Risk of Recurrence of Adverse Events Following Immunization: A Systematic Review
CONTEXT: Reimmunizing patients who had an adverse event following immunization (AEFI) is sometimes a challenge because there are limited data on the risk and severity of AEFI recurrence.
OBJECTIVE: To summarize the literature on the risk of AEFI recurrence.
DATA SOURCES: PubMed, Embase, and Cochrane library.
STUDY SELECTION: We included articles in English or French published before September 30, 2016. Articles were selected if they estimated the risk of AEFI recurrence in at least 5 individuals. Studies with experimental vaccines were excluded.
DATA EXTRACTION: Data on study design, setting, population, vaccines, and AEFI recurrence were extracted.
RESULTS: Twenty-nine articles were included. Among patients with a history of hypotonic hyporesponsive episode (n = 398), anaphylaxis (n = 133), or seizures (n = 60) who were reimmunized, events recurred in 0% to 0.8%. Allergic-like events recurred in 30 of 594 reimmunized patients. Fever recurred in 0% to 84% of 836 reimmunized patients, depending on the vaccine and dose number. Among children with extensive limb swelling after the fourth dose of diphtheria-tetanus-acellular pertussis vaccine, recurrence was higher when the fifth dose was given withthe full-antigen formulation (78%) compared with the reduced-antigen formulation (53%, P = .02)
LIMITATIONS: Many studies, included few patients, and those with severe AEFIs were often not reimmunized.
CONCLUSIONS: Despite vaccines being administered to millions of people annually, there are few studies in which researchers evaluated AEFI recurrence. Published studies suggest that reimmunization is usually safe. However in these studies, severe cases were often not reimmunized.
- AEFI —
- adverse event following immunization
- ALE —
- allergic-like event
- CI —
- confidence interval
- DTaP —
- diphtheria-tetanus-acellular pertussis vaccine
- dTap —
- reduced-antigen diphtheria-tetanus-acellular pertussis vaccine
- DTaP±Hib/HepB/IPV —
- DTaP with or without Hib, HepB, and IPV
- DTP —
- diphtheria-tetanus toxoids-pertussis vaccine
- DTwP —
- diphtheria, tetanus, whole-cell pertussis vaccine
- ELS —
- extensive limb swelling
- HepB —
- hepatitis B
- HHE —
- hypotonic hyporesponsive episode
- Hib —
- Haemophilus influenzae type b
- HPV —
- human papilloma virus
- IIV —
- inactivated influenza vaccine
- IPV —
- injectable polio vaccine
- MMR —
- ORS —
- oculorespiratory syndrome
- RCT —
- randomized controlled trial
- RR —
- risk ratio
For vaccines to be fully effective and induce long-term protective immunity, individuals should receive all recommended doses. Vaccine recipients who experienced an adverse event following immunization (AEFI) are sometimes afraid that the adverse event might recur with future immunizations, and this can lead to avoidance or delay of subsequent immunizations. Most existing recommendations regarding the management of patients who had an AEFI are based on expert opinion and supported by limited scientific data.1,2
The aim of this systematic review was to summarize the literature on the risk of AEFI recurrence (defined as an occurrence of the same AEFI after the administration of another dose of the same vaccine or vaccines sharing common antigens) and identify predictors of recurrence. In addition, we sought to determine if the risk of an adverse event following reimmunization was higher in patients who already had the same adverse event at the previous immunization compared with those who did not. These results are expected to inform physicians when discussing continuation of immunization with patients who previously experienced an AEFI and to support future immunization guidelines for these patients.
We conducted a systematic review of studies published in English and French before September 30, 2016 in Medline via PubMed, Embase, and the Cochrane library. Ethical approval was not required because only published articles were included in this review.
The search strategy was developed in consultation with an experienced medical library scientist using the preferred reporting items for systematic reviews and meta-analysis of observational studies recommendations.3,4 The search combined keywords (with corresponding synonyms, Medical Subject Headings and Emtree terms) referring to our intervention (ie, “reimmunization” and “immunization”) and outcome (ie, “adverse events”). No restriction on study type or population was used to get a full perspective of the research that has been done to date. The search strategy in Medline via PubMed is available in Supplemental Table 5.
