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A Randomized, Double-blind, Active-controlled Phase III Trial of a Cell Culture-derived Quadrivalent Inactivated Influenza Vaccine in Healthy South Korean Children and Adolescents 6 Months to 18 Years of Age

Eun, Byung Wook MD, PhD*; Lee, Taek Jin MD, PhD; Lee, Jina MD, PhD; Kim, Ki Hwan MD, PhD§; Kim, Dong Ho MD, PhD; Jo, Dae Sun MD, PhD; Shin, Sun Hee MD, PhD**; Kim, Hun PhD††; Kim, Kyung-Ho PhD††; Kim, Yun-Kyung MD, PhD‡‡

The Pediatric Infectious Disease Journal: September 2019 - Volume 38 - Issue 9 - p e209–e215
doi: 10.1097/INF.0000000000002406
Vaccine Reports
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Background: Cell culture-derived influenza vaccines have several important advantages over egg-based influenza vaccines. The quadrivalent influenza vaccine may offer broader protection against seasonal influenza than trivalent influenza vaccine by containing 1 more B strain. The purpose of this study was to evaluate the immunogenicity and safety of NBP607-QIV, a novel cell culture-derived inactivated quadrivalent influenza vaccine (cIIV4), in children and adolescents.

Methods: This phase III, randomized, double-blind, multicenter trial in children/adolescents (6 mo to 18 yr) was conducted in South Korea during 2014–2015 season. Subjects were randomized 4:1 to receive either NBP607-QIV or control inactivated trivalent influenza vaccine. Hemagglutination inhibition antibody titers were assessed in prevaccination and 28 days postvaccination sera. Safety data were collected for up to 6 months postvaccination.

Results: A total of 454 participants completed the study. Three-hundred sixty-six subjects received cIIV4 and 88 subjects received inactivated trivalent influenza vaccine. Overall, NBP607-QIV met the immunogenicity criteria of Committee for Medicinal Products for Human Use for each of the 4 strains. Between the NBP607-QIV and control groups, immunogenicity endpoints were comparable. Participants younger than 3 years of age had lower immunologic responses to 2 influenza B strains in both NBP607-QIV and control group. No deaths, vaccine-related serious adverse events (AEs) or withdrawals because of AEs were reported. The solicited AEs reported were generally of mild intensity.

Conclusions: NBP607-QIV, a novel cIIV4, showed good immunogenicity to all 4 influenza strains and had tolerable safety profiles in children and adolescents. Moreover, NBP607-QIV was more immunogenic against influenza B compared with the control, an egg-based subunit vaccine.

From the *Department of Pediatrics, Eulji University Eulji General Hospital, Seoul, Republic of Korea

Department of Pediatrics, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea

Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine

§Department of Pediatrics, Severance Children’s Hospital, Yonsei University College of Medicine

Department of Pediatrics, Korea Cancer Center Hospital, Seoul, Republic of Korea

Department of Pediatrics, Chonbuk National University Children’s Hospital, Chonbuk National University Medical School, Jeonju, Republic of Korea

**Department of Pediatrics, Dongtan Sacred Heart Hospital

††SK Bioscience, Seongnam

‡‡Department of Pediatrics, Korea University Ansan Hospital, Gyeonggi-do, Republic of Korea.

Accepted for publication April 30, 2019.

H.K. and K-H.K. who are employees of SK Bioscience Corporation. All authors have submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. This work was supported by the SK Bioscience Corporation, Seongnam, Republic of Korea (SK Bioscience was spun off from SK Chemicals Corporation on July 2, 2018). The other authors have no conflicts of interest to disclose.

Ki Hwan Kim, MD, PhD is currently at the Department of Pediatrics, Incheon St. Mary’s Hospital, The Catholic University of Korea, Incheon, Korea.

Address for correspondence: Yun-Kyung Kim, MD, PhD, Division of Pediatric infectious disease, Department of Pediatrics, Korea University Ansan Hospital, 123, Jeokgeum-ro, Danwon-gu, Ansan-si, Gyeonggi-do, 15355, Republic of Korea. E-mail: byelhana@korea.ac.kr.

