pallor or cyanosis or failure to observe or to recall skin .... (or cyanosis), limpness, and reduced responsiveness. ... Cyanotic or pallid breath-holding spells.
Oct 30, 2009 - pertussis toxin, endotoxin, adenylate cyclase toxin and tracheal cytotoxin, which are known to play a role in pathogenesis and immune evasion ...
Bacterial survival is aided by ciliostasis related to the tracheal cytotoxin (TCT) and impaired leukocyte function due to PT and the adenylate cyclase (AC) toxin.
Apr 25, 2014 - We estimated age-appropriate DTaP dose completion and the proportion of children receiving a. âmixedâ DTaP vaccination ..... vaccination series were approximately 4â5% (ranging up to 19% in sensitivity analyses) ..... counted fee
Sep 6, 2017 - Universidad Nacional de La Plata, CCT-CONICET La Plata, La Plata, Argentina. Maternal safety through pertussis vaccination and subsequent ...
Anti-DT IgG, anti-PT IgG, anti-Prn IgG, and anti-FHA IgG antibody titers were comparable for ...... questions or comments should be addressed to the author. ... Berti E, Chiappini E, Orlandini E, Galli L, de Martino M. Pertussis is still common.
Published by Oxford University Press for the Infectious Diseases Society of ... from a manual to an automated extraction with participation of ... pital microbiology laboratory (culture); through the regional ..... The Australian Immunisation Hand- b
Regional Office for South-East Asia, New Delhi, India; 5Bill & Melinda Gates Foundation, Seattle, ... and Nigeria remained endemic for WT poliovirus in 2016.
Oct 5, 2017 - mitigated the clinical signs of pertussis, including leukocytosis and .... both a compatible procedure code and a diagnostic code during an ... on ICD-9 codes in the preceding 12 months and patients with a prior diagnosis of.
Jan 3, 2012 - study was underpowered, and the 13% relative risk ..... http://www.goldcopd.org/uploads/users/files/GOLDReport_April112011.pdf. ... Management. 2nd ed. San Diego, CA: Academic Press; 2009:425-432. 6. Message SD, Johnston SL. Infections.
Sep 22, 2014 - almost 80000 children, their data were compared with those of. â¼100000 nonvaccinated ..... GrÃ¼ber C, Illi S, Lau S, et al; MAS-90 Study. Group.
weeks, when the animal would have already clearedthe infection (Fig. 1), 6 U of serum antibodies to PT per ml were demonstrated; the amounts increased steadily thereafter. (Fig. 6A).A weak antibody response to FHA was detected at 6, 8,and 12 weeks po
pertactin and a B. perussis sonic extract in serum remained below detectable levels up to 12 weeks after infection. The lack of a detectable IgG response to the ...
Public_Health_Management_of_Pertussis_2012_PB65.01-_Oct_2012.pdf. Accessed 12 August .... Skoff TH, Kenyon C, Cocoros N, et al. Sources of .... Barger-Kamate B, Knoll MD, Kagucia EW, et al; for the Pneumonia Etiology Re- search for ...
1996. Immunology of herpes simplex virus. In Genital and Neonatal Herpes. L.R. Stanberry, editor. John Wiley & Sons, Ltd., Bristol, UK. 49â91. 21. Bot, A., S. Bot, ...
Fumiki Hirahara,â Hidechika Okada,â¡ Dennis Klinman,Â§ and Kenji Hamajima* ...... We thank Akiko Takada for her technical assistance, and Tomoko Takeishi.
Apr 1, 1978 - few children after pertussis vaccination, occur un- .... pneumonia. 2. 1969. 7 ... Admitted to hospital with pyrexia, signs and symptoms of.
New York: Holt. Janet, P. (1877). Une illusion d'optique interne [An illusion of internal perspective]. Revue Philosophique de la France etl'Etranger, 3, 497-. 502.
some articles, and Erik Arthur for coding some moderators. The au- thors also thank ...... *Dinges, N. G., Tollefson, G., Parks, G. A., & Hollenbeck, A. R.. (1978).
Jun 12, 1996 - Clinical trials in Sweden (2, 21), Italy (19), and Germany ..... Arciniega, J. L., R. D. Shahin, W. N. Burnette, T. D. Bartley, D. W. Whiteley,.
Dec 12, 2013 - by an Inactivated Bovine Ephemeral Fever Vaccine ... Bovine ephemeral fever (BEF) is an economically important viral vector-borne cattle ...
Jun 11, 2012 - virusâneutralising antibody in the oro-nasal pharyngeal region . ... 7 months of age were used in the experiments. The ani- .... tive antigen wells at serial dilutions from 1:100 to. 1:4000. ..... The six month window of pro-.
