Video Abstract

Video Abstract

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BACKGROUND:

Administering inactivated influenza vaccine (IIV), 13-valent pneumococcal conjugate vaccine (PCV13), and diphtheria-tetanus-acellular pertussis (DTaP) vaccine together has been associated with increased risk for febrile seizure after vaccination. We assessed the effect of administering IIV at a separate visit from PCV13 and DTaP on postvaccination fever.

METHODS:

In 2017–2018, children aged 12 to 16 months were randomly assigned to receive study vaccines simultaneously or sequentially. They had 2 study visits 2 weeks apart; nonstudy vaccines were permitted at visit 1. The simultaneous group received PCV13, DTaP, and quadrivalent IIV (IIV4) at visit 1 and no vaccines at visit 2. The sequential group received PCV13 and DTaP at visit 1 and IIV4 at visit 2. Participants were monitored for fever (≥38°C) and antipyretic use during the 8 days after visits.

RESULTS:

There were 110 children randomly assigned to the simultaneous group and 111 children to the sequential group; 90% received ≥1 nonstudy vaccine at visit 1. Similar proportions of children experienced fever on days 1 to 2 after visits 1 and 2 combined (simultaneous [8.1%] versus sequential [9.3%]; adjusted relative risk = 0.87 [95% confidence interval 0.36–2.10]). During days 1 to 2 after visit 1, more children in the simultaneous group received antipyretics (37.4% vs 22.4%; P = .020).

CONCLUSIONS:

In our study, delaying IIV4 administration by 2 weeks in children receiving DTaP and PCV13 did not reduce fever occurrence after vaccination. Reevaluating this strategy to prevent fever using an IIV4 with a different composition in a future influenza season may be considered.

What’s Known on This Subject:

Simultaneous inactivated influenza vaccine (IIV), DTaP, and PCV13 administration has been associated with increased risk of febrile seizure after vaccination in children aged 6 to 23 months. Administering IIV and PCV13 together has been associated with an increased risk of fever in young children.

What This Study Adds:

In this prospective, randomized, open-label clinical trial in children aged 12 to 16 months, administering IIV at a separate visit from PCV13 and DTaP vaccines did not reduce the occurrence of fever after administration of these vaccines, compared with simultaneous vaccination.

Young children commonly experience fever after many routinely administered vaccines.1  Certain pediatric vaccines have also been associated with an increased risk of febrile seizure (FS), such as measles-containing and diphtheria-, tetanus-, and whole-cell pertussis–containing vaccines.2  Likewise, an increased risk of FS was observed with inactivated influenza vaccine (IIV) during the 2010–2011 influenza season, specifically on the day of and the day after vaccination.35  Risk for FS was higher for children aged 6 to 23 months when IIV was coadministered with either pneumococcal conjugate vaccine or diphtheria- tetanus- and acellular pertussis–containing vaccines and highest when all 3 vaccines (diphtheria-tetanus-acellular pertussis [DTaP]) were given together.3,4,6  An observational clinical study in children aged 6 to 23 months also revealed that during the 2011–2012 influenza season, fever occurred more frequently when IIV was coadministered with 13-valent pneumococcal conjugate vaccine (PCV13) compared with when either vaccine was administered without the other product.7 

One potential strategy for decreasing risk of fever and potentially FS after vaccination is administering vaccines sequentially over 2 visits rather than simultaneously during 1 visit. Therefore, we conducted a study to assess fever after simultaneous versus sequential PCV13, DTaP vaccine, and quadrivalent inactivated influenza vaccine (IIV4) administration in young children at an age of peak FS risk.8  Our primary objective was to compare the proportions of children with fever after IIV was administered simultaneously with PCV13 and DTaP vaccine versus sequentially at 2 visits. Because FS is rare after immunization, FS occurrence was not a primary or secondary study outcome. The research hypothesis was that the total proportion of children with fever would be higher in children receiving all 3 vaccines simultaneously versus those receiving them sequentially.

A prospective, randomized, open-label, clinical trial was conducted at Duke University Health System (hereafter Duke) and Kaiser Permanente Northern California (KPNC) Vaccine Study Center. Eligible children were enrolled from August 2017 to December 2018 and randomly assigned (1:1) to 1 of 2 groups: simultaneous or sequential vaccination. The protocol was approved by the respective institutional review boards. The Centers for Disease Control and Prevention relied on the determination of the Duke Institutional Review Board. The study was registered under ClinicalTrials.gov identifier NCT03165981.

Children were recruited during scheduled visits to receive their routine immunizations. At enrollment, children were required to be 12 to 16 months of age and current with Advisory Committee on Immunization Practices (ACIP)–recommended immunizations.9  Children with a history of seizure (including FS) or who had a first-degree relative with a history of FS were excluded. Vaccination was delayed or children were excluded if they had a moderate to severe acute illness, if they had a temperature ≥38.0°C, or if they had received antipyretics within 72 hours preceding or at visit 1. In addition, children were excluded if their parents planned to administer antipyretics prophylactically. Modified eligibility criteria were applied for all participants at visit 2 because some children received IIV4 at this visit (see the Supplemental Information for a complete listing of eligibility criteria).

Enrollment and Randomization

After obtaining written informed consent, study staff reviewed eligibility criteria, demographic information, and medical histories, including medications and immunizations. Eligible children were randomly assigned to groups in a Web-based Research Electronic Data Capture (REDCap) platform by using a permuted block randomization scheme stratified by study site developed in SAS version 9.4 (SAS Institute, Inc, Cary, NC).