Inactivated quadrivalent influenza vaccine (IIV4) formulations include 2 influenza A virus strains (H1N1 and H3N2) and 2 B lineage strains (Yamagata and Victoria).1 IIV4 can offer broader coverage over inactivated trivalent influenza vaccine (IIV3), which includes only 1 B strain.1 Several IIV4s have been licensed in some countries and used in children over 36 months of age with intramuscular formulation. Cell culture-derived influenza vaccines (ccIVs) have advantages in preparing for pandemics over egg-based influenza vaccines: theoretically shorter production time (less than 3 mo); large-scale producing capacity independent of eggs supply. Also, ccIVs can be a safer option for individuals with an egg allergy.2

A recent phase III trial conducted in Republic of Korea during the 2014/2015 influenza season demonstrated the safety and immunogenicity of a ccIV4 candidate in healthy adults.3 Here, we report the first results of a phase III trial investigating the safety, immunogenicity of ccIV4 in children and adolescents over 6 months of age, which was conducted similarly to another phase III trial of ccIV3 in children and adolescents over 6 months of age.4 This ccIV4 phase III study adopted almost the same study design as the ccIV3 phase III study in children and adolescents including the control vaccine, but the 7-day safety profile of first 30 subjects was evaluated by the safety review board to determine continuation of subject enrollment.

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MATERIALS AND METHODS

Ethics

The study was conducted in accordance with the Declaration of Helsinki and the standards of International Council for Harmonisation guidance and Good Clinical Practice. The protocol and consent forms were approved by the institutional review board of each participating study site and Korea Ministry of Food and Drug Safety. Informed written consent was obtained from all parents or legally acceptable representatives and participants who could understand the following a detailed explanation of schedules and the contents of the study. And participants 12 years old or older were also provided with written informed consents.

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Subjects

Individuals 6 months to 18 years old who had not been previously vaccinated against influenza with a 2014–2015 Northern Hemisphere formulation in the previous 6 months were considered for study inclusion. They were excluded if they had received another vaccination within 4 weeks before inclusion; were allergic to any influenza vaccine; had a known or suspected congenital or acquired immunodeficiency; had moderate or severe acute illness/infection or a temperature ≥38.0°C or had recently received immunosuppressive or corticosteroid treatment, immune globulins, blood or blood-derived products. Women were excluded if they were pregnant, lactating or of childbearing potential and not using adequate birth control. Enrollment was stratified by age at each site into 3 age groups (6–35 mo, 3–8 yr and 9–18 yr).

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Vaccines

The study vaccine (NBP607-QIV Lot no.: CT3DS201) was a 0.5 mL Madin-Darby canine kidney (MDCK) cell culture-derived quadrivalent, inactivated subunit influenza vaccine loaded into prefilled syringes containing 15 µg of hemagglutinin per strain; it was produced by SK Bioscience (Seongnam, Republic of Korea). According to the recommendations of the World Health Organization, the vaccine was formulated to include the following 4 influenza virus strains: A/Christchurch/16/2010 (H1N1)-like virus, A/Texas/50/2012 (H3N2)-like virus, B/Massachusetts/2/2012 (Yamagata lineage)-like virus and B/Brisbane/60/2008 (Victoria lineage)-like virus. The control vaccine containing only 1 B strain was a 0.25 mL or 0.5 mL commercial egg-derived trivalent, inactivated subunit vaccine (AgrippalS1, Lot no.: 148402 and 147001, respectively, Novartis Vaccine and Diagnostics Srl, Siena, Italy) provided in prefilled syringes containing 7.5 µg or 15 µg of hemagglutinin per strain.

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Study Design

This was a phase III, multicenter, randomized, double-blind and controlled clinical trial performed at 8 centers in South Korea from September 2014 to June 2015. The primary objective was to demonstrate the immunogenicity of NBP607-QIV in Korean children or adolescents over 6 months of age.

Subjects were randomly assigned in a 4:1 ratio immediately before vaccination to receive either NBP607-QIV or control vaccine by a randomization table produced by block randomization method.

The participants received different doses of the vaccine according to their ages. The participants from 6 months to <3 years of age received 0.25 mL of vaccine, and the participants from 3 to ≤18 years of age received 0.5 mL of vaccine. Independent pharmacists and vaccinators unblinded were involved for managing the vaccines to maintain double-blind, and when administering 0.25 mL of NBP607-QIV, half the contained volume was discarded first and the entire remaining 0.25 mL was injected. Subjects younger than 9 years of age who had not been previously immunized against influenza or last received seasonal trivalent influenza vaccine before the 2010–2011 season but did not receive a vaccine containing 2009 (H1N1) antigen received 2 doses of vaccine with 1 injection at day 0 and the other at day 28.

