Varicella Vaccination Two-Dose Recommendations

†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 mono-graph(s). Recommendations for use and other information set out herein may differ from that set out in the product mono-graph(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

NACI first recommended universal varicella in 1999 (1) and published updated guidance in 2002 and 2004 (2,3), as well as in the varicella chapter of the Canadian Immunization Guide, 7^th Edition, 2006 (4). More recent epidemiology has been published regarding the effect of single-dose childhood varicella vaccination programs in the United States. In this statement, NACI reviews this epidemiology, the development of varicella vaccination programs in Canada and the U.S., and outlines the rationale for recommending a two-dose primary vaccination schedule for varicella in children.

As a component of the NACI’s evidence-based decision-making, the Public Health Agency of Canada (PHAC) contracted a systematic literature review to summarize scientific studies on the benefits and limitations of a one- or two-dose varicella vaccination schedule for children 12 months to 12 years of age. That report (5) was used to prepare this Advisory Committee Statement (ACS) and will be available on the NACI website of PHAC at: http://www.phac-aspc.gc.ca/naci-ccni/index-eng.php#lr.

Objectives for Varicella Immunization in Canada

The objectives for varicella immunization in Canada were determined at a national consensus conference on vaccine preventable diseases in Quebec City in June 2005 (6). A specific goal for varicella disease control is to reduce illness and death due to complications from varicella through immunization by:

• • Achieving a reduction of 70% and 90% in the incidence of varicella by 2010 and 2015 respectively;

• • Decreasing varicella-related hospitalization rates by 80% by 2010; and

• • Decreasing varicella-related deaths by 80% by 2010.

To achieve these disease-reduction targets, specific goals were set for varicella immunization coverage, namely:

• • To achieve and maintain age-appropriate immunization coverage in 85% of children by their second birthday, in 85% of susceptible children by their seventh birthday and in 85% of susceptible adolescents by their 17^th birthday by 2010;

• • To achieve and maintain 100% demonstrated varicella immunity in health care workers, by either history of disease, positive serology or prior immunization; and to vaccinate if not immune, unless contraindicated, by 2010;

• • To screen 100% of pregnant women annually for immunity to varicella, by either history of disease, prior immunization or positive serology, by 2010. Achieve and maintain immunization coverage with varicella vaccine in 100% of postpartum women without evidence of immunity, unless contraindicated, by 2010.

Canadian Varicella Epidemiology and Immunization Program Status

Univalent varicella vaccine was first approved in Canada in December 1998. By 2004, two refrigerator-stable univalent varicella vaccines were available for use (3). For primary immunization of children 12 months to 12 years of age, NACI currently recommends a single dose of vaccine for susceptible healthy children, and two doses administered three months apart for susceptible children with specific immunodeficiency diseases such as acute lymphocytic leukemia (ALL) and Human Immunodeficiency Virus (HIV) infection, provided strict prerequisites are met. For susceptible healthy individuals 13 years and older, vaccination with two doses administered four to six weeks apart is recommended (3,7).

In July 2007, a combination measles-mumps-rubella-varicella vaccine (MMRV, Priorix-Tetra^TM, GlaxoSmithKline Inc.) was authorized in Canada and is the subject of a separate NACI statement (8). The primary immunization of healthy children 12 months to 12 years of age with MMRV, using a two-dose schedule, was authorized with a minimum interval of four weeks between the doses.

Publicly funded routine varicella immunization programs were implemented by provinces and territories between 2000 and 2007 (Table 1) (5). Currently healthy children are offered a single varicella vaccine dose at either 12 months (in 11 provinces and territories) or 15 months of age (in Ontario and Nunavut) (5). Most jurisdictions also offer a variety of catch-up programs for susceptible older children and adolescents (Table 1).

Table 1. Initiation Dates for universal, Publicly Funded Primary and Catch-up Varicella Immunization Programs for Children 12 months to 12 Years of Age in Canadian Provinces and Territories (as of December 2009).

Province or territory	Start mo./yr.	Age at primary immunization for healthy children (1 dose)	Catch-up immunization of susceptible children (1 dose)
Prince Edward Island	April 2000	12 months	Nil
Alberta	March 2001	12 months	At preschool & in Grade 6 (completed)
Northwest Territories	Sept. 2001	12 months	Between 18 mos. & 4 years old
Nova Scotia	Sept. 2002	12 months	Between 1 & 6 years old
Nunavut	Sept. 2002	15 months	Nil
Ontario	Sept. 2004	15 months	At preschool (completed)
New Brunswick	Sept. 2004	12 months	Nil
Manitoba	Oct. 2004	12 months	At preschool & in Grade 4
Newfoundland & Labrador	Jan. 2005	12 months	At preschool
Saskatchewan	Jan. 2005	12 months	In Grade 6
British Columbia	Jan. 2005	12 months	At preschool & in Grade 6
Quebec	Jan. 2006	12 months	At preschool & in Grade 4
Yukon	Jan. 2007	12 months	Nil

Assessing the impact of publicly funded varicella vaccine programs in Canada to date has been challenging because of the limited disease surveillance systems and vaccine coverage data.

