|
Indian Pediatr 2016;53: 329-333 |
|
Systematic Review of Effectiveness of
Varicella Vaccines: A Critical Appraisal
|
Source Citation: Marin M, Marti M, Kambhampati A,
Jeram SM, Seward JF. Global varicella vaccine effectiveness: A
meta-analysis. Pediatrics. 2016;137:1-10.
Section Editor: Abhijeet Saha
|
Summary
In this systematic review and descriptive
meta-analysis, the authors examined the post-licensure estimates of
varicella vaccine effectiveness (VE) among healthy children.
Publications that reported original data on dose-specific varicella VE
among immunocompetent children were included. Random effects
meta-analysis models were used to obtain pooled one dose VE estimates by
disease severity (all varicella and moderate/severe varicella). Within
each severity category, pooled VE by vaccine and by study design were
assessed. The pooled 1-dose VE was 81% (95% CI 78%, 84%) against all
varicella and 98% (95% CI 97%, 99%) against moderate/severe varicella
with no significant association between VE and vaccine type or study
design. For 1-dose, median VE for prevention of severe disease was 100%
(mean 99.4%). The pooled 2-dose VE against all varicella was 92% (95% CI
88%, 95%), with similar estimates by study design. The
authors conclude that one dose of varicella vaccine was moderately
effective in preventing all varicella, and highly effective in
preventing moderate/severe varicella, with no differences by vaccine.
The second dose adds improved protection against all varicella.
Commentaries
Evidence-based Medicine Viewpoint
Relevance: Varicella (chickenpox) is an
infectious disease with considerable individual and public health
significance, as well as economic impact, especially in developed
countries [1]. Vaccines developed to prevent serious forms of chickenpox
and (hopefully) long-term complications such as herpes zoster have been
available for the past few years. A program of universal coverage with
Varicella vaccine was initiated in the United States 10 years ago, and
the majority of efficacy data originate from that setting. In contrast,
individual European countries have variable vaccination policies,
despite generally acceptable efficacy and cost-effectiveness [2]. A
recent systematic review confirmed the efficacy of vaccination to
prevent herpes zoster in elderly people, demonstrating almost 50%
reduction in incidence [3]. Although the review reported increased
occurrence of side effects, most of these were not severe. Economic
evaluations also suggest that vaccination to prevent varicella zoster
may be cost-effective in developed countries [4,5].
However, there is also a divergent view [6] which
suggests that declining varicella infection in children (on account of
vaccination) reduces the ‘natural boosting’ effect of sub-clinical
exposures in the community. Since vaccine-induced immunity is not
life-long, this would necessitate booster dose(s) in later life. When
the added costs are factored in, a vaccination program may no longer be
cost-effective [6]. This view is supported by the detection of increased
occurrence of zoster among adults, following universal vaccination
programs. There is limited data on universal varicella vaccination
efficacy or cost-effectiveness from developing countries [7,8]. Data
from India are limited to reports of outbreaks [9,10] or trials of sero-efficacy
[11,12], and thereby indirect suggestions that vaccination may be
beneficial. Against this backdrop, the recent systematic review by
Marin, et al. [13], examining the protective efficacy of
varicella vaccination (i.e effectiveness), is both timely and
relevant. Although efficacy (in research settings) has been amply
demonstrated previously, this is perhaps the first systematic evaluation
of vaccine effectiveness (in real world settings).
Critical appraisal: Table I
presents a critical appraisal of the systematic review using standard
tools [14]. Overall, the review met the major criteria for a good
quality review. However, some of the methodological refinements
associated with a Cochrane systematic review were not undertaken. One
serious methodological limitation was the absence of quality assessment
of each included study (see Table I).