Aug 15, 1996 - and Bltmd Bank, University Hospital Leiden, Building I E3-Q, P. O. Box 9600. ... E. v. d. V., R. O., C. J. M. M.], and Tumor Immunology Program, Loyola ... 1Supported by Grants NKB 90-23 and NKB 93-588 from the Dutch ...
Nov 10, 2016 - acid (C12) to the lipid A moiety of LPS, thus increasing its biological potency .... were re-dissolved in the lysis solution and subjected to 2D gel.
Duration of Pertussis Immunity After DTaP Immunization: A Meta-analysis Ashleigh McGirr, MPH, David N. Fisman, MD, MPH, FRCPC
Pertussis incidence is increasing, possibly due to the introduction of acellular vaccines, which may have decreased the durability of immune response. We sought to evaluate and compare the duration of protective immunity conferred by a childhood immunization series with 3 or 5 doses of diphtheria-tetanus-acellular pertussis (DTaP).
BACKGROUND AND OBJECTIVES:
We searched Medline and Embase for articles published before October 10, 2013. Included studies contained a measure of long-term immunity to pertussis after 3 or 5 doses of DTaP. Twelve articles were eligible for inclusion; 11 of these were included in the metaanalysis. We assessed study quality and used meta-regression models to evaluate the relationship between the odds of pertussis and time since last dose of DTaP and to estimate the probability of vaccine failure through time.
RESULTS: We found no signiﬁcant difference between the annual odds of pertussis for the 3- versus 5-dose DTaP regimens. For every additional year after the last dose of DTaP, the odds of pertussis increased by 1.33 times (95% conﬁdence interval: 1.23–1.43). Assuming 85% vaccine efﬁcacy, we estimated that 10% of children vaccinated with DTaP would be immune to pertussis 8.5 years after the last dose. Limitations included the statistical model extrapolated from data and the different study designs included, most of which were observational study designs.
Although acellular pertussis vaccines are considered safer, the adoption of these vaccines may necessitate earlier booster vaccination and repeated boosting strategies to achieve necessary “herd effects” to control the spread of pertussis.
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
Pertussis, a highly contagious upper respiratory infection caused by Bordetella pertussis, is a poorly controlled vaccine-preventable disease in Canada, despite relatively high vaccine coverage rates.1,2 Disease incidence is highest in infants, with mortality rates greatest in infants younger than 3 months3; however, the burden of disease among adolescents and adults has recently increased considerably.3 Although this increase has been attributed to a multitude of factors, including aging of undervaccinated cohorts4 and more sensitive laboratory testing methods,5 recent reports have suggested that waning immunity of vaccinated individuals may also contribute to the resurgence of pertussis.6–10 Vaccination against pertussis was introduced in Canada in 19431 and was associated with a marked decline in the incidence of pertussis.3 However, small outbreaks of pertussis continued to persist with predictable seasonality.4 In 1997–1998, an acellular preparation of pertussis vaccine (diphtheria-tetanus-acellular pertussis [DTaP]) was introduced in Canada. This combination vaccine was associated with fewer side effects and had a better safety proﬁle than the previously used diphtheria-tetanuswhole cell pertussis (DTwP) vaccine.11,12 There are currently 2 types of acellular preparations licensed for use. The children’s preparation, DTaP, contains high concentrations of antigens for diphtheria, tetanus, and acellular pertussis while the adolescent/adult formulation, Tdap, contains high concentrations of antigens for tetanus, but lower concentrations of antigens for diphtheria and acellular pertussis.1 Recommendations in Canada call for DTaP immunizations at 2, 4, and 6 months and between 12 and 23 months of age. A childhood booster vaccine (of either DTaP or Tdap) is recommended between ages 4 and 6.1,13 Additional boosters for adolescents and adults are recommended between ages 14 and 16
and once again as an adult.1,14 Although a similar 5-dose DTaP vaccine series is used in Canada and the United States, globally there are a wide variety of DTaP vaccination schedules that are recommended. In many European countries, a 3-dose DTaP vaccine series is offered, often in conjunction with a booster vaccine for school-aged children aged 4 to 9 years.15 The 3-dose schedule typically recommends vaccination at 2, 3, and 4 months; 2, 4, and 6 months; or 3, 5, and 11 months of age.15 However, despite widespread implementation of these different immunization programs and associated levels of uptake, pertussis persists. A previous review by Wendelboe et al16 summarized several studies relating to the duration of protective immunity conferred by natural infection with pertussis, with DTwP, and with DTaP. However, this study was published in 2005, well before the existence of much of the current literature. In addition, the review did not include a meta-analysis of the key results. Thus, we believe there is a critical need for a systematic literature review and meta-analysis to evaluate the weight of evidence about waning pertussis immunity from available studies, and to synthesize this evidence. Understanding waning immunity and its impact on the disease burden of pertussis in different age groups is critical to designing vaccination programs to control the spread of pertussis in the community. Although ethical issues surround the feasibility of a randomized controlled trial to
evaluate vaccine-induced waning immunity, decisions still need to be made on optimal vaccine strategies, and systematic review and metaanalysis provide a mechanism whereby such decisions can be informed by the best available data. Our objectives were to (1) synthesize the current literature surrounding waning immunity to pertussis after vaccination with 3 and 5 childhood doses of DTaP and (2) estimate the duration of protective immunity to pertussis after 3 and 5 doses of DTaP using meta-analytic techniques.