The titles and abstracts of the publications identified were independently screened for eligibility by 2 investigators (J.G.Z., M.K.); interrater discrepancies were resolved by discussion and consensus. Additional articles were identified by reviewing the reference lists of retrieved articles. J.G.Z. selected the full-text articles. A flow diagram outlining the selection process is presented in Fig 1. We included all studies in which researchers estimated the risk of AEFI recurrence or that described the outcome of reimmunization among patients with a history of AEFI. Exclusion criteria were the following: experimental vaccines (eg, malaria), cancer vaccines, vaccines administered at more than 5-year intervals (eg, yellow fever) and studies in which fewer than 5 patients were reimmunized. Recurrence was defined as the occurrence of the same adverse event following reimmunization. Reimmunization was defined as administration of vaccine(s) that had common antigens with those implicated in the initial AEFI. The case definitions of each evaluated AEFI are presented in Table 1.
For each study, the risk of bias with respect to our review question was assessed by using a standardized form adapted from the guidelines of the National Institute for Health and Care Excellence6 and Risk Of Bias In Non-Randomized Studies - of Interventions7 (Supplemental Tables 6, Supplemental Fig 3 and 4). Risk of bias was rated as “low,” “moderate,” “serious,” “critical,” or “unclear.”7
Data on country, year of publication, study design, vaccine(s), population, duration of follow-up, and AEFI recurrence were extracted from the articles that met eligibility criteria and were entered into a spreadsheet. Risk of AEFI recurrence was calculated as follows: the number of patients with recurrence divided by the total number of patients reimmunized. Owing to the differences between the studies, a DerSimonian and Laird random-effects approach was used for the pooled estimates. The variances of the risks estimated in the individual studies were stabilized with the Freeman-Tukey transformation before pooling.8 Heterogeneity was assessed by using the I2 statistics, interpreted as low (0%–40%), moderate (30%–60%), substantial (50%–90%), and considerable (75%–100%) heterogeneity.9 Subgroup analyses per vaccine dose number and type (eg, whole-cell or acellular pertussis) were conducted to explore clinical heterogeneity.
We compared the occurrence of adverse events following reimmunization in various subgroups, including vaccine recipients with a history of AEFI versus those without, type of vaccine administered, and severity of the initial AEFI. Comparisons were performed by using risk ratios (RRs) with 95% confidence intervals (CIs), 2-tailed χ2 tests, or Fisher’s exact tests with statistical significance defined as P < .05. Pooled analyses were performed with Stata version 13.0 and the remaining with SAS, version 9.3.
Among the 3883 articles retrieved, 29 met the inclusion criteria, 6 of which (20%) were identified from the reference lists of other articles (Fig 1).5,10–37 The articles were published between 1982 and 2016. Most (n = 27, 93%) studies were observational,5,10–24,27–37 and 14 (48%) were prospective (Table 2). In the various studies, AEFIs were collected through patient and/or parental reports (n = 12), physician report or patient and/or parental report (n = 7), hospital records and/or chart review (n = 7), passive surveillance database (n = 2), or physician report (n = 1) (Table 2). Most studies included only children aged <18 years (n = 18, 62%), of which 12 (67%) studies included only children ≤6 years. The remaining studies included adults aged 18 years or older (n = 3, 10%) or both children and adults (n = 8, 28%). All studies included both sexes, except for 2 studies in which researchers described adverse events following human papilloma virus (HPV) immunization in girls.14,30 Researchers evaluated the recurrence risk of the following AEFIs: allergic-like events (ALEs) (n = 13), hypotonic hyporesponsive episodes (HHEs) (n = 7), fever (n = 5), extensive limb swelling (ELS) (n = 3), seizures (n = 3), pain (n = 3), apnea (n = 2), decreased appetite (n = 2), persistent crying (n = 2), drowsiness (n = 2), vomiting (n = 2), and Henoch-Schonlein purpura (n = 1). Typically, several vaccines or adverse events were evaluated in the same study; researchers in 9 studies assessed the risk of recurrence of 1 specific AEFI (fever, apnea, ELS, oculorespiratory syndrome [ORS], ALE, or HHE) after administration of 1 or several vaccines (Table 2). Among the studies in which researchers assessed vaccine-specific risks of AEFI recurrence, the most frequently studied vaccines were the diphtheria-tetanus-acellular pertussis vaccine (full-antigen, DTaP or reduced-antigen, dTap formulations) or diphtheria-tetanus whole-cell pertussis vaccine (DTwP) (n = 12), followed by inactivated influenza vaccine (IIV) (n = 6), HPV vaccine (n = 2), diphtheria-tetanus toxoids vaccine (DT) (n = 1), and New Zealand meningococcal B vaccine (n = 1).
