Abstract

Background.

Children under 3 years of age may benefit from a double-dose of inactivated quadrivalent influenza vaccine (IIV4) instead of the standard-dose.

Methods.

We compared the only United States-licensed standard-dose IIV4 (0.25 mL, 7.5 µg hemagglutinin per influenza strain) versus double-dose IIV4 manufactured by a different process (0.5 mL, 15 µg per strain) in a phase III, randomized, observer-blind trial in children 6–35 months of age (NCT02242643). The primary objective was to demonstrate immunogenic noninferiority of the double-dose for all vaccine strains 28 days after last vaccination. Immunogenic superiority of the double-dose was evaluated post hoc. Immunogenicity was assessed in the per-protocol cohort (N = 2041), and safety was assessed in the intent-to-treat cohort (N = 2424).

Results.

Immunogenic noninferiority of double-dose versus standard-dose IIV4 was demonstrated in terms of geometric mean titer (GMT) ratio and seroconversion rate difference. Superior immunogenicity against both vaccine B strains was observed with double-dose IIV4 in children 6–17 months of age (GMT ratio = 1.89, 95% confidence interval [CI] = 1.64–2.17, B/Yamagata; GMT ratio = 2.13, 95% CI = 1.82–2.50, B/Victoria) and in unprimed children of any age (GMT ratio = 1.85, 95% CI = 1.59–2.13, B/Yamagata; GMT ratio = 2.04, 95% CI = 1.79–2.33, B/Victoria). Safety and reactogenicity, including fever, were similar despite the higher antigen content and volume of the double-dose IIV4. There were no attributable serious adverse events.

Conclusions.

Double-dose IIV4 may improve protection against influenza B in some young children and simplifies annual influenza vaccination by allowing the same vaccine dose to be used for all eligible children and adults.

Influenza has a high incidence and burden in children [1–4]. In particular, influenza B is reported to cause a disproportionate number of influenza-related deaths in children [5]. Routine vaccination of children against influenza is recommended in the United States [6] and other countries. Quadrivalent influenza vaccines containing 2 influenza A strains and 2 influenza B strains are increasingly used in vaccination programs to replace trivalent vaccines.

Inactivated influenza vaccines (IIVs) are administered to adults and children from 3 years of age at a dose of 0.5 mL, containing 15 µg of hemagglutinin (HA) per virus strain. In children under 3 years of age, the United States-licensed standard-dose is 0.25 mL, containing 7.5 µg of HA per virus strain. Both the 15 µg and 7.5 µg doses are available for this age group in some countries, including Canada, Brazil, Mexico, Finland, and the United Kingdom. The 7.5 µg dose was introduced in the 1970s to reduce reactogenicity, including febrile convulsions, associated with the whole virus vaccines available at the time [7–11]. However, young children mount a variable immune response to the 7.5 µg dose [12–14]. Currently available split virus vaccines are better tolerated than whole virus vaccines [10, 15, 16], questioning the practice of using the 7.5 µg dose with IIVs.

The inactivated quadrivalent influenza vaccine (IIV4) manufactured in Quebec, Canada by GSK Vaccines is licensed at a double-dose (15 µg per antigen) for children from 6 months of age in Canada and Mexico, but it is currently only licensed for children 3 years of age and older in the United States. The only IIV4 licensed for use in children 6–35 months of age in the United States is Sanofi Pasteur’s Fluzone Quadrivalent in a standard-dose (7.5 µg per antigen). No other IIV is approved in the United States in this age group either because immunogenic noninferiority to Fluzone could not be demonstrated [17, 18] or because of excessive reactogenicity [19, 20].

If the double-dose vaccine could be administered in young children without adverse effects on tolerability, this age group may benefit from potentially improved immunogenicity. In this study, we describe a phase III study that compared the safety and immunogenicity of a double-dose IIV4 manufactured by GSK Vaccines with the United States-approved standard-dose IIV4 in children 6–35 months of age.

METHODS

This was a phase III, randomized, controlled, observer-blind, multicenter trial in children 6–35 months of age (ClinicalTrials.gov Identifier NCT02242643). The trial was approved by independent ethics committees or institutional review boards, conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice (ICH-GCP) guidelines, ICH Harmonised Tripartite guideline for pediatric populations, and US regulatory requirements. Parents or legally acceptable representatives provided written informed consent.

Participants, Vaccines, and Study Design

Children in stable health were recruited in the United States and Mexico during the 2014–15 influenza season (Supplementary Appendix). The double-dose IIV4 (GSK Vaccines, Quebec, Canada) contained 15 μg HA of each of the 4 strains: A/California/7/2009 (A/H1N1), A/Texas/50/2012 (A/H3N2), B/Brisbane/60/2008 (B/Victoria), and B/Massachusetts/2/2012 (B/Yamagata). The standard-dose IIV4 (Fluzone Quadrivalent; Sanofi Pasteur, Swiftwater, PA) contained 7.5 μg of HA of each of the same strains.

Children were randomized 1:1 to double-dose or standard-dose IIV4. Allocation to a study group at the investigator site was performed using an internet-based randomization system (SBIR). The randomization algorithm used a minimization procedure to balance the composition of treatment groups, accounting for age (6–17 and 18–35 months), center, and influenza vaccine priming status. The study aimed to enroll 40%–50% of children in the 6–17 months age group. Children were considered vaccine-primed if they had received 2 or more doses of influenza vaccine since July 1, 2010 or at least 1 dose of the 2013–14 influenza vaccine. Vaccine-primed children received a single dose on day 0. Vaccine-unprimed children received 1 dose on day 0 and another on day 28.

Study Endpoints

Blood for serologic testing was obtained on days 0 and 28 from primed children and on days 0 and 56 from unprimed children. The following parameters were derived from hemagglutination inhibition (HI) titers: (1) geometric mean titer (GMT), (2) seroconversion rate (SCR), (3) seroprotection rate (SPR), and (4) mean geometric increase (MGI). Seroconversion rate was defined as the percentage of participants with either (1) prevaccination reciprocal HI titer <1:10 and a postvaccination reciprocal titer ≥1:40 or (2) prevaccination reciprocal titer ≥1:10 and at least a 4-fold increase in postvaccination reciprocal titer. Seroprotection rate was defined as the percentage of participants who attained reciprocal HI titers of ≥1:40. Mean geometric increase was defined as the geometric mean of the within-subject ratios of the postvaccination/prevaccination reciprocal HI titer.

Parents recorded solicited injection site and general symptoms on the day of vaccination and for the next 6 days. Spontaneously reported symptoms were recorded until 28 days after vaccination. Serious adverse events (SAEs), potential immune-mediated diseases, and medically attended adverse events were recorded until the final study contact on day 180. Monitoring for febrile seizures was carried out throughout the study.

Study Objectives

The primary objective was to demonstrate immunogenic noninferiority of the double-dose versus the standard-dose IIV4 28 days after completion of the vaccination course. Noninferiority criteria were met if, for each of the 4 vaccine strains, the upper limit of the 95% confidence interval (CI) of the GMT ratio (standard-dose/double-dose) was ≤1.5 and the upper limit of the 95% CI of the difference in SCR (standard-dose minus double-dose) was ≤10%.