Vaccination

Children in the simultaneous group received 0.5 mL PCV13 (PREVNAR 13; Pfizer, New York, NY), 0.5 mL DTaP vaccine (INFANRIX; GlaxoSmithKline, Brentford, United Kingdom), and 0.25 mL IIV4 (Fluzone Quadrivalent; Sanofi Pasteur, Swiftwater, PA) at visit 1 and returned for a dental health education visit 2 weeks later (visit 2). Children in the sequential group received PCV13 and DTaP vaccine at visit 1, followed by IIV4 and a dental health education 2 weeks later (visit 2). Coadministration of other ACIP-recommended vaccines was allowed only at visit 1. All vaccines were administered according to the ACIP General Best Practice Guidelines for Immunization.10 

Temperature Measurement

Study staff measured and recorded the child’s temperature using a temporal artery thermometer (Medical Scanner Model TAT-2000C; Exergen, Watertown, MA) at visits 1 and 2. Parents were provided the temporal thermometer and instructed to measure and record their child’s temperature at approximately the same time each day and if their child felt feverish at any time on days 1 to 8 after both visits. If >1 temperature was measured on the same day, the highest temperature for that day was reported. Fever was graded for severity by using similar cutoff values, as referenced in the package insert for Fluzone Quadrivalent11  (Supplemental Table 5).

Antipyretic Use, Medical Care Use, FSs, and Solicited Symptoms

Parents recorded use of antipyretic medications, medical care use, and occurrence of FS each day beginning on the evening of the study visits through day 8 (Supplemental Table 6). Parents also rated solicited symptoms (fussiness or irritability, change in eating habits, and sleepiness) (Supplemental Table 5). Parents were instructed to notify study staff if their child had a temperature ≥39.6°C or any other severe solicited symptom.

Follow-up

Parents documented temperatures, antipyretic use, medical care use, FS, and solicited symptoms using either the REDCap Internet-based memory aid12  or a paper memory aid, per their choice. Parents using REDCap were sent a daily e-mail reminder to complete the memory aid and were called, if needed, to facilitate data reporting. Parents using paper memory aids were called 2 days after each visit and returned them at the subsequent study visit or by mail.

Serious Adverse Events

Medical records were reviewed to determine if any FS or serious adverse events (SAEs), as defined by 21 CFR §312.3213  occurred.

Parental Perceptions of Vaccination Schedule

At the end of the study period, parents completed either a REDCap or paper survey regarding their perceptions about their child’s assigned vaccine schedule.

The day of and the day after (days 1–2) the 2 visits during which vaccines could potentially be administered was the fever risk window of primary interest.14  The primary study outcome was to determine the proportion of children with fever (temperature ≥38.0°C or ≥100.4°F) on the first 2 days (days 1–2) after visit 1 and visit 2 combined; a child with fever after both visits was counted as 1 event. Secondary outcomes were used to assess proportions for each visit separately and to assess, on days 1 to 2 after the visits both separately and combined, the proportions of children with grade 2 or grade 3 fever (temperature ≥38.6°C or ≥101.4°F), the mean number of consecutive days of fever, and medical care use for fever, defined as a telephone call, medical office visit, emergency department visit, or hospital admission.

Exploratory outcomes included the following: the mean peak temperature of children with fever and the proportions of children with antipyretic use for fever on days 1 to 2 after both visits combined; the proportion of children with fever of any grade and grade 2 or grade 3 fever on at least 1 day and the mean number of consecutive days of fever per subject on days 3 to 8 after each visit separately and combined; medical care use for fever on days 3 to 8 after each visit; the proportions of children with solicited systemic adverse events (excluding fever) at different levels of severity (grades 1, 2, and 3) on days 1 to 8 after each visit; the occurrence of FS and SAEs during the study period; and the proportions of parents reporting positive and negative perceptions about their vaccination schedule experience for each survey item.

Proportions were compared between the simultaneous and sequential groups by using stratified Mantel-Haenszel tests to control for the randomization block of the study site (Duke or KPNC). Analyses of continuous variables were performed by using Wilcoxon rank tests. The 2-sided α level was set at .05 without any adjustments for multiple comparisons. The relative risks (RRs) and corresponding 95% confidence intervals (CIs) for fever occurrence were calculated, with the sequential group serving as the reference. There were 2 study populations analyzed: the intent-to-treat (ITT) and per-protocol (PP) populations. The ITT population included any child enrolled and randomly assigned who received at least 1 study vaccine at visit 1. The PP population was a subset of the ITT population, which excluded children without valid temperature information on days 1 to 2 after visits 1 or 2 or those with a prespecified major protocol violation defined by the study investigators.

The planned enrollment was for 280 children, and we allowed for a 10% drop-out rate, anticipating 252 children enrolled and evaluable for the primary study outcome. If the true proportion of children who had fever on days 1 to 2 after visit 1 and/or visit 2 combined in the simultaneous group was 36% and the true proportion in the sequential group was 18%, it was estimated that there would be 90% power to reject the null hypothesis of no difference between groups, with a 2-sided α = .05 level.7  A twofold increase was selected on the basis of a previous study in which fever after simultaneous administration of IIV and PCV13 was compared with fever after administration of IIV or PCV13 without the other product.7 

A total of 221 children were enrolled, randomly assigned, and included in the ITT population (Duke: 108; KPNC: 113), of whom 206 were included in the PP population (simultaneous group: 99; sequential group: 107) (Fig 1). Enrollment was halted early at both sites because of unanticipated widespread influenza activity in the respective geographic regions that made delaying influenza vaccination unethical. The children in the PP population had a median age of 14.6 months; were mostly white, non-Hispanic, and privately insured; and were not attending day care; 93.2% were receiving either their first or only dose of influenza vaccine for the season, and 89.8% received a nonstudy vaccine at visit 1 (Table 1).

FIGURE 1

Consolidated Standards of Reporting Trials diagram.

FIGURE 1

Consolidated Standards of Reporting Trials diagram.