Overall, the risk of bias in the individual studies was rated as low in 8 (28%) of the studies, moderate in 15 (52%), and serious in 6 (21%) (Fig 2).
Allergic-like signs and symptoms can be caused by a variety of conditions. Three of these conditions were described in the studies retrieved: ALEs, anaphylaxis, and ORS. ORS is a non–immunoglobin E–mediated adverse event that typically starts 2 to 24 hours after influenza immunization and often affects 2 systems, causing bilateral conjunctivitis, facial edema, and upper respiratory signs and symptoms (cough, sore throat, hoarseness, dyspnea, chest tightness, and lingual and/or pharyngeal edema).38
Researchers in 8 studies described reimmunization of patients with a history of ALEs after immunization.16–20,22,30,37 Before reimmunization, all patients underwent a clinical evaluation (description of the ALE and medical history) by a specialist (an allergist, pediatrician, or emergency physician), with or without skin testing with the vaccine. Overall, 594 children and adults were reimmunized at a hospital or clinic: 148 were reimmunized with a single full dose, 59 received 2 graded doses, and for 389 patients, the reimmunization protocol was not described. However, for 373 (96%) of these patients, the authors specified that individualized precautions (eg, premedication, temporally separated single injections, and alternative brand and/or administration in a hospital as a single dose or 4 graded doses) were applied when deemed necessary. Among the 594 patients reimmunized, ALEs recurred in 30 (5% [95% CI, 3.3 to 6.8]), none of whom experienced anaphylaxis. All recurrences were mild and self-limited except for 1 female child with severe food and respiratory allergies who developed urticaria and bronchospasm after being reimmunized with measles-mumps-rubella (MMR) vaccine. Her symptoms subsided immediately after treatment. The risk of recurrence of ALEs was higher in 1 study based on the German passive surveillance system17 (61.5%, 8 of 13) than in the 7 hospital- or clinic-based studies (3.8%, 22 of 581, P < .0001).
Researchers in 2 studies evaluated the risk of recurrence of anaphylaxis in 133 patients receiving various vaccines16,21 (Table 3). All but 1 had negative skin testing with the vaccine. Ninety-five (71%) were reimmunized with a single dose, and 38 (29%) were reimmunized with 3 graded doses (10%, 30%, and 60% of the total dose at 1-hour intervals). No anaphylaxis or ALEs occurred after reimmunization.
The risk of recurrence of ORS after immunization only with IIV was evaluated in 4 studies.23–26 The risk of recurrence estimated by the 2 randomized controlled trials (RCTs)25,26 was higher than that estimated by researchers in the 2 retrospective studies23,24 (67 of 180 = 37% vs 48 of 488 = 10%, P < .001). The estimated risk of recurrence varied from year to year depending on the manufacturer of the vaccine but was not influenced by age, sex, number of previous influenza vaccine doses, or the severity of the previous ORS episode. Patients with a history of ORS were 3.3 to 4 times more likely to develop ORS compared with vaccine recipients without such history. In the study by Skowronski et al,24 4 of 6 patients described their recurrence as milder, and the remaining 2 considered their recurrence as being of the same severity as the first episode. Recurrences did not dissuade patients from continuing immunization.
Injection Site Reactions
Three types of injection site reactions were assessed: ELS, pain, and redness and/or swelling at the injection site. In 3 studies, 55 of 98 (56% [95% CI, 9.8 to 46.3]) children with ELS after the fourth dose of DTaP had a recurrence after the fifth dose (DTaP/ reduced-antigen diphtheria-tetanus-acellular pertussis vaccine [dTap]).5,9,10 Among the 55 children who had a recurrence, none had fever >38.5°C. The injected arm was spontaneously painful (without touch or movement) in 3 subjects, and symptoms were severe enough to prevent daily activities in 3 patients. In the study conducted by Quinn et al,12 64% of patients reported spontaneous resolution of the ELS within 4 days of immunization. All 55 children recovered completely within 19 days of immunization. In 2 studies, children were reimmunized with either the full- (DTaP) or reduced-antigen (dTap) vaccine.12,14 The risk of recurrence of swelling was 1.5-fold higher when using DTaP (31 of 40, 78%) compared with dTap (20 of 38, 53%) P = .02. After reimmunization, patients in both the DTaP and dTap groups had seroprotective antibody levels.