If the primary objective was achieved, the secondary objective was to evaluate whether double-dose IIV4 produced an immune response against each of the vaccine strains that met Center for Biologics Evaluation and Research (CBER) criteria, ie, the lower limit of the 95% CI of the SCR was ≥ 40% and the lower limit of the 95% CI of the SPR was ≥ c>70%. Additional secondary objectives were to (1) evaluate GMT, SPR, SCR, and MGI at 28 days after completion of the vaccination course, (2) describe the safety and reactogenicity of the vaccines, and (3) evaluate the relative risk of fever with double-dose versus standard-dose during the 2-day postvaccination period.

A post hoc evaluation was conducted to compare the immune response of the double-dose versus the standard-dose using CBER criteria conventionally applied to establish vaccine lot-to-lot consistency. Immunogenic superiority of the double-dose was concluded if the lower limit of the 95% CI of the GMT ratio (double-dose/standard-dose) was >1.5 and the lower limit of the 95% CI of the difference in SCR (double-dose minus standard-dose) was >10%.

Statistics

Enrollment of 1200 children per group (1020 evaluable subjects assuming an attrition rate of 15%) was planned to allow a global statistical power of 99% for the primary objective evaluation. The immunogenicity analysis was based on the per-protocol cohort and the safety analysis was based on the intent-to-treat cohort (Supplementary Appendix). Subgroup analyses according to age and priming status were conducted on the per-protocol cohort.

The overall type I error for the study was 5%. If the primary objective was met, the secondary objective of CBER criteria evaluation was tested to provide supportive evidence of immunogenicity. Calculation of 95% CIs is described in the Supplementary Appendix. The group GMT ratio was computed using an analysis of covariance model on the log-transformed titers. Analyses of immunogenicity excluded participants with missing or nonevaluable measurements at the postvaccination time point. Study power was calculated using PASS 2005 (Supplementary Appendix).

RESULTS

A total of 2424 and 2041 children were included in the intent-to-treat cohort and per-protocol cohort, respectively (Figure 1). Demographics were similar in both vaccine groups (Table 1). In the per-protocol cohort, 57.5% of children were vaccine-primed; mean age was 24.6 and 13.3 months for primed and unprimed children, respectively. Other demographic characteristics were similar in primed and unprimed children (Table 1).

Figure 1.

Participant disposition.

Figure 1.

Participant disposition.

Table 1.

Participant Demographics (Per-Protocol Cohort)

 All Children (Regardless Of Priming Status, 6–35 Months) Primed Children (6–35 Months) Unprimed Children (6–35 Months) 
Characteristic Double-Dose IIV4 N = 1013 Standard-Dose IIV4 N = 1028 Double-Dose IIV4 N = 587 Standard-Dose IIV4 N = 586 Double-Dose IIV4 N = 426 Standard-Dose IIV4 N = 442 
Age at first vaccination, months, mean (SD) 19.7 (8.7) 19.9 (8.9) 24.5 (6.2) 24.8 (6.1) 13.1 (7.2) 13.5 (7.9) 
Age 6–17 months, n (%) 400 (39.5) 401 (39.0) 74 (12.6) 69 (11.8) 326 (76.5) 332 (75.1) 
<12 months, n (%) 213 (21.0) 226 (22.0) 213 (50.0) 226 (51.1) 
Age 18–35 months, n (%) 613 (60.5) 627 (61.0) 513 (87.4) 517 (88.2) 100 (23.5) 110 (24.9) 
Female, n (%) 462 (45.6) 496 (48.2) 264 (45.0) 283 (48.3) 198 (46.5) 213 (48.2) 
Geographic ancestry, n (%) 
 Caucasian/European 647 (63.9) 667 (64.9) 393 (67.0) 400 (68.3) 254 (59.6) 267 (60.4) 
 African/African American 143 (14.1) 140 (13.6) 89 (15.2) 78 (13.3) 54 (12.7) 62 (14.0) 
 American Indian or Alaskan Native 23 (2.3) 18 (1.8) 15 (2.6) 13 (2.2) 8 (1.9) 5 (1.1) 
 South East Asian 17 (1.7) 20 (1.9) 11 (1.9) 14 (2.4) 6 (1.4) 6 (1.4) 
 Other 183 (18.1) 183 (17.8) 79 (13.5) 81 (13.8) 104 (24.4) 102 (23.1) 
 All Children (Regardless Of Priming Status, 6–35 Months) Primed Children (6–35 Months) Unprimed Children (6–35 Months) 
Characteristic Double-Dose IIV4 N = 1013 Standard-Dose IIV4 N = 1028 Double-Dose IIV4 N = 587 Standard-Dose IIV4 N = 586 Double-Dose IIV4 N = 426 Standard-Dose IIV4 N = 442 
Age at first vaccination, months, mean (SD) 19.7 (8.7) 19.9 (8.9) 24.5 (6.2) 24.8 (6.1) 13.1 (7.2) 13.5 (7.9) 
Age 6–17 months, n (%) 400 (39.5) 401 (39.0) 74 (12.6) 69 (11.8) 326 (76.5) 332 (75.1) 
<12 months, n (%) 213 (21.0) 226 (22.0) 213 (50.0) 226 (51.1) 
Age 18–35 months, n (%) 613 (60.5) 627 (61.0) 513 (87.4) 517 (88.2) 100 (23.5) 110 (24.9) 
Female, n (%) 462 (45.6) 496 (48.2) 264 (45.0) 283 (48.3) 198 (46.5) 213 (48.2) 
Geographic ancestry, n (%) 
 Caucasian/European 647 (63.9) 667 (64.9) 393 (67.0) 400 (68.3) 254 (59.6) 267 (60.4) 
 African/African American 143 (14.1) 140 (13.6) 89 (15.2) 78 (13.3) 54 (12.7) 62 (14.0) 
 American Indian or Alaskan Native 23 (2.3) 18 (1.8) 15 (2.6) 13 (2.2) 8 (1.9) 5 (1.1) 
 South East Asian 17 (1.7) 20 (1.9) 11 (1.9) 14 (2.4) 6 (1.4) 6 (1.4) 
 Other 183 (18.1) 183 (17.8) 79 (13.5) 81 (13.8) 104 (24.4) 102 (23.1) 

Abbreviatioins: IIV4, inactivated quadrivalent influenza vaccine; N, number of participants included in analysis; n, number of participants in stated category; SD, standard deviation.

Immunogenicity

Both vaccines were immunogenic against all vaccine strains in terms of GMT values (Figure 2). Immunogenic noninferiority of the double-dose IIV4 versus the standard-dose IIV4 was demonstrated for all vaccine strains (Figure 3). Seroconversion rate, SPR, and MGI values were higher in the double-dose group compared with the standard-dose group in the whole study population (6–35 months of age, regardless of priming status; Table 2). The lower limit of the 95% CI for SCR was ≥40% for the double-dose IIV4 against all vaccine strains (Table 2), meeting CBER criteria for demonstration of adequate immunogenicity. For SPR, the lower limit of the 95% CI was ≥70% for all strains except B/Victoria (Table 2).

Figure 2.