METHODS Search Criteria A literature search was conducted by using both Medline and Embase databases. In consultation with a research librarian at the University of Toronto, the search strategy consisted of key words and medical subject headings. Similar terms and synonyms were combined with an “OR” operator, and these distinct components were linked together with an “AND” operator. Search terms included “whooping cough,” “pertussis,” “diphtheria-tetanusacellular pertussis vaccine,” “timefactors,” “follow-up studies,” “drug efﬁcacy,” “outcome assessment,” and “treatment duration.” The search strategies were carried out without limits on October 10, 2013. The unique search strategies for each database can be found in Table 1. To ensure completeness, the reference lists of the included studies
TABLE 1 Search Strategies Used in the 2 Different Databases Database
“exp Whooping Cough/ep, im, pc [Epidemiology, Immunology, Prevention & Control]” AND “exp Child/ OR exp Adolescent/” AND “exp Follow-Up Studies/ OR exp Time Factors/ OR exp Immunization Schedule/” AND “exp Diphtheria-Tetanus-Pertussis Vaccine/ad, im, st [Administration & dosage, Immunology, Standards] OR exp Diphtheria-Tetanus-acellular Pertussis Vaccines/ad, im, st [Administration & Dosage, Immunology, Standards] OR exp Pertussis Vaccine/ad, im [Administration& Dosage]” “exp pertussis/dt, ep, pc [Drug Therapy, Epidemiology, Prevention]” AND “exp diphtheria pertussis tetanus vaccine/dt [Drug Therapy] OR exp pertussis vaccine/dt [Drug Therapy” AND “exp drug efﬁcacy/ OR exp follow up/ OR exp risk assessment/ or exp outcome assessment/ or exp treatment duration/” AND “child/ OR adolescent”
MCGIRR and FISMAN
were searched to identify any studies that had not been captured by the original literature search.
Study Selection Relevancy Screen We reviewed the titles and abstracts of the retrieved articles to assess for relevancy. All primary research articles, not including modeling studies, that assessed a measure of long-term immunity (.18 months of follow-up) were included. Studies in which pertussis immunity was not an outcome, studies about diphtheriatetanus toxoids-pertussis (DTP) or DTwP, studies about strategies to improve vaccine uptake, and studies about adverse events after vaccination were excluded at this stage. Abstracts published in languages other than English were translated by using Google Translate to assess relevancy.17 Agreement between the 2 reviewers was assessed by using the k statistic, and where discrepancies on the study inclusion criteria existed, they were resolved by discussion and consensus.
validity (bias and confounding), and power.18,19 Each question was scored as a 0 or 1, except for 1 question (reporting of confounders), which was scored from 0 to 2. For the purpose of this study, the instrument was modiﬁed by removing the question about power because the different study designs each have their own sample size requirement. One author (A.M.) analyzed the quality of the included studies. Study quality categories were assigned on the basis of the following modiﬁed Downs and Black scores: excellent (25–27), good (19–24), fair (14–18), and poor (#13).
Data Abstraction Data from the relevant articles were abstracted to calculate odds ratios and SEs comparing the odds of pertussis for each year since the last dose of DTaP, where available. One year after the last dose of DTaP was
chosen as the referent because the majority of articles presented the results this way. When available, measures of association and SEs were taken directly from the articles, and where tabular data existed, measures of association and corresponding SEs were calculated manually. In 1 case, the referent data were obtained from a previously published article from the same research study.20 When the odds ratios were presented by using a continuous predictor of time since last dose of DTaP, the logistic model was extrapolated to calculate odds ratios and SEs for each year. Risk ratios for the serologic studies were calculated by comparing the risk of vaccine failure at the given time period with the risk of vaccine failure 1 year post–vaccine administration (assumed to be 18.8% for the 5-dose series and 17.7% for the 3-dose series, as per previous studies of the same cohorts of subjects21,22). Risk
Full-Text Review The full texts of the studies screened for inclusion were read and included in the review if they met the predeﬁned full-text inclusion criteria. Speciﬁcally, studies that used either 3 or 5 childhood doses of DTaP and that included a measure of time since vaccination were included. To ensure completeness of the literature search, the references of the included studies were scanned and relevant articles were included in the systematic review.
