As a result of the societal and clinical impact of varicella, universal routine vaccination has been implemented in several countries worldwide. In the United States, where 1-dose varicella universal routine vaccination was introduced in 1995, there have been substantial reductions in the number of varicella cases, varicella-related ambulatory visits, hospitalizations and deaths.1–3 Outside of the United States, implementation of varicella universal routine vaccination in Germany, Italy (7 regions as of January 2012) and Uruguay has also resulted in decreased rates of hospitalizations and complications.4–8 However, in a recent review, 1-dose varicella vaccination was estimated to be only ~85% effective in preventing disease, resulting in cases of breakthrough varicella.9
Breakthrough varicella is defined as the appearance of a pruritic maculopapulovesicular rash with onset >42 days after vaccination without any other apparent cause.10 Whilst breakthrough varicella is generally milder (eg, involves fewer lesions, mostly papules, a lower rate of fever and shorter duration) than natural varicella, it is still a cause for concern due to varicella zoster virus (VZV) transmission from the breakthrough rash. Additionally, it can establish latency to cause herpes zoster.11 Breakthrough varicella is caused by primary or secondary vaccine failure. Primary vaccine failure could be defined as the failure to seroconvert or the failure to mount a protective immune response after vaccination despite seroconversion, whereas secondary vaccine failure is the gradual waning of immunity over time.
In response to cases of breakthrough varicella, several countries have implemented recommendations for a 2-dose varicella vaccination schedule. Indeed, the second dose of varicella vaccine has been shown to increase effectiveness from 86% to 98%.12 However, the optimal timing for the second dose is currently unknown. Knowledge on the relative contributions of primary and secondary vaccine failure to the incidence of breakthrough varicella would influence decision making because a trend toward more primary than secondary vaccine failure would favor a shorter interval and vice versa. As more countries consider implementing varicella vaccination, it is important to know whether a short (months between doses) or a long (years between doses) immunization schedule will provide optimal control of the disease. Therefore, a review of the literature has been carried out to assess the incidence and causes of varicella vaccine failure.
Search Strategy and Selection Criteria
Published literature (PubMed, conference abstracts, Google Scholar and Medscape) on live-attenuated vaccine failure associated with 1 and 2 doses of varicella-containing vaccine was reviewed (1995 to January 2012). Limits included: English, humans, clinical trials, randomized controlled trial, meta-analyses and reviews. Search terms encompassed: “varicella vaccine failure,” “waning varicella immunity,” “breakthrough varicella,” “(measles mumps rubella varicella or MMRV) vaccine failure,” “varicella vaccine seroconversion” and “varicella vaccine catch-up.” Exclusion criteria included studies in immunocompromised patients, as the varicella vaccine is not routinely given to this patient group, and postoutbreak control.
Cited articles were chosen on the relevance of their contents (eg, content on breakthrough varicella, varicella outbreaks, postvaccination antibody titers, vaccine failure, etc.), and each article was studied for references that were missed by the initial search. This was not intended as a systematic review.
One-dose Varicella Vaccine Effectiveness
Since 1995, there have been 19 publications describing 21 varicella outbreaks in vaccinated populations in day-care centers and elementary schools worldwide and 1 meta-analysis of 16 of these outbreaks (Table 1).13–32 Of these publications, 14 are from the United States where varicella universal routine vaccination has been employed since 1995. However, published outbreak reports represent just a small number of the outbreaks that actually occurred and most likely represent a bias toward outbreaks where issues occurred (ie, a large number of cases). Indeed, a total of 190 outbreaks were reported to the Centers for Disease Control and Prevention from 24 jurisdictions throughout the United States in 2004.33 This indicates that vaccine failure after 1-dose varicella vaccination is more prevalent than the published literature would suggest.
In published outbreaks, vaccination coverage rates for 1 dose of varicella-containing vaccines were 30–97% (Table 1).13–32 In these studies, vaccine effectiveness varied from 20% to 100% against disease of any severity and 85.5% to 100% for moderate/severe disease (Table 1).13–32 Breakthrough varicella rates ranged from 0% to 42%, which appeared to have no association with vaccination coverage. For instance, the study with the lowest coverage (30%) showed the highest effectiveness (100%), as no vaccinated child developed breakthrough varicella15; however, this could be explained by study size as only 20 children attended the day-care center involved. It is therefore possible that vaccine coverage in a population experiencing an outbreak of varicella may not correlate with vaccine effectiveness.