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TABLE 1

Participant Characteristics: PP Population

Simultaneous (n = 99)Sequential (n = 107)Total (N = 206)
Age, mo, median (range) 14.1 (12–16.6) 14.8 (12–16.9) 14.6 (12–16.9) 
Sex, n (%)    
 Male 51 (51.5) 52 (48.6) 103 (50.0) 
 Female 48 (48.5) 55 (51.4) 103 (50.0) 
Race, n (%)    
 American Indian or Alaskan native only 7 (7.1) 9 (8.4) 16 (7.8) 
 Asian only 6 (6.1) 11 (10.3) 17 (8.3) 
 Native Hawaiian or other Pacific Islander only 0 (0.0) 2 (1.9) 2 (1.0) 
 Black only 10 (10.1) 6 (5.6) 16 (7.8) 
 White only 52 (52.5) 57 (53.3) 109 (52.9) 
 >1 race 18 (18.2) 19 (17.8) 37 (18.0) 
 Unknown or not reported 6 (6.1) 3 (2.8) 9 (4.4) 
Ethnicity, n (%)    
 Hispanic 21 (21.2) 22 (20.6) 43 (20.9%) 
 Non-Hispanic 78 (78.8) 85 (79.4) 163 (79.1) 
Insurance, n (%)    
 Any private 63 (63.6) 84 (78.5) 147 (71.4) 
 Public 18 (18.2) 10 (9.3) 28 (13.6) 
 None 18 (18.2) 13 (12.1) 31 (15.0) 
No. children living in home, median (range) 2 (1–7) 2 (1–5) 2 (1–7) 
Day care, n (%)    
 Full-time, 4–5 d/wk 22 (22.2) 34 (31.8) 56 (27.2) 
 Part-time, ≤3 d/wk 17 (17.2) 16 (14.9) 33 (16.0) 
 None 60 (60.6) 57 (53.3) 117 (56.8) 
Gestational age at delivery, wk, median (range) 39 (34–42) 39 (34–42) 39 (34–42) 
Wt at delivery, kg, median (range) 3.444 (2.013–4.678) 3.402 (1.588–4.876) 3.402 (1.588–4876) 
Receipt of first or only dose of influenza vaccine for the season, n (%) 90 (90.9) 102 (95.3) 192 (93.2) 
Receipt of second dose of influenza vaccine for the season, n (%) 9 (9.1) 5 (4.7) 14 (6.8) 
Receipt of additional concomitant vaccine at visit 1, n (%)a 87 (87.9) 98 (91.6) 185 (89.8) 
 MMRV vaccine 29 (29.3) 41 (38.3) 70 (34.0) 
 Hib conjugate vaccine 73 (73.7) 89 (83.2) 162 (78.6) 
 Hepatitis A vaccine 38 (38.4) 45 (42.1) 83 (40.3) 
Simultaneous (n = 99)Sequential (n = 107)Total (N = 206)
Age, mo, median (range) 14.1 (12–16.6) 14.8 (12–16.9) 14.6 (12–16.9) 
Sex, n (%)    
 Male 51 (51.5) 52 (48.6) 103 (50.0) 
 Female 48 (48.5) 55 (51.4) 103 (50.0) 
Race, n (%)    
 American Indian or Alaskan native only 7 (7.1) 9 (8.4) 16 (7.8) 
 Asian only 6 (6.1) 11 (10.3) 17 (8.3) 
 Native Hawaiian or other Pacific Islander only 0 (0.0) 2 (1.9) 2 (1.0) 
 Black only 10 (10.1) 6 (5.6) 16 (7.8) 
 White only 52 (52.5) 57 (53.3) 109 (52.9) 
 >1 race 18 (18.2) 19 (17.8) 37 (18.0) 
 Unknown or not reported 6 (6.1) 3 (2.8) 9 (4.4) 
Ethnicity, n (%)    
 Hispanic 21 (21.2) 22 (20.6) 43 (20.9%) 
 Non-Hispanic 78 (78.8) 85 (79.4) 163 (79.1) 
Insurance, n (%)    
 Any private 63 (63.6) 84 (78.5) 147 (71.4) 
 Public 18 (18.2) 10 (9.3) 28 (13.6) 
 None 18 (18.2) 13 (12.1) 31 (15.0) 
No. children living in home, median (range) 2 (1–7) 2 (1–5) 2 (1–7) 
Day care, n (%)    
 Full-time, 4–5 d/wk 22 (22.2) 34 (31.8) 56 (27.2) 
 Part-time, ≤3 d/wk 17 (17.2) 16 (14.9) 33 (16.0) 
 None 60 (60.6) 57 (53.3) 117 (56.8) 
Gestational age at delivery, wk, median (range) 39 (34–42) 39 (34–42) 39 (34–42) 
Wt at delivery, kg, median (range) 3.444 (2.013–4.678) 3.402 (1.588–4.876) 3.402 (1.588–4876) 
Receipt of first or only dose of influenza vaccine for the season, n (%) 90 (90.9) 102 (95.3) 192 (93.2) 
Receipt of second dose of influenza vaccine for the season, n (%) 9 (9.1) 5 (4.7) 14 (6.8) 
Receipt of additional concomitant vaccine at visit 1, n (%)a 87 (87.9) 98 (91.6) 185 (89.8) 
 MMRV vaccine 29 (29.3) 41 (38.3) 70 (34.0) 
 Hib conjugate vaccine 73 (73.7) 89 (83.2) 162 (78.6) 
 Hepatitis A vaccine 38 (38.4) 45 (42.1) 83 (40.3) 

MMRV, measles, mumps, rubella, and varicella.

a

No other concomitant vaccines were administered, including MMRV vaccines.

Nearly all fever episodes and days of fever on days 1 to 2 after the study visits occurred after visit 1 (Table 2 [PP population], Supplemental Table 7 [ITT population], Fig 2). For our primary outcome, the proportions of children with fever on days 1 to 2 after visits 1 and 2 combined were similar between the simultaneous (8.1%) and sequential groups (9.3%), adjusted for study site (RR 0.87; 95% CI 0.36–2.10). Proportions were also similar after visit 1. Furthermore, there were no observed differences between the groups in the proportion of children with grade 2 or 3 fever on days 1 to 2 after either visit, alone or combined. The maximum number of consecutive days of fever starting on days 1 to 2 after visit 1 for all children was 3 days, and the mean number of days of consecutive fever did not differ between groups (1.3 vs 1.4 days, respectively). Likewise, the mean peak temperature on days 1 to 2 after visits 1 and 2 combined did not differ between groups (38.4°C vs 38.5°C, respectively).