Geometric mean titer for all vaccine strains in all children 6–35 months of age regardless of priming status and in each subgroup prevaccination and 28 days after completion of vaccination series (per-protocol cohort). CI, confidence interval; IIV4, inactivated quadrivalent influenza vaccine.

Figure 2.

Geometric mean titer for all vaccine strains in all children 6–35 months of age regardless of priming status and in each subgroup prevaccination and 28 days after completion of vaccination series (per-protocol cohort). CI, confidence interval; IIV4, inactivated quadrivalent influenza vaccine.

Figure 3.

Noninferiority of the double-dose versus the standard-dose in all children 6–35 months of age regardless of priming status: geometric mean titer (GMT) ratio and difference in seroconversion rate (SCR) at 28 days after completion of vaccination series (per-protocol cohort). CI, confidence interval; IIV4, inactivated quadrivalent influenza vaccine.

Figure 3.

Noninferiority of the double-dose versus the standard-dose in all children 6–35 months of age regardless of priming status: geometric mean titer (GMT) ratio and difference in seroconversion rate (SCR) at 28 days after completion of vaccination series (per-protocol cohort). CI, confidence interval; IIV4, inactivated quadrivalent influenza vaccine.

Table 2.

Immunogenicity Against Each Vaccine Strain at 28 Days After Completion of Vaccination Series in All Children 6–35 Months of Age Regardless of Priming Status (Per-Protocol Cohort)

 A/H1N1 A/H3N2 B/Yamagata B/Victoria 
Endpoint Value Value Value Value 
GMT, 1/DIL (95% CI) 
 Double-dose 1013 98.8 (90.3–108.2) 1013 97.7 (90.3–105.7) 1013 257.5 (240.9–275.3) 1013 55.1 (50.8–59.8) 
 Standard-dose 1028 84.4 (76.9–92.6) 1028 84.3 (77.6–91.6) 1028 164.2 (151.8–177.6) 1028 33.4 (30.6–36.4) 
SCR, % (95% CI) 
 Double-dose 972 73.7 (70.8–76.4) 972 76.1 (73.3–78.8) 974 85.5 (83.2–87.7) 973 64.9 (61.8–67.9) 
 Standard-dose 980 67.3 (64.3–70.3) 980 69.4 (66.4–72.3) 980 73.8 (70.9–76.5) 980 48.5 (45.3–51.6) 
SPR, % (95% CI) 
 Double-dose 1013 80.4 (77.8–82.8) 1013 82.2 (79.7–84.5) 1013 97.0 (95.8–98.0) 1013 66.0 (63.0–69.0) 
 Standard-dose 1028 75.4 (72.6–78.0) 1028 77.8 (75.2–80.3) 1028 88.6 (86.5–90.5) 1028 49.8 (46.7–52.9) 
MGI (95% CI) 
 Double-dose 972 9.0 (8.4–9.7) 972 10.7 (10.0–11.6) 974 12.7 (11.7–13.7) 973 8.7 (8.1–9.4) 
 Standard-dose 980 7.7 (7.1–8.3) 980 8.9 (8.2–9.7) 980 8.1 (7.5–8.8) 980 5.4 (5.0–5.8) 
 A/H1N1 A/H3N2 B/Yamagata B/Victoria 
Endpoint Value Value Value Value 
GMT, 1/DIL (95% CI) 
 Double-dose 1013 98.8 (90.3–108.2) 1013 97.7 (90.3–105.7) 1013 257.5 (240.9–275.3) 1013 55.1 (50.8–59.8) 
 Standard-dose 1028 84.4 (76.9–92.6) 1028 84.3 (77.6–91.6) 1028 164.2 (151.8–177.6) 1028 33.4 (30.6–36.4) 
SCR, % (95% CI) 
 Double-dose 972 73.7 (70.8–76.4) 972 76.1 (73.3–78.8) 974 85.5 (83.2–87.7) 973 64.9 (61.8–67.9) 
 Standard-dose 980 67.3 (64.3–70.3) 980 69.4 (66.4–72.3) 980 73.8 (70.9–76.5) 980 48.5 (45.3–51.6) 
SPR, % (95% CI) 
 Double-dose 1013 80.4 (77.8–82.8) 1013 82.2 (79.7–84.5) 1013 97.0 (95.8–98.0) 1013 66.0 (63.0–69.0) 
 Standard-dose 1028 75.4 (72.6–78.0) 1028 77.8 (75.2–80.3) 1028 88.6 (86.5–90.5) 1028 49.8 (46.7–52.9) 
MGI (95% CI) 
 Double-dose 972 9.0 (8.4–9.7) 972 10.7 (10.0–11.6) 974 12.7 (11.7–13.7) 973 8.7 (8.1–9.4) 
 Standard-dose 980 7.7 (7.1–8.3) 980 8.9 (8.2–9.7) 980 8.1 (7.5–8.8) 980 5.4 (5.0–5.8) 

Abbreviations: CI, confidence interval; DIL, dilution; GMT, geometric mean titer; MGI, mean geometric increase; N, number of participants included in analysis; SCR, seroconversion rate; SPR, seroprotection rate.

Immunogenicity was higher in the double-dose group compared with the standard-dose group, particularly against vaccine B strains in children 6–17 months of age and unprimed children (Table 3; Figure 2). When the unprimed group was further evaluated by age, it could be seen that the main difference between vaccines occurred in children 6–17 months of age. These observations prompted us to perform the post hoc evaluation comparing the immune response elicited by the vaccines in the whole study population and according to age group and priming status. The analysis indicated superior immunogenicity of the double-dose IIV4 against both vaccine B strains in children 6–17 months of age and all unprimed children. In children 6–17 months of age, the GMT ratio was 1.89 (95% CI, 1.64–2.17) for B/Yamagata and 2.13 (95% CI, 1.82–2.50) for B/Victoria (Figure 4 and Supplementary Table 1). Corresponding values in all unprimed children were 1.85 (95% CI, 1.59–2.13) and 2.04 (95% CI, 1.79–2.33). Superior immunogenicity of the double-dose was also observed for the same groups in terms of SCR difference (Figure 4 and Supplementary Table 1).

Table 3.

Comparison of Immunogenicity of the Double-Dose Versus the Standard-Dose According to Age and Priming Status at 28 Days After Completion of Vaccination Series (Per-Protocol Cohort)