The PHAC national surveillance system for varicella is passive, so significant under-reporting of cases is expected. In addition, varicella is not a reportable disease in many provinces and territories. Further, the case definition for reporting requires laboratory confirmation of the infection, which is not performed by the majority of clinicians, and varicella infection with milder symptoms due to the effect of previous immunization may not be recognized by clinicians.

The available data on varicella are summarized below:

• • Active surveillance for children hospitalized with varicella in Canada is conducted by the Immunization Monitoring Program, Active (IMPACT), which operates in 12 tertiary-care pediatric hospitals in eight provinces. IMPACT is managed by the Canadian Paediatric Society (CPS) and funded by PHAC. IMPACT has published data on the epidemiology of pediatric hospitalized varicella cases in the pre-vaccine era 1991–1996, and on the costs attributable to varicella in Canada (9,10). Post-vaccine era epidemiology were presented recently at a scientific meeting and are summarized here (11). Five provinces and territories began publicly funded programs in 2000–2002 (Prince Edward Island, Nova Scotia, Alberta, Northwest Territories and Nunavut). The IMPACT hospitals in Halifax, Edmonton and Calgary serve as tertiary referral centres for the first four of these jurisdictions and have seen an 84% decline in hospitalizations (i.e. nine cases in 2006 and eight cases in 2007 at all three centres, as compared to a mean of 50 hospitalizations per year reported between 1999 and 2002). The other provinces and territories began programs later (in 2004–2006), and had observed a 65% reduction in hospitalizations at the other nine IMPACT centres (89 cases in 2007 at all nine centres, compared to a mean of 253 cases per year between 1999 and 2004). The percentage of hospitalized children in all 12 IMPACT centres who had previously received single-dose varicella vaccination increased from < 1% in 1999–2002, to 2%–5% in 2003–2005 and 10%–12% in 2006–2007, indicating that breakthrough disease accounted for an increasing but relatively small proportion of hospital admissions over time.

  The epidemiology of varicella in Canada in the pre-vaccine era was shown to be similar to that in the U.S. and European countries, with disease occurring predominantly in healthy children 1 to 4 years and 5 to 9 years of age (9,11-13). A study in Alberta (14) using health care and hospitalization databases for the period from 1986 to 2002 documented a declining trend in varicella disease incidence even before vaccine availability, but there was a more significant decline in disease among children <1 year and 1 to 4 years of age in 2001–2002, compatible with a vaccination program effect (which began in 2001).

• • A decreasing incidence of varicella following introduction of vaccine was observed in Ontario based on hospitalization data, emergency room and physician visits. Kwong et al. (15) assessed the effects of the private availability of varicella vaccine in 1999–2004 and the subsequent publicly funded vaccination program in 2005–2006, compared with the pre-vaccine era (1992–1998). Hospitalization data were obtained from the Canadian Institute of Health Information (CIHI), and the ER and physician visits obtained from the Ontario Health Insurance Plan (OHIP) databases. The rates of hospitalizations, ER visits and physician visits decreased only by 9%, 23% and 29%, respectively, after private availability, but fell by 53%, 43%, and 45%, respectively, after publicly funded vaccination began (both time periods compared with the pre-vaccine era). The greatest decreases after introduction of publicly funded vaccination were observed in the 1- to 4-year-old age group, which was the age group targeted by the immunization program. There were smaller decreases observed in children under 1 year of age and in 5 to 9 year-old children, suggesting indirect protection, or a herd-immunity effect.

• • It is not known if the frequency of varicella outbreaks has changed since the introduction of vaccine programs in Canada. This outcome is measured in the U.S., with the published outbreaks summarized in the varicella review prepared for PHAC (5). There are no accepted guidelines for the investigation or management of community varicella “outbreaks” in Canada, and no publications describing outbreaks in Canadian day care centres or schools in either pre- or post-vaccine eras were found in our review process.

• • Immunization coverage in Canadian children is estimated by the National Immunization Coverage Surveys (NICS), conducted by PHAC every two years using a telephone survey method since 2002 (16). The single-dose varicella vaccine coverage by the second birthday nationally was estimated to be 32% in 2004 and 58% in 2006 (PHAC, unpublished information). In Alberta and Saskatchewan, where varicella vaccination is predominantly provided through public health clinics and computerized immunization records are maintained, varicella vaccine coverage in 2007–2008 by the second birthday was 88% (regional coverage varies from 67% to 95%) in Alberta and 75% for Saskatchewan (personal communication E. Sartison, Alberta Health, and R. Tuchscherer, Saskatchewan Health). The Saskatchewan estimate may be lower than the true coverage, as it does not include coverage in communities that are thought to have excellent coverage but are currently not in the computerized immunization registry.

United States Varicella Epidemiology and Immunization Program Status

Varicella vaccine was licensed in the U.S. in 1995, with a single dose recommended for susceptible children aged 12 months to 12 years, and two doses for susceptible adolescents and adults. Varicella vaccination coverage in the U.S. among children aged 19–35 months increased from 27% in 1997 to 90% in 2007 (17,18). In June 2006, the Advisory Committee on Immunization Practices (ACIP) changed their recommendations for varicella vaccine (17). The ACIP recommended that children < 13 years of age routinely receive two doses of varicella-containing vaccine, with the first dose administered at 12 to 15 months of age and the second dose at 4 to 6 years of age, with a catch-up second dose for school-age children. However, the available published studies have shown that the second varicella vaccine dose can be administered at an earlier age, as long as the interval between the doses is at least three months.