TABLE 2

Occurrence of Any Fever (Temperature ≥ 38.0°C) and Grade 2 or 3 Fever (Temperature ≥ 38.6°C) by Follow-up Time Period (Days 1–2 and Days 3–8) After Visit 1 and Visit 2 Combined and Visit 1 and Visit 2 Separately, PP Population

OutcomeStudy GroupFever Absent, n (%)Fever Present, n (%)PRR (95% CI)a
Days 1–2      
 Any fever after visit 1 and visit 2 combined Simultaneous 91 (91.9) 8 (8.1) .759 0.87 (0.36–2.10) 
Sequential 97 (90.7) 10 (9.3) 
 Grade 2 or 3b fever after visit 1 and visit 2 combined Simultaneous 95 (96) 4 (4) .610 0.73 (0.21–2.48) 
Sequential 101 (94.4) 6 (5.6) 
 Any fever after visit 1 Simultaneous 91 (91.9) 8 (8.1) .941 0.97 (0.39–2.40) 
Sequential 98 (91.6) 9 (8.4) 
 Grade 2 or 3b fever after visit 1 Simultaneous 95 (96) 4 (4) .832 0.87 (0.24–3.13) 
Sequential 102 (95.3) 5 (4.7) 
 Any fever after visit 2 Simultaneous 99 (100) 0 (0) .341 Undefined 
Sequential 106 (99.1) 1 (0.9) 
 Grade 2 or 3b fever after visit 2 Simultaneous 99 (100) 0 (0) .341 Undefined 
Sequential 106 (99.1) 1 (0.9) 
Days 3–8      
 Any fever after visit 1 and visit 2 combined Simultaneous 88 (88.9) 11 (11.1) .844 1.08 (0.49–2.38) 
Sequential 96 (89.7) 11 (10.3) 
 Grade 2 or 3 fever after visit 1 and visit 2 combined Simultaneous 96 (97) 3 (3) .366 0.54 (0.14–2.10) 
Sequential 101 (94.4) 6 (5.6) 
 Any fever after visit 1 Simultaneous 93 (93.9) 6 (6.1) .684 0.81 (0.29–2.25) 
Sequential 99 (92.5) 8 (7.5) 
 Grade 2 or 3c fever after visit 1 Simultaneous 96 (97) 3 (3) .544 0.65 (0.16–2.64) 
Sequential 102 (95.3) 5 (4.7) 
 Any fever after visit 2 Simultaneous 93 (93.9) 6 (6.1) .425 1.64 (0.48–5.58) 
Sequential 103 (96.3) 4 (3.7) 
 Grade 2 or 3d fever after visit 2 Simultaneous 99 (100) 0 (0) .331 Undefined 
Sequential 106 (99.1) 1 (0.9) 
OutcomeStudy GroupFever Absent, n (%)Fever Present, n (%)PRR (95% CI)a
Days 1–2      
 Any fever after visit 1 and visit 2 combined Simultaneous 91 (91.9) 8 (8.1) .759 0.87 (0.36–2.10) 
Sequential 97 (90.7) 10 (9.3) 
 Grade 2 or 3b fever after visit 1 and visit 2 combined Simultaneous 95 (96) 4 (4) .610 0.73 (0.21–2.48) 
Sequential 101 (94.4) 6 (5.6) 
 Any fever after visit 1 Simultaneous 91 (91.9) 8 (8.1) .941 0.97 (0.39–2.40) 
Sequential 98 (91.6) 9 (8.4) 
 Grade 2 or 3b fever after visit 1 Simultaneous 95 (96) 4 (4) .832 0.87 (0.24–3.13) 
Sequential 102 (95.3) 5 (4.7) 
 Any fever after visit 2 Simultaneous 99 (100) 0 (0) .341 Undefined 
Sequential 106 (99.1) 1 (0.9) 
 Grade 2 or 3b fever after visit 2 Simultaneous 99 (100) 0 (0) .341 Undefined 
Sequential 106 (99.1) 1 (0.9) 
Days 3–8      
 Any fever after visit 1 and visit 2 combined Simultaneous 88 (88.9) 11 (11.1) .844 1.08 (0.49–2.38) 
Sequential 96 (89.7) 11 (10.3) 
 Grade 2 or 3 fever after visit 1 and visit 2 combined Simultaneous 96 (97) 3 (3) .366 0.54 (0.14–2.10) 
Sequential 101 (94.4) 6 (5.6) 
 Any fever after visit 1 Simultaneous 93 (93.9) 6 (6.1) .684 0.81 (0.29–2.25) 
Sequential 99 (92.5) 8 (7.5) 
 Grade 2 or 3c fever after visit 1 Simultaneous 96 (97) 3 (3) .544 0.65 (0.16–2.64) 
Sequential 102 (95.3) 5 (4.7) 
 Any fever after visit 2 Simultaneous 93 (93.9) 6 (6.1) .425 1.64 (0.48–5.58) 
Sequential 103 (96.3) 4 (3.7) 
 Grade 2 or 3d fever after visit 2 Simultaneous 99 (100) 0 (0) .331 Undefined 
Sequential 106 (99.1) 1 (0.9) 

—, not applicable.

a

The sequential group is the reference group, and adjustment was made for study sites.

b

No grade 3 fever (temperature ≥ 39.6°C) was reported on days 1–2 after visits 1 or 2. Grade 2 fever was a temperature ≥38.6°C to ≤39.5°C.

c

One child in the simultaneous group and 2 children in the sequential group had grade 3 fever during days 3 to 8 after visit 1. Of these, only 1 (sequential group) received measles, mumps, rubella, and varicella vaccines.

d

No grade 3 fever was reported on days 3–8 after visit 2.

FIGURE 2

Percentage of days with fever (temperature ≥ 38.0°C) on days 1 to 2 and days 3 to 8 after visits 1 and 2 by study group (PP population).

FIGURE 2

Percentage of days with fever (temperature ≥ 38.0°C) on days 1 to 2 and days 3 to 8 after visits 1 and 2 by study group (PP population).