Outside of outbreak studies, the effectiveness of a single dose of vaccine against disease of any severity reported by varicella surveillance in the United States and case-control studies falls in the range of 71% to 87%.2,9,12,34,35 A review of 19 studies (including outbreak reports) from the United States found that the median 1-dose effectiveness was 85%.9 Additionally, 2 studies from Israel indicated vaccine effectiveness of 88% and 92%.36,37 One-dose vaccine effectiveness determined by a meta-analysis of 16 outbreaks worldwide was 72%.14 A large epidemiological study from Taiwan that investigated the incidence of breakthrough varicella in over 1,000,000 vaccinated children found that 1-dose vaccine effectiveness was 82.6%.38 Together, these data represent a rough average of 80% vaccine effectiveness for 1 dose of varicella vaccine against any varicella disease and an approximate vaccine failure rate of 20%. As with outbreak studies, effectiveness against severe/moderate disease was a lot higher than for disease of any severity.9,35,37
Differentiating between primary and secondary vaccine failure in outbreak analyses is difficult, as measurement of antibody levels postvaccination cannot determine whether the affected individual had primary or secondary vaccine failure. Additionally, secondary vaccine failure can have a similar clinical presentation to primary vaccine failure in those whose immunity has waned completely.39
Several risk factors have been proposed to increase varicella vaccine failure and are debated in the literature, including vaccine titer,40 immunization at a young age (particularly below 12–15 months),18,19,26,34,38,41–44 time since vaccination with other live virus vaccines,34,42,43 history of eczema,22,27,43 asthma23,26 vaccine brand30 and the use of oral or inhaled corticosteroids.26,34,42,43
A placebo-controlled trial conducted before the licensure of GlaxoSmithKline Vaccine’s varicella vaccine set the scene for assessing the impact of varicella vaccination at population level.40 In this study, infants and toddlers aged 10–30 months received placebo or varicella vaccine at (high) release titer (10,000–15,850 plaque forming units [pfu]) or (low) expiry titer (630–1260 pfu). The seroconversion rates for the high and low titer vaccines were 100% and 99.4%, respectively, when measured by immunofluorescence assay (IFA).
The protection rate over a period of 29 months (mean) was 88% for the high titer and 55% for the low titer vaccines against any varicella disease. Overall, vaccine efficacy was lower for those vaccinated at 10–18 months (64%) than those vaccinated at 19–24 months of age (82%). These results indicated that vaccine titer and age at the time of vaccination are major determinants of clinical protection, which is lower than what could be expected from the high IFA seroconversion rates.
The importance of time since vaccination as a cause of vaccine failure is discussed further below.
Evidence for Primary Vaccine Failure
As shown in Table 2,40,45–72 across all studies 0–24% of subjects failed to seroconvert after primary vaccination, depending on age group, vaccine titer and vaccine lot. Importantly, the assays used to assess antibody titers vary between publications, which appeared to affect the outcome. For instance, assessment of seroconversion rates with enzyme-linked immunosorbent assay (ELISA) and IFA methods generally reported high seroconversion rates (>90%), whereas assessment with the validated fluorescent antibody to membrane antigen (FAMA) assay generally showed lower seroconversion rates of 76–84%.52,57 Indeed, the FAMA assay is the only assay that has been validated in a real-life setting, where a positive titer correlated with protection following household exposure to varicella.73,74 Additionally, 6-week postvaccination FAMA antibody titers have also been inversely correlated with the likelihood of developing breakthrough varicella over 10 years of follow-up.50 The high seroconversion rates (>90%) as assessed by ELISA and IFA methods have been proposed to be due to an initial burst of immunity after vaccination that may not be adequate to instigate a memory T-cell response.75 Interestingly, this could be overcome by a higher dose of vaccine,40 or with a second dose of varicella vaccine, which has been shown to boost VZV-specific cell-mediated immune responses in children after vaccination.71,76
Using the glycoprotein ELISA employed by Merck & Co., Inc. (NJ) to measure VZV antibody concentrations, an arbitrary value of ≥5 glycoprotein ELISA units 6 weeks postvaccination correlates with a 3.5-fold reduced risk of breakthrough varicella, although this has never been verified in contact settings or correlated to the FAMA assay.53 Additionally, the correlate of protection could not be ascertained from this study as it did not include a control group. Indeed, using this value as a threshold for protection, there is a wide range of primary vaccine failure (5–24%) after 1-dose varicella vaccination with a single brand.55,64 The reason for such variance is unclear.