An active surveillance program for varicella in the U.S. has tracked varicella-related illness since 1995. Conducted by the U.S. Centers for Disease Control and Prevention (CDC) in conjunction with local health authorities, these Varicella Active Surveillance Projects (VASP) in three communities (Antelope Valley, Calif., Travis County, Tex., and West Philadelphia, Pa.) report varicella and zoster (shingles) cases every two weeks, with collection of demographic data, vaccination status and the clinical severity. In addition, the U.S. public health system has investigated and managed numerous varicella outbreaks since varicella vaccine was available in 1995. Proof of varicella vaccination is required in 44 states for entry into childcare and/or school. Consequently, outbreaks of varicella that occurred in childcare and school settings were investigated. This has strained public health resources (17,19-21).

The data from VASP sites, other prospective surveillance studies and analyses of outbreaks have confirmed the benefit of single-dose vaccination programs in the U.S., summarized as follows:

• • There has been a reduction in varicella disease incidence. By 2000, the number of reported varicella cases had declined by 71%–84% (22), concomitant with an increase in the vaccination coverage among children 19–35 months old in the three VASP sites to 74%–84%. The greatest drop in incidence occurred in children aged 12 months to 4 years (83%–90% reduction), but incidence also declined in non-immunized age groups, suggesting that indirect protection (herd immunity) had occurred. Since 2001, only two VASP sites have continued active surveillance (Antelope Valley and West Philadelphia). In 2005, vaccination coverage in these two sites had increased to 90%, with a corresponding drop in disease incidence by 91% (17,23).

• • There has been a reduction in varicella-related hospitalizations. In a study conducted in the U.S. during 1993–2001, Davis et al. reported that varicella-related hospitalizations declined by 75% (24). In another U.S. study conducted during 1994–2001, Zhou et al. reported that the varicella-related hospitalization rate declined by 88% (25). In the latter study, hospitalization rates declined by 91% among children aged <10 years, 92% among children and adolescents aged 10 to 19 years, and 78% among adults aged 20 to 49 years. The varicella-related hospitalizations in two VASP sites also declined from 2.4–4.2 hospitalizations per 100,000 population during 1995–1998, to 0.8 per 100,000 population in 2005 (17,23). Level II-3 Evidence, Quality good. (See Table 4)

• • There has been a reduction in mortality due to varicella. The number of varicella-related deaths in the U.S. decreased from 115 in 1995 to 26 in 2001 and to 16 in 2003 (17,26). The mortality rates decreased from an average of 0.41 deaths per million population during 1990–1994 to 0.14/million during 1999– 2001. The decline was observed in all age groups under 50 years; the greatest reduction (92%) occurred among children aged 12 months to 4 years (to 0.09 deaths/million population), and a slightly lower reduction (88%) among children aged 5 to 9 years (to 0.10 deaths/million population) (17,26). The impact on mortality rate in persons over 50 years of age cannot be determined, as deaths in this age group cannot be reliably attributed to varicella (as opposed to zoster and other medical complications).

• • Follow-up of children in the pre-licensure varicella vaccine studies, though limited in duration, have demonstrated a reduced risk for zoster in vaccinated children (including children with acute leukemia who were vaccinated), as compared with unvaccinated children who had developed wild-type varicella (3,27-30). When zoster occurs, it may be caused by reactivation of wild-type or, less commonly, vaccine virus (29).

• • There appears to be a reduction in the proportion of invasive Group A Streptococcal (iGAS) disease cases associated with varicella since the introduction of the vaccine. A study in Chicago from 1993–2001 showed a decrease in proportion of varicella-related iGAS from 27% to 2% (31).

Limitations of a Single-Dose Vaccine Recommendation for Children in the U.S.

In spite of the high vaccination coverage achieved and the observed benefits outlined above with the implementation of single-dose primary immunization of children 12 months to 12 years of age, the CDC has identified limitations of the single-dose recommendation in achieving varicella disease control. These limitations are summarized below:

• • Although varicella disease incidence has reached a nadir, the number of cases is now remaining constant with no further decline despite vaccine coverage rates of 90% in VASP sites as well as in states with well-established vaccine and surveillance programs (17,32).

• • There appears to be an upward shift in the median age at disease onset for children with and without history of immunization. For instance, in Antelope Valley the median age of breakthrough (or vaccine-modified) disease onset in vaccinated children rose from 5 years to 8 years, and in unvaccinated children from 5 years to 13 years. In West Philadelphia, the shift in median age in unvaccinated cases was more marked, from 6 years to 19 years. Should this trend continue, the concern is that varicella disease may be shifted to the adult age group, which is known to be associated with more severe complications (33).