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The proportions of children with at least 1 day of fever on days 3 to 8 after either visit, separately or combined, also did not significantly differ between groups (Table 2 [PP population], Supplemental Table 7 [ITT population]). The mean number of consecutive days of fever per subject starting on days 3 to 8 after each visit, both separately and combined, did not vary between the simultaneous and sequential groups. After visits 1 and 2, the mean duration of fever was 1.3 days in both groups. When assessing both visits combined, the mean duration of fever was 1.4 and 1.6 days in the simultaneous and sequential groups, respectively.

Overall, antipyretics were used more often for any reason on days 1 to 2 after visit 1 (12.6%) versus visit 2 (1.0%). When comparing the simultaneous group with the sequential group, there was a significantly higher proportion of children receiving antipyretics for any reason (including fever) in the simultaneous group (37.4%) versus the sequential group (22.4%) on days 1 to 2 after visit 1 (P = .020). Likewise, there were more days of antipyretic use in the simultaneous group after visit 1 (Fig 3). This difference was not observed after visit 2. When considering antipyretic use for fever only, the proportions were not statistically different on days 1 to 2 after each visit or both visits combined between the simultaneous and sequential groups (Table 3 [PP population], Supplemental Table 8 [ITT population]). Differences between groups in antipyretic use among children with a documented fever of ≥38.0°C were also explored; no differences on days 1 to 2 after both visits combined were observed.

FIGURE 3

Percentage of days with antipyretic use on days 1 to 2 and days 3 to 8 after visits 1 and 2 by study group (PP population).

FIGURE 3

Percentage of days with antipyretic use on days 1 to 2 and days 3 to 8 after visits 1 and 2 by study group (PP population).

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TABLE 3

Antipyretic Use for Parent-Reported Fever and for Any Indication on Day 1 or 2 After Visit 1 and Visit 2 and Visit 1 and Visit 2 Combined, PP Population

Reason for Antipyretic UseStudy GroupNo Antipyretic Use, n (%)Antipyretic Use, n (%)PRR (95% CI)a
Parent-reported fever after visit 1 and visit 2 combined Simultaneous 82 (82.8) 17 (17.2) .152 1.67 (0.82–3.41) 
Sequential 96 (89.7) 11 (10.3) 
Any indication after visit 1 and visit 2 combined Simultaneous 59 (59.6) 40 (40.4) .014 1.66 (1.10–2.49) 
Sequential 81 (75.7) 26 (24.3) 
Parent-reported fever after visit 1 Simultaneous 83 (83.8) 16 (16.2) .144 1.73 (0.82–3.64) 
Sequential 97 (90.7) 10 (9.3) 
Any indication after visit 1 Simultaneous 62 (62.6) 37 (37.4) .020 1.66 (1.08–2.56) 
Sequential 83 (77.6) 24 (22.4) 
Parent-reported fever after visit 2 Simultaneous 98 (99) 1 (1) .956 1.08 (0.07–17.8) 
Sequential 106 (99.1) 1 (0.9) 
Any indication after visit 2 Simultaneous 94 (94.9) 5 (5.1) .639 1.36 (0.38–4.92) 
Sequential 103 (96.3) 4 (3.7) 
Reason for Antipyretic UseStudy GroupNo Antipyretic Use, n (%)Antipyretic Use, n (%)PRR (95% CI)a
Parent-reported fever after visit 1 and visit 2 combined Simultaneous 82 (82.8) 17 (17.2) .152 1.67 (0.82–3.41) 
Sequential 96 (89.7) 11 (10.3) 
Any indication after visit 1 and visit 2 combined Simultaneous 59 (59.6) 40 (40.4) .014 1.66 (1.10–2.49) 
Sequential 81 (75.7) 26 (24.3) 
Parent-reported fever after visit 1 Simultaneous 83 (83.8) 16 (16.2) .144 1.73 (0.82–3.64) 
Sequential 97 (90.7) 10 (9.3) 
Any indication after visit 1 Simultaneous 62 (62.6) 37 (37.4) .020 1.66 (1.08–2.56) 
Sequential 83 (77.6) 24 (22.4) 
Parent-reported fever after visit 2 Simultaneous 98 (99) 1 (1) .956 1.08 (0.07–17.8) 
Sequential 106 (99.1) 1 (0.9) 
Any indication after visit 2 Simultaneous 94 (94.9) 5 (5.1) .639 1.36 (0.38–4.92) 
Sequential 103 (96.3) 4 (3.7) 

—, not applicable.

a

The sequential group is the reference group, and adjustment was made for study sites.

No child had medical care use for fever on days 1 to 2 after visit 1 or 2. After visit 1, 2 children in the simultaneous group received medical care for fever on day 5. After visit 2, 1 child in the sequential group received medical care for fever on days 6 and 7.

There was no difference between groups with respect to changes in eating habits or sleepiness or drowsiness after either visit nor in the level of fussiness or irritability during the 8 days after visit 1 (Fig 4). After visit 2, there was a significantly higher proportion of children with fussiness of varying degrees of severity in the sequential group (50%) when compared with the simultaneous group (33%) (P = .010).

FIGURE 4

Solicited systemic symptoms (days 1–8) by study group (PP population). A, After visit 1. B, After visit 2.

FIGURE 4

Solicited systemic symptoms (days 1–8) by study group (PP population). A, After visit 1. B, After visit 2.

Close modal

No FSs and 1 SAE occurred during the study. The SAE, assessed as unrelated to the vaccines received, occurred in a child in the sequential group. Thirteen days after receiving PCV13, DTaP vaccine, and Haemophilus influenzae type b (Hib) vaccine (a nonstudy vaccine) at visit 1, the child developed fever, upper respiratory symptoms, decreased oral intake, and dehydration, resulting in hospitalization; symptoms resolved within 2 days.