Quality Assessment A modiﬁed version of the Downs and Black critical appraisal tool for randomized and nonrandomized studies was used to evaluate the quality of the included studies.18 This validated and widely used instrument contains 27 questions pertaining to reporting, external validity, internal
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FIGURE 1 Flowchart of studies included in the review and meta-analysis.
MCGIRR and FISMAN
Serologic follow-up study of RCT
Double-blind crossover Study
Klein et al, Northern 2012 (10) California
Misegades California et al, 2012 (47)
Witt et al, Marin County, 2012 (59) California
Zinke et al, Germany 2010 (61)
Zepp et al, Germany 2007 (60)
Tartof et al, Minnesota/ 2013 (9) Oregon
Study, year (source)
Children born between National Notiﬁable 2000–2010 1998 and 2003 with 5 Diseases recorded doses of Surveillance DTaP with last between System and ages 4 and 6 Immunization Information Systems Kaiser Permanente January 2006–June Kaiser Permanente 2011 Northern California Northern California members born after 1999 without Tdap or databases any pertussis vaccine between ﬁfth dose and PCR test date Reports to local 2010–December Children aged 4 to 10 2010 from 15 California health counties (Alameda, Del departments and medical Norte, El Dorado, records Fresno, Madera, Marin, Merced, Orange, Riverside, San Diego, San Luis Obispo, Santa Clara, Santa Cruz, Sonoma, and Stanislaus) Kaiser Permanente March Children and adolescent electronic 2010–October members of Kaiser medical records 2010 Permanente Medical Center in San Rafael, California ATP cohort from July Healthy German children earlier RCT, 2006–December between 7 and 9 y of Study B (Zinke 2006 age who had been et al, 200970) immunized with DTPaHBV-IPV-Hib vaccine in previous RCT ATP cohort from Not speciﬁed German adolescents who earlier RCT (Knuf were enrolled and et al, 200669) complied with the protocol of a previous RCT who had available immunogenicity data
TABLE 2 Characteristics of Included Studies
3, 4, 5, and Anti-PT $5 EL U/mL 12–18 mo of age, 4–6 y of age
3, 4, 5, and Anti-PT $5 EL U/mL 12–18 mo of age, 4–6 y of age
2, 4, 6, and 15–18 mo, 4–6 y of age
Probable and conﬁrmed cases as deﬁned by Council of State and Territorial Epidemiologists, suspected cases as deﬁned by the California Department of Public Health PCR positive for pertussis
2, 4, 6, and 15–18 mo, 4–6 y
Examined age at receipt of ﬁfth dose but found no difference
Kaiser Permanente Stratiﬁcation Medical Center (vaccine population as effectiveness a whole via screening method) NA Seropositivity rates
Age (4 to ,7, 7 to ,10, and 10 to 12), gender, medical clinic, race/ ethnicity Gender, age at 3 controls per case, Logistic enrollment, regression selected through reporting accounting for and age at clustering by ﬁfth dose clinicians county and were assessed as physician potential confounders, but none found to be PCR negative for Conditional PCR positive for pertussis and PCR pertussis and logistic PCR negative for regression negative for parapertussis parapertussis (conditioned on calendar time)
Log binomial model of calculated incidence rates
2, 4, 6, and 15–18 mo, 4–6 y
Age-speciﬁc populations of Minnesota and Oregon
Conﬁrmed cases as Council of State and Territorial Epidemiologists
Loss of Immunity “Case Deﬁnition”
2, 4, 6, and 15–18 mo, 4–6 y
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Follow-up of previous RCT
Serum antibody study
Loss of Immunity “Case Deﬁnition”
Swedish Institute October Swedish children 3, 5, and 12 mo Culture or PCR for Infectious 1997–September of age conﬁrmed 2004 pertussis, Disease Control, Statistics regardless of symptoms Sweden, clinical chart review Newborn infants enrolled 2, 4, and 6 mo Cough lasting .20 Patients previously Patients enrolled 1990–1995 in original RCT of age d with enrolled in RCT bacteriologic or (Simondon et al, serologic 199771) conﬁrmation or link to documented case October Swedish children born 3, 5, and 12 mo Culture- or PCRSwedish Institute for Infectious 1997–September between January 1996 of age conﬁrmed 2000 and September 2000 pertussis, Disease Control, regardless of Statistics Sweden, clinical symptoms chart review Patients enrolled in December 1999 Healthy Italian children 5 3, 5, and 11 mo Positive ELISA (EU/ clinic at and 6 y old who were of age mL) for anti-PT, University of born premature and cutoff value not Bologna given 3 doses of DTaP speciﬁed as an infant Newborn infants enrolled 2, 4, and 6 mo Laboratory-conﬁrmed Patients remaining October 1995–October in original RCT of age pertussis infection under 1998 and spasmodic surveillance at cough lasting stage 3 of RCT $14 d or cough (Greco et al, lasting $21 d 199620) Patients enrolled in December Healthy Italian children 5 3, 5, and 11 mo Positive ELISA (EU/ clinics at the 1999–January and 6 y old either of age mL) for anti-PT, University of 2000 given 3 doses of DTaP cutoff value not Palermo and the as an infant or had speciﬁed clinical pertussis as an University of Bologna infant
Vaccine efﬁcacy None using persontime incidence density
Intensity of exposure, birth rank, height-forage index at 7 mo
ATP, According to Protocol; DTPa-HBV-IPV-Hib, ; EL, ELISA units; ELISA, enzyme-linked immunosorbent assay; EU, ELISA units; NA, not applicable; anti-PT, pertussis antitoxin; RCT, randomized controlled trial.