Pain at the injection site was evaluated in 3 studies.10,15,28 Moderate to severe pain recurred more frequently in children reimmunized with whole-cell pertussis vaccines (DTwP2: 36% [95% CI, 26.1 to 45.4]; DTwP3: 35% [95% CI, 23.1 to 46.7]) than acellular pertussis vaccines (DTaP2: 12% [95% CI, 4.2 to 20]; DTaP3: 9% [95% CI, −0.7 to 18.9]). A history of moderate to severe pain at the previous immunization increased the risk of having it again at the next immunization, especially in patients receiving acellular pertussis vaccine (RR: 6.3 [95% CI, 3.4 to 11.5] for DTaP and 2.9 [95% CI, 2.2 to 4.0] for DTwP) (Table 4).
The risk of recurrence of apnea was evaluated in 2 studies.34,35 In the first study, Flatz-Jequier et al35 monitored 64 very low birth weight preterm infants (mean birth weight of 886 g, gestational age <32 weeks) during their first 3 immunizations at 2, 3, and 4 months of age, whereas Clifford et al34 monitored 30 preterm (gestational age <37 weeks) and 8 term (gestational age ≥37 weeks) infants during their first 4 immunizations at 2, 4, 6, and 12 months of age. At the first, second, and third immunizations, all infants received DTaP–injectable polio vaccine (IPV)–Haemophilus influenzae type b (Hib)–hepatitis B (HepB) and pneumococcal conjugate vaccines, and some additionally received rotavirus vaccine, influenza vaccine, and respiratory syncytial virus monoclonal antibody. At the fourth immunization, infants received MMR vaccine, Hib, and meningococcal C vaccines. At the second immunization, 13 (18% [95% CI, 9.3 to 27.3]) of 71 preterm infants had a recurrence of apnea that was as severe as the initial episode (Table 3). No recurrences of apnea occurred among the 8 term infants (4 had underlying conditions, including metabolic disorder, cardiac disease, probable viral meningitis, and multiple allergies). Five of the 13 children with recurrences received subsequent immunizations, and none experienced additional episodes of apnea. Clifford et al34 identified 2 predictors of recurrent apnea: lower birth weight and ongoing hospitalization for complications related to prematurity. A 10-g increase in birth weight was associated with a 6% reduction in the odds of recurrent apnea (odds ratio 0.94 [95% CI, 0.89 to 1.00]). The odds of recurrence were 23 times higher in infants hospitalized for complications related to prematurity (odds ratio 23 [95% CI, 2 to 272]).
The 6 studies in which researchers evaluated the risk of HHE recurrence5,19,29–32 included 398 children, of whom 3 (0.8% [95% CI, 0.2 to 2.2]) had a recurrence. In the 4 studies in which researchers specifically identified the risk of HHE recurrence after DTaP or DTwP vaccines, only 1 of the 306 reimmunized children experienced a recurrence (0.3% [95% CI, 0 to 1.8])6,26,28,29 (Table 3).
Researchers in 5 studies evaluated the risk of recurrence of fever upon reimmunization with DTaP or DTwP (n = 3) vaccines,10,15,28 influenza vaccine (n = 1),27 or various vaccines (n = 1)19 (Tables 3 and 4).
For DTwP vaccine, the risk of recurrence of fever after the second dose (vaccine recipients aged 4 months) or third dose (vaccine recipients aged 6 months) ranged from 33% to 64%.10,15,28 The risk was highest after the fourth dose (84%)28 (Table 3). Fever was also more likely to occur among children with a history of fever after a previous dose versus children without previous fever (pooled RR 1.9 [95% CI, 1.6 to 2.2] Table 4). In the study by Baraff et al,10 the severity of initial fever (<39°C vs ≥39°C) had no impact on the risk of recurrence.
For DTaP vaccine, the risk of recurrence of fever was estimated at 21% and 18% after the second and third doses, respectively. Fever was more likely to occur among children with a history of fever after the previous dose compared with those without previous fever (RRs of 4.7 [95% CI, 2.3 to 9.9] and 2.6 [95% CI, 1.6 to 4.4] after DTaP2 and DTaP3, respectively) (Table 4). In the study by Deloria et al,11 recurrence of fever was higher among DTwP recipients compared with DTaP recipients after dose 3 (RR: 2.1 [95% CI, 1.2 to 3.7]) but not dose 2 (RR: 1.5 [95% CI, 0.7 to 3.4]).
Recurrence of fever after influenza immunization occurred in 198 (52% [95% CI, 47.1 to 57.1]) of 380 children aged 6 months to 4 years (Table 3). Recurrences were generally shorter in duration and associated with a lower maximum temperature than the initial episode.27 The use of antipyretics was not reported by the authors.