After obtaining blood, the vaccine was administered as a single intramuscular injection, and subjects were observed for 30 minutes. The second blood sample was obtained on days 28–35 after last vaccination. The primary immunogenicity objective was to evaluate the immunogenicity of NBP607-QIV in terms of the Committee for Medicinal Products for Human Use (CHMP) criteria among healthy children and adolescents. Secondary immunogenicity objectives aimed to compare the immunogenicity of the study vaccine (NBP607-QIV vs. AgrippalS1). Safety objectives included the evaluation of solicited local and systemic adverse events (AEs), spontaneously reported unsolicited AEs and serious AEs (SAEs). Safety data were collected for up to 6 months postvaccination. Written informed consent was obtained from all parents, or legally acceptable representatives of the participants included in the trial.

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Immunogenicity Assessment

Serum samples were assessed for hemagglutination-inhibiting (HI) antibodies to each hemagglutinin of the A/H1N1, A/H3N2, B/Yamagata and B/Victoria strains contained in the vaccine using a standard assay with use of cell-derived hemagglutinin antigens and chicken erythrocytes at the SK Bioscience Life Science Research Institute.5 HI antibody titers that were below the detection limit (ie, <1:10) were assigned a value of 1:5. The 3 immunogenicity endpoints after vaccination were the proportion of subjects with antibody titers of 1:40 or more on HI assay (seroprotection rate), the proportion of subjects with either seroconversion (a change in HI titer from <1:10 to ≥1:40) or a 4-fold or more increase in antibody titer (seroconversion rate) and geometric mean titer ratio (GMR) [ie, the ratio of the geometric mean titer (GMT) after vaccination to the GMT before vaccination].6 Serologic response, as measured by HI antibody titers, was assessed using the criteria set by the CHMP of the European Medicines Agency. To confirm protective immunogenicity based on the CHMP criteria, all of the following criteria must be met: seroprotection rates >70%, seroconversion rates >40% or GMRs >2.5.5

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Safety and Reactogenicity Assessment

Parents were supplied with diary cards on which to record occurrence and measurements of solicited injection site (local) and systemic reactions, including daily temperature, for days 0 to day 7 after each vaccination and any unsolicited AEs, that is, those occurring from each vaccination to the next study visit. AEs considered related to the vaccination were termed adverse drug reactions, solicited reactions occurring from day 8 were considered unsolicited adverse reactions. Parents were reminded by telephone calls on day 3 to 7 to complete the diary card and asked whether any reactions had occurred. Reactions were graded for severity, grades 1, 2 or 3, by parents or legally acceptable representatives using predefined scales. SAEs or AEs necessitating medical assistance were to be reported immediately to the study sponsor. Causality of AEs was assessed by the investigator at each subsequent study visit as being either not related, or related to the vaccination(s).

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Statistics

Immunogenicity analyses were run on the per-protocol set, which included all enrolled subjects who received the vaccine correctly, provided evaluable serum samples at relevant time points and had no major protocol deviations. Safety was analyzed for all subjects exposed to study vaccines. The sample size for the immunogenicity subsets of the NBP607-QIV group was estimated in compliance with the requirements of the current CHMP guideline for influenza vaccines (CPMP/BWP/214/96). Considering a 10% dropout rate, a sample size of 59 subjects was estimated to provide sufficient power (90%) to examine the primary immunogenicity objective based on the data of a phase 1/2 NBP607 clinical trial. However, more than 300 subjects were determined to be enrolled to the study to validate NBP607-QIV with sufficient safety and immunogenicity data since this was the world’s first time that the ccIV4 (NBP607-QIV) was administered to children and adolescents. Therefore, we planned to enroll over 360 subjects for the NBP607-QIV group and over 90 subjects for the control vaccine (AgrippalS1) group. All statistics were generated using SAS software (Version 9.3; SAS Institute Inc., 100 SAS Campus Drive Cary, NC). Immunogenicity and safety profiles were compared between NBP607-QIV and control vaccine recipients. We compared these results between age groups. Immunogenicity data were expressed in terms of GMT (mean ± standard deviation) and CHMP criteria with two-sided 95% confidence intervals (CIs). Two-sided 95% CIs for GMTs and GMRs were calculated using the normal approximation of log-transformed titers, and percentages were calculated with approximate or exact 95% CIs. Safety data were described as the proportion of study subjects reporting local and systemic adverse reactions. Student’s t test was used to compare GMTs and GMRs between the 2 groups, while the χ2 test or the Fisher exact test were conducted to analyze categorical variables. Results were considered statistically significant if the P value was less than 0.05.