Salmaso, Piemonte, Follow-up of et al Veneto, previous 2001 (55) FriuliRCT Venezia Giulia, and Puglia, Italy Esposito, Italy Serum et al antibody 2001 (38) study
Esposito Italy et al, 2002 (39)
Olin et al, Sweden Surveillance 2003 (51) (except study Gothenburg and area)
Niakhar, Lacombe et al, Senegal 2004 (44)
Gustafsson Sweden Surveillance et al, (except study 2006 (41) Gothenburg and area)
Misegades et al (48) Klein et al Lacombe et al (10) (44) Gustafsson et al (41) Esposito et al, 2002 (39) Esposito et al, 2001 (38)
The studies included in the analysis differed in terms of deﬁning loss of immunity. The clinical studies compared the incidence of pertussis for every year since the vaccine was administered with the use of various case deﬁnitions of pertussis. Two of
Study, year (source)
Of the included studies, 2 were casecontrol studies,10,47 2 were cohort studies,9,59 3 were follow-up studies from previously conducted randomized controlled trials,44,55,61 2 were surveillance studies,41,51 2 were serum antibody studies,38,39 and 1 was a double-blind crossover study60 (Table 2). Despite searching without limits on publication dates, the included studies with 5 doses of DTaP were all published between 2010 and 2013 and the included studies with 3 doses of DTaP were all published between 2001 and 2006. The majority of the 5-dose included studies were conducted in the United States (California,10,47,59 Minnesota,9 and Oregon9), with the remaining 5-dose studies conducted in cities across Germany.60,61 Almost all of the 3-dose studies were conducted in Europe (Italy38,39,55 and Sweden41,51), although 1 study was conducted in Senegal.44
Olin et al Salmaso et al Tartof et al Witt et al (51) (55) (9) (59)
Of the 389 potentially relevant articles identiﬁed through the literature search, 339,10,31–61 underwent full-text review. Agreement between the independent reviewers with respect to the title/abstract scan was fair (k = 0.61). Six9,10,47,59–61 of these studies ﬁt the 5-dose eligibility criterion to be included in this review and 6 studies38,39,41,44,51,55 met the 3-dose criterion (Fig 1). None of the articles published in languages other than English met inclusion criteria. No additional articles were identiﬁed through hand-searches of reference lists.
Reporting External validity Internal validity Bias Confounding Total Quality rating
Zinke et al (61) Zepp et al (60)
Included Studies in Review
All data analysis and statistical modeling were performed by using the metafor package in R Statistical Software.24,25 Publication bias was assessed by using funnel plots with asymmetry between the measures of association and SEs quantiﬁed by using Egger’s test.26 Random-effects models using the DerSimonian-Laird estimator were used to pool the results between the included studies once heterogeneity, as assessed by using Higgins’ I2 statistic, among the outcomes was considered.27,28 A metaregression model using the DerSimonian-Laird estimator was ﬁt to the data to evaluate the relationship between the odds ratio of pertussis and time since last DTaP vaccination.27 To evaluate the importance of the number of doses and the type of pertussis “diagnosis” (ie, clinical versus serologic), we included these variables in the meta-regression model and evaluated the change in the estimate of the main effect. Using a range of vaccine efﬁcacy estimates from the United States and Canada we were able to anchor the probability of vaccine failure for the ﬁrst year since DTaP series completion.1,29,30 We assumed that the probability of vaccine failure followed an exponential distribution, where the probability of immunity at some time t was P(I)t =VE(exp[2 lt]), with VE being the efﬁcacy of vaccination during the initial period after series completion, and l representing the rate of vaccine failure. Under this scheme, the mean duration of immunity among those who initially respond to the vaccine is 1/l. With the rare disease assumption, the predicted odds ratios from the meta-regression were assumed to approximate risk ratios, allowing for the creation of
Downs and Black Criteria
functions of probability of vaccine failure through time.