The vast majority of survey respondents were mothers, and most agreed or strongly agreed that recommended vaccines are safe for children (Table 4). In addition, most liked or strongly liked the vaccination group to which their child was assigned. When compared with the sequential group, a larger proportion of parents in the simultaneous group reported liking that their child was protected from influenza early. The majority of parents (56%) disliked bringing their child to the doctor’s office twice, with a larger proportion of parents in the sequential group reporting this (65% vs 48%). When compared with the sequential group, larger proportions of parents in the simultaneous group disliked their child having a fever and other side effects and having too many injections at the same time.

TABLE 4

Parental Perceptions Survey

Simultaneous (n = 96), n (%)Sequential (n = 94), n (%)Total (N = 190), n (%)
1. What is your relationship to the child?    
 Mother 89 (92.7) 81 (86.2) 170 (89.5) 
 Father 6 (6.2) 13 (13.8) 19 (10.0) 
 Other relative, legal guardian 1 (1.0) 0 (0.0) 1 (0.5) 
 Nonrelative, legal guardian 0 (0.0) 0 (0.0) 0 (0.0) 
2. How much do you agree with the following statement? “Recommended vaccines are safe for children.”    
 Strongly agree 63 (65.6) 60 (63.8) 123 (64.7) 
 Agree 31 (32.3) 32 (34.0) 63 (33.2) 
 Disagree 1 (1.0) 2 (2.1) 3 (1.6) 
 Strongly disagree 1 (1.0) 0 (0.0) 1 (0.5) 
3. Please tell us how much you liked the vaccination schedule your child was assigned during the study.    
 Strongly like 37 (38.5) 30 (32.6) 67 (35.6) 
 Like 57 (59.4) 55 (59.8) 112 (59.6) 
 Dislike 2 (2.1) 7 (7.6) 9 (4.8) 
 Strongly dislike 0 (0.0) 0 (0.0) 0 (0.0) 
4. What aspects of the study did you like? (check all that apply)    
 My child did not have a fever 58 (60.4) 58 (61.7) 116 (61.0) 
 My child did not have other side effects such as pain, fussiness, changes in sleep, etc 40 (41.7) 52 (55.3) 92 (48.4) 
 My child got protected from the flu early in flu season 75 (78.1) 62 (66.0) 137 (72.1) 
 My child had fewer injections at the same time 21 (21.9) 52 (55.3) 73 (38.4) 
 The toothbrush and education materials I received for my child 67 (69.8) 58 (61.7) 125 (65.8) 
 Other 10 (10.4) 8 (8.5) 18 (9.5) 
5. Which option selected in question 4 did you like the most?    
 My child did not have a fever 17 (17.7) 22 (23.4) 39 (20.5) 
 My child did not have other side effects such as pain, fussiness, changes in sleep, etc 15 (15.6) 19 (20.2) 34 (17.9) 
 My child got protected from the flu early in flu season 44 (45.8) 27 (28.7) 71 (37.4) 
 My child had fewer injections at the same time 6 (6.2) 14 (14.9) 20 (10.5) 
 The toothbrush and education materials I received for my child 6 (6.2) 7 (7.4) 13 (6.8) 
 Other 8 (8.3) 5 (5.3) 13 (6.8) 
6. What aspects of the study did you dislike? (check all that apply)    
 Bringing child to doctor’s office twice 46 (47.9) 61 (64.9) 107 (56.3) 
 My child had a fever 14 (14.6) 7 (7.4) 21 (11.0) 
 My child had other side effects such as pain, fussiness, changes in sleep, etc 24 (25.0) 13 (13.8) 37 (19.5) 
 My child did not get protected from the flu early in the flu season 1 (1.0) 7 (7.4) 8 (4.2) 
 My child received too many injections at the same time 27 (28.1) 6 (6.4) 33 (17.4) 
7. Which option selected in question 6 did you dislike the most?    
 Bringing child to doctor’s office twice 32 (38. 1) 52 (59.1) 84 (48.8) 
 My child had a fever 11 (13.1) 3 (3.4) 14 (8.1) 
 My child had other side effects such as pain, fussiness, changes in sleep, etc 13 (15.5) 9 (10.2) 22 (12.8) 
 My child did not get protected from the flu early in the flu season 1 (1.2) 4 (4.6) 5 (2.9) 
 My child received too many injections at the same time 20 (23.8) 5 (5.7) 25 (14.5) 
 Other 7 (8.3) 15 (17.0) 22 (12.8) 
8. How easy was it to use the thermometer in this study?    
 Very easy 60 (62.5) 54 (57.4) 114 (60.0) 
 Easy 32 (33.3) 35 (37.2) 67 (35.3) 
 Difficult 4 (4.2) 5 (5.3) 9 (4.7) 
 Very difficult 0 (0.0) 0 (0.0) 0 (0.0) 
9. How easy was the method you chose to report your child’s information (temperature and side effects) to the study team?    
 Very easy 73 (76. 8) 66 (70.2) 139 (73.5) 
 Easy 22 (23.2) 26 (27.7) 48 (25.4) 
 Difficult 0 (0.0) 2 (2.1) 2 (1.0) 
 Very difficult 0 (0.0) 0 (0.0) 0 (0.0) 
Simultaneous (n = 96), n (%)Sequential (n = 94), n (%)Total (N = 190), n (%)
1. What is your relationship to the child?    
 Mother 89 (92.7) 81 (86.2) 170 (89.5) 
 Father 6 (6.2) 13 (13.8) 19 (10.0) 
 Other relative, legal guardian 1 (1.0) 0 (0.0) 1 (0.5) 
 Nonrelative, legal guardian 0 (0.0) 0 (0.0) 0 (0.0) 
2. How much do you agree with the following statement? “Recommended vaccines are safe for children.”    
 Strongly agree 63 (65.6) 60 (63.8) 123 (64.7) 
 Agree 31 (32.3) 32 (34.0) 63 (33.2) 
 Disagree 1 (1.0) 2 (2.1) 3 (1.6) 
 Strongly disagree 1 (1.0) 0 (0.0) 1 (0.5) 
3. Please tell us how much you liked the vaccination schedule your child was assigned during the study.    
 Strongly like 37 (38.5) 30 (32.6) 67 (35.6) 
 Like 57 (59.4) 55 (59.8) 112 (59.6) 
 Dislike 2 (2.1) 7 (7.6) 9 (4.8) 
 Strongly dislike 0 (0.0) 0 (0.0) 0 (0.0) 
4. What aspects of the study did you like? (check all that apply)    
 My child did not have a fever 58 (60.4) 58 (61.7) 116 (61.0) 
 My child did not have other side effects such as pain, fussiness, changes in sleep, etc 40 (41.7) 52 (55.3) 92 (48.4) 
 My child got protected from the flu early in flu season 75 (78.1) 62 (66.0) 137 (72.1) 
 My child had fewer injections at the same time 21 (21.9) 52 (55.3) 73 (38.4) 
 The toothbrush and education materials I received for my child 67 (69.8) 58 (61.7) 125 (65.8) 
 Other 10 (10.4) 8 (8.5) 18 (9.5) 
5. Which option selected in question 4 did you like the most?    
 My child did not have a fever 17 (17.7) 22 (23.4) 39 (20.5) 
 My child did not have other side effects such as pain, fussiness, changes in sleep, etc 15 (15.6) 19 (20.2) 34 (17.9) 
 My child got protected from the flu early in flu season 44 (45.8) 27 (28.7) 71 (37.4) 
 My child had fewer injections at the same time 6 (6.2) 14 (14.9) 20 (10.5) 
 The toothbrush and education materials I received for my child 6 (6.2) 7 (7.4) 13 (6.8) 
 Other 8 (8.3) 5 (5.3) 13 (6.8) 
6. What aspects of the study did you dislike? (check all that apply)    
 Bringing child to doctor’s office twice 46 (47.9) 61 (64.9) 107 (56.3) 
 My child had a fever 14 (14.6) 7 (7.4) 21 (11.0) 
 My child had other side effects such as pain, fussiness, changes in sleep, etc 24 (25.0) 13 (13.8) 37 (19.5) 
 My child did not get protected from the flu early in the flu season 1 (1.0) 7 (7.4) 8 (4.2) 
 My child received too many injections at the same time 27 (28.1) 6 (6.4) 33 (17.4) 
7. Which option selected in question 6 did you dislike the most?    
 Bringing child to doctor’s office twice 32 (38. 1) 52 (59.1) 84 (48.8) 
 My child had a fever 11 (13.1) 3 (3.4) 14 (8.1) 
 My child had other side effects such as pain, fussiness, changes in sleep, etc 13 (15.5) 9 (10.2) 22 (12.8) 
 My child did not get protected from the flu early in the flu season 1 (1.2) 4 (4.6) 5 (2.9) 
 My child received too many injections at the same time 20 (23.8) 5 (5.7) 25 (14.5) 
 Other 7 (8.3) 15 (17.0) 22 (12.8) 
8. How easy was it to use the thermometer in this study?    
 Very easy 60 (62.5) 54 (57.4) 114 (60.0) 
 Easy 32 (33.3) 35 (37.2) 67 (35.3) 
 Difficult 4 (4.2) 5 (5.3) 9 (4.7) 
 Very difficult 0 (0.0) 0 (0.0) 0 (0.0) 
9. How easy was the method you chose to report your child’s information (temperature and side effects) to the study team?    
 Very easy 73 (76. 8) 66 (70.2) 139 (73.5) 
 Easy 22 (23.2) 26 (27.7) 48 (25.4) 
 Difficult 0 (0.0) 2 (2.1) 2 (1.0) 
 Very difficult 0 (0.0) 0 (0.0) 0 (0.0) 