• • Although the total number of outbreaks has fallen in the VASP sites, childcare centres and schools continued to report outbreaks between 2001 and 2005 (23,34). Outbreaks occurred despite varicella vaccination coverage rates of 75%–97% (35,45) In these outbreaks, vaccine effectiveness (VE) for any disease severity was estimated to be in the range of 70%–85%, except for two studies where VE was 20% and 44% respectively (38,42). However, vaccine was >90% effective in preventing severe disease. Further details on each outbreak are outlined in the varicella review on the NACI–PHAC website (5).

• • The index cases in some outbreaks were vaccinated children who developed breakthrough varicella and transmitted the infection to others (38). Approximately 60%–80% of break-through disease is mild (with <50 lesions) (46,47). However, those with moderate or severe breakthrough disease (associated with ≥50 lesions) were found to be just as likely to transmit the infection as unvaccinated cases with wild-type disease. Those with <50 lesions were approximately one third as contagious (47). Furthermore, the proportion of breakthrough disease among all reported cases increased steadily in the VASP sites, from 3.5% in 1997 to 24% in 2000, and to 78% in 2005 (46). Although breakthrough disease is considerably milder than wild-type varicella in unvaccinated children, it is still associated with complications in approximately 5% of cases (including encephalitis). Breakthrough disease often presents with atypical rash — predominantly maculopapular and of shorter duration, rather than the classical vesicular rash. The atypical appearance poses diagnostic challenges for the clinician, and may be the reason why physician visits for breakthrough disease were twice as common as visits for wild-type disease in the VASP sites. Breakthrough disease may also require laboratory confirmation by a polymerase chain reaction (PCR) test rather than standard serological tests (48). Children previously vaccinated with a single dose of varicella vaccine who subsequently develop neoplastic or other immunosuppressive disease may develop significant breakthrough disease, requiring antiviral treatment (49).

• • Primary vaccine failure appears to be partly responsible for breakthrough disease (50-53). In the pre-licensure clinical trials for Varivax^TM (Merck & Co., Inc.) a proprietary gpELISA test was used to determine varicella antibody responses, with a level of > 0.6 gpELISA units set as the criterion for seropositivity; 97% of children 1 to 12 years old achieved this level post-vaccination after a single dose. Subsequent studies indicate that a higher titer of ≥ 5.0 gpELISA units provided better protection against breakthrough disease (children with this titer were 3.5 times less likely to have disease, compared with those with < 5 gpELISA units) (54). Only 85.7% of children who received a single dose of vaccine achieved ≥ 5.0 gpELISA units, compared with 99.6% of children who received two doses (53,55). Another study using a different antibody test, Fluorescent Antibody against Membrane Antigen (FAMA), found that only 76% of children achieved a FAMA titer of >1:4 (correlate of protection) at 16 weeks after a single-dose (17,50). Ninety-four percent of susceptible adults who routinely receive two primary vaccine doses develop FAMA titers of >1:4 (56).

• • Studies have attempted to address whether the age at vaccination increases the risk for primary vaccine failure. In childcare and school outbreaks reported in the U.S., the investigators analyzed multiple risk factors for vaccine failure, including age at vaccination and time since vaccination. The data for the age at vaccination were conflicting, with some studies suggesting that there was a higher risk for breakthrough disease in children vaccinated at < 15 months of age compared to those vaccinated at ≥ 15 months of age (36,39,57-59), while other outbreak studies did not find this a significant risk factor (35,38,59). A recent review of post-licensure trials with Varivax^TM has addressed this issue, looking at antibody responses of cohorts ofren immunized at 12 to 14 months, 15 to 17 months and 18 to 23 months of age: the seroconversion rates and geometric mean titers (GMTs) were similar in all three groups (60). This conclusion was supported by a study in northern California, which similarly found no association between age at vaccination and risk for subsequent breakthrough disease (61).

• • Waning immunity (secondary vaccine failure) may also account for subsequent breakthrough disease, with several outbreak studies in the U.S. reporting that time since vaccination was an important risk factor (35,38,39,59,62). A Canadian study reported an average breakthrough rate of 3.1% per year over a relatively short follow-up period of three years. (28) VASP data from 1995–2004 in Antelope Valley showed an overall breakthrough disease rate of 9.5% over the surveillance period, with greater time since vaccination as a risk factor for moderate to severe breakthrough disease (the risk ratio for moderate to severe breakthrough disease was 2.6 (95% CI: 1.2–5.8) for children immunized at least five years previously, compared with those immunized within the previous five years. The annual rate of breakthrough disease in Antelope Valley also increased from 1.6 cases per 1,000 person-years (95% CI: 1.2–2.0) within one year after vaccination, to 9.0 per 1,000 person-years (95% CI: 6.9–11.7) at five years, and 58.2 per 1,000 person-years (95% CI: 36.0 - 94.0) at nine years after vaccination (32). Finally, a case-control study conducted in Connecticut also found a high VE of 97% in the first year, falling to VE of 84% at two to eight years post-vaccination (63).

Benefits and Potential Limitations of a Two-Dose Varicella Vaccination Schedule in Children

Evidence to support the potential benefits of a two-dose varicella vaccine schedule is found in studies in which a two-dose schedule was used. This consists of follow-up studies of children enrolled in a randomized controlled trial of one- and two-dose vaccine schedules, the immune responses to one- and two-dose schedules, a retrospective outbreak investigation, and modelling studies. Table 2 summarizes what is currently known about the benefits and limitations of one- and two-dose primary immunization schedules.