TABLE 3 Quality Assessment of the Included Studies
ratios and incident rate ratios were assumed to approximate odds ratios according to the rare disease assumption.23 These odds ratios and corresponding SEs were entered manually into a spreadsheet for analysis.
MCGIRR and FISMAN
the studies used polymerase chain reaction (PCR) laboratory methods only,10,59 2 of the studies used culture or PCR methods regardless of symptoms,41,51 1 used a cough lasting .20 days with bacteriologic or serologic conﬁrmation or link to a documented case,44 and 1 used laboratory conﬁrmed pertussis infection and spasmodic cough lasting $14 days or cough lasting $21 days.55 The remaining 2 studies used the Council of State and Territorial Epidemiologists–conﬁrmed case deﬁnition9 and the conﬁrmed/ probable case deﬁnition in conjunction with the suspected case deﬁnition from the California Department of Public Health.47 The serologic studies compared the number of individuals who had levels of immunologic markers above a certain threshold for every year since the vaccine was administered. Two of the studies explicitly deﬁned seropositivity as anti-PT ($5 EL U/mL),60,61 whereas 2 deﬁned seropositivity as positivity by using an enzyme-linked
immunosorbent assay without a clear description of cutoff.38,39 These varying clinical and serologic case deﬁnitions of pertussis likely contributed to the observed heterogeneity between the studies (Table 2).
Quality Assessment The included studies had a diverse range of quality. Two studies were assessed as “good” quality,10,44 9 studies were assessed as “fair” quality,9,38,39,41,47,51,55,59,60 and 1 study was assessed as “poor” quality61 (Table 3). Of the 4 categories assessed with the modiﬁed Downs and Black rating scale, reporting showed the biggest variability in scores. Most commonly, studies scored poorly because of undeﬁned study aims, vague or no description of the study participant characteristics, and no mention of participants lost to follow-up.
Included Studies in Meta-analysis One study59 was excluded from the meta-analysis because of
contamination of the measure of association. The study participants were classiﬁed as being up-to-date for age of immunization according to the US Centers for Disease Control and Prevention Guidelines but were grouped into age categories of 2 to 7 years of age, 8 to 12 years of age, and 13 to 18 years of age. Because the Centers for Disease Control and Prevention recommends a booster immunization at 10 to 12 years of age, some of the participants in the 8- to 12-year age category and most of the participants in the 13- to 18-year age category would have had the adolescent booster vaccine already. The authors highlighted this as a potential reason for the lower attack rates of pertussis in the older age groups. To ensure comparability of the estimates, the results from this study were removed from the metaanalysis. The study by Klein et al10 contained 2 control groups (PCR-negative controls and matched controls) and used them to calculate 2 different
FIGURE 2 Funnel plots and P values from Egger’s test evaluating the risk of publication bias for the odds ratios of pertussis for years 2 to 6 after the last dose of DTaP. OR, odds ratio.
PEDIATRICS Volume 135, number 2, February 2015
association. Similarly, the study by Salmaso et al55 contained 2 study populations: 1 that was vaccinated with a DTaP vaccine made by SmithKline Beecham and the other that was vaccinated with a DTaP vaccine made by Chiron-Biocine. As such, we included both sets of results from each of these studies in the analysis, for a total of 13 distinct estimates.
Meta-analysis Results Publication Bias There was no evidence of publication bias for any of the years since the last DTaP vaccine, with all funnel plots showing symmetry between the measure of association and the SE according to Egger’s test (Fig 2).
Pooled Effects Summary measures of association along with the observed Higgins’ I2 measure of heterogeneity for every year since the last dose of DTaP are shown in Fig 3. The pooled odds ratios of pertussis were found to increase with the time since the last dose of DTaP, suggesting considerable waning immunity. Between-study heterogeneity was also found to increase for every year since the last dose of DTaP, with year 2 showing moderate heterogeneity and years 3 to 6 showing substantial heterogeneity (Fig 4). This increasing heterogeneity in effect estimates as the time since last DTaP vaccine increases is likely due to a compounding effect of the heterogeneity in the study designs.
