association), Dr. N. Sicard (Canadian Public Health Association), Dr. V. Senikas (Society of Obstetricians and Gynaecologists of Canada), Dr. P. Plourde (Committee to Advise on Tropical Medicine and Travel), Dr. P. Van Buynder (Council of Chief Medical Officers of Health).

Ex-Officio Representatives: Ms. M. FarhangMehr (Centre for Immunization and Respiratory Infectious Diseases), Dr. S. Desai (Centre for Immunization and Respiratory Infectious Diseases), LCol (Dr.) James Anderson (Department of National Defence), Dr. Ezzat Farzad (First National and Inuit Health Branch – Office of Community Medicine), Dr. J. Xiong (Biologics and Genetic Therapies Directorate), Dr. D. Elliot (Centre for Immunization and Respiratory Infectious Diseases), Dr. P. Varughese (Centre for Immunization and Respiratory Infectious Diseases), Dr. R. Pless (Centre for Immunization and Respiratory Infectious Diseases).

Preamble

The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific and public health advice relating to immunization. The Public Health Agency of Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of the Public Health Agency of Canada’s Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

Introduction

This statement reviews the one available measles-mumps-rubella-varicella (MMRV) vaccine, Priorix-Tetra^TM, GlaxoSmithKline (GSK) Inc., authorized for use in Canada, and makes recommendations for its use.

Measles-mumps-rubella (MMR) vaccine has been available in Canada since the 1970s, and univalent varicella vaccine has been available since 1998. MMR and univalent varicella vaccines cannot be administered in the same syringe, necessitating two injections at separate sites. The availability of a combined MMRV vaccine enables vaccine providers to reduce the number of injections.

Epidemiology

Please refer to the measles, mumps, rubella and varicella chapters in the most recent Canadian Immunization Guide (CIG) for the epidemiology of these individual diseases (1). NACI has also published a mumps vaccine update in response to mumps outbreaks, which affected previously immunized adolescents and adults from 2004 to 2007 in the United Kingdom, the United States and Canada (2). NACI recommends a routine two-dose schedule for measles, and in 2007 extended the two-dose recommendation to include mumps (including catch-up second dose for children in schools and post-secondary institutions) (1,2). All provinces and territories in Canada currently provide two doses of MMR for children, with the first dose at 12 months and the second at either 18 months or 4 to 6 years of age. This complies with the two-dose recommendation for measles and mumps, with possible benefit also against rubella.

Since 1999, NACI’s recommendation for varicella vaccine has been for a single dose for children 12 months to 12 years old and two doses for persons ≥13 years old (1,3). The U.S. Advisory Committee on Immunization Practices (ACIP) recommended a single-dose varicella vaccine schedule in 1995, and in 2006 recommended that children aged 12 months to 12 years now receive two doses for the primary series, using either univalent varicella or combination MMRV vaccine (4). As part of the review of evidence for this ACS, a literature review on varicella epidemiology in Canada was prepared for NACI and will be published on the NACI website (http://www.phac-aspc.gc.ca/naci-ccni/index-eng.php#lr). Recent reviews of the epidemiology of varicella in Canada and the U.S. are available and were reviewed by NACI (4-6). The rationale for the NACI recommendations supporting two-dose primary varicella immunization of children 12 months to 12 years of age is included in a separate statement, entitled “Varicella Vaccination Two-Dose Recommendations,” and will not be repeated here (7).

Preparations Authorized for Immunization

The MMRV vaccine manufactured by GlaxoSmithKline (GSK) Inc., Priorix-Tetra^TM, was authorized for use in Canada on July 30, 2007. The minimum Tissue Culture Infective Dose 50% ^(TCID50^{) /Cell Culture Infective Dose (CCID}50^{) for each} component antigen in MMRV is shown in Table 1. Since MMRV may replace the individual component vaccines, the ^TCID50 ^{for MMR and varicella vaccines available in Canada} are also shown in Table 1 for comparison. MMRV does not contain thimerosal or other preservatives, but has trace amounts of neomycin sulphate and sorbitol. The Priorix-Tetra^TM vial and syringe are latex-free.

Table 1. Comparison of MMRV, MMR and Varicella (Var.) Vaccines by manufacturer.

Manufacturer	GlaxoSmithKline (GSK) Inc.			Merck Inc.
Vaccines	MMR (PriorixTM)	Var. (VarilrixTM)	MMRV (Priorix-TetraTM)	MMR (MMR-IITM)	Var. (Varivax-IIITM)	MMRV-U.S. (ProQuadTM)
Authorized for use in Canada	Yes	Yes	Yes	Yes	Yes	No**
Measles strain	Schwarz ≥ 3,3 log10 CCID50	Nil	Schwarz ≥ 3.0 log10 CCID50	Enders (Edmondston) ≥ 3.0 log10 CCID50	Nil	Enders (Edmondston) ≥ 3.0 log10 TCID50
Mumps strain	RIT4385JL* ≥ 3.7 log10 CCID50	Nil	RIT4385 JL ≥ 4.4 log10 CCID50	JL (B level) ≥ 3.7 log10 CCID50	Nil	JL ≥ 4.3 log10 TCID50
Rubella strain	Wistar RA 27/3 ≥ 3.0 log10 CCID50	Nil	Wistar RA 27/3 ≥ 3.0 log10 CCID50	Wistar RA 27/3 ≥ 3.0 log10 CCID50	Nil	Wistar RA 27/3 ≥ 3.0 log10 TCID50
Varicella strain	Nil	Oka ≥ 3.3 log10 PFU	Oka ≥ 3.3 log10 PFU	Nil	Oka-Merck ≥ 3.13 log10 PFU	Oka-Merck ≥ 3.99 log10 PFU
Age group	≥ 12 mos.	≥ 12 mos.	≥ 9 mos.*** - 6 years of age****	≥ 12 mos.	≥ 12 mos.	12 mos.–12 yrs.
Storage	Refrigerator	Refrigerator	Refrigerator	Refrigerator	Refrigerator	Freezer

* JL = Jeryl Lynn mumps vaccine strain. ** ProQuad^TM is not authorized in Canada as of September 2009 (shown here to allow comparison of the minimum potencies of vaccine antigens). *** Authorized for use at 9 to 11 months of age, but not recommended by NACI. **** May be used in individuals up to 12 years of age based upon previous experience with separate component vaccines Priorix^TM and Varilrix^TM.