Table I: Critical Appraisal of the Systematic Review on Varicella Vaccine Effectiveness [13]
Parameter |
Comment |
Validity |
Is there a clearly focused clinical question? |
Although the
authors did not present an explicit PICO question, the following
can be discerned: What is the protective efficacy/ effectiveness
(Outcome) of varicella vaccination (Intervention) versus no
vaccination (Comparator) among otherwise healthy children
(Population)? |
What are the criteria for selection of studies? |
The authors
searched for publications from 1995 to mid-December 2014
(approximately ten year period) reporting protective efficacy of
Varicella vaccine in immuno-competent children (age not
specified). They did not restrict any study design or language. |
Is the literature search method specified? |
The authors
presented the precise search strategy, databases searched (total
four), and dates of searching. The method used suggests low
probability of missing relevant publications. However, it is
possible that additional unpublished data may be available with
relevant Health Ministries, vaccine manufacturers, and possibly
insurance companies/reimbursement agencies. |
Have the identified studies been evaluated for methodological
quality? |
The authors
included various study designs, but did not attempt to assess
methodological quality of individual studies. Although sub-group
analysis by study design was performed separately, no
sensitivity analysis (by methodological quality) was performed.
This could compromise the results as lower quality studies
generally over-estimate the effect. Since methodological quality
was not assessed, the additional issue of independent appraisal
by multiple authors and calculation of concordance, could not be
considered. |
Is it appropriate to combine the results from different
studies? |
The
Supplementary data summarizes the extracted information from
each study viz. (i) Country, (ii) Vaccine type, (iii) Study
design, (iv) Study setting, (v) Age of included participants,
(vi) Sample size and (vii) Study period. From this data, it is
difficult to judge whether all studies were appropriate for
combining into a pooled analysis. However, the authors undertook
additional analyses by Study design, Vaccine type, and a
meta-regression including both in the model. |
Results |
Were the results consistent from one study to another?
|
All the
studies included in the meta-analysis demonstrated protective
efficacy suggesting an overall consistent effect. However, there
was considerable heterogeneity (I2 88%) suggesting unexplored
variations among studies. A random effects model was used in the
meta-analysis. |
|
|
What were the overall results of the review? |
Effectiveness for one dose of vaccine, All Varicella: |
|
• Monovalent
vaccine: 0.81 (95% CI 0.78, 0.84) |
|
• Polyvalent
(MMRV) : 0.55 (95% CI 0.08, 0.78) |
|
Moderate and
severe Varicella: 0.98 (95% CI 0.97, 0.99) |
|
Severe
Varicella: Pooled VE not presented |
|
Effectiveness
for two doses of vaccine, All Varicella: |
|
• Monovalent
vaccine: 0.92 (95% CI 0.88, 0.95) |
|
• Polyvalent
vaccine (MMRV): 0.91 (95% 0.65, 0.98) |
How precise were the results? |
The pooled
effect had narrow confidence intervals. This was true for the
combined analyses as well as all subgroup analyses (i.e by
vaccine type and by study design). |
Applicability |
Is the local population similar to the peopleincluded in the
original studies? |
All the
studies included in the systematic review originated from
developed countries with different baseline risks, variable
disease burden, diverse public health priorities and health-care
systems. |
Is the intervention feasible in my setting? |
At the present
time, universal Varicella vaccination of Indian children is
precluded by paucity of knowledge of disease burden, public
health impact of Varicella (in childhood and later years), and
unknown effectiveness and cost-effectiveness. The baseline risk
would determine the number-needed-to-vaccinate even if
protective efficacy of the magnitude demonstrated in this
systematic review was considered. |
|
|
Have all the clinically relevant results been taken into
consideration? |
This
systematic review did not consider vaccine related adverse
effects (although this may not have been the focus of the
review), impact on Varicella zoster, and cost-effectiveness.
|
Do the benefits outweigh the potential harm? |
In terms of
prevention of Varicella, there is clear benefit. Harm can be
assessed only after studying the factors listed above. |
On the plus side, the authors used clear definitions
for terms such as Varicella and disease severity. They also prudently
considered relevant confounders and undertook subgroup analysis based on
type of vaccine, monovalent versus combination (MMRV) vaccine,
and type of study design. Single dose vaccination was analyzed
separately from two dose regimen.
It appears that the authors did not convert outcomes
from individual studies into a uniform format of relative risk (RR) or
odds ratio (OR), but used a formula to calculate vaccine effectiveness
(from individual study OR and RR). Therefore, NNT could not be
calculated from individual studies and the pooled data. The authors
rightly explored publication bias and did identify the same, which
indirectly suggests that studies failing to identify/report negative
results (i.e inadequate vaccine effectiveness) may have been
missed. The authors observed that a significant number of publications
were related to outbreaks, and suggested how this could impact the
overall result.