Meta-regression FIGURE 3 Forest plots showing the pooled odds ratios of pertussis for years 2 to 6 versus year 1 after the last dose of DTaP. Pooled odds ratios were calculated by using random-effects models with the DerSimonian-Laird estimator. CB, Chiron-Biocine vaccine; I2, Higgins’ I2 measure of heterogeneity; MN, Minnesota; (OR), Oregon; OR, odds ratio; RE, random effects model; SB, SmithKline Beecham.
odds ratios for pertussis. Because the 2 control groups were compared with the same case group, we used only the estimates for the PCR-negative controls because the authors believed
this measure contained the least amount of bias. The study by Tartof et al9 contained 2 distinct study populations (Minnesota and Oregon) with separate measures of
The results from the ﬁnal metaregression model suggest that the odds of pertussis for every year since the last dose of DTaP was estimated to increase by a multiple of 1.33 (95% conﬁdence interval: 1.23–1.43) (Table 4, Fig 5). Because the odds ratio associated with the years since last DTaP variable did not change appreciably when the number of doses variable was included, there is
MCGIRR and FISMAN
predicted probability of vaccine failure through time (Fig 6). From this analysis, the average duration of vaccine protection from DTaP is ∼3 years, assuming 85% vaccine efﬁcacy. With this loss of protection, we predict that only 10% of the children vaccinated with DTaP would be protected by 8.5 years after the last dose, but this could be higher or lower with alternate assumptions regarding vaccine efﬁcacy.
Relationship between heterogeneity between studies (as measured with Higgins’ I2) and time since last DTaP. Higgins’ I2 is a measure of the total variation between studies due to heterogeneity.28
TABLE 4 b Coefﬁcients and Corresponding SEs for the 3 Different Meta-regression Models Model 1 Model 2 Model 3
Years Since Last DTaP
0.321 (0.14) 20.053 (0.14) 20.003 (0.11)
0.289 (0.06) 0.26 (0.05) 0.2862 (0.04)
0.719 (0.14) 0.695 (0.11)
SEs are shown in parentheses. b coefﬁcients represent the log of the odds ratio for every unit increase in the predictor variable.
FIGURE 5 Odds ratios of pertussis for each year since the last dose of DTaP. The circles, inversely weighted by study variability, represent the odds ratios calculated from each of the studies examining 5 doses of DTaP, whereas the inverted triangles represent the odds ratios from the studies examining 3 doses of DTaP included in the meta-analysis. The black line represents the ﬁtted meta-regression curve accounting for the effects of time. In this meta-regression curve, dose type was assumed to be constant at 5 doses and the diagnosis type was assumed to be constant at “clinical.” MN, Minnesota; OR, Oregon.
evidence to suggest that the duration of protective immunity from DTaP is the same for those given 3 or 5 doses of the vaccine (Table 4). Similarly, when the deﬁnition of loss of immunity variable was included, the odds ratio again did not change appreciably, suggesting that the duration of protective immunity from DTaP is the same for the studies measuring clinical markers of
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pertussis and those measuring serologic markers (Table 4). However, the addition of these variables changes the absolute risk of pertussis, with a higher risk of pertussis in the studies examining the 5-dose vaccine series and a lower risk of pertussis in the studies that used serologic outcomes (Table 4). Using the above estimated odds ratio of 1.33, we created curves of the
DISCUSSION Understanding the duration of protective immunity conferred by a vaccine is critical to the development of immunization guidelines and programs. To our knowledge, this is the ﬁrst systematic review and meta-analysis of the duration of protective immunity to pertussis after routine childhood immunization with DTaP. Our ﬁndings suggest that the odds of pertussis increase by 1.33 times (95% conﬁdence interval: 1.23–1.43) for every additional year since the last dose of DTaP. With this loss of protection, we predict that only 10% of the children vaccinated with DTaP would be protected by 8.5 years after the last dose, assuming an initial vaccine efﬁcacy of 85%.1,30 Although we found that the odds of pertussis for every year since the last dose of DTaP did not depend on the number of doses, we did ﬁnd that there was a greater absolute risk of pertussis in the studies examining 5 doses of DTaP and a lower absolute risk of pertussis in the serologic studies. Because the participants in the 5-dose studies were older, on average, than the participants in the 3-dose studies, this ﬁnding may highlight the increased risk of pertussis in older age groups. Although infants ,1 year remain at highest risk of pertussis, recent surveillance reports from the United States and Canada indicate that age groups with the next highest incidence of pertussis include 7- to
studies, thereby reducing the potential for publication bias.26 By searching multiple databases and the references of included studies, we are conﬁdent that the search captured all relevant published studies, and we found no evidence for publication bias using Egger’s test and analysis of the funnel plots (Fig 2).
FIGURE 6 Estimated probability of vaccine failure for different levels of vaccine efﬁcacy.