 A/H1N1 A/H3N2 B/Yamagata B/Victoria 
Endpoint Value Value Value Value 
6–17 months (regardless of priming status) 
GMT, 1/DIL (95% CI) 
 Double-dose 400 42.7 (37.1–49.0) 400 58.9 (52.2–66.4) 400 151.0 (137.4–165.9) 400 68.7 (61.8–76.3) 
 Standard-dose 401 43.2 (37.3–50.0) 401 54.8 (47.9–62.7) 401 79.1 (70.9–88.1) 401 31.9 (28.4–35.7) 
SPR, % (95% CI) 
 Double dose 400 61.3 (56.3–66.1) 400 70.3 (65.5–74.7) 400 94.3 (91.5–96.3) 400 78.3 (73.9–82.2) 
 Standard-dose 401 59.9 (54.9–64.7) 401 67.8 (63.0–72.4) 401 77.6 (73.2–81.5) 401 51.4 (46.4–56.4) 
SCR, % (95% CI) 
 Double-dose 376 58.5 (53.3–63.5) 376 69.1 (64.2–73.8) 376 79.5 (75.1–83.5) 376 77.4 (72.8–81.5) 
 Standard-dose 375 57.6 (52.4–62.7) 375 66.7 (61.6–71.4) 375 61.9 (56.7–66.8) 375 50.4 (45.2–55.6) 
MGI (95% CI) 
 Double-dose 376 6.0 (5.3–6.8) 376 10.2 (9.0–11.6) 376 12.3 (10.7–14.3) 376 12.3 (11.0–13.8) 
 Standard-dose 375 6.1 (5.2–7.1) 375 8.8 (7.7–10.2) 375 6.1 (5.3–7.0) 375 5.7 (5.1–6.4) 
18–35 months (regardless of priming status) 
GMT, 1/DIL (95% CI) 
 Double-dose 613 170.9 (155.2–188.3) 613 136.0 (123.7–149.6) 613 364.8 (336.7–395.3) 613 47.8 (42.6–53.6) 
 Standard-dose 627 129.6 (116.3–144.3) 627 111.1 (100.6–122.7) 627 262.1 (239.3–287.1) 627 34.4 (30.4–38.8) 
SPR, % (95% CI) 
 Double-dose 613 92.8 (90.5–94.7) 613 90.0 (87.4–92.3) 613 98.9 (97.7–99.5) 613 58.1 (54.1–62.0) 
 Standard-dose 627 85.3 (82.3–88.0) 627 84.2 (81.1–87.0) 627 95.7 (93.8–97.1) 627 48.8 (44.8–52.8) 
SCR, % (95% CI) 
 Double-dose 596 83.2 (80.0–86.1) 596 80.5 (77.1–83.6) 598 89.3 (86.5–91.7) 597 57.0 (52.9–61.0) 
 Standard-dose 605 73.4 (69.7–76.9) 605 71.1 (67.3–74.7) 605 81.2 (77.8–84.2) 605 47.3 (43.2–51.3) 
MGI (95% CI) 
 Double-dose 596 11.7 (10.7–12.8) 596 11.1 (10.1–12.1) 598 12.9 (11.8–14.0) 597 7.0 (6.4–7.7) 
 Standard-dose 605 8.9 (8.1–9.8) 605 9.0 (8.2–9.9) 605 9.7 (8.9–10.6) 605 5.2 (4.7–5.7) 
Primed (regardless of age) 
GMT, 1/DIL (95% CI) 
 Double-dose 587 158.8 (143.3–176.0) 587 118.4 (107.5–130.3) 587 334.3 (306.4–364.7) 587 38.1 (34.0–42.8) 
 Standard-dose 586 115.0 (102.6–128.9) 586 90.4 (81.8–100.0) 586 242.2 (219.1–267.7) 586 26.7 (23.6–30.3) 
SPR, % (95% CI) 
 Double-dose 587 90.6 (88.0–92.9) 587 87.2 (84.2–89.8) 587 98.1 (96.7–99.1) 587 49.4 (45.3–53.5) 
 Standard-dose 586 82.1 (78.7–85.1) 586 80.2 (76.7–83.4) 586 93.7 (91.4–95.5) 586 40.1 (36.1–44.2) 
SCR, % (95% CI) 
 Double-dose 570 80.5 (77.0–83.7) 570 77.9 (74.3–81.2) 572 86.5 (83.5–89.2) 571 48.0 (43.8–52.2) 
 Standard-dose 563 70.3 (66.4–74.1) 563 67.1 (63.1–71.0) 563 78.0 (74.3–81.3) 563 38.4 (34.3–42.5) 
MGI (95% CI) 
 Double-dose 570 10.9 (10.0–12.0) 570 10.0 (9.1–10.9) 572 10.7 (9.9–11.6) 571 5.6 (5.1–6.1) 
 Standard-dose 563 8.5 (7.7–9.3) 563 7.6 (6.9–8.3) 563 8.2 (7.6–8.9) 563 4.0 (3.6–4.4) 
Unprimed (regardless of age) 
GMT, 1/DIL (95% CI) 
 Double-dose 426 51.4 (44.7–59.1) 426 75.0 (66.0–85.3) 426 179.8 (163.7–197.4) 426 91.7 (83.8–100.3) 
 Standard-dose 442 56.0 (48.4–64.8) 442 76.8 (66.9–88.3) 442 98.1 (88.1–109.3) 442 44.8 (40.1–50.0) 
SPR, % (95% CI) 
 Double-dose 426 66.2 (61.5–70.7) 426 75.4 (71.0–79.4) 426 95.5 (93.1–97.3) 426 89.0 (85.6–91.8) 
 Standard-dose 442 66.5 (61.9–70.9) 442 74.7 (70.3–78.7) 442 81.9 (78.0–85.4) 442 62.7 (58.0–67.2) 
SCR, % (95% CI) 
 Double-dose 402 63.9 (59.0–68.6) 402 73.6 (69.0–77.9) 402 84.1 (80.1–87.5) 402 88.8 (85.3–91.7) 
 Standard-dose 417 63.3 (58.5–67.9) 417 72.4 (67.9–76.7) 417 68.1 (63.4–72.6) 417 62.1 (57.3–66.8) 
MGI (95% CI) 
 Double-dose 402 6.9 (6.1–7.8) 402 11.8 (10.4–13.4) 402 16.0 (13.9–18.5) 402 16.2 (14.8–17.8) 
 Standard-dose 417 6.8 (5.9–7.8) 417 11.2 (9.7–12.9) 417 8.0 (6.9–9.3) 417 8.0 (7.2–8.8) 
Unprimed (6–17 months) 
GMT, 1/DIL (95% CI) 
 Double-dose 326 36.2 (31.3–41.9) 326 56.7 (49.7–64.8) 326 146.8 (132.5–162.7) 326 84.6 (76.7–93.3) 
 Standard-dose 332 38.0 (32.5–44.4) 332 54.1 (46.6–62.7) 332 71.1 (63.6–79.4) 332 35.5 (31.5–40.0) 
SPR, % (95% CI) 
 Double-dose 326 57.4 (51.8–62.8) 326 68.7 (63.4–73.7) 326 94.2 (91.0–96.5) 326 87.4 (83.3–90.8) 
 Standard-dose 332 57.2 (51.7–62.6) 332 68.4 (63.1–73.3) 332 75.9 (70.9–80.4) 332 55.1 (49.6–60.6) 
SCR, % (95% CI) 
 Double-dose 304 54.9 (49.2–60.6) 304 68.4 (62.9–73.6) 304 79.3 (74.3–83.7) 304 87.2 (82.9–90.7) 
 Standard-dose 309 55.0 (49.3–60.7) 309 68.0 (62.4–73.1) 309 58.9 (53.2–64.4) 309 54.4 (48.6–60.0) 
MGI (95% CI) 
 Double-dose 304 5.5 (4.7–6.3) 304 10.3 (8.9–11.9) 304 12.8 (10.7–15.1) 304 15.7 (14.0–17.6) 
 Standard-dose 309 5.5 (4.6–6.5) 309 9.1 (7.7–10.6) 309 5.6 (4.7–6.6) 309 6.5 (5.8–7.3) 
Unprimed (18–35 months) 
GMT, 1/DIL (95% CI) 
 Double-dose 100 161.7 (125.9–207.7) 100 187.0 (143.6–243.6) 100 347.7 (296.3–407.9) 100 119.2 (96.8–146.7) 
 Standard-dose 110 180.9 (141.0–232.1) 110 222.0 (173.3–284.4) 110 260.0 (217.5–310.8) 110 90.5 (73.2–111.8) 
SPR, % (95% CI) 
 Double-dose 100 95.0 (88.7–98.4) 100 97.0 (91.5–99.4) 100 100 (96.4–100) 100 94.0 (87.4–97.8) 
 Standard-dose 110 94.5 (88.5–98.0) 110 93.6 (87.3–97.4) 110 100 (96.7–100) 110 85.5 (77.5–91.5) 
SCR, % (95% CI) 
 Double-dose 98 91.8 (84.5–96.4) 98 89.8 (82.0–95.0) 98 99.0 (94.4–100) 98 93.9 (87.1–97.7) 
 Standard-dose 108 87.0 (79.2–92.7) 108 85.2 (77.1–91.3) 108 94.4 (88.3–97.9) 108 84.3 (76.0–90.6) 
MGI (95% CI) 
 Double-dose 98 13.9 (11.6–16.8) 98 18.0 (14.1–23.1) 98 32.5 (26.3–40.1) 98 18.0 (15.3–21.2) 
 Standard-dose 108 12.4 (10.2–15.1) 108 20.7 (15.6–27.4) 108 22.8 (18.4–28.3) 108 14.2 (11.9–16.8) 