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RESULTS

Subjects

Between September 30, 2014, and December 18, 2015, a total of 454 subjects were enrolled in a 4:1 ratio. Enrolled subjects were randomized to either the NBP607-QIV (366 subjects) or control (88 subjects) group (Fig. 1). Demographic and baseline characteristics were well matched between the 2 groups, as shown in Table 1. One subject was excluded from the safety analysis set because neither NBP607-QIV nor control vaccines was administered. Among the 453 subject safety analysis set, 3 subjects were excluded from the full analysis set because of missing immunogenicity assessment and 5 subjects were excluded from the per-protocol analysis set because of protocol deviation (Fig. 1).

TABLE 1

TABLE 1

FIGURE 1

FIGURE 1

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Immunogenicity

NBP607-QIV met all CHMP criteria at 28 days postvaccination (Table 2). Seroprotection rates were 97.5% for influenza A/H1N1, 98.9% for influenza A/H3N2, 85.6% for influenza B/Massachusetts (Yamagata lineage) and 81.4% for influenza B/Brisbane (Victoria lineage). Likewise, seroconversion rates were 62.8% for influenza A/H1N1, 57.8% for influenza A/H3N2 and 59.4% for influenza B/Massachusetts (Yamagata lineage) and 50.0% for influenza B/Brisbane (Victoria lineage). GMRs ranged from 3.6 for influenza B/Brisbane (Victoria lineage) to 4.5 for influenza A/H1N1.

TABLE 2

TABLE 2

According to age groups divided into 6–35 months, 3–8 years and 9–18 years, seroprotection rates, seroconversion rates and GMRs were also summarized for each strain to assess variation in immune responses due to age (Table 3).

TABLE 3

TABLE 3

When NBP607-QIV was compared with the control vaccine (AgrippalS1), both met the CHMP criteria for influenza A/H1N1, A/H3N2 and B/Massachusetts (Yamagata lineage) (Table 2). However, the control vaccine did not satisfy the CHMP criteria for influenza B/Brisbane (Victoria lineage) which is not contained in the control vaccine. In older children 3–8 years old, NBP607-QIV showed significantly higher seroprotection rate (92.9% vs. 76.7%; P = 0.02), seroconversion rate (61.9% vs. 20.0%; P < 0.01) and GMR (4.1 vs. 2.2; P < 0.01) for influenza B/Brisbane (Victoria lineage) compared with the control vaccine. In adolescents 9–18 years old, NBP607-QIV showed significantly higher seroprotection rate (95.3% vs. 83.9%; P = 0.04), seroconversion rate (43.3% vs. 22.6%; P = 0.03) and GMR (3.0 vs. 2.0; P = 0.02) for influenza B/Brisbane (Victoria lineage) compared with the control vaccine.

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Reactogenicity

Solicited local and systemic AEs reported within 7 days of vaccination are shown in Table 4. Within 7 days of immunization, a total of 217 solicited local AEs occurred in 131 of 365 subjects (35.9%) in the NBP607-QIV group, while 58 events in 37 of 88 subjects (42.1%) in the control group (AgrippalS1). Most local AEs (85.5%, 235 among 275 cases) were mild that resolved within 3 days: 85.7% (186 among 217 cases) in the NBP607-QIV group and 84.5% (49 among 58 cases) in the control group. There were 176 solicited systemic AEs reported in 25.8% of the NBP607-QIV group (94 among 365 subjects), and 39 events in 22.7% of the control group (20 among 88 subjects). The most frequently reported systemic AEs (85.1%, 183 among 215 cases) were mild: 85.2% (150 among 176 cases) in the NBP607-QIV group and 84.6% (33 among 39 cases) in the control group. The occurrence of each solicited local and systemic AE was comparable between the NBP607-QIV and control group in all age groups with 1 exception: redness was more frequently reported in the NBP607-QIV group in subjects 9–11 years old. The most common local AEs were pain and tenderness across age and vaccine groups, while the most frequent systemic events were irritability and fatigue, followed by sleepiness.