Table 2. Potential or Proven Benefits and Limitations of 1-Dose and 2-Dose Primary Varicella Vaccination in Children (see relevant section in text for references).

Potential outcomes	One dose	Two doses
Reduce varicella disease incidence, as compared to the pre-vaccine era	Yes, by ~64% over an 80-year projection period *	Yes, by ~86% over an 80-year projection period *
Reduce hospitalization	Yes	Anticipate further reduction
Reduce mortality	Yes	Anticipate further reduction
Reduce zoster incidence (all ages), as compared to pre-vaccine era	Yes, by ~5% over an 80-year projection period *	Yes, by ~11% over 80-year projection period *
Reduce zoster in the vaccinees	Yes	Anticipate further reduction
Reduce risk of secondary invasive Group A Streptococcus infection	Yes (shown in the study by Patel et al.)	Anticipate further reduction
Breakthrough disease (severity)	Yes (in 7%–30%; the majority were mild cases)	Yes, further reduction (in ~2%; all cases were mild)
Breakthrough cases can transmit infection	Yes (especially if breakthrough disease is moderate–severe)	Unknown (due to anticipated small number of cases)
Reduce outbreaks	Yes, but outbreaks continue to occur in childcare centres and schools in the U.S.	Anticipate further reduction (still too early to ascertain)
Antibody levels	Lower seroconversion rates in post-licensure studies (after resetting the seroprotective titer to a higher level – see text)	Significant boosting after the second dose whether administered 3 months later (2 doses of univalent vaccine) or 6 weeks to 4 years later (with 2 doses of MMRV)
Waning immunity	Yes (based on outbreak studies)	Anticipate less waning immunity (but rate of decline is unknown) *
Shift of varicella disease to older ages	Shifted to mean of 22 years for wild type, and 41 years for breakthrough disease *	Shifted to mean of 32 years for wild type, and 48 years for breakthrough disease *
Cost-effectiveness	Cost-saving, for a single dose at 12 mos.*	Cost-effectiveness ratios per QALY gained of 2-dose versus 1-dose vaccination: $106,000 (2 doses in the second year of life), $41,000 (2 doses at 12 mos. & preschool) and $28,000 (2 doses at 12 mos. & Grade 4), respectively *.

* Predicted in the model by Brisson et al., using base-case assumptions (71,72)

• • Kuter et al. prospectively followed 2,196 children for break-through disease over a 10-year period. These children had received either one dose or two doses of VarivaxTM administered three months apart at between 12 months and 12 years of age. As the children were potentially exposed to (and boosted by) wild-type disease during that time, the GMT of varicella antibody, monitored yearly, actually rose over time (rather than declined, as one might have expected from waning immunity). The initial GMT achieved after two doses was considerably higher than after one dose (142.6 v 12.5 gpELISA units, respectively). The cumulative risk of breakthrough disease was 7.3% in the one-dose group, versus 2.2% in the two-dose group at the end of the 10-year follow-up period (i.e. a 3.3-fold lower risk of breakthrough disease in the two-dose group) (5,53,64). In addition to this clinical protection, there was evidence for greater humoral and cell-mediated responses to two doses as compared with one dose (64,65).

• • The duration of immunity derived from two primary doses during childhood, other than the studies just cited, is unknown.

• • The adverse event rates after two doses compared with one dose were not reported in the Kuter study. Adverse events were less common after the second dose of univalent varicella vaccine in individuals ≥13 years old, and in select immunocompromised children in whom two-dose regimens were studied. Discussion of adverse event rates after two doses of MMRV is found in NACI’s MMRV advisory committee statement (8).

• • A 2006 school outbreak study in Arkansas assessed vaccine effectiveness of one-dose versus two-dose varicella vaccination, and found a lower attack rate (AR) among children who had received two doses of varicella vaccine (AR 10.4%), compared with those who had received one dose (AR 14.6%) (66). This was very early after the ACIP recommendation for two-dose catch-up vaccination in outbreak management was published. Varicella vaccination coverage amongst the schoolchildren during the outbreak was very high (97%), but only 39% had received two doses while 58% had received one dose. Further studies are needed to determine if the AR will fall further, once two-dose coverage is much higher.

• • Modelling studies can provide useful information about the potential effects of vaccine programs. In these mathematical models, assumptions about vaccine efficacy, safety, coverage and other factors are made and the subsequent impact on health outcomes projected. Although complex, these projections can assist in decision-making. Brisson et al. have modelled the potential effects of varicella vaccine programs on the epidemiology of varicella (chickenpox) and varicella-zoster (shingles) (67-70). In 2009, at the request of NACI and the Canadian Immunization Committee (CIC), the PHAC commissioned Brisson et al. to assess what the impact and cost-effectiveness of changing from a routine one-dose to a two-dose varicella vaccination schedule would be for Canadian children, with the second dose provided at different ages. These studies will be published shortly (71,72). A summary of the results is provided here; the reader is referred to the primary studies for details on assumptions and methods. Under base-case assumptions, this 2009 model predicts that over an 80-year projection period, one-dose childhood vaccination will reduce varicella and zoster cases from the pre-vaccine era by 64% (worst case=14%, best case=96%) and 5% (worst case=2%, best case=22%), respectively (73). This is largely due to an increase in the incidence of breakthrough varicella (with some wild-type disease) beginning 10 to 20 years after the initiation of childhood immunization programs and getting progressively larger over the subsequent decades. The model predicts that with the decline in disease numbers, there is a shift of the average age of wild-type varicella cases to 22 years, and breakthrough disease to approximately 41 years of age. Consistent with Brisson’s earlier model, there is estimated to be an initial increase in zoster cases, with subsequent decline.