Sexton et al36 evaluated the risk of Henoch-Schonlein purpura recurrence after administration of an outer membrane meningococcal B vaccine to 6 New Zealanders aged <10 years, of whom 3 received 1 additional dose and 3 received 2 additional doses. Among the 6 reimmunized children, 1 presented with mild self-limited proteinuria after the second dose. He received his third vaccine dose without further events.
Researchers in 3 studies evaluated the risk of recurrence of seizures after immunization.19,30,33 Nicolosi et al19 and Gold et al30 evaluated the risk of seizures after various vaccines (hepatitis A or B, meningococcal vaccines, pneumococcal vaccines, and MMR; DTaP with or without Hib, HepB, and poliomyelitis antigens [DTaP±Hib/HepB/IPV]); none of the 52 children reimmunized between 1 month and 16 years of age had a recurrence (Table 3). In the third study, Crawford et al33 reported no recurrences of syncopal seizures among 8 girls aged 8 to 26 years who were reimmunized in the supine position with HPV vaccine. The authors of the studies described above did not specify if any additional measures (eg, antipyretics or anticonvulsants) were taken to reduce recurrence of seizures.
Overall, vomiting, persistent crying, decreased appetite, and drowsiness recurred in 15%, 24%, 25%, and 35% of the reimmunized patients, respectively (Table 3).
In this review of 29 studies presenting the outcome of reimmunization of patients who experienced AEFIs, it appears that the risk of recurrence of serious AEFIs (anaphylaxis, seizures, or apnea in term infants) was low (<1%). For minor to moderate AEFIs (fever, ELS, ORS, ALEs, sleepiness, thrombocytopenia, decreased appetite, vomiting, or persistent crying), the risk of recurrence ranged from 4% to 48%, and recurrences were generally less severe or equally severe compared with the initial episode.
Researchers in 7 of 8 studies reported a low risk of recurrence of ALEs. The high risk of recurrence (62%) observed by Zent et al20 may be explained by a reporting bias related to professionals being more likely to report severe or recurrent cases to the passive surveillance system of the German Pharmacovigilance Department, thus leading to an overestimation of the risk of recurrence. None of the 727 patients with a history of ALE or anaphylaxis in the included studies developed anaphylaxis after reimmunization. This finding supports the Joint Task Force on Practice Parameters 2012 practice guidelines, which state that patients who experienced an ALE after immunization can be safely reimmunized when appropriate precautions are taken.39 However, these findings may not apply to patients with severe ALEs or positive skin tests because they were often not reimmunized in the studies reviewed. There was great variability in the management of patients with an ALE after immunization. Seitz et al21 reimmunized patients with graded doses despite negative skin testing to the vaccine, suggesting that the ALE was not an immunoglobulin E–mediated reaction. There may be a need for guidelines39–41 to be evaluated and validated to standardize practices.
Approximately half of children with ELS after the fourth dose of DTaP had a recurrence at reimmunization, but few patients with recurrent events developed systemic signs, symptoms, or an altered general state, and all cases resolved without sequelae. ELS reactions after immunization are dramatic but usually painless. Parents should be reassured that these reactions are usually benign and should not prevent subsequent immunizations that will protect their children against severe diseases. There was no study in which researchers directly compared the risk of ELS among children with and without a past history of ELS, but recurrences appear to occur more frequently than the expected background frequency of 2% to 5% among children 4 to 6 years of age.42,43 Vaccines with lower diphtheria and pertussis antigens content (dTap and dTap-IPV), which confer protective immunity while reducing the risk of occurrence and/or recurrence of ELS, should be recommended in these patients.12,14,42–46
Recurrence of moderate to severe pain at the injection site varied with the type of vaccine. Whereas the absolute risk of pain was higher with DTwP (35%–36%) compared with DTaP (9%–12%), the relative risk comparing patients with versus without a previous event was higher in DTaP recipients (RR: 4.6 to 7.7 for DTaP and 3 for DTwP). Physical interventions (eg, no aspiration, simultaneous injections, or injection in the buttock) and psychological interventions (eg, verbal, video, or music distraction) should be considered to reduce the severity or perception of pain.47–50
Children who had a history of fever after immunization were at higher risk of developing fever after subsequent immunizations, especially with DTaP (RR 2.6 to 4.7 for DTaP versus RR 1.5 to 1.8 for DTwP).10,15,28 For both vaccines, the risk of recurrence of fever after dose 2 and 3 was similar within each study.10,15,28 One study revealed an increased risk of recurrence after DTwP dose 4,28 but we could not evaluate if the difference was statistically significant because the number of patients reimmunized was not reported. Severe fevers (≥39°C and ≥40°C) did not recur, and recurrent febrile episodes were usually milder than the initial episode. Prophylactic antipyretics or reduced-antigen formulation vaccine (ie, dTap) can be used to reduce either the occurrence or the severity of fever,51–53 but their effect on recurrence is still to be evaluated. Both measures have been associated with a decreased vaccine immunogenicity response, and this should be taken into consideration in the risk/benefit evaluation.44,45,53,54
In this review, researchers reported a risk of recurrence after DTaP ±Hib/HepB/IPV and DTwP vaccines of <0.8% in all the studies that included patients with HHE.5,29,31,32 However, the risk of recurrence after DTwP combined with Hib, injectable poliomyelitis, or HepB antigens, which is currently used in low- and middle-income countries, was not evaluated.