The authors noted data on waning of vaccine-induced
immunity over time. However, a critical issue of whether this could
translate to greater episodes of Varicella in the immunized or older age
groups; and/or whether it could result in increased burden of herpes
zoster, was not considered.
Extendibility: Almost the entire body of
evidence included in this systematic review originated from developed
countries with vastly different status of population risk,
epidemiological factors affecting transmission, and access to
health-care. Therefore, it is not possible to directly extrapolate the
favorable results of vaccine protective efficacy (i.e
effectiveness) to our setting. Further, none of the studies was
conducted in a setting that could be even considered similar.
Conclusion: Varicella vaccine appears to offer a
high degree of protection against varicella; this is higher for more
severe forms of the disease, and better with two doses. The results are
robust irrespective of vaccine type and study design used to address the
issue.
Funding: None; Competing interest: None
stated.
References
1. Paganino C, Alicino C, Trucchi C, Albanese E,
Sticchi L, Icardi G. Herpes Zoster: The rationale for the introduction
of vaccination in Italy. J Prev Med Hyg. 2015;56:E33-6.
2. Helmuth IG, Poulsen A, Suppli CH, Mølbak K.
Varicella in Europe – A review of the epidemiology and experience with
vaccination. Vaccine. 2015;33:2406-13.
3. Gagliardi AM, Andriolo BN, Torloni MR, Soares BG.
Vaccines for preventing herpes zoster in older adults. Cochrane Database
Syst Rev. 2016;3:CD008858.
4. de Boer PT, Wilschut JC, Postma MJ.
Cost-effectiveness of vaccination against herpes zoster. Hum Vaccin
Immunother. 2014;10:2048-61.
5. Unim B, Saulle R, Boccalini S, Taddei C,
Ceccherini V, Boccia A, et al. Economic evaluation of Varicella
vaccination: Results of a systematic review. Hum Vaccin Immunother.
2013;9:1932-42.
6. Goldman GS, King PG. Vaccination to prevent
varicella: Goldman and King’s response to Myers’ interpretation of
Varicella Active Surveillance Project data. Hum Exp Toxicol.
2014;33:886-93.
7. Bardach A, Cafferata ML, Klein K, Cormick G,
Gibbons L, Ruvinsky S. Incidence and use of resources for chickenpox and
herpes zoster in Latin America and the Caribbean—a systematic review and
meta-analysis. Pediatr Infect Dis J. 2012;31:1263-8.
8. Paternina-Caicedo A, De la Hoz-Restrepo F,
Gamboa-Garay O, Castañeda-Orjuela C, Velandia-González M, Alvis-Guzmán
N. How cost effective is universal varicella vaccination in developing
countries? A case-study from Colombia. Vaccine. 2013;31:402-9.
9. Singh MP, Chandran C, Sarwa A, Kumar A, Gupta M,
Raj A, et al. Outbreak of chickenpox in a union territory of
North India. Indian J Med Microbiol. 2015;33:524-7.
10. Verma R, Bairwa M, Chawla S, Prinja S, Rajput M.
Should the chickenpox vaccine be included in the national immunization
schedule in India? Hum Vaccine. 2011;7:874-7.
11. Lalwani S, Chatterjee S, Balasubramanian S,
Bavdekar A, Mehta S, Datta S, et al. Immunogenicity and safety of
early vaccination with two doses of a combined measles-mumps-rubella-varicella
vaccine in healthy Indian children from 9 months of age: A phase III,
randomized, non-inferiority trial. BMJ Open. 2015;5:e007202.
12. Mitra M, Faridi M, Ghosh A, Shah N, Shah R,
Chaterjee S, et al. Safety and immunogenicity of single dose live
attenuated varicella vaccine (VR 795 Oka strain) in healthy Indian
children: A randomized controlled study. Hum Vaccin Immunother.
2015;11:443-9.
13. Marin M, Marti M, Kambhampati A, Jeram SM, Seward
JF. Global varicella vaccine effectiveness: A meta-analysis. Pediatrics.
2016;137:1-10.
14. Abalos E, Carroli G, Mackey ME, Bergel E.
Critical Appraisal of Systematic Reviews. Available from:
http://apps.who.int/rhl/Critical%20appraisal%20of%
20systematic%20reviews.pdf. Accessed April 14, 2016.