Notably, the MMRV vaccines available in Canada and the United States are different (Table 1). In Canada the only MMRV vaccine available is Priorix-Tetra^TM. In the U.S. the licensed MMRV vaccine is ProQuad^TM, manufactured by Merck Inc.

Apart from discussing the rate of febrile seizures observed after the first dose of the Merck Inc. MMRV vaccine (ProQuad^TM) in the Adverse Reactions section below, the remainder of this NACI statement will focus solely on the GSK MMRV vaccine Priorix-Tetra^TM. A separate statement will be published later, should ProQuad^TM receive authorization for use in Canada.

Efficacy and Immunogenicity

MMRV has been studied in children 9 months to 6 years of age. All published studies on MMRV to date have reported on immunogenicity and safety data only, with no data regarding clinical efficacy.

The available assays to detect varicella antibody in blood include complement fixation (CF), latex agglutination (LA), indirect immunofluorescence assay (IFA), neutralization test (NT), enzyme-linked immunosorbant assay (ELISA) and fluorescent antibody to membrane antigen (FAMA) (3). The NT and FAMA tests correlate best with protection from disease but are cumbersome to perform and not readily available. Commercial antibody test kits employing LA and standard ELISA are usually able to detect the higher varicella antibody titers, which develop after wild-type infection, but may lack the sensitivity to detect the lower antibody titers typically found after single-dose vaccination (3). In contrast, FAMA and a more specific glycoprotein ELISA (gpELISA) test are considered sensitive enough to detect antibody levels post-vaccination. The pre-licensure Varivax^TM and ProQuad^TM studies for the most part utilized Merck Inc.’s proprietary gpELISA test, whereas studies involving GSK’s Varilrix^TM and Priorix-Tetra^TM vaccines used an IFA and ELISA test (3,8). Since the correlation of antibody levels detected by different tests is largely unknown, it is not possible to make direct comparisons between the different manufacturers’ products.

With one exception, most studies defined seropositivity as having a measles ELISA titer ≥ 150 mIU/mL, mumps ELISA titer ≥ 231 IU/mL, rubella ELISA titer ≥ 4 IU/mL and varicella IFA titer ≥ 4 (dilution). One study used mumps plaque reduction ^{neutralization titer (seropositive if titer > 28ED}50^{) instead of} ELISA (9). Seroconversion was defined as converting from seronegative before, to seropositive after vaccination. The studies can be stratified according to number of doses of MMRV administered at various ages, with the level of evidence graded in Table 2. Immunological data from these studies have also been reviewed in a recent publication (10).

Table 2. Summary of the Seroconversion (SC) Rates and Geometric Mean Titers (GMT) in Published Studies after 1 or 2 Doses of MMRV Vaccine.

Study authors and journal [level of evidence]	Countries	# doses, N recd MMRV	Previous MMR, V	MMRV* schedule, N	Timing of tests	Measles		Mumps		Rubella		Varicella
						%SC	GMT	%SC	GMT	%SC	GMT	%SC	GMT
Nolan et al. Vaccine Dec 2002 (11) [II-2 (fair)]	Australia	1 dose N=79	Nil	12 mos.	Post	98	2,964	97	1,212	98	57.3	93	53.9
Knuf et al. Pediatr Infect Dis J Jan 2006 (12) [II-2 (good)]	Germany, Austria	2 doses N=311	Nil	12 mos. and 6 wks. later	Post-2 only	100	6,103.9	98	1,465.4	100	101.5	100	4,932.1
Vesikari et al. Pediatr Infect Dis J Feb 2007 (13) [II-2 (good)]	Finland	2 doses N=48	Nil	1 to 2 yrs. and 5 to 6 yrs.	Pre-2 Post-2	98 100	1,694 2,091	83 98	676 1,534	100 100	30 100	85 100	161 1,585
Goh et al. Infection May 2007 (14) [II-2 (good)]	Singapore	2 doses N=134	Nil	9 mos. and	Post-1	93	2,907.7	85	977.8	100	64	100	406.4
				12 mos.	Post-2	100	4,199.7	100	2,140.7	100	98	100	4,074.7
Zepp et al. Eur J Pediatr Aug 2007 (15) [II-2 (good)]	Germany	1 dose N=451	Nil	12-23 mos.	Post-MMRV CoAdmin**	97.1 95.1	4,419.2 3,441.8	80.1 80.3	916.4 923.3	100 99.3	53.5 48.1	100 98.5	316.0 288.6
Schuster et al. Pediatr Infect Dis J Aug 2008 (9) [II-2 (good)]	Germany	2 doses N=732	Nil	10–21 mos. & 6 wks. later	Pre-2 Post-2	94.5 98.3	2,584.7 3,755.9	96.1 99.4	157.9 589.4	99.7 99.7	62.9 122.6	95.5 99.7	80.4 1,903.3
Gillet et al. Vaccine Jan 2009 (16) [II-2 (good)]	France, Germany, Italy	1 dose followed by 1 dose V 6–8 wks. Later Total N=197	MMR ≥ 6 wks. previously (exact age unspecified)	15 mos.–2 yrs. N=88 (varies with vaccine Ag)	Pre-MMRV Post-MMRV Post-V	87.5 98.9 -	1,485.5 2,428.1 -	92 100 -	927.2 5,662.7 -	96.6 100 -	92.7 122.9 -	4.6 97.6 100	- 93.2 1,312.4
				2 to 6 yrs. N=107 (varies with vaccine Ag)	Pre-MMRV Post-MMRV Post-V	95.3 100 -	1,811.5 2,833.0 -	92.5 100 -	1,348.5 6,603.7 -	99.1 100 -	90.4 165.7 -	11.2 97.9 100	- 88.2 1,109.6
Halperin et al. Vaccine May 2009 (17) [II-2 (good)]	Canada, Italy, Belgium	1 dose N=195	MMR+V at 12 mos.	15–75 mos. (med=54 mos.)	Pre Post	96.4 100	1,872.2 2,375.3	94.3 100	1,381.4 3,940.9	99.5 100	86.0 159.4	97.9 100	93.2 2,532.7