TABLE 4

TABLE 4

During the 28 days after vaccination, unsolicited AEs were reported by 95 NBP607-QIV recipients (26.0%) and 21 control vaccine recipients (23.9%), which was a finding without statistical significance (P = 0.68). All subjects with unsolicited AEs recovered/recovering without sequelae, and no vaccine-related SAEs were reported up to 6 months postvaccination.

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DISCUSSION

This study showed that a new MDCK cell culture-derived inactivated, subunit, quadrivalent influenza vaccine (NBP607-QIV, SK Bioscience) has induced satisfactory antibody responses for all 4 strains in ≥3 years old groups. The antibody responses were similar to those induced by IIV3 for the 3 strains in common and were higher with NBP607-QIV for the B/Victoria strain that was not in IIV3. Together with the previous phase III study, these results suggest that NBP607-QIV vaccination provides sufficient immunity for adults and for children as young as 3 years old.7 However, participants younger than 3 years of age had weak seroprotection rate to 2 influenza B strains in both NBP607-QIV and control group. According to clinical studies conducted with influenza vaccines that are currently in the market, seroprotection rate for B strains in young children did not satisfy the immunogenicity criteria of CHMP similar to this study. It is assumed that young children may easily show a 4-fold increase, but may not achieve the seroprotection criterion for B strains.

This study found comparable reactogenicity and tolerable safety profiles for NBP607-QIV and control group in children/adolescents. Among all vaccinees, no participants have discontinued a study due to an AE and no vaccine-related SAEs, no AEs of special interest and no safety issues or concerns have been reported. This demonstrates that the addition of a second B strain to IIV3 does not affect its safety, which agrees with reports for other quadrivalent inactivated vaccines.8–10

The results of our study are in accordance with the previous phase III trial assessing this ccIV4 candidate and with several other clinical trials, which have shown that quadrivalent vaccines are as immunogenic as their trivalent counterparts for the matched influenza strains and that the 2 vaccine formulations have comparable safety profiles.7,11,12 Thus, the addition of a second B strain to a licensed trivalent vaccine offers additional protection against influenza B without interrupting the immunogenicity of the 3 shared strains, and with little, if any, impact on vaccine safety or reactogenicity.

This study has some points that need to be considered. First, although required for vaccine licensure, HI assay alone may not fully characterize the protective humoral immune response to influenza vaccine. Additional assays (eg, seroneutralization assays) would help comprehensive understanding of humoral response. Second, although high HI antibody titers generally correlate with protection for adults, the correlation is weaker in young children.13,14 Therefore, the use of the previous criteria for influenza vaccines may not be appropriate when evaluating influenza vaccines in young children. The latter of which were shown to require HI titers >1:110 to achieve 50% protection although the cutoff of 1:110 was limited to response for H3N2 virus and the correlate for influenza B or some A strains may differ.15 Thirdly, this study suggested another possibility that children 6–35 months of age had weaker immune response, especially to 2 influenza B strains (Fig. 2). A reduced immune response to influenza antigens in younger children has also been observed in the other study,16 hence 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.17

FIGURE 2

FIGURE 2

In summary, NBP607-QIV, a novel cell culture-derived IIV4, showed good immunogenicity to all 4 influenza strains and had tolerable safety profiles in children and adolescents. Moreover, NBP607-QIV offers broader immune response to influenza B compared with the control, an egg-based subunit vaccine and might help reduce influenza-related disease burden in children and adolescents.

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ACKNOWLEDGMENTS

The authors appreciate the NBP607-QIV study team and all study participants and the parents of the children who participated for providing samples and data for this work. The SK Bioscience Corporation participated in study design; the collection, analysis and interpretation of data; writing of the report; and the decision to submit the article for publication.

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Keywords:

influenza vaccines; cell culture techniques; influenza; vaccines; inactivated; quadrivalent

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