This systematic review has limitations. Although every effort was made to ensure a comprehensive search, some articles may have been missed. Our search was limited to articles published in English or French and did not include the gray literature. Despite the large number of AEFIs targeted in our search, we did not find any studies with 5 individuals or more that estimated the risk of recurrence of several AEFIs. Studies on the recurrence of serious or rare AEFIs are unlikely to be conducted for ethical reasons (risk of death or permanent sequelae) or feasibility (too few patients). All studies were conducted in developed countries; a different pattern of the risk of recurrence might be observed in low- and middle-income countries because of differences in vaccine products, schedules, or ethnicities. Only 2 of the 29 studies reviewed were RCTs. AEFI case definitions, study design, age groups, and targeted vaccines varied from one study to another, which limited the comparability of results. As a result of these clinical and methodological differences, most of the pooled estimates displayed substantial heterogeneity and should be considered with caution. Most study participants were children; adults and especially the elderly may have different recurrence risks. With severe cases being less often reimmunized, the risk of recurrence may have been underestimated. The number of patients per AEFI was frequently small, leading to estimates with broad CIs and limited statistical power to detect a small risk of recurrence. The largest studies (including >500 vaccine recipients with and without a history of an AEFI) were performed before 1995. The paucity of recent large studies is all the more regrettable given that most vaccines currently in use were introduced after 1995 and underwent large pre- and postlicensure safety evaluations. To guide clinicians, prelicensure clinical RCTs should report not only the risk of occurrence of AEFI but also the risk of recurrence when the vaccine requires several doses. In a context of vaccine hesitancy and growing concerns regarding vaccine safety, evaluating the risk of recurrence of all AEFIs should become part of the standard evaluation of vaccine safety. Specialized immunization networks such as the Clinical Immunization Safety Assessment (United States), the Surveillance of Adverse Events Following Vaccination In the Community (Australia), and the Specialized Immunization Clinics (Canada) are ideal platforms for the continuous and prospective evaluation of AEFI recurrence.
Despite vaccines being administered to millions of people annually, few studies have been conducted by researchers seeking to evaluate the risk of AEFI recurrence. Based on the published literature, reimmunization appears to be safe for patients with mild to moderate AEFIs. However, the data are insufficient to draw firm conclusions regarding the safety of reimmunization after a severe AEFI. High-quality studies by researchers estimating the vaccine-specific risk of recurrence and predictors of recurrence for each AEFI are needed to inform evidence-based immunization practices in this population.
- Accepted May 19, 2017.
- Address correspondence to Gaston De Serres, MD, PhD, Institut national de santé publique du Québec, 2400 Avenue d’Estimauville, Quebec City, QC G1E 7G9, Canada. E-mail:
FINANCIAL DISCLOSURE: Except for those listed in the conflicts of interest, the authors have nothing to disclose.
FUNDING: This study was funded by the Canadian Immunization Research Network, which is sponsored by the Public Health Agency of Canada and the Canadian Institutes of Health Research.
POTENTIAL CONFLICT OF INTEREST: Dr De Serres has received investigator-initiated grants from GlaxoSmithKline and Pfizer and travel reimbursement to attend an ad hoc advisory board meeting of GlaxoSmithKline; Dr Top has received in-kind research support from Pfizer and a grant from GlaxoSmithKline; and the other authors have indicated they have no potential conflicts of interest to disclose.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2017-1760.
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- Copyright © 2017 by the American Academy of Pediatrics