* Only MMRV groups are included in this table; please refer to the original studies for the results in the control groups. ** CoAdmin group = MMRV and DTaP-IPV-HBV-Hib given concurrently. Seroconversion (or seropositive for pre-vaccination titer) is as defined by the authors. Please refer to the original publications for the 95% confidence intervals (CI) for SC and GMT, and comparisons with the respective control groups. Note that GMTs are comparable within each study, and should not be compared between studies. mos. = months of age; yrs. = years of age; wks. = weeks between doses; V = univalent varicella vaccine; recd .= received

Nolan et al. compared a single dose of MMRV with MMR plus varicella (MMR+V) or MMR alone in 240 children (80 in each group) aged 12 months in Australia. The seroconversion (SC) rate after MMRV for measles, mumps, rubella and varicella was 98%, 97%, 98% and 93%, respectively (11). The SC rates and geometric mean titers (GMTs shown for the MMRV group in Table 2) for individual components were not significantly different from those achieved after MMR+V or MMR alone.

Knuf et al. randomized 371 children in Germany and Austria to two doses of MMRV, and 123 children to MMR+V followed by MMR (control group) (12). The first dose was given after the first birthday, and the second dose six to eight weeks later. The MMRV vaccine had a minimum potency (10^4.4) of mumps vaccine virus similar to the commercial vaccine authorized in Canada. Serology was only performed after the second dose of vaccine. The seroconversion rate after two doses of MMRV was 100% for measles, rubella and varicella, and 98% for mumps. The GMTs after two doses of MMRV are shown in Table 2. The GMT for varicella was significantly higher in the MMRV group (4,932.1) as compared with the control group (155.2), which had only received one dose of varicella vaccine. The measles GMT was also significantly higher in the MMRV group (6,103.9 mIU/mL) as compared with the control group (3,719.2 mIU/mL), both of which received two doses of measles-containing vaccine. Overlapping of the 95% confidence intervals for the two groups’ mumps GMTs was noted: two-dose MMRV (1,465.4 IU/mL) and one-dose MMR +V followed by MMR (1,667.8 IU/mL).

Vesikari et al. randomized 94 children in Finland to either two doses of MMRV, or MMR followed by MMRV (13). The first dose at 1 to 2 years of age involved an experimental dose-ranging lot of the GSK MMRV or Merck Inc.’s MMR-II. Serology was performed before and after the second dose. The seroconversion rate after the second dose of MMRV was 100% for measles, rubella and varicella, and 98% for mumps. In this study, the measles, mumps and rubella GMTs were similar in both study groups. As expected, the varicella GMT was higher in the two-dose MMRV group (1,585), compared with the MMR/MMRV control group (172).

Goh et al. randomized 300 children in Singapore to two doses of MMRV or MMR+V, the first dose at 9 months of age and the second at 12 months (14). The premise was that maternal varicella antibody would have disappeared by 9 months of age; indeed, only 21 (0.07%) children were seropositive for varicella at baseline before the first dose, and were excluded from further analysis. The seroconversion rate for measles, mumps, rubella and varicella after the first MMRV dose was 93%, 85%, 100% and 100%, respectively, and 100% for all components after the second MMRV dose. There was a clear boost in GMTs for each vaccine component from first to second MMRV dose, and the GMTs were generally comparable between MMRV and MMR+V groups, with some exceptions. The measles GMT was significantly higher in the MMRV group after the first and second doses (2,907.7 mIU/mL and 4,199.7 mIU/mL, respectively), as compared with the MMR+V group (1,188.5 mIU/mL and 2,006.3 mIU/mL, respectively). The varicella GMT was similar between the groups after the first dose, but significantly higher in the MMRV group after the second dose (4,074.6) than in the MMR +V group (2,289.8). The reason for the differences is unclear, as ^{both products contained components with similar TCID}50 ^doses.

Zepp et al. randomized 451 German children aged 12 to 23 months to either a single dose of MMRV or MMRV co-administered with the booster dose of DTaP-IPV-HBV-Hib (CoAdmin group) (15). The results of the responses to individual vaccine antigens in both groups are summarized in Table 2, and further discussed and graded in the section below on the simultaneous administration with other vaccines.