Of interest there is data suggesting that some children without detectable antibodies are still protected against infection by cell-mediated immunity.77 This would imply that antibodies do not play a direct role in immunity to VZV. Indeed, it is unclear whether varicella antibodies play a direct role in vaccine-specific protection or whether they are just a surrogate marker for vaccine-specific T-cell responses that accompany seroconversion.78 However, if 1-dose vaccine effectiveness is approximately 80% and seroconversion is a proxy marker for protection, most cases of breakthrough varicella can be accounted for by primary vaccine failure.
Two case-control studies from the United States and China examined whether vaccine effectiveness is time dependent.34,79 In the 8-year study from the United States, vaccine effectiveness dropped from 97% in the first year postvaccination to 86% in the second year and then remained stable.34 In the study from China, effectiveness was also shown to drop after the first year and then remain stable; however, this result was not statistically significant.79 These effectiveness measures conflict with a 3-year retrospective study from Taiwan where 81% of cases occurred during the first year postvaccination.80 However, these studies all indicate 1-dose primary vaccine failure in populations with circulating VZV because the varicella breakthrough rate does not increase over time.
Evidence for Secondary Vaccine Failure
Increased incidence and severity of breakthrough varicella with time is an indicator of secondary vaccine failure. Of the 29 publications that reported on breakthrough varicella rates with time (Table 3),10,13,16,18,19,22,23,25–28,30,32,34,41,43,44,46,50,53,54,66,70,73,74,79–82 9 showed an increased risk with time of breakthrough varicella; this increased risk was generally observed around 4–5 years postvaccination. However, 7 of these publications were outbreak studies, which by design are based on limited population size and therefore not adequately powered to detect any drop in protection according to time since vaccination.
A large retrospective study of over 11,000 children found that time since vaccination is an important risk factor for breakthrough varicella, with both incidence and severity increasing over a 10-year period.10 Whilst a strength of this study is that decreasing exposure levels were controlled for, this study did not use laboratory confirmation for cases of breakthrough varicella, which, as the disease tends to be very mild, can be confused with other causes of papulovesicular rashes. Indeed, one of the strengths of the case-control study conducted in the United States, which showed no secondary vaccine failure after the first year postvaccination, was that the authors required VZV DNA-positive samples from lesions for diagnosis of varicella.34
In a meta-analysis of varicella outbreaks, the authors modeled vaccine effectiveness against time since vaccination (up to 6 years) from 4 outbreaks.14 This analysis found that the pattern of vaccine effectiveness fitted models of waning immunity with a linear or exponential course.14 However, other longer-term studies with up to 20 years of follow-up73,74 found long-term persistence of antibodies or have shown that the rate and severity of breakthrough varicella does not increase with time, suggesting a limited rate of secondary vaccine failure.41,50,66,74,81
Long-term studies do not indicate significant waning immunity after varicella vaccination, as they have shown that there is no increase in breakthrough varicella between 4 and 8 years after vaccination.34,41,70,79 A mathematical model fitted to the rate of breakthrough varicella in subjects of 3 clinical trials showed that, in the worst-case scenario (88% protected after vaccination, that is, 12% primary vaccine failure), the incidence of breakthrough varicella would increase in the first few years postvaccination and then plateau at 3% per year for up to 6 years postvaccination.83 Although this was extrapolated from a clinical trial which used a low titer vaccine lot currently not in production, it does appear to fit the patterns observed in case-control studies.34,79
It should be emphasized that the results of long-term studies can be difficult to evaluate in areas where wild-type virus still circulates, as this can provide natural boosting to the immune system, reducing secondary vaccine failure. Therefore, as circulating wild-type virus is reduced by universal routine vaccination, secondary vaccine failure could increase. In fact, time since vaccination was only identified as a risk factor for breakthrough varicella in 2002,19 7 years into the United States vaccination program. Moreover, it can be difficult to interpret long-term studies in countries where coverage rates change considerably over the years. As coverage rates plateau in the future, further long-term surveillance studies are required to fully assess the rate of secondary vaccine failure.