 A/H1N1 A/H3N2 B/Yamagata B/Victoria 
Endpoint Value Value Value Value 
6–17 months (regardless of priming status) 
GMT, 1/DIL (95% CI) 
 Double-dose 400 42.7 (37.1–49.0) 400 58.9 (52.2–66.4) 400 151.0 (137.4–165.9) 400 68.7 (61.8–76.3) 
 Standard-dose 401 43.2 (37.3–50.0) 401 54.8 (47.9–62.7) 401 79.1 (70.9–88.1) 401 31.9 (28.4–35.7) 
SPR, % (95% CI) 
 Double dose 400 61.3 (56.3–66.1) 400 70.3 (65.5–74.7) 400 94.3 (91.5–96.3) 400 78.3 (73.9–82.2) 
 Standard-dose 401 59.9 (54.9–64.7) 401 67.8 (63.0–72.4) 401 77.6 (73.2–81.5) 401 51.4 (46.4–56.4) 
SCR, % (95% CI) 
 Double-dose 376 58.5 (53.3–63.5) 376 69.1 (64.2–73.8) 376 79.5 (75.1–83.5) 376 77.4 (72.8–81.5) 
 Standard-dose 375 57.6 (52.4–62.7) 375 66.7 (61.6–71.4) 375 61.9 (56.7–66.8) 375 50.4 (45.2–55.6) 
MGI (95% CI) 
 Double-dose 376 6.0 (5.3–6.8) 376 10.2 (9.0–11.6) 376 12.3 (10.7–14.3) 376 12.3 (11.0–13.8) 
 Standard-dose 375 6.1 (5.2–7.1) 375 8.8 (7.7–10.2) 375 6.1 (5.3–7.0) 375 5.7 (5.1–6.4) 
18–35 months (regardless of priming status) 
GMT, 1/DIL (95% CI) 
 Double-dose 613 170.9 (155.2–188.3) 613 136.0 (123.7–149.6) 613 364.8 (336.7–395.3) 613 47.8 (42.6–53.6) 
 Standard-dose 627 129.6 (116.3–144.3) 627 111.1 (100.6–122.7) 627 262.1 (239.3–287.1) 627 34.4 (30.4–38.8) 
SPR, % (95% CI) 
 Double-dose 613 92.8 (90.5–94.7) 613 90.0 (87.4–92.3) 613 98.9 (97.7–99.5) 613 58.1 (54.1–62.0) 
 Standard-dose 627 85.3 (82.3–88.0) 627 84.2 (81.1–87.0) 627 95.7 (93.8–97.1) 627 48.8 (44.8–52.8) 
SCR, % (95% CI) 
 Double-dose 596 83.2 (80.0–86.1) 596 80.5 (77.1–83.6) 598 89.3 (86.5–91.7) 597 57.0 (52.9–61.0) 
 Standard-dose 605 73.4 (69.7–76.9) 605 71.1 (67.3–74.7) 605 81.2 (77.8–84.2) 605 47.3 (43.2–51.3) 
MGI (95% CI) 
 Double-dose 596 11.7 (10.7–12.8) 596 11.1 (10.1–12.1) 598 12.9 (11.8–14.0) 597 7.0 (6.4–7.7) 
 Standard-dose 605 8.9 (8.1–9.8) 605 9.0 (8.2–9.9) 605 9.7 (8.9–10.6) 605 5.2 (4.7–5.7) 
Primed (regardless of age) 
GMT, 1/DIL (95% CI) 
 Double-dose 587 158.8 (143.3–176.0) 587 118.4 (107.5–130.3) 587 334.3 (306.4–364.7) 587 38.1 (34.0–42.8) 
 Standard-dose 586 115.0 (102.6–128.9) 586 90.4 (81.8–100.0) 586 242.2 (219.1–267.7) 586 26.7 (23.6–30.3) 
SPR, % (95% CI) 
 Double-dose 587 90.6 (88.0–92.9) 587 87.2 (84.2–89.8) 587 98.1 (96.7–99.1) 587 49.4 (45.3–53.5) 
 Standard-dose 586 82.1 (78.7–85.1) 586 80.2 (76.7–83.4) 586 93.7 (91.4–95.5) 586 40.1 (36.1–44.2) 
SCR, % (95% CI) 
 Double-dose 570 80.5 (77.0–83.7) 570 77.9 (74.3–81.2) 572 86.5 (83.5–89.2) 571 48.0 (43.8–52.2) 
 Standard-dose 563 70.3 (66.4–74.1) 563 67.1 (63.1–71.0) 563 78.0 (74.3–81.3) 563 38.4 (34.3–42.5) 
MGI (95% CI) 
 Double-dose 570 10.9 (10.0–12.0) 570 10.0 (9.1–10.9) 572 10.7 (9.9–11.6) 571 5.6 (5.1–6.1) 
 Standard-dose 563 8.5 (7.7–9.3) 563 7.6 (6.9–8.3) 563 8.2 (7.6–8.9) 563 4.0 (3.6–4.4) 
Unprimed (regardless of age) 
GMT, 1/DIL (95% CI) 
 Double-dose 426 51.4 (44.7–59.1) 426 75.0 (66.0–85.3) 426 179.8 (163.7–197.4) 426 91.7 (83.8–100.3) 
 Standard-dose 442 56.0 (48.4–64.8) 442 76.8 (66.9–88.3) 442 98.1 (88.1–109.3) 442 44.8 (40.1–50.0) 
SPR, % (95% CI) 
 Double-dose 426 66.2 (61.5–70.7) 426 75.4 (71.0–79.4) 426 95.5 (93.1–97.3) 426 89.0 (85.6–91.8) 
 Standard-dose 442 66.5 (61.9–70.9) 442 74.7 (70.3–78.7) 442 81.9 (78.0–85.4) 442 62.7 (58.0–67.2) 
SCR, % (95% CI) 
 Double-dose 402 63.9 (59.0–68.6) 402 73.6 (69.0–77.9) 402 84.1 (80.1–87.5) 402 88.8 (85.3–91.7) 
 Standard-dose 417 63.3 (58.5–67.9) 417 72.4 (67.9–76.7) 417 68.1 (63.4–72.6) 417 62.1 (57.3–66.8) 
MGI (95% CI) 
 Double-dose 402 6.9 (6.1–7.8) 402 11.8 (10.4–13.4) 402 16.0 (13.9–18.5) 402 16.2 (14.8–17.8) 
 Standard-dose 417 6.8 (5.9–7.8) 417 11.2 (9.7–12.9) 417 8.0 (6.9–9.3) 417 8.0 (7.2–8.8) 
Unprimed (6–17 months) 
GMT, 1/DIL (95% CI) 
 Double-dose 326 36.2 (31.3–41.9) 326 56.7 (49.7–64.8) 326 146.8 (132.5–162.7) 326 84.6 (76.7–93.3) 
 Standard-dose 332 38.0 (32.5–44.4) 332 54.1 (46.6–62.7) 332 71.1 (63.6–79.4) 332 35.5 (31.5–40.0) 
SPR, % (95% CI) 
 Double-dose 326 57.4 (51.8–62.8) 326 68.7 (63.4–73.7) 326 94.2 (91.0–96.5) 326 87.4 (83.3–90.8) 
 Standard-dose 332 57.2 (51.7–62.6) 332 68.4 (63.1–73.3) 332 75.9 (70.9–80.4) 332 55.1 (49.6–60.6) 
SCR, % (95% CI) 
 Double-dose 304 54.9 (49.2–60.6) 304 68.4 (62.9–73.6) 304 79.3 (74.3–83.7) 304 87.2 (82.9–90.7) 
 Standard-dose 309 55.0 (49.3–60.7) 309 68.0 (62.4–73.1) 309 58.9 (53.2–64.4) 309 54.4 (48.6–60.0) 
MGI (95% CI) 
 Double-dose 304 5.5 (4.7–6.3) 304 10.3 (8.9–11.9) 304 12.8 (10.7–15.1) 304 15.7 (14.0–17.6) 
 Standard-dose 309 5.5 (4.6–6.5) 309 9.1 (7.7–10.6) 309 5.6 (4.7–6.6) 309 6.5 (5.8–7.3) 
Unprimed (18–35 months) 
GMT, 1/DIL (95% CI) 
 Double-dose 100 161.7 (125.9–207.7) 100 187.0 (143.6–243.6) 100 347.7 (296.3–407.9) 100 119.2 (96.8–146.7) 
 Standard-dose 110 180.9 (141.0–232.1) 110 222.0 (173.3–284.4) 110 260.0 (217.5–310.8) 110 90.5 (73.2–111.8) 
SPR, % (95% CI) 
 Double-dose 100 95.0 (88.7–98.4) 100 97.0 (91.5–99.4) 100 100 (96.4–100) 100 94.0 (87.4–97.8) 
 Standard-dose 110 94.5 (88.5–98.0) 110 93.6 (87.3–97.4) 110 100 (96.7–100) 110 85.5 (77.5–91.5) 
SCR, % (95% CI) 
 Double-dose 98 91.8 (84.5–96.4) 98 89.8 (82.0–95.0) 98 99.0 (94.4–100) 98 93.9 (87.1–97.7) 
 Standard-dose 108 87.0 (79.2–92.7) 108 85.2 (77.1–91.3) 108 94.4 (88.3–97.9) 108 84.3 (76.0–90.6) 
MGI (95% CI) 
 Double-dose 98 13.9 (11.6–16.8) 98 18.0 (14.1–23.1) 98 32.5 (26.3–40.1) 98 18.0 (15.3–21.2) 
 Standard-dose 108 12.4 (10.2–15.1) 108 20.7 (15.6–27.4) 108 22.8 (18.4–28.3) 108 14.2 (11.9–16.8) 