Schuster et al. randomized children between 10 and 21 months of age in Germany to two doses of MMRV 42 days apart (732 subjects), or MMR+V followed 42 days later by MMR (238 subjects) in 2005 (9). Serology was performed before and 42 days after each dose; unlike the earlier studies, the mumps serology was done using neutralization testing rather than ELISA. The seroconversion rates and GMTs for measles, mumps, rubella and varicella after the first and second doses were comparable between the groups (Table 2). In particular, the seroconversion rate for varicella was 95.5% and GMT was 80.4 after the first MMRV, improving to 99.7% and 1,903.3 after the second MMRV, respectively. In contrast, the comparison group had a varicella seroconversion rate of 95.6% and GMT of 84.0 after the first dose of MMR+V, and 97.5% and GMT of 80.3 after the second dose of MMR.

In a study by Gillet et al. conducted in Germany, France and Italy, children who had previously received a single MMR dose were randomized at either 15 to 23 months or 2 to 6 years of age (with ≥ 6 weeks after the first MMR dose) to receive an MMRV dose, followed by a univalent varicella vaccine dose six to eight weeks later (the MMRV group, N=195), or MMR plus univalent varicella vaccine doses simultaneously, followed by another univalent varicella vaccine dose six to eight weeks later (the MMR+V group, N=197) (16). The seropositive rates after the first MMR and before MMRV were approximately 88% for measles, 92% for mumps, 97% for rubella and 5% for varicella for the 15- to 23-month-old subgroup and 95%, 93%, 99% and 11%, respectively for the 2- to 6-year-old subgroup (see Table 2). After the MMRV dose, the seropositivity improved to 100% for mumps and rubella, 99% for measles and 98% for varicella. The varicella seropositivity improved to 100% after the subsequent univalent varicella vaccine dose administered six to eight weeks later. There was significant boost in GMT for measles, mumps and rubella after the MMRV for both age subgroups (Table 2). After MMRV, the GMT for varicella was 93.2, increasing by 14-fold to 1,312.4 after the subsequent univalent varicella vaccine dose in the 15 to 23 month-old subgroup; for the 2- to 6-year-old subgroup, the varicella GMT was 88.2, increasing almost 13-fold to 1,109.6 after the univalent varicella vaccine. The increases in antigen-specific seropositivity rates in the MMRV and MMR+V (control) age subgroups were comparable (controls not shown in Table 2). In general, the baseline GMTs in the MMR+V control subgroups were similar or slightly higher, when compared with the MMRV subgroups; however, there was significant boosting of GMTs for each vaccine antigen in the control subgroups, comparable with the MMRV subgroups (not shown in Table 2; refer to original publication).

Halperin et al. conducted a study in Canada, Italy and Belgium, where 390 children previously immunized with MMR and univalent varicella vaccines after the first birthday were randomized to either MMRV or MMR+V as the second dose at 15 to 75 months of age (median 54 months) (17). Before the dose of MMRV, 96%, 94%, 99% and 98% of subjects were seropositive for measles, mumps, rubella and varicella respectively. The seropositive rate at six to eight weeks after MMRV increased to 100% for each component, with a notable 27-fold increase in varicella GMT (from 93.2 to 2,532.7, see Table 2). The MMR+V control group also achieved 99% to 100% seropositivity, with comparable GMTs to the MMRV group. For varicella, the GMT was 2,532.7 after MMRV and 2,555.1 after MMR+V.

From the results of the studies summarized above, it is clear that significant boosting for all vaccine components occurs whether the second MMRV dose is administered six weeks after the first dose at 12 months of age, or at 15 months up to 5 to 6 years of age.

Antibody Persistence and Breakthrough Disease with Three-Year Follow-Up Post-Vaccination

The persistence of antibodies against measles, mumps, rubella and varicella was determined yearly, for up to three years after receipt of two doses of MMRV vaccine administered during the second year of life (10,12,18-21). Of the children randomized to two doses of MMRV or MMR+V (371 and 123 subjects, respectively) in the study by Knuf et al., 296 and 105 subjects were followed up at one year, 273 and 101 at two years, and 225 and 79 at three years post-vaccination, respectively (10,12). By the third year post-vaccination, seropositivity for measles, mumps, rubella and varicella was 99%, 97.4%, 100% and 99.4% for the MMRV group, respectively (using ELISA test for measles, mumps and rubella, and IFA for varicella) (10). The seropositivity rate for each vaccine antigen at three years in the MMRV group was slightly higher than, or identical with (rubella only), the MMR+V control group. The GMT for varicella antibody was noticeably higher in the MMRV group (225.5), as opposed to the MMR+V group (105.8) at the three-year follow-up, although the clinical significance of this is unknown (10).

There were relatively few breakthrough varicella cases noted by the end of the three-year follow-up period, with only two mild cases among the 225 subjects completing follow-up in the MMRV group, and five cases among the 79 subjects (four with mild and one with moderate severity) followed up in the MMR+V group (10).

Recommended Usage

In a separate statement, NACI recommends that children 12 months to 12 years of age receive two doses of varicella-containing vaccine for primary immunization, as this has been shown to reduce the risk of breakthrough (vaccine-modified) disease. Since MMRV has been authorized for a two-dose primary schedule and provides an opportunity to reduce the number of injections, MMRV may be used in place of individual MMR and varicella vaccines. NACI does not at this time specify any preference for using either MMRV vaccine, or MMR and univalent varicella vaccines separately. The upper age limit of 12 years is based on previous immunogenicity and safety experience with the manufacturer’s individual component vaccines (Priorix^TM and Varilrix^TM), and will remain the recommended upper age limit until such time as data are available regarding MMRV use in adolescents and adults. NACI recommendation – Grade A.