  Under base-case assumptions, moving to a two-dose childhood schedule is predicted to reduce varicella and zoster by an additional 22% (worst case=0%, best case=83%) and 6% (worst case=0%, best case=14%), respectively (73). Providing the second dose at preschool is expected to have a greater effect on reducing long-term varicella incidence, as compared with two doses during the second year of life. A two-dose program could be expected to cumulatively reduce varicella by 86% and zoster by 11% over the 80-year projection period. There is estimated to be a further increase in the average age of wild-type (to 32 years of age) and breakthrough disease (to 48 years of age); however, this upward shift in age is offset by the anticipated further reduction in disease incidence, as compared to the one-dose schedule. In the model, providing the second dose at preschool is expected to have a greater effect on reducing long-term varicella incidence, as compared with two doses during the second year of life. Both schedules had similar effects on long-term zoster incidence. In the sensitivity analysis, the incremental effectiveness of the second dose is particularly sensitive to the true vaccine efficacy and population-mixing effect.

• • The cost-effectiveness in Canada of two-dose versus one-dose childhood schedules was also calculated using the same model assumptions as above (the source and extent of health care costs are also described) (72). The economic analysis was for an 80-year period, discounted at 5% per year, and conducted from the perspective of the ministry of Health (the payee for the vaccine programs and health care costs, as they relate to varicella and zoster disease). At $30 per vaccine dose, a one-dose univalent vaccine infant series with 90% coverage is estimated to be cost-saving, by preventing 6.2 million varicella cases in Canada, but generating an extra 0.3 million zoster cases (73). Moving to a two-dose vaccination program four years after introduction of the one-dose schedule, the model analyzed three different two-dose strategies, either providing (i) both doses in the second year of life, (ii) the doses at 12 months and preschool, or (iii) the doses at 12 months and Grade 4. The model predicts a net cost of $144.8 million, $104.8 million and $89 million for the three strategies, respectively. The cost-effectiveness ratio (CER) for the three two-dose strategies is estimated to be approximately $106,000, $41,000 and $28,000 per Quality-Adjusted Life-Year (QALY) gained, respectively. According to the World Health Organization (WHO), an intervention is considered very cost-effective if the CER is less than the per capita GDP, and cost-effective if the CER is between one and three times the per capita GDP (72,74,75). Therefore, in Canada a CER of < $40,000 per QALY gained is considered very cost-effective, between $40,000–$120,000 per QALY gained is cost-effective, and > $120,000 per QALY gained is not cost-effective. Nevertheless, in reality it is difficult to conclude which is the best and most cost-effective strategy, as it depends very much on the feasibility to fit the second dose into an already crowded childhood schedule, and the coverage ultimately achieved. Note that this cost-effectiveness analysis did not assess using combination MMRV as a two-dose schedule.

  The Brisson model (with modifications based on local data) has also been used to predict the post-vaccination (1-dose and 2-dose) epidemiology (not cost-effectiveness) of varicella and zoster disease in Australia and Finland (76,77). The results and conclusions from these two publications are similar to the 2009 Brisson model, albeit based on different assumptions.

•    ◦ The risk of zoster in children who receive two vaccine doses instead of one dose is also unknown. In the study by Kuter et al., only two cases of zoster were reported during the 10 years of follow-up, both in the single-dose group. Theoretically the risk for zoster should be less with two doses, but further studies are needed.

•    ◦ The epidemiology of zoster (shingles) in the adult population as a result of varicella vaccine programs is as yet unclear, due to the conflicting results in available studies (78-80). In the model by Brisson et al. assessing the effect of mass immunization with a single dose of vaccine at 12 months of age and a variety of catch-up single-dose strategies, an initial rise in zoster cases during the first 30 to 40 years after initiating childhood immunization programs was predicted, assuming adults have reduced boosting effects from infected children due to the decreasing varicella incidence. The incidence of zoster would then subsequently fall dramatically below the baseline (pre-vaccination) incidence when the vaccinated cohort arrives in later adulthood (67). Studies to date in the United States are inconclusive, with one showing a stable incidence of zoster, while another showed an increase (79,80). The effect of having a zoster vaccine for persons 60 years and over was not factored in to the Brisson model commissioned by PHAC.

NACI Recommendations

Background

NACI affirms the goals for national varicella disease control established at the consensus conference in Quebec City in 2005. Routine childhood varicella immunization programs in the U.S. (since 1995) and Canada (after 2000) have resulted in significant declines in varicella disease incidence, varicella-related hospitalizations and mortality within 10 to 15 years. The accumulated evidence to date suggests that children 12 months to 12 years of age would benefit from a two-dose primary schedule, for improved control of varicella disease. Since the pre-vaccine epidemiology of varicella disease in Canada is very similar to the U.S., it is likely that breakthrough disease occurs in Canada, even though it is not being actively reported nor investigated in the context of varicella “outbreaks.”