Abbreviations: CI, confidence interval; DIL, dilution; GMT, geometric mean titer; MGI, mean geometric increase; N, number of participants included in analysis; SCR, seroconversion rate; SPR, seroprotection rate.

Figure 4.

Comparison of immunogenicity of the double-dose versus the standard-dose in all children 6–35 months of age regardless of priming status and in each subgroup: geometric mean titer (GMT) ratio and difference in seroconversion rate (SCR) at 28 days after completion of vaccination series (per-protocol cohort). CI, confidence interval; IIV4, inactivated quadrivalent influenza vaccine.

Figure 4.

Comparison of immunogenicity of the double-dose versus the standard-dose in all children 6–35 months of age regardless of priming status and in each subgroup: geometric mean titer (GMT) ratio and difference in seroconversion rate (SCR) at 28 days after completion of vaccination series (per-protocol cohort). CI, confidence interval; IIV4, inactivated quadrivalent influenza vaccine.

Safety and Reactogenicity

Pain was the most common solicited injection site symptom, occurring in approximately 40% of children in both vaccine groups; severe (grade 3) pain occurred in 2.9% (95% CI, 2.0–4.1) and 1.7% (95% CI, 1.0–2.6) of children with the double-dose and standard-dose, respectively (Table 4). Fever (38.0°C) was reported in approximately 8% of children up to 7 days postvaccination; fever >39.0°C occurred in approximately 2% of children (Table 4). During the 2-day postvaccination period (days 0–1), the incidence of fever (≥38.0°C) was similar in both groups (Table 4), and the relative risk (double-dose/standard-dose) was 0.97 (95% CI, 0.62–1.52; P = .9777). Twenty-two SAEs occurred in the double-dose group and 21 in the standard-dose group (Table 4), none considered related to vaccination. Febrile seizure was reported in 5 children in the double-dose group and in 4 children in the standard-dose group (Table 4).

Table 4.