10-year-olds (United States) and 10- to 14-year-olds (Canada).62,63 The lower absolute risk of pertussis in the studies examining serologic outcomes may be due to the sensitivity of these testing methodologies and their corresponding anti-PT (pertussis antitoxin) cutoff levels. It is important to highlight the limitations of studies included in this review. Most studies were observational in nature,9,10,38,39,41,47,51,59 allowing for biases and confounding to distort measures of association. Although 3 studies adjusted for potential confounders of interest (age, gender, race/ethnicity, age at ﬁfth dose of DTaP, medical clinic; Table 2),9,10,47 others did not, which may have contributed to over- or underestimates of the duration of protective immunity. Caseascertainment bias could have affected individual study results: where nasopharyngeal swabs were necessary for conﬁrmation of the case deﬁnition of pertussis,9,10,41,44,47,51,59 physicians may have been more likely to test sicker or more medically complex patients due to the invasive nature of the procedure, which could alter estimates of effect. One of the studies speciﬁcally addressed this concern and implemented standardized procedures for collecting nasopharyngeal swabs for ongoing coughs, regardless of other clinical characteristics.55 Serologic follow-up studies38,39,60,61 would not be affected by this type of
case-ascertainment bias, but all serologic follow-up studies38,39,60,61 were funded by vaccine companies producing DTaP, potentially inducing biases of another nature. As with all systematic reviews, this study had a number of limitations. Primarily, the follow-up periods for the studies included in the metaanalysis ranged from 2 to 6 years, limiting estimates to this relatively brief period. We extrapolated metaregression results because longerduration studies were not identiﬁed. Although we believe this assumption was necessary, it nonetheless presents a limitation in the interpretation of the results. In addition, we found considerable between-study heterogeneity, possibly an artifact of varying case deﬁnitions, study designs, and study populations. Third, the 3- and 5-dose series each included different dosing schedules (Table 2), which may have added to the observed heterogeneity. However, this systematic review and meta-analysis is the ﬁrst of its kind to synthesize the information and provide a credible estimate on the duration of vaccine-induced immunity to pertussis. The review methods were robust and captured a wide range of studies in multiple languages and countries of publication. Although translation with the use of Google Translate is imperfect, it allowed us to determine citation relevance for non-English
The results from this meta-analysis have important policy implications, mainly surrounding boosting strategies for adolescents to ensure that “herd effects” of pertussis are maintained. Although an adolescent Tdap booster is offered in Canada, it is recommended for teenagers aged 14 to 16 years,1 which may be too late and leave those aged 10 to 14 years susceptible to pertussis. The adolescent Tdap booster is recommended for youth between 10 and 12 years of age in the United States and in many European countries,15,64 which may represent more appropriate timing. In addition, the results from this analysis have implications for repeated pertussis vaccinations in adults. Previous research has highlighted the importance of repeat Tdap immunization for each pregnancy.65 It has also been suggested that a decennial booster strategy with Tdap may be an effective and cost-effective way to control the spread of pertussis among adults.66–68 Although the risk of pertussis infection may be lower in adults, assuming waning immunity to Tdap is similar to waning immunity to DTaP, repeated booster vaccines will be necessary to maintain a population with high levels of vaccine coverage for pertussis. Our ﬁndings also provide epidemiologists and mathematical modelers with credible data inputs for modeling studies. The weight of the evidence suggests that the average duration of protective immunity to pertussis after the ﬁfth dose of DTaP is ∼3 to 4 years, a key parameter in many studies evaluating
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vaccination strategies and their economic impact. However, this estimate of the probability of vaccine failure is sensitive to the initial vaccine efﬁcacy. The parameterization of the function can be modiﬁed to generate predictive values of duration of protection for different levels of vaccine efﬁcacy. In summary, we performed a systematic literature review to understand the relationship between the risk of pertussis and time since pertussis vaccination. We found evidence of waning immunity and estimated that the average duration of vaccine protection from DTaP is ∼3 years, assuming 85% vaccine efﬁcacy. With this loss of protection, we predict that only 10% of the children vaccinated with DTaP would be protected by 8.5 years after the last dose. With a preschool booster offered for children aged 4 to 6 years, our ﬁndings suggest that very few children over age 10 would be protected against pertussis, signaling the need for an earlier adolescent Tdap booster in Canada.
ACKNOWLEDGMENTS We thank Carla Hagstrom for her help in creating the literature search strategy. REFERENCES 1. Public Health Agency of Canada. Canadian immunization guide. In: Public Works and Government Services. 7th ed. Ottawa, Canada: Public Health Agency of Canada; 2006 2. McWha L, MacArthur A, Badiani T, Schouten H, Tam T, King A. Measuring up: results from the National Immunization Coverage Survey, 2002. Can Commun Dis Rep. 2004;30(5):37–50 3. Galanis E, King AS, Varughese P, Halperin SA; IMPACT Investigators. Changing epidemiology and emerging risk groups for pertussis. CMAJ. 2006;174(4):451–452 4. Ntezayabo B, De Serres G, Duval B. Pertussis resurgence in Canada largely caused by a cohort effect. Pediatr Infect Dis J. 2003;22(1):22–27
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