Evidence for Optimal Interval Between Doses
It has been suggested that high antibody titers are required for optimal protection against varicella, rather than seroconversion per se, and that 2 doses are required to achieve this.84,85 Numerous studies have assessed antibody titers in children after administration of 2 doses of vaccine given at various intervals (4 weeks to 6 years; Table 4).49,58,62–65,71,86–93 These studies indicate that geometric mean antibody concentrations increase roughly 10-fold (range 5- to 39-fold) after the second dose of vaccine in children, irrespective of timing between doses. Such a large increase in antibody titers after the second dose suggests inadequate priming after the first dose and thus minimal induction of memory cells, resulting in vaccinees who are not fully protected after 1 dose.94
The boosting effect in geometric mean antibody concentrations observed with the short interval for the second dose is atypical of most live viral vaccines75 and suggests that an incomplete immune response is mounted after the first dose. In addition to the large booster effect of the second dose, the generally mild nature of breakthrough varicella would also seem to suggest that priming of the immune system takes place following vaccination.75,94 In this respect, a second dose would not be a booster for waning immunity but would instigate completion of the necessary immune response.
On this basis, the literature suggests that a second dose should be given soon after the first dose to cover the individuals with primary vaccine failure and those who did not mount an adequate response for protection despite an initial antibody response (also termed primary vaccine failure by the definition laid out in this article). Furthermore, evidence also suggests that antibody titers fall during the first year postvaccination,52,57 which, even if this reflects a type of rapid waning immunity, indicates that the second dose should be given soon after the first because antibody titers are correlated with protection.50,53 Therefore, administering the second dose of the vaccine within the second year of life may be optimal. The second dose should be given at least 4 weeks after the first, as clinical trials have not assessed shorter intervals (Table 4).49,58,62,63,65,71,86–93 One study in adolescents and adults, who have always been given 2 doses of vaccine due to the lowered immunogenicity of the vaccine in this age group, found that delaying the second dose to 8 weeks compared with 4 weeks induced higher antibody titers.95 Additionally, a recent study of 2 doses of MMRV has shown that higher antibodies titers are induced if the second dose is given 12 months versus 4 weeks after the first dose (Table 4).49,58,62,63,65,71,86–93 However, there were 2 cases of breakthrough varicella 5 and 10 months after the first dose in the 12-month interval group, and no cases in the 4-week interval group, despite a similar rate of varicella contact.62
Implementation of a Short-interval 2-dose Schedule
Short-interval 2-dose varicella immunization schedules should reduce the period of time that a child with primary vaccine failure is unprotected, reducing the risk of breakthrough disease. There are a number of different options for implementation of short-interval 2-dose varicella vaccination in the second year of life: 1) vaccination with 2 doses of monovalent vaccine; 2) vaccination with 2 doses of MMRV vaccine; 3) vaccination with a combination of 2 doses of MMR and varicella vaccine and/or MMRV. However, implementation of a short interval between doses should always be evaluated with respect to the overall vaccination schedule. A public health evaluation of the advantages and disadvantages of alternative vaccination schedules should be carefully performed.
For ease of scheduling, a combination of MMRV or monovalent vaccines can be used to allow flexibility for the administration of 2 doses of varicella vaccine. For instance, in Germany, both MMRV and monovalent vaccines are licensed under 2-dose schedules.96 This option is especially pertinent for the United States, where the second dose of MMR is currently suggested for children aged 4–6 years.97 In this instance, the use of a monovalent vaccine would allow the second dose to be administered in the second year of life. This is currently permitted in the United States varicella vaccination schedule as long as there is a minimum of 3 months between doses.98 Another possibility that may be considered to implement the short-interval 2-dose schedule for varicella is shifting the age at which the second dose of MMR is administered from 4−6 years to 18 months of age. This option may minimize administration costs for the immunization program (less patient visits/administration costs, for example, needles and reduced time dedicated by healthcare professionals) and will help support improved coverage for both MMR and varicella vaccination.