Safety Outcomes Reported Throughout the Study (Intent-to-Treat Cohort)

 Double-Dose IIV4 N = 1207a Standard-Dose IIV4 N = 1217a 
Adverse event No. Patients With Symptom % (95% CI) No. Patients With Symptom % (95% CI) 
Solicitedb injection site symptoms during 7-day postvaccination period 
Pain 509 44.0 (41.1–46.9) 462 40.1 (37.3–43.0) 
 Grade 3c 34 2.9 (2.0–4.1) 19 1.7 (1.0–2.6) 
Redness 16 1.4 (0.8–2.2) 16 1.4 (0.8–2.2) 
 Grade 3c 
Swelling 11 1.0 (0.5–1.7) 0.4 (0.1–1.0) 
 Grade 3c 
Solicited general symptoms during 7-day postvaccination period 
Drowsiness 471 40.6 (37.8–43.5) 471 40.9 (38.0–43.8) 
 Grade 3c 36 3.1 (2.2–4.3) 34 3.0 (2.1–4.1) 
Fever (≥38.0°C) 91 7.9 (6.4–9.6) 86 7.5 (6.0–9.1) 
 >39.0°C 25 2.2 (1.4–3.2) 17 1.5 (0.9–2.4) 
Irritability/fussiness 630 54.4 (51.4–57.3) 582 50.5 (47.6–53.4) 
 Grade 3c 61 5.3 (4.0–6.7) 45 3.9 (2.9–5.2) 
Loss of appetite 391 33.7 (31.0–36.5) 385 33.4 (30.7–36.2) 
 Grade 3c 26 2.2 (1.5–3.3) 19 1.6 (1.0–2.6) 
Unsolicited (spontaneously reported) symptoms during 28-day postvaccination period 
All 549 45.5 (42.6–48.3) 537 44.1 (41.3–47.0) 
 Grade 3c 70 5.8 (4.5–7.3) 75 6.2 (4.9–7.7) 
 Related to vaccine 71 5.9 (4.6–7.4) 71 5.8 (4.6–7.3) 
Fever reported during 2-day postvaccination period 
All (≥38.0°C) 42 3.6 (2.6–4.9) 43 3.7 (2.7–5.0) 
Febrile seizured during entire study period 
All 0.4 (0.1–1.0) 0.3 (0.1–0.8) 
Medically attended evente during entire study period 
All 727 60.2 (57.4–63.0) 719 59.1 (56.3–61.9) 
Potential immune-mediated disease during entire study periodf 
All 1g 0.1 (0.0–0.5) 1g 0.1 (0.0–0.5) 
Serious adverse event during entire study periodh 
All 22 1.8 (1.1–2.7) 21 1.7 (1.1–2.6) 
 Double-Dose IIV4 N = 1207a Standard-Dose IIV4 N = 1217a 
Adverse event No. Patients With Symptom % (95% CI) No. Patients With Symptom % (95% CI) 
Solicitedb injection site symptoms during 7-day postvaccination period 
Pain 509 44.0 (41.1–46.9) 462 40.1 (37.3–43.0) 
 Grade 3c 34 2.9 (2.0–4.1) 19 1.7 (1.0–2.6) 
Redness 16 1.4 (0.8–2.2) 16 1.4 (0.8–2.2) 
 Grade 3c 
Swelling 11 1.0 (0.5–1.7) 0.4 (0.1–1.0) 
 Grade 3c 
Solicited general symptoms during 7-day postvaccination period 
Drowsiness 471 40.6 (37.8–43.5) 471 40.9 (38.0–43.8) 
 Grade 3c 36 3.1 (2.2–4.3) 34 3.0 (2.1–4.1) 
Fever (≥38.0°C) 91 7.9 (6.4–9.6) 86 7.5 (6.0–9.1) 
 >39.0°C 25 2.2 (1.4–3.2) 17 1.5 (0.9–2.4) 
Irritability/fussiness 630 54.4 (51.4–57.3) 582 50.5 (47.6–53.4) 
 Grade 3c 61 5.3 (4.0–6.7) 45 3.9 (2.9–5.2) 
Loss of appetite 391 33.7 (31.0–36.5) 385 33.4 (30.7–36.2) 
 Grade 3c 26 2.2 (1.5–3.3) 19 1.6 (1.0–2.6) 
Unsolicited (spontaneously reported) symptoms during 28-day postvaccination period 
All 549 45.5 (42.6–48.3) 537 44.1 (41.3–47.0) 
 Grade 3c 70 5.8 (4.5–7.3) 75 6.2 (4.9–7.7) 
 Related to vaccine 71 5.9 (4.6–7.4) 71 5.8 (4.6–7.3) 
Fever reported during 2-day postvaccination period 
All (≥38.0°C) 42 3.6 (2.6–4.9) 43 3.7 (2.7–5.0) 
Febrile seizured during entire study period 
All 0.4 (0.1–1.0) 0.3 (0.1–0.8) 
Medically attended evente during entire study period 
All 727 60.2 (57.4–63.0) 719 59.1 (56.3–61.9) 
Potential immune-mediated disease during entire study periodf 
All 1g 0.1 (0.0–0.5) 1g 0.1 (0.0–0.5) 
Serious adverse event during entire study periodh 
All 22 1.8 (1.1–2.7) 21 1.7 (1.1–2.6) 

Abbreviations: CI, confidence interval; IIV4, inactivated quadrivalent influenza vaccine; N, number of participants included in analysis.

aFor solicited injection site and general symptoms, only children for whom diary cards were returned are included (injection site symptoms: N = 1156 for double-dose IIV4 and N = 1151 for standard-dose IIV4; general symptoms: N = 1159 for double-dose IIV4 and N = 1152 for standard-dose IIV4).

bAll solicited injection-site symptoms were considered related to vaccination.

cGrade 3 events were defined as follows: pain: child cried when the limb was moved or the limb was spontaneously painful; redness and swelling: >100 mm surface diameter; drowsiness and irritability/fussiness: prevented normal activity; loss of appetite: did not eat at all; spontaneously reported symptom: prevented normal activity.

dIn the double-dose group, seizures occurred 5, 50, 88, 106, and 168 days after the first vaccine dose. In the standard-dose group, 1 seizure occurred 178 days after the first vaccine dose and the others 39, 74, and 80 days after the second vaccine dose. All children recovered, and none of the seizures was considered by the investigator to be related to vaccination.

eHospitalization, emergency room visit, medical practitioner visit.

fAutoimmune diseases and other inflammatory and/or neurologic disorders that may or may not have an autoimmune etiology, according to a protocol-specified list or investigators’ judgment.

gKawasaki’s disease in the double-dose group and erythema multiforme in the standard-dose group, neither related to vaccination.

hSerious adverse events were defined as any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongs hospitalization, or results in disability or incapacity.

There was a modest increase in reactogenicity with regard to general symptoms in children 6–17 months of age compared with those aged 18–35 months with both the double-dose and standard-dose vaccines. With the double-dose vaccine, the fold-difference between the younger and older age groups ranged from 1.3 for loss of appetite to 2.7 for fever ≥38.0°C. With the standard-dose, the fold-difference ranged from 1.2 for loss of appetite to 1.6 for drowsiness and fever ≥38.0°C. The difference between age groups was unlikely to be due to chance because, in general, 95% CIs did not overlap. However, there were overlapping 95% CIs and thus no apparent age group differences with the standard-dose vaccine for fever ≥38.0°C and loss of appetite.

DISCUSSION

The introduction of IIV4 provides an opportunity to review long-accepted practices in administration of influenza vaccines. Since the 1970s, the standard-dose of IIVs in children less than 3 years of age has been 7.5 µg per antigen, half the dose given to older children and adults. The lower dose was intended to reduce reactogenicity and febrile convulsions observed with the whole virus vaccines that were in use at the time [7–11]. However, young children mount a variable immune response to this lower dose, especially against vaccine B strains [12–14]. In particular, vaccine-naive children less than 3 years of age mount a lower immune response compared with older or vaccine-primed children [14, 21–23]. The immune response in this vulnerable group could be improved by a change in practice to administer the double-dose, ie, same dose as used for children 3 years of age and above, and for adults. Increasing the immunogenicity of IIVs for young children is expected to improve their effectiveness, because the postvaccination HI antibody titer is inversely related to the risk of illness [24, 25]. However, there is controversy regarding the HI antibody titer necessary to offer high-level effectiveness [24, 25].