Includes all parents who responded to the survey regardless of study population. Percentages were calculated on the basis of the total number of responses per survey item, allowing for nonresponse.

Administering influenza vaccination at the same visit as other childhood vaccines is recommended by the ACIP because it allows children to be protected earlier from vaccine-preventable diseases and reduces the chance for missed vaccinations.10  Contrary to our hypothesis, results from our study did not suggest that spacing IIV4 from PCV13 and DTaP vaccine reduced the likelihood of fever. Fever occurred in similar proportions of children who received PCV13, DTaP vaccine, and IIV4 simultaneously compared with children who received PCV13 and DTaP vaccine at the first visit then IIV4 2 weeks later. Likewise, during days 1 to 2 after each visit, there were no differences between groups with respect to the height and number of consecutive days of fever or antipyretic use for either reported or documented fever. Also, no parent sought the use of medical services for fever during days 1 to 2 after the study visits, although it is possible that anticipatory guidance regarding potential vaccine side effects, including fever, could have influenced this outcome. No child had an FS during the study period. Additionally, many parents preferred not to return for an additional clinic visit, which sequential administration necessitated in this study. For young children who present for their first lifetime influenza vaccine at the same visit when DTaP vaccine and PCV13 are due, deferring the IIV would require 2 additional clinic visits for influenza vaccination in the season.

The proportions of children with fever reported in our study on days 1 to 2 after simultaneous administration of PCV13, DTaP vaccine, and IIV4 (8%) was much lower than the proportion of children in a study by Stockwell et al7  in which 38% of the children who received trivalent inactivated influenza vaccine (IIV3) and PCV13, with or without DTaP vaccine, developed a fever on days 1 to 2 after vaccination. Although temporal artery thermometers were used in both studies to measure temperatures and the same cutoff was used for defining fever, the studies differed in that ours was a randomized clinical trial and the study by Stockwell et al7  was observational and included children <12 months of age. The studies were performed during different seasons, and the IIV administered in the Stockwell et al7  study (2011–2012) was trivalent, whereas in this study, it was quadrivalent and contained different influenza A subtypes (H3N2 and H1N1) in addition to a second influenza B type.15,16  The IIV strains used in the 2011–2012 season were the same as those used in the 2010–2011 season when the Vaccine Safety Datalink identified a signal for FS after IIV3.3,7  In the 2017–2018 influenza season, the Vaccine Safety Datalink did not detect a signal for seizures after IIV in children aged 6 to 59 months, suggesting that the IIV formulation used in our study may have been less pyrogenic than that of the earlier seasons.5  Less than 1% of the children in our study who received IIV4 alone had a fever on days 1 to 2 after vaccination. In a previous study conducted during 3 influenza seasons (2013–2016), we similarly observed no fever among 59 children aged 6 to 48 months on days 1 to 2 after vaccination with IIV3 or IIV4 alone when antipyretics were not given. The fever proportions we observed on days 1 to 2 after visit 1 were also consistent with fever proportions noted in the PCV13 package insert on days 1 and 2 after a fourth dose of PCV13 administered with other routine vaccines (6.3%–6.4% on day 1 and 7.3%–9.7% on day 2) and were consistent with what we observed in a previous study of IIV3 when administered concomitantly with 7-valent pneumococcal conjugate vaccine and DTaP vaccine in young infants.17 