There are currently no data on the use of MMRV for susceptible children or adults in post-exposure or outbreak situations involving wild-type measles, mumps, rubella and varicella viruses; however, MMRV would not be required in outbreaks or exposures involving any single viral pathogen, where either MMR or univalent varicella vaccine may be utilized. As noted under “Contraindications” below, persons with impaired immune function, including primary or secondary immunodeficiency disorders, should not receive MMRV. For disease prevention in post-exposure situations involving immunocompromised children and adults, varicella zoster immune globulin (VariZIG™) should be used to prevent varicella, and immune serum globulin (ISG) to prevent measles (refer to the Canadian Immunization Guide 2006, pp. 353–62) (1,22). NACI recommendation – Grade A.

Schedule and Dosage

MMRV is supplied in single-dose vials containing lyophilized powder. It has to be mixed with the diluent, which is supplied in ampoules or prefilled syringes. The reconstituted dose is ^{0.5 mL, and contains the minimum TCID}50 ^{potency shown in} Table 1 for measles, mumps, rubella and varicella viruses.

Primary Immunization

NACI recommends that the first dose of MMRV be administered at 12 to 15 months of age, and the second at 18 months or at 4 to 6 years of age (preschool). As stipulated in the product monograph, the doses may be administered more closely together, with a preferred minimum interval of six weeks between doses. NACI recommendation – Grade A.

Since the most effective age for administering the second dose is currently unknown, the permissible range for the timing of the second dose allows jurisdictions with existing two-dose MMR programs to provide the second MMRV dose at 18 months or 4 to 6 years of age. Vaccine providers also have the option of providing the second dose any time between these two ages, for those who do not wish to wait until preschool to complete the two-dose series. An advantage for the second dose at 18 months is that it boosts the varicella antibody response, which may be suboptimal after the first dose at 12 months, and corrects primary vaccine failure (see the NACI statement “Varicella Vaccination Two-Dose Recommendations” (7)). The studies outlined in the immunogenicity section above demonstrated a significant boosting in varicella antibody levels when the second MMRV was administered as close as six weeks after the first dose (Table 2). The ACIP in the U.S. recommends the second dose of MMRV at 4 to 6 years of age, which would boost immunity before school entry. However, since breakthrough disease and outbreaks have occurred in preschool children (at day care centres), a second dose would have to be provided earlier than 4 to 6 years to protect children during the preschool years (4,23).

Catch-up Immunization

Two doses of MMRV a minimum of six weeks apart may also be administered up to 12 years of age as catch-up for those not previously immunized with MMR and varicella vaccines, who are therefore susceptible to these vaccine-preventable diseases. NACI recommendation – Grade B.

Children under 12 years of age who have had only one dose of a varicella-containing vaccine should generally be offered a second dose as a catch-up. If the child has already received two doses of MMR previously, then the second varicella dose should be provided as a univalent varicella preparation. If the child has received only one dose of MMR and one dose of varicella vaccine, then the second dose can be provided as MMRV, or as MMR and varicella separately. See the tables in the concurrent NACI statement “Varicella Vaccination Two-Dose Recommendations” (7) for specific timelines regarding catch-up vaccination. NACI recommendation – Grade B.

In general, those with a history of laboratory-confirmed breakthrough disease need not receive the second varicella-containing vaccine dose. In deciding on the timing of the second dose, vaccine providers should consider factors such as the current age of the child, attendance at a day care centre or school (especially at the outset of a cluster of varicella cases), and the previous number of doses of MMR vaccine received.

Route of Administration

Priorix-Tetra™ should be injected subcutaneously (SC), or intramuscularly (IM) in the deltoid region of the upper arm. A study of healthy children randomized to receive MMRV either subcutaneously or intramuscularly found the vaccine to be well tolerated and highly immunogenic when administered through either route (24).

The vaccine should be administered subcutaneously in subjects with bleeding disorders (e.g., thrombocytopenia or any coagulation disorder). The vaccine should not be administered intravascularly or intradermally.

Booster Doses and Re-Immunization

Based on the available information, booster dose(s) of MMRV is/are not recommended after the primary series of two doses.

Serologic Testing

Serologic testing for measles, mumps, rubella and varicella antibodies post-immunization with MMRV vaccine is unnecessary and not recommended, either before, between or after the primary two-dose series. The commonly available laboratory tests (e.g., ELISA, IFA) used to document immunity after wild-type varicella infection may not be sensitive enough to detect protective antibody levels, especially after a single dose of varicella-containing vaccine (it is still unknown if the higher titers seen after two doses of varicella-containing vaccine are detected by these tests) (3).

Storage Requirements

The lyophilized product should be protected from light. The vaccine should only be reconstituted with the diluent supplied by the manufacturer for this purpose. Both lyophilized product and diluent should be stored in a refrigerator at 2°C to 8°C. It should not be frozen. The expiry date of the vaccine is indicated on the label and packaging.

The reconstituted vaccine should be administered as soon as possible; if necessary, reconstituted vaccine may be stored in a refrigerator at 2°C to 8°C for up to eight hours.

Simultaneous Administration with Other Vaccines

MMRV can be given simultaneously (but at separate injection sites) with DTaP, Hepatitis B, IPV, Hib, and pneumococcal conjugate 10 vaccines.