In the present study, both the double-dose and the standard-dose IIV4s were immunogenic against all vaccine strains in primed and unprimed children 6–35 months of age. The primary objective of the study—to fulfill US licensure criteria by demonstrating immunogenic noninferiority of the investigational IIV4 to a licensed IIV4 and acceptable safety of the investigational IIV4—was achieved. Most children receiving the double-dose IIV4 seroconverted (SCRs, 64.9%–85.5%), and most children achieved seroprotection (SPRs, 66.0%–97.0%). Similar immune responses have been achieved with the double-dose IIV4 in children of the same age in small studies conducted in 3 prior seasons [26–28].

Greater antibody responses were observed with the double-dose IIV4 compared with the standard-dose, prompting us to perform a post hoc analysis to evaluate whether the double-dose elicited a superior immune response in terms of the CBER criteria usually applied to establish lot-to-lot consistency of influenza vaccines. In this analysis, the double-dose IIV4 did not reach superiority to the standard-dose in the overall population, the older age group (18–35 months), or previously primed children. However, in the younger age group (6–17 months) and in all unprimed children, the double-dose IIV4 met the applied superiority immune response criteria compared with the standard-dose against the B strains. It should be noted that the unprimed group was predominantly 6–17 months of age.

Several previous studies have compared the HI antibody response elicited by a double-dose versus a standard-dose IIV. The results of the present large phase III study contrast with those of a phase II study comparing GSK’s double-dose IIV4 with the United States-approved standard-dose inactivated trivalent influenza vaccine (IIV3) (the corresponding IIV3 to the licensed IIV4 comparator used in the present study) [26]. In the phase II study, the immune response with the double-dose and the standard-dose was similar against the strains common to both vaccines, but the sample size was too small to reliably detect differential immunogenicity against the vaccine B strains, especially in children 6–17 months of age [26]. Two other small studies compared the immunogenicity of the United States-approved IIV3 administered as a standard or double-dose to young children in different years, with contrasting results [21, 29]. A 2008–09 trial found that a double-dose IIV3 elicited a higher immune response than a standard-dose in vaccine-unprimed children 6–23 months of age, reaching statistical significance in children 6–11 months of age for 2 of 3 vaccine strains [21]. However, a 2010–12 trial found no difference in immunogenicity between standard-dose versus double-dose IIV3s in unprimed children [29]. This prior experience highlights the necessity for trials of adequate size to reliably establish treatment benefit, and it suggests that observations made in 1 year may not be repeated in other years, because the baseline immunity of young children may vary. Furthermore, the dose effect on immunogenicity among IIVs may differ according to their manufacturing process [23, 26].

In the present study, the double-dose and standard-dose IIV4s had a similar reactogenicity profile despite the higher antigen content and volume of the double-dose. Injection site symptoms, including pain, occurred at a similar rate in both groups. There was no difference in the rate of fever over the 2-day postvaccination period between the 2 groups. Febrile seizures occurred at a similar rate in both groups, none were reported within 2 days of vaccination, and none were considered related to the vaccine. The finding that the higher antigen dose and volume in this study did not adversely affect tolerability in children confirms previous findings from studies comparing reactogenicity and safety of double-dose versus standard-dose IIVs [21–23, 26, 29], and IIV4s versus IIV3s [26, 27, 30–32].

CONCLUSIONS

In conclusion, a double-dose IIV4 may afford greater protection in young children against influenza B. Increased protection against influenza B, a potentially serious and life-threatening illness particularly in young children [33], would be a beneficial clinical outcome. Use of the same vaccine dose for all eligible ages would also simplify the annual influenza vaccine campaign and reduce cost [34] and logistic complexity. This study provides evidence to support a change in clinical practice to use a double-dose IIV4 (15 µg per antigen) in all children 6 months of age and older, once that dosing for a vaccine product has been approved.

Supplementary Data

Supplementary materials are available at Journal of The Pediatric Infectious Diseases Society online.

Notes

Acknowledgments. We are indebted to the participating study volunteers and their parents, clinicians, nurses, and laboratory technicians at the study sites. In particular, we thank Christopher Chambers, Larkin Wadsworth, Wendy Daly, William Johnston, Michael Levin, William Douglas, Agnes Schultz, Edward Zissman, Terry Poling, Paul Bernhardson, Brad Brabec, Stephen Russel, and Mary Tipton who provided support and cared for study participants. We thank the teams of GSK Vaccines, in particular, Silvija Jarnjak, Arshad Amanullah, Els Praet, and Rafik Bekkat-Berkani. Finally, we thank Mary L. Greenacre (An Sgriobhadair, UK, on behalf of GSK Vaccines) for providing medical writing services and Bruno Dumont and Véronique Gochet (Business and Decision Life Sciences, on behalf of GSK Vaccines) for editorial assistance and manuscript coordination.

Author contributions. All authors participated in the design or implementation or analysis of the study, interpretation of the study, and the development of this manuscript. All authors had full access to the data and gave final approval before submission.

Financial support. This work was supported by GlaxoSmithKline Biologicals SA. GlaxoSmithKline Biologicals SA paid for all costs associated with the development of this manuscript.

Potential conflicts of interest. V. K. J., L. W., and P. L. were employed by the GSK group of companies at the time of the study. V. K. J. is currently employed by the Bill and Melinda Gates Foundation. L. W. is currently employed by Merck Research Laboratory. P. L. is currently employed by Pfizer. O. O.-A., J. S., V. C., and B. L. I. are currently employed by the GSK group of companies. V. K. J., L. W., O. O.-A., P. L., and B. L. I. currently hold shares in the GSK group of companies. J. B. D. reports payments from the GSK group of companies, during the conduct of the study, and reports grants and others from the GSK group of companies, Pfizer, Sanofi Pasteur, and MedImmune for consultancy services, outside the submitted work. M. L. L. reports payments from the GSK group of companies, during the conduct of the study. N. P. K. reports payments from the GSK group of companies, during the conduct of the study, and grants from Sanofi Pasteur, Novartis, Pfizer, Protein Science, MedImmune, Merck & Co, and Nuron Biotech, outside the submitted work. B. L. H. reports payments and nonfinancial support from the GSK group of companies, during the conduct of the study. J. S. H. reports payments from the GSK group of companies, during the conduct of the study. A. C. M. reports payments from the GSK group of companies, during the conduct of the study.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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Author notes

aPresent Affiliation: Bill and Melinda Gates Foundation, Seattle, Washington.
bPresent Affiliation: Merck Research Laboratory, North Wales, Pennsylvania.
cPresent Affiliation: GSK Pharmaceuticals, King of Prussia, Pennsylvania.
dPresent Affiliation: Pfizer VRD, Collegeville, Pennsylvania.
Correspondence: B. L. Innis, MD, GSK Vaccines, King of Prussia, PA 19406 (bruce.2.innis@gsk.com).
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Supplementary data