Reduction in Risk With Short- Versus Long-interval Immunization Schedules
Assuming no waning immunity and breakthrough varicella rates of 1–3% per year (Table 3),10,13,16,18,19,22,23,25–28,30,32,34,41,43,44,46,50,53,54,66,70,73,74,79–82 changing the timing of the second dose from age 4–6 years to the second year of life could prevent around 2-fold cumulative cases of breakthrough varicella. Undoubtedly, this figure is an overestimation as increasing varicella vaccination coverage would reduce the opportunity for contracting the disease; however, a high primary vaccine failure rate could allow continued circulation of the virus. Additionally, implementation of a short immunization schedule would be especially important for countries that introduce varicella vaccination because wild-type virus circulates more in those countries than in countries that have already reduced incidence of the disease due to varicella vaccination.
Effectiveness of 2-dose Schedules
Two-dose schedules have been implemented in a variety of countries worldwide, including the United States and Germany. Unlike the United States, Germany employs short-interval varicella vaccination where both doses are given in the second year of life. Recent outbreak reports from Germany and the United States have varied on the effectiveness of a second dose of varicella vaccine. In Germany, a second dose of MMRV within the second year of life (66% second-dose coverage) increased vaccine effectiveness from 62% to 94% in outbreak situations.30 Long-term follow-up of clinical trials where 2 doses were given in a short interval (3 months between doses) also showed that 2 doses provide more protection than a single dose.90 In the United States, where a longer schedule is used, 2 studies have shown that a second dose of vaccine increases vaccine effectiveness by up to 98%.12,99 The short schedule should theoretically protect children earlier in life as it allows early revaccination of children with primary vaccine failure.98 As the duration of immunity to 2 doses of varicella vaccine is currently unknown, continued surveillance and prospective studies are required.
All published evidence (1995 to 2012) for varicella vaccine failure strongly supports a 2-dose schedule in order to obtain effective control of the disease.12,29,30,90,100 A review of the literature indicated a relatively high rate of primary vaccine failure among recipients of 1-dose varicella vaccine and limited convincing evidence of secondary vaccine failure. Furthermore, vaccine effectiveness decreases after the first year postvaccination and then remains stable, a pattern predictive of primary vaccine failure. This suggests that the second dose of varicella vaccine should be given as close to the first as possible (minimum interval of 4 weeks based on clinical trials), to prevent a large number of people remaining vulnerable to infection and to reduce the risk of breakthrough varicella. However, individual countries should consider how shortening the interval between doses could impact second-dose vaccination coverage, especially if this warrants an additional visit to the doctor for vaccination. A comparison of vaccine efficacy between the United States and Germany, which employ different varicella vaccination schedules, is warranted in the future. Our findings need to be placed in the context of an important limitation of the selection criteria employed in this review. Published outbreak reports represented only a small number of the varicella outbreaks that actually occurred. Our review did not assess vaccine failure from the varicella outbreaks reported only to the Centers for Disease Control and Prevention. Therefore, we expect that vaccine failure after 1-dose varicella vaccination is more prevalent than what published literature would suggest. To conclude, we propose that a short interval between 2 doses of the varicella vaccine might be preferable to reduce breakthrough varicella, especially in countries that will introduce varicella vaccination and where the wild-type virus circulates predominantly.
The authors would like to thank Prof. Jacques Senterre for his contribution to this work. The authors would also like to thank Dr. Elizabeth Hutchinson who carried out the literature search and provided medical writing assistance on behalf of Fishawack Communications Ltd and Amrita Ostawal (consultant writer to GlaxoSmithKline group of companies) for medical writing assistance.
Priorix-Tetra and Varilrix are trademarks of GlaxoSmithKline group of companies. M-M-R-II, ProQuad and Varivax are trademarks of Merck and Co., Inc. Changchun and Shanghai are manufactured by Changchun Institute of Biologic Products (Changchun, China) and Shanghai Institute of Biologic Products (Shanghai, China), respectively. Okavax is a trademark of Varicella Biken, The Research Foundation for Microbial Diseases of Osaka University, Osaka, Japan.
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