A study by Zepp et al. randomized children 12 to 23 months old in Germany to a single dose of MMRV (137 subjects), DTaP-HBV-IPV/Hib (135 subjects), or MMRV and DTaP-HBV-IPV/Hib (CoAdmin group, 134 subjects) (15). The MMRV used cont^{ained a slightly lower mumps TCID}50 ^{(103.7) as opposed to the} commercial product in Canada (10^4.4). Seroconversion to measles, mumps, rubella and varicella was achieved by 95%, 80%, 99% and 98% of subjects in the CoAdmin group, as compared with 97%, 80%, 100% and 100% in the MMRV-only group, respectively (15). The GMTs were comparable between the groups with respect to mumps and rubella, but slightly lower for measles (3,441.8 mIU/mL versus 4,419.2 mIU/mL) and varicella (288.6 versus 316.0) in the CoAdmin group compared with the MMRV-only group. Seroconversion rates and GMTs for antibodies to diphtheria, tetanus, hepatitis B (HBsAb), pertussis toxin, filamentous hemagglutinin, pertactin, polio 1, polio 2, polio 3 and PRP (Hib) were high (93%–100%), and comparable between the DTaP-HBV-IPV/Hib group and the CoAdmin group. The GMT for HBsAb was higher in the CoAdmin group (6,017mIU/mL) compared with the DTaP-HBV-IPV/Hib group (4,602.4 mIU/mL).

An open, controlled study by Vesikari et al. examined the safety, reactogenicity and immunogenicity of a booster dose of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) when co-administered with MMRV vaccine. The study randomized 325 healthy 12- to 14-month-old children to one of three groups (Group 1: PHiD-CV and MMRV vaccine, followed six to eight weeks later by MMRV and DTPa-HBV-IPV/Hib vaccines; Group 2: DTPa-HBV-IPV/Hib and MMRV vaccines followed six to eight weeks later by PHiD-CV and MMRV vaccine; Group 3: PHiD-CV and DTPa-HBV-IPV/Hib vaccine during one vaccination visit). The investigation revealed that PHiD-CV and MMRV vaccine can be co-administered without compromising the safety and immunogenicity profiles of either vaccine. Co-administration resulted in an additive effect in terms of the reactogenicity of the vaccines but did not exacerbate the individual reactogenicity profiles (25).

No published immunogenicity data are currently available when simultaneously administering MMRV with meningococcal C conjugate, meningococcal quadrivalent conjugate, pneumococcal conjugate 7, pneumococcal polysaccharide 23 or influenza vaccines. However, there are currently no theoretical reasons why co-administration with these other vaccines would interfere with the response to MMRV vaccine.

Apart from the study by Vesikari et al., in which one group received sequential MMR and MMRV vaccines from two different manufacturers, there is insufficient information on the interchangeability of MMR and MMRV vaccines (13).

Adverse Reactions

Data from the published studies and from the manufacturer’s database of over 6,700 administered doses have shown that MMRV is well tolerated. Adverse events were followed for 42 days post-vaccination. When MMRV was given as a single dose to children after the first birthday, pain was observed in 11%, redness in 52%, swelling in 17%, any degree of fever in 29% (but only 10% with fever ≥ 39.5°C) and vesicular rash in about 4% (11). This was comparable to the MMR+V or MMR groups.

When two primary doses of MMRV were administered six to eight weeks apart after 12 months of age, the first dose was associated with a higher rate of adverse events; i.e., pain in 8% to 12%, redness in 30%, swelling in 10%, fever in 60% to 68% (10% ≥ 39.5°C), and measles/rubella-like or varicella-like rashes in 3% to 5% (9,12). These rates were comparable to the group given MMR+V, except for fever, which was significantly lower in the MMR+V group, 50% (10% ≥ 39.5°C). The rates were lower after the second dose of MMRV; pain in 9% to 14%, redness in 33%, swelling in 14%, fever in 36% to 43% (5% ≥ 39.5°C) and measles/rubella-like rash in 1% (9,12).

When MMRV was administered as the second dose at 15 to 75 months of age after having previously received MMR+V after the first birthday, the rates for pain were 33% (pain on moving the limb in 1%), redness 37% (>20 mm in 14%), swelling 22% (>20 mm in 5%), fever 19% (2% ≥ 39.5°C) (17). These were not significantly different from the control group, which received MMR+V as the second dose, except for pain, which was lower in the MMR+V group (24%). A similar observation was made in the study by Vesikari et al. where pain was reported by 73% in the group receiving second-dose MMRV (after previous MMRV) and 58% in the group receiving MMRV (after previous MMR) (13).

When MMRV was administered at least six weeks after previous MMR in 15 to 23 month-old and 2 to 6 year-old children in the study by Gillet et al., the rates of generalized rash, varicella-like rash, measles or rubella-like rash, local pain and swelling were all comparable to the corresponding control subgroups, who received MMR+V (16). However, local site (any size) redness was significantly more common in the MMRV group (28%), when compared to the MMR+V group (12% to 13%) for the 15 to 23month-old age group, but not the 2 to 6 year-old age group. Redness measuring > 20 mm was not significantly different between study and control groups for either age group. Fever ≥ 38.0°C occurring within 14 days post-vaccination in 15 to 23 month-old children was more common in the MMRV subgroup (41%), than in the MMR+V subgroup (32%). For the 2 to 6 year-old children, the proportion reporting fever ≥ 38.0°C was similar for the MMRV and MMR+V subgroups (16% and 21%, respectively). The rates of fever ≥38.0°C were also significantly higher in the 15 to 23 month-old, as compared with the 2 to 6 year-old children in both study and control groups. However, the rate of Grade 3 fever (i.e., ≥ 39.5°C) post-vaccination was not significantly different between study and control groups (2% to 3% each). Fever ≥38.0°C was also documented up to 42 days post-vaccination; the rates were consistently higher in the MMRV subgroups (53% and 30% for the 15 to 23 month-old and 2 to 6 year-old age groups), compared with the MMR+V subgroups (44% and 30%, respectively).