The ideal timing of the second dose of varicella vaccine is unknown. Although Kuter et al.’s study of a two-dose schedule reported a 10-year vaccine effectiveness of 98.3% in children vaccinated three months apart, there are no other clinical studies assessing the long-term epidemiological outcome of other dosing intervals (e.g. at 12 months and 4 to 6 years) (53). The ACIP in the U.S. has chosen to recommend the latter interval, i.e., second varicella vaccine dose at 4 to 6 years of age, for boosting children with waning immunity (17). Theoretically this may provide immunity lasting into the adolescent years, although this has not been studied. A disadvantage of a longer interval between doses is that children with primary vaccine failure after the first dose will be unprotected between the scheduled doses, with potential for day care and pre-kindergarten outbreaks (66). If a higher antibody threshold (correlate of seroprotection) is necessary to prevent breakthrough disease after the first vaccine dose, providing the second dose closer to the first dose (e.g. with two routine doses at 12 and 15 months, or at 12 and 18 months of age) should correct the primary vaccine failure and avoid breakthrough cases in children between infancy and the preschool age group.

The availability of combined measles-mumps-rubella-varicella (MMRV) vaccines in the U.S. (ProQuad^TM, Merck Inc.) and Canada (see concurrent NACI statement on Priorix-Tetra^TM, GSK Inc.) provides an advantage in being able to reduce the number of vaccine injections in children (8). Priorix-Tetra^TM has been authorized for a two-dose schedule in children, with the manufacturer recommending a preferred interval of six weeks and a minimum interval of four weeks. Priorix-Tetra^TM is effective in boosting antibody responses when administered at six weeks, or up to six years after previous individual MMR and varicella vaccinations (8). At the time of writing, Quebec is the only jurisdiction that utilizes MMRV in place of MMR and univalent varicella vaccine, using a single-dose schedule at 12 months.

NACI’s varicella vaccine recommendations are used by both public health authorities to implement publicly funded vaccine programs and by individual vaccine providers (physicians and nurses to immunize individual patients). Decisions about implementation of publicly funded two-dose programs will depend on the incremental cost-effectiveness, feasibility and other considerations of the Erickson and De Wals analytical framework for new immunization programs (81). It is acknowledged that the highest two-dose vaccine coverage can best be achieved with publicly funded provincial and territorial programs.

There are at present no published data on the interchangeability of the two available univalent varicella vaccines (Varivax^TM and Varilrix^TM) in a two-dose primary schedule. Studies of two-dose schedules have utilized the same manufacturer’s univalent vaccine or MMRV vaccine.

Recommendations (summarized in Tables 3A and 3B):

Table 3A. Recommended Ages and Intervals for 2-Dose Primary Varicella Immunization, Based on Choice of Vaccine(s), with First Dose Given at 12–15 Months of Age.

Vaccine for 1st dose	Vaccine for 2nd dose	Minimum recommended interval between the doses*
MMRV	MMRV	6 weeks apart
MMRV	Var.	3 months apart**
Var.	Var.	3 months apart
Var.	MMRV	3 months apart**

Var. = varicella vaccine, MMRV = measles-mumps-rubella-varicella. * With the option for programmatic scheduling of 2nd dose at either 18 months or 4 to 6 years of age. ** Based on expert opinion (no data).

Table 3B. Recommended Options for Catch-up Varicella-Containing Vaccine, to 12 years.

Prior immunization	Recommended options for catch-up (minimum intervals shown)
0 dose MMR & 0 dose Var.	2 doses MMRV (at least 6 weeks apart) OR 2 doses each of MMR and Var. (simultaneously, but at different sites, at least 3 months apart)
1 dose MMR & 1 dose Var.	1 dose MMRV (at least 6 weeks after the last MMR and 3 months after the last Var. vaccine) OR 1 dose each of MMR (at least 4 weeks after the prior MMR) and Var. (at least 3 months after the prior Var. dose). These MMR and Var. doses can be given simultaneously, but at separate sites. If not given simultaneously, the MMR and Var. doses must be separated by at least 4 weeks
1 dose MMR & 0 dose Var.	1 dose MMRV (at least 6 weeks after the prior MMR), followed by 1 dose Var. (at least 3 months after this MMRV dose), OR 1 dose Var (at least 4 weeks after last MMR dose), followed by 1 dose MMRV (at least 3 months after this Var dose)
2 doses MMR & 1 dose Var.	1 dose Var. (at least 4 weeks after the last MMR dose AND at least 3 months after the prior Var. dose)
2 doses MMR & 0 dose Var.	2 doses Var. (given at least 3 months apart, AND with the first Var. dose at least 4 weeks after the last MMR dose)
1 dose MMRV & 0 dose Var.	1 dose MMRV (at least 6 weeks after the prior MMRV) OR 1 dose each of MMR (at least 6 weeks after the prior MMRV) and Var. (at least 3 months after the prior MMRV dose). These MMR and Var. doses can be given simultaneously, but at separate sites. If not given simultaneously, the MMR and Var. doses must be separated by at least 4 weeks
1 dose MMR & 1 dose MMRV (or vice versa)	1 dose of Var. (at least 4 weeks after the prior MMR AND at least 3 months after the prior MMRV, whichever was last)

Var. = varicella vaccine, MMRV = measles-mumps-rubella-varicella

Table 4. Quality and Strength of Evidence (84-86).