Overall, when compared with the sequential group, an additional 15% of children in the simultaneous group received antipyretics for any reason on days 1 to 2 after visit 1; however, significant differences between groups in antipyretic use for fever were not observed. Although intent to administer prophylactic antipyretics was an exclusion criterion, more children in the simultaneous group could have received them for this purpose. It is possible that antipyretics given to children in the simultaneous group for reasons other than fever could have masked some fever, making observed differences in fever rates less apparent.

Our study had several additional limitations. The study was not blinded, so parents might have been more likely to report symptoms or use antipyretics knowing that their children received more vaccines. We believe this less likely to be true of an objective outcome such as fever. In addition, this was a single-year study, and influenza vaccine composition changes from year to year. Fever rates after influenza vaccination could vary from season to season depending on the vaccine composition. Additionally, because of unanticipated widespread influenza activity, our study ended enrollment early. Although enrollment goals were not met, because of low proportions of children with fever, it is unlikely that a detectable difference in fever would have been observed even with a larger sample size. Early seasonal influenza activity underscored the importance of being able to administer the influenza vaccine simultaneously with other routine immunizations. Lastly, because we excluded children at higher risk of FS, the results may not be generalizable to that particular population of children.

Our study did not suggest that administering IIV4 2 weeks apart from PCV13 and DTaP vaccine in children aged 12 to 16 months reduced the risk of fever occurrence after vaccination or altered clinical severity of the fever during the 2017–2018 influenza season. Because we assessed 1 IIV4 product during a single influenza season, reevaluating this strategy to prevent fever and FS in a future influenza season by using an IIV4 product with a different composition or dosage may be considered.

We acknowledge the contributions of the following study team members: Duke University (Marek Poniewierski, MD, MS, MS; Amelia Thompson, MD; Lynn Harrington, RN, BSN; Lori Hendrickson, RN, BSN; Liz Schmidt; Jennifer Michael; Stephanie Smith; Victoria Jakushokas; Luis Ballon; Erica Suarez; Joyce Gandee; and Kristen Gunnell), Kaiser Permanente Vaccine Study Center (Janelle Baires, RN, and Kristin Goddard, MPH), and the Centers for Disease Control and Prevention (Frank DeStefano, Oidda Museru, Lisa Grohskopf, Fiona Havers, and Tamara Pilishvili).

In addition, we acknowledge the assistance and support of the following pediatric practices: Durham Pediatrics, Regional Pediatrics, and Duke Children’s Primary Care. We also thank all the children and parents who participated in this study.

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Deidentified individual participant data will not be made available.

Dr Walter worked on the study design, reviewing data collection instruments, reviewing the data analysis, drafting the initial manuscript, and reviewing and revising the manuscript; Dr Klein worked on the study design, reviewing data collection instruments, reviewing the data analysis, and reviewing and revising the manuscript; Drs Wodi and Broder worked on conceptualizing the study and study design, reviewing the data analysis, reviewing data collection instruments, and reviewing and revising the manuscript; Mr Rountree worked on the study design, reviewing data collection instruments, overseeing the data analysis, and reviewing and revising the manuscript; Mr Todd worked on the study design, drafting data collection instruments, developing the database, reviewing the data analysis, and reviewing and revising the manuscript; Ms Weisner worked on the study design, reviewing data collection instruments, collecting data, and reviewing and revising the manuscript; Dr Duffy and Ms Marquez worked on the study design, reviewing the data analysis, and reviewing and revising the manuscript; and all authors approved the final manuscript as submitted.

This trial has been registered at www.clinicaltrials.gov (identifier NCT03165981).

FUNDING: Supported by the Centers for Disease Control and Prevention (Clinical Immunization Safety Assessment Project contracts 200-2012-53663/0009 to Duke University and 200-2012-53662/0006 to Kaiser Permanente Northern California).

     
  • ACIP

    Advisory Committee on Immunization Practices

  •  
  • CI

    confidence interval

  •  
  • DTaP

    diphtheria-tetanus-acellular pertussis

  •  
  • FS

    febrile seizure

  •  
  • Hib

    Haemophilus influenzae type b

  •  
  • IIV

    inactivated influenza vaccine

  •  
  • IIV3

    trivalent inactivated influenza vaccine

  •  
  • IIV4

    quadrivalent inactivated influenza vaccine

  •  
  • ITT

    intent-to-treat

  •  
  • KPNC

    Kaiser Permanente Northern California

  •  
  • PCV13

    13-valent pneumococcal conjugate vaccine

  •  
  • PP

    per-protocol

  •  
  • REDCap

    Research Electronic Data Capture

  •  
  • RR

    relative risk

  •  
  • SAE

    serious adverse event

  •  
  • VSD

    Vaccine Safety Datalink

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: Dr Klein reports potential conflicts due to support received from GlaxoSmithKline, Sanofi Pasteur, Pfizer, Merck, Protein Science (now Sanofi Pasteur), Dynavax, and MedImmune; the other authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: Dr Klein reports research support from GlaxoSmithKline, Sanofi Pasteur, Pfizer, Merck, Protein Science (now Sanofi Pasteur), Dynavax, and MedImmune; the other authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data