Joseph L Mathew
Department of Pediatrics,
PGIMER, Chandigarh, India.
Email:
[email protected]
Immunization Expert’s Viewpoint
This systematic literature review and descriptive
meta-analysis selected 42 studies to evaluate the vaccine effectiveness
(VE) to prevent varicella with 1 or 2 doses. These studies originated
from the United States (23), China (4), Germany (3), Israel (3), Italy
(2), Spain (2), Taiwan (2), Australia (1), Turkey (1), and Uruguay (1).
In the final analysis, it was seen 1-dose had moderate effectiveness
with 81% (95% CI 78%, 84%) to all varicella and 98% (95% CI 97%, 99%)
against moderate to severe varicella. The stratified VE results of
different vaccines with 1-dose showed: Varivax 82%, Varilrix 77%, other
vaccines 86% and mixed/multiple vaccines 81% with 1-dose. In the
meta-regression analysis, no significant association was found between
VE and vaccine type [1]. Of the studies analyzed, most had 100%
prevention of severe varicella, irrespective of 1- or 2-dose schedule
[2].
There were eight studies with 2 doses and most of
them have showed slightly better VE for all varicella. The VE of the
only study with two doses of MMRV/ Priorix tetra was 91% (95% CI 65%,
98%) [1]. One of the limitations of this outcome was that the VE was
assessed primarily during the outbreak, and all were clinically
diagnosed which may tend to show underperformance of the vaccine [1].
The pooled VE estimates for 1-dose primarily were
within the first decade. Within this time frame, some studies showed
higher vaccine failure with time since vaccination (cut-off of 3,4 and 5
years), but other studies did not find this association [3-14]. Varivax
showed decline of VE in 1 and 2 years after vaccination from 97% to 86%,
but not subsequently after 7 years follow-up [15]. In another study at
US, it showed a decline in VE from 94 % till 5 years to 88% at 5 to 9
years, and 82% after 10 years. Bayer, et al. [16], in their
meta-analysis of outbreak data, concluded waning immunity based on data
from four studies which all showed decrease in VE by time since
vaccination for an average 4 to 6 years. Though most studies showed a
decline in immunity, the results were not adjusted for likelihood of
exposure or force of infection, which may have changed with time due to
the changing epidemiology with routine vaccination program [1].
In 1995, United States adopted 1-dose routine
vaccination policy, with coverage of 90% and had a significant decline
(more than 90%) of varicella infection, and related hospitalization or
death [17-19]. But after a decade or so, inspite of significant decline
in disease and severity, there were varicella outbreaks (although less
in number, smaller in size and short duration) even in highly vaccinated
populations [20,21]. Hence after nearly 10 years, 2-dose schedule was
adopted in the policy of United States, which further decreased the
outbreaks and related hospitalizations. Spain introduced 2-dose
schedules from the beginning, and reported 98.5% decline in incidence in
5 years [22].
After detailed analysis of various studies, IAP
Committee of Immunization in 2011 decided to adopt the 2-dose schedule
for India. Though there was no published Indian data to support the
outbreak or incidence of breakthrough infection, but based on expert
opinion and sporadic incidences of varicella infection post-vaccination
as experienced by many, it was decided to recommend two doses to provide
higher effectiveness and immunity to individuals who opted for the
prevention.
Unfortunately we do not have any VE data in India,
and most of the analyzed data are from high-income countries where
epidemiology is different. For public policy, it would be difficult to
make any recommendation based on this meta-analysis as most studies have
been done in low prevalence countries.
Funding: None; Competing interest: None
stated.
References
1. Marin M, Marti M, Kambhampati A, Jeram SM, Seward
JF. Global varicella vaccine effectiveness: A meta-analysis. Pediatrics.
2016;137:1-10.
2. Huang WC, Huang LM, Chang IS, Tsai FY, Chang LY.
Varicella breakthrough infection and vaccine effectiveness in Taiwan.
Vaccine. 2011;29:2756–60.
3. Wang Z, Yang H, Li K, Zhang A, Feng Z, Seward JF,
et al. Single dose varicella vaccine effectiveness in school
settings in China. Vaccine. 2013;31:3834-8.