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 (36).
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.

• • Healthy children 12 months to 12 years of age should receive two doses of varicella-containing vaccine (univalent varicella or MMRV) for primary immunization. NACI recommendation – Grade A.

  A two-dose vaccine schedule is anticipated to further reduce varicella (both wild-type and breakthrough) disease incidence, increase herd immunity, potentially decrease disease outbreaks, as well as minimize the number of cases occurring in adolescents and adults (even with the anticipated shift to a higher mean age for varicella disease in a highly vaccinated population). Options for the choice of vaccine for the second varicella-containing dose (univalent vaccine or MMRV) are listed in Table 3B, and depend on the vaccines and number of doses previously administered for primary immunization (univalent vaccine, MMR or MMRV). Children who had previously received a single dose of univalent varicella vaccine after the first birthday as part of provincial and territorial routine vaccination programs, should be immunized with a second varicella-containing vaccine dose. Until data on the interchangeability of different manufacturers’ varicella-containing vaccines are available, NACI recommends that the same manufacturer’s univalent varicella vaccine and/or MMRV be used to complete the two-dose schedule unless unavoidable implementation barriers are present (e.g. the same manufacturer’s vaccine used for the first dose is not available).

  Susceptible adolescents ≥ 13 years of age and adults should continue to receive two doses of varicella vaccine (univalent vaccine only, as MMRV is not authorized in this age group) a minimum of six weeks apart (this interval is consistent with the product monographs of all available varicella vaccines authorized for use in Canada). NACI recommendation – Grade A.

• • The first varicella-containing vaccine dose should be administered at 12 to 15 months of age. NACI recommendation – Grade A.

• • With regard to scheduling of the second dose of varicella-containing vaccines:

•    ◦ If the first dose administered is the univalent vaccine, the second varicella dose may be administered ≥ three months later (in 12 month to 12 year-olds) in the form of univalent vaccine (based on available studies that used no less than a three-month interval between doses) OR MMRV may be used as the second dose, with a minimum interval of three months between the doses. The upper age limit authorized for the use of MMRV is 12 years of age, although most of the publications that studied MMRV use in children administered the vaccine at no later than 6 years of age (8). NACI recommendation – Grade A.

•    ◦ If the first dose administered is the combination MMRV, the second MMRV dose may be administered at a preferred minimum interval of six weeks between the doses (as stipulated in the product monograph). Providers have the option of administering the second MMRV at 18 months or 4 to 6 years (8), with consideration of the potential advantages and disadvantages discussed above. The univalent varicella vaccine may also be used as the second dose after first dose MMRV at a minimum of three months later. If univalent varicella vaccine and MMR are given (instead of MMRV), they can be administered during the same visit, but at separate anatomical sites. If not given at the same visit, univalent varicella vaccine and MMR must be given at least 4 weeks apart. NACI recommendation – Grade A.

• • Children who have developed laboratory-proven varicella infection are not expected to benefit from varicella vaccine, although there is no anticipated harm from receipt of vaccine in this instance. There are no data to assist decision making. Thus, children who have received a single dose of varicella vaccine and develop laboratory-confirmed breakthrough infection do not require a second dose of a varicella-containing vaccine. NACI recommendation – Grade I.

• • When indicated, children with selected immunodeficiency diseases fulfilling clinical prerequisites [e.g. asymptomatic or mildly symptomatic HIV infection and adequate CD4 cell counts, children in remission from acute lymphocytic leukemia (ALL)] are already recommended to receive two doses of univalent varicella vaccine with close monitoring. MMRV vaccine is not currently recommended for these children, as there are no published efficacy and safety data in this population. Vaccine providers are directed to the most recent version of the Canadian Immunization Guide and NACI’s recent update on the use of varicella vaccine in persons infected with HIV for further details (3,7,82,83). NACI recommendation – Grade B.

Surveillance, Research and Future Priorities

In order to assess the true impact of implementing a two-dose schedule for children in Canada, surveillance for varicella and zoster disease has to be improved. While mathematical modelling has allowed us to predict possible future outcomes, ongoing surveillance is needed to ascertain whether these projections are accurate. With the availability of zoster vaccine in Canada for adults ≥ 60 years of age, it will be important to determine if this could prevent or reduce the anticipated rise in zoster cases due to declining varicella cases in children. For varicella, an active reporting surveillance system similar to the two VASP sites in the U.S. would be ideal, but expensive. Determining two-dose vaccine coverage would also be important in defining varicella vaccine effectiveness over time. An anticipated paradox in surveillance is that while the number of cases of breakthrough disease will be reduced after implementation of a two-dose schedule, it may be more difficult to diagnose these cases (which would be milder and possibly present with an atypical rash).