In the study where MMRV was administered simultaneously with DTaP-HBV-IPV/Hib, the rate of localized redness, swelling and rash at the MMRV and DTaP-HBV-IPV/Hib injection sites in the CoAdmin group was comparable to those in the single (individual) vaccine groups (15). The rate of fever in the CoAdmin group was comparable with the MMRV group (76% versus 74% respectively), which were both higher than the DTaP-HBV-IPV/Hib group (48%), suggesting that the MMRV was more likely responsible for the fever in the CoAdmin group.

Febrile Seizures after First Dose of ProQuad™ in the U.S. (Currently Not Authorized in Canada)

Febrile seizures are reported in 2% to 5% of children between the ages of 3 months and 5 years (26). They are frequently associated with underlying viral infections and may follow childhood immunizations. Febrile seizures that are generalized but short-lived (< 15 minutes), that occur at the height of the fever and that do not recur after treating the fever are generally considered benign, with an excellent neurological prognosis (27). A benign febrile seizure occurring after immunization is not considered a contraindication for future vaccination with either the same, or other childhood vaccines (CIG 2006, p. 77 (1)).

Febrile seizures that may occur after MMRV vaccination deserve further discussion because of an association recently reported in the U.S (28). The rate of febrile seizure in children receiving the first dose of ProQuad^TM, Merck Inc. (currently not authorized in Canada), was higher when compared with children receiving MMR and varicella vaccines administered separately. In a post-licensure study using the Vaccine Safety Datalink or VSD [with 43,353 children aged 12 to 23 months who received MMRV vaccine and 314,599 children who received MMR and varicella (MMR+V) vaccines separately], the febrile seizure rate seven to 10 days after vaccination was nine per 10,000 vaccinations among the MMRV recipients, compared with four per 10,000 vaccinations among the MMR+V recipients (adjusted odds ratio = 2.3; 95% confidence interval [CI]: 1.6–3.2; p<0.0001) (28).

It was estimated that one additional febrile seizure would occur among every 2,000 children immunized with MMRV, compared with children vaccinated with MMR+V. Of the 166 children who experienced febrile seizures after vaccination, 26 (16%) were hospitalized, with no fatality.

In a separate post-marketing study by Merck Inc. involving children aged 12 to 60 months (where 99% were aged 12 to 23 months), the investigators reported a 2.3 times (95% CI: 0.6–9.0) higher relative risk for febrile seizures five to 12 days after MMRV vaccination (n = 14,263 children; rate = 5 per 10,000 vaccinations), when compared with a historic control group of children vaccinated with MMR+V at the same visit (n = 14,263 children; rate = 2 per 10,000 vaccinations) (29). This study by Merck Inc. was later expanded to encompass a larger sample size, n = 31,298 children for each of two groups, with similar results. The rate of febrile seizures five to 12 days after first vaccination with MMRV was 0.7/1,000 doses, as compared with 0.32/1,000 doses in the MMR+V group (RR = 2.2, 95% CI: 1.04–4.65).

The incidence of febrile seizures after a second dose of ProQuad^TM administered at 4 to 6 years of age in the U.S. was not assessed by the VSD and Merck Inc. studies (28). However, the second dose of ProQuad^TM is less likely to cause fever as compared with the first dose, and the risk of febrile seizure is lower among children aged 4 to 6 years than in infants. In February 2008, the ACIP changed its 2007 recommendations by no longer expressing a preference for use of MMRV vaccine over separate injections of MMR vaccine and varicella vaccine (implying either MMRV or MMR+V may be used for the first dose) (28).

Febrile Seizures after Priorix-Tetra^TM

The rate of febrile seizures after the administration of the GSK’s MMRV vaccine Priorix-Tetra^TM has not been reported to be higher when compared with MMR+V administered separately. This is in spite of the observed higher rate of fever (≥ 38.0°C, although not for ≥ 39.5°C) after the first dose of MMRV in children under 2 years of age. It is unclear whether the less common occurrence of febrile seizure can be attributed to the lower potency of varicella present in Priorix-Tetra^TM, compared with ProQuad^TM (Table 1), or whether studies of Priorix-Tetra^TM to date have been too small to detect a true difference in febrile seizures. In the study by Schuster et al., where two doses of MMRV, or MMRV followed by MMR were administered six weeks apart in children 10 to 21 months of age, febrile seizure was uncommon and comparable in both MMRV [three out of 732 (0.4%); only one of the three was deemed to be related to vaccination] and MMR+V [one out of 232 (0.4%)] groups (9). Gillet et al. also documented febrile seizures occurring in their cohort of 458 children aged 15 months to 6 years previously vaccinated with MMR, and randomized to receive either MMRV, or MMR+V followed by a dose of V six to eight weeks later. Only one patient in the control group had a febrile seizure after both the MMR+V and V vaccinations (16). Consequently, larger post-licensure studies may be needed to document if there is any increase in febrile seizure rates after Priorix-Tetra^TM.

For surveillance purposes, the Immunization Monitoring Program, Active (IMPACT) surveillance system in Canada is designed to provide data on children hospitalized for febrile seizures after receiving childhood vaccines (which would include MMRV) in 12 pediatric tertiary care centres. Vaccine providers are also encouraged to report any cases presenting with febrile seizures within 30 days post-MMRV to the Canadian Adverse Event Following Immunization Surveillance System (CAEFISS) at PHAC. In April 2008, Quebec replaced separate MMR and univalent varicella vaccination with a single dose of Priorix-Tetra^TM for routine immunization of children at 12 months of age. The Institut national de santé publique du Québec conducts ongoing surveillance for adverse events following immunization, and may be able to determine the rate of febrile seizures in children after receiving Priorix-Tetra^TM.