4. Lee BR, Feaver SL, Miller CA, Hedberg CW,
Ehresmann KR. An elementary school outbreak of varicella attributed to
vaccine failure: policy implications. J Infect Dis. 2004;190:477-83.
5. Spackova M, Wiese-Posselt M, Dehnert M,
Matysiak-Klose D, Heininger U, Siedler A. Comparative varicella vaccine
effectiveness during outbreaks in day-care centres. Vaccine.
2010;28:686-91.
6. Galil K, Lee B, Strine T, Baughman AL, Eaton
M, Montero J, et al. Outbreak of varicella at a day-care center
despite vaccination. N Engl J Med. 2002;347:1909-15.
7. Centers for Disease Control and Prevention (CDC).
Outbreak of varicella among vaccinated children–Michigan, 2003. MMWR
Morb Mortal Wkly Rep. 2004; 53:389-92.
8. Haddad MB, Hill MB, Pavia AT, Green CE, Jumaan
AO, De AK, et al. Vaccine effectiveness during a varicella
outbreak among school children: Utah, 2002–2003. Pediatrics.
2005;115:1488-93.
9. Tugwell BD, Lee LE, Gillette H, LorberEM, HedbergK,
Cieslak PR. Chickenpox outbreak in a highly vaccinated school
population. Pediatrics. 2004;113:455-9.
10. Lee LE, Ho H, Lorber E, Fratto J, Perkins S,
Cieslak PR. Vaccine-era varicella epidemiology and vaccine effectiveness
in a public elementary school population, 2002–2007. Pediatrics.
2008;121:e1548-54.
11. Lopez AS, Guris D, Zimmerman L, Gladden L, Moore
T, Haselow DT, et al. One dose of varicella vaccine does not
prevent school outbreaks: is it time for a second dose? Pediatrics.
2006;117:e1070-7.
12. Lu L, Suo L, Li J, Zhai L, Zheng Q, Pang X,
et al. A varicella outbreak in a school with high one dose
vaccination coverage, Beijing, China. Vaccine. 2012; 30:5094-8.
13. Marin M, Nguyen HQ, Keen J, Jumaan AO, Mellen
PM, Hayes EB, et al. Importance of catch-up vaccination:
experience from a varicella outbreak, Maine, 2002–2003. Pediatrics.
2005;115:900-5.
14. Galil K, Fair E, Mountcastle N, Britz P, Seward
J. Younger age at vaccination may increase risk of varicella vaccine
failure. J Infect Dis. 2002;186:102–5.
15. Vázquez M, LaRussa PS, Gershon AA, Niccolai LM, Muehlenbein
CE, Steinberg SP, et al. Effectiveness over time of varicella
vaccine. JAMA. 2004;291:851-5.
16. Bayer O, Heininger U, Heiligensetzer C, von Kries
R. Meta-analysis of vaccine effectiveness in varicella outbreaks.
Vaccine. 2007;25:6655-60.
17. Guris D, Jumaan AO, Mascola L, Watson BM, Zhang
JX, Chaves SS, et al. Changing varicella epidemiology in active
surveillance sites–United States, 1995–2005. J Infect Dis.2008;
197:S71-5.
18. Lopez AS, Zhang J, Brown C, Bialek S. Varicella-related
hospitalizations in the United States, 2000–2006: The 1-dose varicella
vaccination era. Pediatrics. 2011; 127: 238-45.
19. Marin M, Zhang JX, Seward JF. Near elimination of
varicella deaths in the US after implementation of the vaccination
program. Pediatrics. 2011;128:214-20.
20. Marin M, Güris D, Chaves SS, Schmid S, Seward JF.
Prevention of varicella: Recommendations of the Advisory Committee on
Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56:1-40.
21. Prevention of varicella: Recommendations for use
of varicella vaccines in children, including a recommendation for a
routine 2-dose varicella immunization schedule. Pediatrics.
2007;120:221-31.
22. Garcia Cenoz M, Castilla J, ChamorroJ, Martinez-Baz
I, Martinez-Artola V, Irisarri F, et al. Impact of universal
two-dose vaccination on varicella epidemiology in Navarre, Spain, 2006
to 2012. Euro Surveill. 2013;18:20552.
Monjori Mitra
Department of Pediatrics,
Institute of Child Health,
Kolkata, India.
|
|
|
|