Risk of Zoster after MMRV

The risk of zoster after vaccination with either one or two doses of MMRV is currently unknown, as the follow-up periods in the studies were not sufficiently long enough to determine this complication rate.

Contraindications

MMRV is contraindicated in:

• • Persons with anaphylaxis after previous administration of MMRV or the corresponding MMR or univalent varicella vaccines (suspected or proven hypersensitivity to one of the vaccine antigens, neomycin or any other component of the vaccine). Note that GSK’s Priorix-Tetra^TM and Varilrix^TM do not contain gelatin (unlike the corresponding Merck Inc. vaccines, ProQuad^TM and Varivax-III^TM, which do). Priorix-Tetra^TM is therefore not a contraindication in persons with a specific hypersensitivity to gelatin.

• • Persons with impaired immune function, including primary or secondary immunodeficiency disorders.

• • Pregnancy should not be a major issue with the use of MMRV since it is not recommended for children over 12 years of age; however, the following points are repeated as a reminder. Pregnancy should be avoided for at least 4 weeks (the manufacturer recommends three months) after vaccination with MMRV. Limited information available to date does not indicate any increased risk of congenital infection after inadvertent exposure to rubella or varicella vaccines (see CIG 2006, p. 108–109) (1). Consequently, inadvertent exposure to MMRV vaccine during pregnancy does not constitute a reason to recommend termination of that pregnancy.

Precautions

• • The measles and mumps components are produced in chick embryo cell culture, while the rubella and varicella components in MRC-5 cells. While MMRV may contain traces of egg protein, the situation should be similar to MMR, where the amount of egg protein appears to be insufficient to cause an allergic reaction in egg-allergic persons (refer to CIG 2006, p. 85–86 for further details) (1). Skin testing with MMRV is not recommended prior to vaccination. As for all vaccines, immunization should be performed by personnel with the capability and facilities to manage adverse events post-vaccination.

• • Transmission of measles, mumps and rubella vaccine viruses from vaccinees to susceptible contacts has not previously been documented even though pharyngeal excretion of the rubella virus may occur from seven to 28 days after vaccination. Transmission of varicella vaccine virus occurs rarely between vaccinees who develop a varicella-like rash and susceptible close contacts (3).

• • Similar to MMR and varicella vaccines, MMRV should be delayed for three to 11 months following the administration of Immune Globulin (IG) or blood products (please refer to the Canadian Immunization Guide 2006, p. 54 for the specific delay period following each product) (1). MMRV need not be delayed if only washed red blood cells (RBCs) or palivizumab (RSV monoclonal antibody) were used.

• • The manufacturer recommends avoidance of salicylate use for six weeks after MMRV immunization because of an association between wild-type varicella, salicylate therapy and Reye’s syndrome. Physicians should weigh the theoretical risks associated with varicella vaccine against the known risks associated with wild-type varicella infection. Adverse events have so far not been reported with the use of salicylates after varicella immunization. Consequently, children and adolescents with conditions requiring chronic salicylate therapy should be considered for immunization, with close subsequent monitoring.

• • Administration of MMRV should be postponed in persons with severe acute febrile illness. The presence of a minor infection, such as an upper respiratory infection with rhinorrhea, should not result in deferral of vaccination.

Other Considerations

The cost-effectiveness of a one-dose and two-dose varicella (univalent vaccine) immunization program for children in Canada has been studied using mathematical modelling of varicella and zoster disease (see further discussion in the NACI statement “Varicella Vaccination Two-Dose Recommendations” (7)). Cost-effectiveness data for Canada using two doses of MMRV in place of univalent varicella vaccine are not yet available.

Research Priorities for MMRV Vaccine

• • To determine the most effective ages for administering a two-dose MMRV schedule, and the duration of long-term protection afforded by two doses of MMRV vaccine in children.

• • To establish post-marketing surveillance in order to determine the febrile seizure and zoster rates after MMRV vaccination in Canada.

• • To determine whether MMRV is effective and safe in susceptible adolescents and adults, as well as in children with selected immunodeficiency disorders (where univalent varicella vaccine is currently permitted if clinical prerequisites are met).

Table 3. Quality and Strength of Evidence (30-32).

Level of evidence based on research design
I	Evidence obtained from at least one properly randomized, controlled trial.
II-1	Evidence obtained from well-designed, controlled trials without randomization.
II-2	Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one centre or research group (including immunogenicity studies).
II-3	Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments could also be included in this category.
III	Opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees.
Quality (internal validity) rating
Good	A study (including meta-analyses or systematic reviews) that meets all design-specific criteria* well.
Fair	A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion* but has no known “fatal flaw.”
Poor	A study (including meta-analyses or systematic reviews) that has at least one design-specific* “fatal flaw,” or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations.
*General design specific criteria are outlined in Harris et al., 2001. (32)
NACI recommendation for immunization: grades
A	NACI concludes that there is good evidence to recommend immunization.
B	NACI concludes that there is fair evidence to recommend immunization.
C	NACI concludes that the existing evidence is conflicting and does not allow making a recommendation for or against immunization; however, other factors may influence decision.
D	NACI concludes that there is fair evidence to recommend against immunization.
E	NACI concludes that there is good evidence to recommend against immunization.
I	NACI concludes that there is insufficient evidence (in either quantity and/or quality) to make a recommendation; however, other factors may influence decision making.